Previously suppressed study by GSK about vaccines

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CONFIDENTIAL 1 Table of Contents 1. INTRODUCTION 2. WORLDWIDE MARKET AUTHORISATION STATUS 3. UPDATE ON REGULATORY AUTHORITY OR MANUFACTURER ACTIONS TAKEN FOR SAFETY REASONS 4. CHANGES TO REFERENCE SAFETY INFORMATION 5. PATIENT EXPOSURE 5.1. Market Experience 6. INDIVIDUAL CASE HISTORIES 7. STUDIES 7.1. Newly-Analysed Studies 7.2. Targeted Safety Studies 7.3. Other Safety Studies 7.4. Published Safety Studies 8. OTHER INFORMATION 8.1. Late-breaking information 8.2. Cumulative review of Gaze palsy 9. OVERALL SAFETY EVALUATION AND CONCLUSION 10. REFERENCES APPENDICES APPENDIX 1 : SUMMARY TABULATION OF INFANRIX HEXA ADVERSE EVENTS APPENDIX 2 : SUMMARY of CASES OF GAZE PALSY SINCE LAUNCH APPENDIX 3 : PSUR – 23 OCTOBER 2010 to 22 OCTOBER 2011 APPENDIX 4 : PSUR – 23 OCTOBER 2009 to 22 OCTOBER 2010 3 3 3 3 4 4 5 5 5 7 7 7 8 8 8 9 9 10 32 48 693 1. INTRODUCTION This summary bridging report integrates the information presented in the two Combined Diphtheria, Tetanus and Acellular Pertussis, Hepatitis B enhanced Inactivated Poliomyelitis and Haemophilus influenzae type B vaccine (Infanrix™ hexa) periodic safety update reports (PSURs) covering the two year period from 23 October 2009 to 22 October 2011. Further details are provided below. Report Number Dates of Report Time Period 16 23 October 2010 – 22 October 2011 1 year 15 23 October 2009 – 22 October 2010 1 year This report presents data on all formulations. 2. WORLDWIDE MARKET AUTHORISATION STATUS Infanrix™ hexa has been approved in 92 countries (see APPENDIX 1 of PSUR 16). 3. UPDATE ON REGULATORY AUTHORITY OR MANUFACTURER ACTIONS TAKEN FOR SAFETY REASONS During the period under review, no actions have been taken for safety reasons concerning withdrawal, rejection, suspension or failure to obtain a renewal of a Marketing Authorisation; neither have there been any dosage modifications, changes in target population, formulation changes, restriction on distribution, or clinical trial suspension. 4. CHANGES TO REFERENCE SAFETY INFORMATION The Reference Safety Information (RSI) in effect at the beginning of the reporting period is the Global Prescriber Information (GPI) of Global Datasheet (GDS) version 9 dated 23 November 2007. Refer to APPENDIX 2A of PSUR 15; the RSI is identified by doubleunderlining within the GPI. During the period of this report one new version (version 10) of the RSI was issued. Refer to APPENDIX 2B of PSUR 15; the RSI is identified as grey shaded text within the GPI. In CSI version 10 dated 21 October 2010 the following changes were implemented:  A warning about the risk of syncope (fainting) after any vaccination was added in the Warnings and Precautions Section: Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints. CONFIDENTIAL 3 The following changes were implemented as well in RSI version 10 compared to version 9, although not mentioned in PSUR 15:  The Company revised the text considered as RSI in the GDS taking into account the fact that any text that refers to ‘negative data’ or ‘no data available’ should not be considered as RSI. As a consequence, the following is no longer considered to be RSI:  Dosage and Administration Section  Interactions Section (except for the key message related to higher incidence of fever reported with Infanrix™ hexa)  Pregnancy and Lactation Section  The sentence The safety profile presented below is based on data from more than 16 000 subjects in the Clinical Trials Section.  Overdosage Section  Several changes were made to the Use and Handling Section:  wording regarding reconstitution of the vaccine was clarified  paragraph related to Bioset presentation was deleted  instructions related to PRTC pre-filled syringe and information related to the vial and vial presentation were added  a statement regarding disposal of unused products or waste material was added 5. PATIENT EXPOSURE 5.1. Market Experience Information on the actual number of people exposed to Infanrix™ hexa in the different countries is not available to the MAH. Therefore, the total patient exposure is approximated by the number of doses distributed which is the most reliable data available with regard to patient exposure for a vaccine in a post-marketing setting. It is important to note that the sales database from which data are retrieved is an in-house ‘living’ database and is subject to updates and corrections depending on information provided by GSK local country subsidiaries (e.g. vaccine doses may be returned by subsidiaries to the central warehouse). These constant updates may result in discrepancies between consecutive queries of the database. During the period covered by this report 24 283 415 doses of Infanrix™ hexa have been distributed. Since launch until the data lock point (DLP) of this report, 72 931 338 doses have been distributed. As vaccination with Infanrix™ hexa can vary between 1 and 4 doses per subject in accordance with local recommendations and compliance with the vaccination schedule, and assuming that one dose distributed corresponds to one dose administered, post-marketing exposure to Infanrix™ hexa during the SBR reporting CONFIDENTIAL 4 period is estimated to be between 6 070 854 and 24 283 415 subjects. The number of subjects exposed since launch until the data lock point of this report is estimated between 18 232 834 and 72 931 338. 6. INDIVIDUAL CASE HISTORIES A total of 2408 reports meeting ICH E2C PSUR criteria have been received during the period of this report. These reports include all serious and non-serious reports from spontaneous notifications (including published reports), but exclude all non-healthcare professional reports and all non-serious reports received solely from regulatory authorities. In addition, unblinded, serious attributable reports arising from clinical studies, post-marketing surveillance studies, named patient use or solicited reports following use of a GSK product have been included. These cases are presented within the summary tabulation in Appendix 1. The tabulation shows the MedDRA System Organ Class (SOC), High Level Group Term (HLGT) and Preferred Term (PT), and the number of unique cases for each adverse event. The total number of cases presented in line listings and summary tabulations in the series of PSURs appended to this summary report is 2388. It should be noted that the data-set for the summary tabulation differs from the data-sets included in the individual PSURs during the time period given that the summary tabulation in this report contains follow-up information on cases previously included in the PSURs. 7. STUDIES 7.1. Newly-Analysed Studies Three new corporate studies relevant to the safety of Infanrix™ hexa were completed and analysed during the period of this report.  Study #112157 (DTPa-HBV-IPV=Hib-MenC-TT-002 PRI) A phase II, openlabel, randomised, multicentre study to evaluate the safety and immunogenicity of GSK Biologicals‟ DTPa-HBV-IPV/Hib-MenC-TT vaccine co- dministered with GSK Biologicals‟ 10-valent pneumococcal conjugate vaccine in healthy infants when administered as a three-dose primary vaccination course at 2, 3 and 4 months of age. The observed incidence of solicited and unsolicited adverse events was in the same range in the 3 groups, i.e. “Hepta” (candidate heptavalent vaccine), “HexaMnC” (Infanrix™ hexa co-administered with conjugate meningococcal vaccine (Menjugate), and “HexaPn” [Infanrix™ hexa co-administered with conjugate pneumococcal vaccine (Synflorix)]; all the vaccines administered in the study were well tolerated. One SAE (thrombocytopenia) reported for a subject in the Hepta CONFIDENTIAL 5 group was considered by the investigator to have a potential causal relationship to vaccination. All serious adverse events reported during the study resolved without sequelae.  Study #110142 (10-PN-PD-DIT-027 PRI) A phase III randomized, single-blind, controlled study to demonstrate the non-inferiority of co-administration of GSK Biological 10-valent pneumococcal conjugate vaccine with Pediacel™ versus coadministration with Infanrix™ hexa, when administered to infants as a three-dose primary vaccination course during the first six months of life and as a booster dose at 11- 13 months of age. This study was conducted with 3 parallel groups: “10Pn-Hexa” group received 10PnPD-DIT and Infanrix™ hexa, “10Pn-PDC” group received 10Pn-PD-DIT and Pediacel and “Prev-PDC” group received Prevenar and Pediacel. The incidences of grade 3 solicited local and general adverse events were low in all study groups. The percentage of doses followed by unsolicited adverse events was in the same range in all groups. Grade 3 unsolicited adverse events with causal relationship to vaccination were rarely reported. No fatal SAEs were reported in this study up to the data lock point. Up to the data lock point, SAEs after primary vaccination were reported in 32 subjects (17 subjects in the 10Pn-Hexa group, 5 subjects in the 10Pn-PDC group and 10 subjects in the Prev-PDC group).One of these SAEs reported for a subject in the 10Pn-Hexa group (apparent life threatening event) was assessed by the investigator to be causally related to vaccination.  Study #111654 (10-PN-PD-DIT-048) A phase III, multi-centre, double-blind, randomised study to assess the non-inferiority of a commercial lot of GlaxoSmithKline (GSK) Biologicals 10-valent pneumococcal conjugate (10Pn-PDDiT) vaccine compared to a clinical phase III vaccine lot, when given as a three-dose primary immunization course. This study was conducted with 2 parallel groups: the “Clin” group received the phase 3 clinical lot of 10Pn-PD-DIT with Infanrix™ hexa or Infanrix-IPV/Hib and HRV, the “Com” group received the commercial lot of 10Pn-PD-DIT with Infanrix™ hexa or Infanrix-IPV/Hib and HRV. All subjects were concomitantly administered a dose of Infanrix™ hexa. The following results are supportive of an acceptable safety profile of the clinical phase III: Unsolicited adverse events: The percentage of doses followed by at least one unsolicited symptom in the 31-day postvaccination period was 16.2% in the Clin group and 17.0% in the Com group. The most frequently reported unsolicited AE in each group was upper respiratory tract infection (5.0% in the Clin group and 6.0% in the Com group). The percentage of doses followed by at least one unsolicited symptom considered by the investigator to be causally related to vaccination and the percentage of doses with grade 3 unsolicited AEs in the 31-day post-vaccination period was at most 1.0% in both groups. No grade 3 unsolicited AEs were considered by the investigator to be causally related to vaccination. CONFIDENTIAL 6 Serious adverse events: No fatal SAEs were reported in this study. A total of 36 non-fatal SAEs were reported for 25 (5.4%) out of 466 vaccinated subjects: 18 subjects (7.7%) in the Clin group and 7 subjects (3.0%) in the Com group. No SAEs were considered by the investigator to be causally related to vaccination. One SAE did not resolve (spinal muscular atrophy) and one SAE (tuberculous meningitis) was still ongoing at the end of this study. The safety information generated in these studies is consistent with the current safety profile of Infanrix™ hexa. 7.2. Targeted Safety Studies There were no planned, ongoing or completed targeted safety studies for Infanrix™ hexa. 7.3. Other Safety Studies The following ongoing studies are not targeted safety studies but were also considered of interest as they may provide useful new information on the safety profile of Infanrix™ hexa:  103506 (DTPA-HBV-IPV-118 PRI) A phase IV, non-randomised, open-label, multi centre study with two parallel groups to assess the immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals combined DTPa-HBV-IPV/Hib vaccine administered as a three-dose primary vaccination course at 2, 4 and 6 months of age in healthy infants in Canada.  113948 (DTPA-HBV-IPV-124 PRI) A phase II, double-blind, randomized, multicentre study to evaluate the safety and immunogenicity of new formulations of GlaxoSmithKline BiologicalsDTPa-HBV-IPV/Hib vaccine when administered to healthy toddlers as a booster dose at 12 to 15 months of age.  114843 (DTPA-HBV-IPV-125 BST:124) A phase II, double-blind, randomized, multicentre study to evaluate the safety and immunogenicity of new formulations of GlaxoSmithKline Biologicals DTPa-HBV-IPV/Hib vaccine when administered to healthy toddlers as a booster dose at 12 to 15 months of age. 7.4. Published Safety Studies A full review of the literature was conducted during the reporting period. Useful information was published during the period concerning:  safety and reactogenicity of Infanrix-IPV+Hib and Infanrix hexa (Lim, 2011). Both vaccines were well tolerated and substitution of DTPa-IPV/Hib with Infanrix hexa at Month 5 reduced the number of injections required at this age by one.  immunogenicity and safety of co-administration of Infanrix hexa with an investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine (ACWW-TT; Knuf, 2011). Pre-specified criteria for nonCONFIDENTIAL 7 inferiority of immunogenicity following co-administration versus separate ACWYTT and Infanrix hexa administration were reached, and the safety profile of coadministration was similar to that of Infanrix hexa alone. These studies did not highlight any safety issue. 8. OTHER INFORMATION 8.1. Late-breaking information One new fatal case (B0762668A) was received after the data lock point as well as new follow-up data for one of the fatal cases (D0072852A) described in Section 6.5.1 Cases with a Fatal Outcome of PSUR 16. Refer to Section 8.2 Late-breaking information of PSUR 16 for further information about these cases. The latest CIOMS forms for these cases are attached in APPENDIX 5C of PSUR 16. 8.2. Cumulative review of Gaze palsy In the assessment report (dated 3 March 2010) of PSUR 14, EMA had the following request: b. During the period of this report 14 cases of gaze palsy have been identified. In ten of the cases, the event was reported in association with concurrent events, mostly convulsions. However, the median TTO is less than one day. In addition, outcome was reported resolved with sequelae in 1 case and unresolved in 1 case. The MAH is requested to provide a detailed cumulative reviewing of cases of Gaze palsy since launch. The events, TTO, outcome and concomitant drugs should be specified Accordingly, a cumulative review of cases of Gaze palsy diagnosed after Infanrix hexa administration was performed. All spontaneous reports in the GSK worldwide safety database reported from Infanrix hexa launch up to a data lock point of 22 October 2011 were included in the analysis. Since launch, 70 spontaneous cases of Gaze palsy were received, corresponding to a reporting frequency of 0.10 per 100 000 Infanrix hexa doses distributed. All cases are summarized in Appendix 2, including time to onset, events, outcome and concomitant drugs reported. In 45/70 cases the event occurred on the same day of vaccination. In all cases Gaze palsy was one of the presenting symptoms of a larger clinical syndrome, i.e. Febrile and nonfebrile Convulsion and Hypotonic-hyporesponsive episode (HHE), which are both listed events in the Infanrix hexa reference safety information. In 43 cases outcome was reported to be ‘Resolved’ or ‘Resolved with sequelae’. In the other cases outcome was either ‘Improved’ (N=1), ‘Unresolved’ (N=6) or ‘Unknown’ (N=20). CONFIDENTIAL 8 The information received with these cases does not provide evidence of a specific safety concern for Gaze Palsy. 9. OVERALL SAFETY EVALUATION AND CONCLUSION From the review of data received during the reporting period and presented in this report, it has been concluded that the safety profile of Infanrix hexa is adequately reflected in the RSI. No further amendments to the RSI are considered necessary at this time. The benefit/risk profile of Infanrix hexa continues to be favourable. The Company will continue to monitor cases of anaemia haemolytic autoimmune, thrombocytopenia, thrombocytopenic purpura, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, haemolytic anemia, cyanosis, injection site nodule, abcess and injection site abscess, Kawasaki’s disease, important neurological events (including encephalitis and encephalopathy), Henoch-Schonlein purpura, petechiae, purpura, haematochezia, allergic reactions (including anaphylactic and anaphylactoid reactions), cases of lack of effectiveness as well as fatal cases. 10. REFERENCES Knuf M, Pantazi-Chatzikonstantinou A, Pfletschinger U et al. An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix™ hexa is immunogenic, with an acceptable safety profile in 12-23-month-old children. Vaccine. 2011 29:25 (4264-4273). Lim FS, Phua KB, Lee BW et al. Safety and reactogenicity of DTPa-HBV-IPV/Hib and DTPa-IPV/I-Hib vaccines in a post-marketing surveillance setting. The Southeast Asian journal of tropical medicine and public health. 2011 42:1 (138-147). CONFIDENTIAL 9 10 CONFIDENTIAL APPENDIX 1 : SUMMARY TABULATION OF INFANRIX HEXA ADVERSE EVENTS SUMMARY TABULATION OF INFANRIX™ HEXA ADVERSE EVENTS 23 OCTOBER 2009 TO 22 OCTOBER 2011 N.B. Events are only considered serious if they fulfil GSK medically serious criteria. GSK medically serious criteria are applied automatically only to events from spontaneous, post-marketing or literature case reports. Events arising from Clinical trial cases are not run against the list of GSK medically serious terms. For this reason events may appear as both serious and non-serious (for further details see section 6.1). It should be noted that the end column of the tabulation presents total of cases with event rather than count of events. System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Anaemia No 12 0 12 Bone marrow failure No 1 0 1 Hypochromic anaemia No 2 0 2 Iron deficiency anaemia No 2 0 2 Microcytic anaemia No 2 0 2 Pancytopenia No 2 0 2 Coagulopathies and bleeding diatheses (excl thrombocytopenic) Haemorrhagic diathesis No 2 0 2 Haemolyses and related conditions Anaemia haemolytic autoimmune No 1 0 1 Jaundice acholuric No 1 0 1 Warm type haemolytic anaemia No 1 0 1 Platelet disorders Idiopathic thrombocytopenic purpura No 11 0 11 Thrombocytopenia Yes 15 0 15 Thrombocytopenic purpura No 5 0 5 Thrombocytosis No 5 0 5 Red blood cell disorders Hypochromasia No 1 0 1 Microcytosis No 1 0 1 Spleen, lymphatic and reticuloendothelial system disorders Lymphadenopathy Yes 0 21 21 Lymph node pain No 0 1 1 Splenomegaly No 2 0 2 White blood cell disorders Agranulocytosis No 1 0 1 Eosinophilia No 0 3 3 Granulocytopenia No 1 0 1 Leukocytosis No 13 0 13 Leukopenia No 3 0 3 Neutropenia No 7 0 7 CONFIDENTIAL 11 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period White blood cell disorder No 1 0 1 Cardiac disorders Cardiac arrhythmias Arrhythmia No 0 1 1 Atrial tachycardia No 1 0 1 Bradycardia No 0 14 14 Cardiac arrest No 6 0 6 Cardio-respiratory arrest No 1 0 1 Sinus tachycardia No 0 1 1 Supraventricular tachycardia No 1 0 1 Tachycardia No 0 10 10 Cardiac disorder signs and symptoms Cardiovascular disorder No 0 4 4 Cardiovascular insufficiency Yes 1 0 1 Cyanosis No 90 17 106 Cardiac valve disorders Mitral valve incompetence No 1 0 1 Heart failures Cardiac failure No 1 0 1 Cardiogenic shock No 1 0 1 Cardiopulmonary failure No 1 0 1 Myocardial disorders Cardiomyopathy No 1 0 1 Congestive cardiomyopathy No 1 0 1 Pericardial disorders Pericarditis No 1 0 1 Congenital, familial and genetic disorders Blood and lymphatic system disorders congenital Haemophilia No 1 0 1 Cardiac and vascular disorders congenital Atrial septal defect No 1 0 1 Metabolic and nutritional disorders congenital Methylmalonic aciduria No 1 0 1 Musculoskeletal and connective tissue disorders congenital Macrocephaly No 1 0 1 Microcephaly No 2 0 2 Talipes No 1 0 1 Neurological disorders congenital Cerebral palsy No 1 0 1 Congenital neuropathy No 1 0 1 Reproductive tract and breast disorders congenital Hydrocele No 2 0 2 Phimosis No 1 0 1 Ear and labyrinth disorders External ear disorders (excl congenital) Auricular swelling No 0 2 2 Cerumen impaction No 0 1 1 Middle ear disorders (excl congenital) Tympanic membrane disorder No 0 1 1 Tympanic membrane hyperaemia No 0 2 2 Tympanic membrane perforation No 0 2 2 Endocrine disorders Thyroid gland disorders Hypothyroidism No 2 0 2 CONFIDENTIAL 12 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Eye disorders Eye disorders NEC Eye disorder No 0 9 9 Eyelid disorder No 0 4 4 Eye oedema No 0 1 1 Eye swelling No 0 1 1 Ocular haemorrhages and vascular disorders NEC Conjunctival haemorrhage No 0 1 1 Ocular infections, irritations and inflammations Conjunctival hyperaemia No 0 2 2 Conjunctivitis No 0 7 7 Eyelid oedema Yes 0 5 5 Ocular neuromuscular disorders Blepharospasm No 0 1 1 Eyelid ptosis No 0 1 1 Eye movement disorder No 0 25 25 Gaze palsy No 43 0 43 Oculogyric crisis No 3 0 3 Ophthalmoplegia No 2 0 2 Pupils unequal No 0 1 1 Strabismus No 0 4 4 Retina, choroid and vitreous haemorrhages and vascular disorders Retinal haemorrhage No 2 0 2 Vision disorders Anisometropia No 0 1 1 Astigmatism No 0 1 1 Diplopia No 0 1 1 Hypermetropia No 0 1 1 Vision blurred No 0 1 1 Visual acuity reduced No 0 1 1 Visual impairment No 0 2 2 Gastrointestinal disorders Abdominal hernias and other abdominal wall conditions Inguinal hernia No 0 1 1 Dental and gingival conditions Gingival bleeding No 0 2 2 Gastrointestinal conditions NEC Gastrointestinal disorder No 0 2 2 Gastrointestinal haemorrhages NEC Haematochezia No 7 2 9 Melaena No 1 0 1 Rectal haemorrhage No 4 0 4 Gastrointestinal inflammatory conditions Colitis No 1 0 1 Enteritis No 1 0 1 Gastritis No 0 1 1 Gastrointestinal inflammation No 0 2 2 Oesophagitis No 0 1 1 Gastrointestinal motility and defaecation conditions Constipation No 0 4 4 Diarrhoea Yes 0 53 53 Diarrhoea haemorrhagic No 3 0 3 CONFIDENTIAL 13 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Frequent bowel movements Yes 0 1 1 Gastrointestinal hypomotility No 0 1 1 Gastrooesophageal reflux disease No 1 7 8 Ileus paralytic No 2 0 2 Intestinal dilatation No 0 1 1 Gastrointestinal signs and symptoms Abdominal distension No 0 6 6 Abdominal pain No 0 10 10 Abdominal pain upper No 0 1 1 Abdominal rigidity No 0 1 1 Abnormal faeces No 0 7 7 Acute abdomen No 1 0 1 Dyspepsia No 0 2 2 Dysphagia No 0 1 1 Faeces discoloured No 0 6 6 Flatulence No 0 6 6 Gastrointestinal pain No 0 2 2 Mucous stools No 0 2 2 Nausea No 0 2 2 Post-tussive vomiting No 0 1 1 Regurgitation No 0 5 5 Vomiting Yes 0 108 108 Gastrointestinal stenosis and obstruction Intestinal obstruction No 1 0 1 Intussusception No 4 0 4 Malabsorption conditions Coeliac disease No 0 1 1 Oral soft tissue conditions Chapped lips No 0 4 4 Cheilitis No 0 6 6 Lip disorder No 0 1 1 Lip haematoma No 0 1 1 Lip oedema Yes 0 1 1 Lip swelling Yes 0 3 3 Mouth haemorrhage No 1 3 3 Oral discharge No 0 1 1 Peritoneal and retroperitoneal conditions Ascites No 2 0 2 Peritoneal disorder No 0 1 1 Salivary gland conditions Lip dry No 0 1 1 Salivary hypersecretion No 0 9 9 Tongue conditions Glossoptosis No 0 1 1 Hypertrophy of tongue papillae No 0 1 1 Protrusion tongue No 0 1 1 Swollen tongue Yes 0 1 1 General disorders and administration site conditions Administration site reactions Application site discolouration No 0 1 1 Injected limb mobility No 0 4 4 CONFIDENTIAL 14 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period decreased Injection site abscess sterile No 0 2 2 Injection site cyst No 0 2 2 Injection site dermatitis Yes 0 1 1 Injection site discolouration No 0 22 22 Injection site eczema No 0 3 3 Injection site erythema Yes 0 190 190 Injection site extravasation No 0 11 11 Injection site haematoma No 0 14 14 Injection site haemorrhage No 0 4 4 Injection site hypersensitivity Yes 0 1 1 Injection site induration Yes 0 83 83 Injection site inflammation No 0 49 49 Injection site mass No 0 5 5 Injection site necrosis No 1 0 1 Injection site nodule No 0 41 41 Injection site oedema Yes 0 64 64 Injection site pain Yes 0 76 76 Injection site pallor No 0 3 3 Injection site papule No 0 1 1 Injection site pruritus No 0 21 21 Injection site rash Yes 0 4 4 Injection site reaction No 0 48 48 Injection site scab No 0 1 1 Injection site scar No 0 1 1 Injection site swelling Yes 0 136 136 Injection site urticaria No 0 1 1 Injection site vesicles Yes 0 7 7 Injection site warmth No 0 62 62 Vaccination site abscess sterile No 1 0 1 Vaccination site erythema Yes 0 1 1 Vaccination site granuloma No 0 1 1 Vaccination site induration Yes 0 3 3 Vaccination site oedema No 0 3 3 Vaccination site pain Yes 0 1 1 Vaccination site reaction No 0 1 1 Vaccination site swelling No 0 2 2 Body temperature conditions Hyperpyrexia No 0 10 10 Hyperthermia No 0 8 8 Hypothermia No 0 4 4 Pyrexia Yes 2 591 593 Device issues Needle issue No 0 1 1 Fatal outcomes Death No 8 0 8 Sudden death No 2 0 2 Sudden infant death syndrome No 12 0 12 General system disorders NEC Abasia No 0 3 3 CONFIDENTIAL 15 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Abscess sterile No 11 0 11 Asthenia No 0 16 16 Chills No 0 10 10 Condition aggravated No 0 3 3 Developmental delay No 0 12 12 Discomfort No 0 4 4 Disease recurrence No 0 1 1 Enanthema No 0 1 1 Extensive swelling of vaccinated limb Yes 0 29 29 Face oedema Yes 0 2 2 Fatigue No 0 34 34 Feeling abnormal No 0 2 2 Feeling cold No 0 3 3 Feeling hot No 0 12 12 Feeling of body temperature change No 0 1 1 Feeling of relaxation No 0 1 1 Foaming at mouth No 0 4 4 Foreign body reaction No 0 3 3 Gait deviation No 0 1 1 Gait disturbance No 0 22 22 Generalised oedema No 0 1 1 General physical health deterioration No 0 18 18 Granuloma No 0 5 5 Ill-defined disorder No 0 40 40 Induration No 0 15 15 Inflammation No 0 35 35 Influenza like illness No 0 1 1 Irritability Yes 0 50 50 Localised oedema No 0 1 1 Local reaction No 0 4 4 Local swelling No 0 8 8 Malaise No 0 34 34 Mucosal inflammation No 0 1 1 Mucous membrane disorder No 0 1 1 Multi-organ failure No 1 0 1 Nonspecific reaction No 0 2 2 Oedema No 0 5 5 Oedema peripheral No 0 57 57 Pain No 0 40 40 Swelling No 0 26 26 Tenderness No 0 1 1 Thirst decreased No 0 2 2 Product quality issues Incorrect product storage No 0 59 59 Product quality issue No 0 33 33 Therapeutic and nontherapeutic effects (excl Adverse drug reaction No 0 1 1 CONFIDENTIAL 16 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period toxicity) Adverse event No 0 2 2 Drug ineffective Yes 0 1 1 No therapeutic response Yes 0 7 7 Therapeutic response decreased Yes 0 1 1 Tissue disorders NEC Cyst No 0 2 2 Dysplasia No 0 1 1 Fibrosis No 0 5 5 Nodule No 0 3 3 Ulcer No 0 1 1 Hepatobiliary disorders Gallbladder disorders Cholecystitis No 1 0 1 Hepatic and hepatobiliary disorders Hepatic function abnormal No 0 2 2 Hepatomegaly No 0 1 1 Hepatosplenomegaly No 0 2 2 Hepatotoxicity No 1 0 1 Hypertransaminasaemia No 1 0 1 Jaundice No 2 0 2 Immune system disorders Allergic conditions Allergy to metals No 0 1 1 Allergy to vaccine Yes 0 1 1 Anaphylactic reaction Yes 6 0 6 Anaphylactic shock Yes 4 0 4 Anaphylactoid reaction Yes 1 0 1 Drug hypersensitivity Yes 0 1 1 Hypersensitivity Yes 0 29 29 Milk allergy No 0 3 3 Type III immune complex mediated reaction No 0 2 2 Immune disorders NEC Immune system disorder No 0 2 2 Immunodeficiency syndromes Selective IgA immunodeficiency No 0 1 1 Infections and infestations Ancillary infectious topics Transmission of an infectious agent via a medicinal product No 1 0 1 Bacterial infectious disorders Bacterial infection No 0 3 3 Bronchitis bacterial Yes 0 1 1 Cellulitis No 9 0 9 Erysipelas No 0 2 2 Escherichia infection No 0 2 2 Escherichia urinary tract infection No 0 3 3 Gastroenteritis bacterial No 1 0 1 Gastroenteritis Escherichia coli No 1 0 1 Gastroenteritis staphylococcal No 1 0 1 Haemophilus infection No 0 6 6 Injection site cellulitis No 0 2 2 CONFIDENTIAL 17 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Meningitis haemophilus No 5 0 5 Meningitis pneumococcal No 2 0 2 Pertussis No 0 62 62 Pneumococcal infection No 0 1 1 Pneumococcal sepsis No 0 1 1 Salmonella sepsis No 1 0 1 Salmonellosis No 0 1 1 Staphylococcal abscess No 0 3 3 Staphylococcal infection No 0 1 1 Streptococcal abscess No 0 2 2 Streptococcal bacteraemia No 0 1 1 Fungal infectious disorders Fungal skin infection Yes 0 1 1 Infections – pathogen unspecified Abdominal abscess No 0 1 1 Abscess No 0 11 11 Abscess limb No 0 1 1 Acute tonsillitis Yes 0 2 2 Bacteraemia No 2 0 2 Bone abscess No 1 0 1 Bronchitis Yes 0 12 12 Bronchopneumonia No 1 0 1 Ear infection No 0 4 4 Encephalitic infection No 1 0 1 Enteritis infectious No 1 0 1 Epiglottitis Yes 1 0 1 Febrile infection No 0 1 1 Gastroenteritis No 9 0 9 Groin abscess No 0 1 1 Impetigo No 0 3 3 Incision site abscess No 0 7 7 Infection No 0 12 12 Infectious peritonitis No 1 0 1 Injection site abscess No 0 20 20 Injection site infection No 0 3 3 Injection site pustule No 0 1 1 Labyrinthitis No 0 1 1 Lung infection No 0 1 1 Mastoiditis No 0 1 1 Meningitis Yes 4 0 4 Meningitis aseptic Yes 2 0 2 Nasopharyngitis Yes 0 13 13 Osteomyelitis No 2 0 2 Otitis media No 0 7 7 Otitis media acute No 0 1 1 Pharyngitis Yes 0 2 2 Pneumonia No 4 0 4 Pneumonia primary atypical No 1 0 1 Purulence No 0 3 3 Purulent discharge No 0 2 2 CONFIDENTIAL 18 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Pyelonephritis No 2 0 2 Rash pustular Yes 0 3 3 Respiratory tract infection Yes 0 6 6 Rhinitis Yes 0 17 17 Sepsis No 8 0 8 Septic shock No 1 0 1 Soft tissue infection No 0 2 2 Sputum purulent No 0 1 1 Subdural empyema No 0 1 1 Tonsillitis Yes 0 3 3 Tracheitis Yes 0 2 2 Upper respiratory tract infection Yes 0 14 14 Urinary tract infection No 1 3 4 Vaccination site abscess No 2 0 2 Vaccination site infection No 0 1 1 Wound infection No 0 1 1 Viral infectious disorders Bronchiolitis No 0 2 2 Croup infectious No 0 2 2 Eczema herpeticum Yes 0 1 1 Exanthema subitum No 0 1 1 Gastroenteritis astroviral No 1 0 1 Gastroenteritis norovirus No 2 0 2 Gastroenteritis rotavirus No 11 0 11 Gastroenteritis viral No 1 0 1 Gianotti-Crosti syndrome No 0 3 3 H1N1 influenza No 0 1 1 Hand-foot-and-mouth disease No 0 1 1 Herpes ophthalmic No 0 1 1 Herpes simplex No 0 1 1 Herpes virus infection No 0 1 1 Herpes zoster Yes 0 2 2 Measles No 0 1 1 Meningitis viral Yes 1 0 1 Pneumonia respiratory syncytial viral No 1 0 1 Respiratory syncytial virus infection No 0 2 2 Rotavirus infection No 0 1 1 Varicella No 0 1 1 Vestibular neuronitis No 0 1 1 Viral infection No 0 8 8 Viral rash Yes 0 3 3 Injury, poisoning and procedural complications Chemical injury and poisoning Maternal exposure during pregnancy No 0 2 2 Injuries NEC Arthropod bite No 0 1 1 Child maltreatment syndrome No 0 2 2 Concussion No 1 0 1 CONFIDENTIAL 19 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Contusion No 0 3 3 Craniocerebral injury No 1 0 1 Fall No 0 7 7 Laceration No 0 1 1 Soft tissue injury No 0 1 1 Medication errors Accidental exposure No 0 2 2 Accidental overdose No 0 10 10 Drug administered at inappropriate site No 0 1 1 Drug administered to patient of inappropriate age No 0 97 97 Drug administration error No 0 33 33 Drug dispensing error No 0 2 2 Drug prescribing error No 0 1 1 Expired drug administered No 0 15 15 Inappropriate schedule of drug administration No 0 161 161 Incorrect dose administered No 0 41 41 Incorrect route of drug administration No 0 30 30 Incorrect storage of drug No 0 43 43 Medication error No 0 2 2 Overdose No 0 33 33 Underdose No 0 38 38 Wrong drug administered No 0 78 78 Wrong technique in drug usage process No 0 165 165 Procedural related injuries and complications NEC Vaccination complication No 0 25 25 Vaccination failure Yes 68 0 68 Investigations Cardiac and vascular investigations (excl enzyme tests) Blood pressure decreased Yes 0 2 2 Cardiac murmur No 0 1 1 Heart rate decreased No 0 2 2 Heart rate increased No 0 6 6 Heart sounds abnormal No 0 1 1 Peripheral pulse decreased No 0 1 1 Pulse absent No 1 0 1 Pulse pressure decreased No 0 1 1 Pulse pressure increased No 0 1 1 Enzyme investigations NEC Blood lactate dehydrogenase increased No 0 1 1 Haematology investigations (incl blood groups) Platelet count decreased Yes 0 2 2 White blood cell count increased No 0 2 2 Hepatobiliary investigations Alanine aminotransferase increased No 1 0 1 CONFIDENTIAL 20 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Ammonia increased No 0 1 1 Aspartate aminotransferase increased No 2 0 2 Hepatic enzyme increased No 1 0 1 Transaminases increased No 7 0 7 Immunology and allergy investigations Allergy test positive Yes 0 1 1 Autoantibody positive No 0 1 1 Blood immunoglobulin E increased No 0 1 1 Blood immunoglobulin M decreased No 0 1 1 Immunology test abnormal No 0 1 1 Metabolic, nutritional and blood gas investigations Blood glucose increased No 0 1 1 Blood lactic acid increased No 0 1 1 Oxygen saturation decreased No 0 14 14 Microbiology and serology investigations Adenovirus test positive No 0 1 1 Bacterial test positive No 0 1 1 Bordetella test negative No 0 1 1 Bordetella test positive No 0 2 2 Clostridium test No 0 1 1 Clostridium test negative No 0 4 4 Corynebacterium test negative No 0 4 4 Cytomegalovirus test positive No 0 1 1 Hepatitis B antibody negative No 0 4 4 Hepatitis B antibody positive No 0 1 1 Hepatitis B antigen positive No 0 1 1 Hepatitis B surface antigen positive No 0 1 1 Rotavirus test positive No 0 1 1 Staphylococcus test positive No 0 1 1 Viral test positive No 0 1 1 Neurological, special senses and psychiatric investigations Electroencephalogram abnormal No 0 2 2 Reflex test normal No 0 1 1 Physical examination topics Body temperature No 0 1 1 Body temperature decreased No 0 3 3 Body temperature fluctuation No 0 1 1 Body temperature increased Yes 0 35 35 Head circumference abnormal No 0 1 1 Lymph node palpable No 0 1 1 Neurological examination abnormal No 0 1 1 Respiratory rate decreased No 0 1 1 Respiratory rate increased No 0 1 1 Weight decreased No 0 8 8 CONFIDENTIAL 21 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Protein and chemistry analyses NEC C-reactive protein increased No 0 13 13 Inflammatory marker increased No 0 2 2 Protein total increased No 0 1 1 Renal and urinary tract investigations and urinalyses Urine output decreased No 0 1 1 White blood cells urine positive No 0 1 1 Water, electrolyte and mineral investigations Serum ferritin increased No 0 1 1 Metabolism and nutrition disorders Acid-base disorders Acidosis No 3 1 4 Ketoacidosis No 0 1 1 Ketosis No 0 1 1 Lactic acidosis No 1 0 1 Metabolic acidosis No 1 0 1 Appetite and general nutritional disorders Appetite disorder No 0 1 1 Decreased appetite Yes 0 40 40 Feeding disorder neonatal No 0 1 1 Hypophagia Yes 0 3 3 Increased appetite No 0 1 1 Weight gain poor No 0 2 2 Diabetic complications Diabetic ketoacidosis No 1 0 1 Electrolyte and fluid balance conditions Dehydration No 0 6 6 Fluid intake reduced No 0 13 13 Hypokalaemia No 2 0 2 Hyponatraemia No 0 3 3 Oligodipsia No 0 18 18 Polydipsia No 0 3 3 Food intolerance syndromes Cow’s milk intolerance No 0 1 1 Lactose intolerance No 0 2 2 Glucose metabolism disorders (incl diabetes mellitus) Hyperglycaemia No 0 1 1 Type 1 diabetes mellitus No 2 0 2 Iron and trace metal metabolism disorders Iodine deficiency No 0 1 1 Iron deficiency No 0 1 1 Metabolism disorders NEC Metabolic disorder No 0 1 1 Protein and amino acid metabolism disorders NEC Hypoalbuminaemia No 0 2 2 Vitamin related disorders Vitamin B12 deficiency No 0 1 1 Musculoskeletal and connective tissue disorders Connective tissue disorders (excl congenital) Myofascitis No 0 1 1 Joint disorders Arthralgia No 0 3 3 CONFIDENTIAL 22 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Arthritis Yes 0 3 3 Joint hyperextension No 0 4 4 Joint range of motion decreased No 0 1 1 Joint stiffness No 0 1 1 Joint swelling No 0 3 3 Muscle disorders Muscle disorder No 0 2 2 Muscle rigidity No 0 8 8 Muscle spasms No 0 16 16 Muscle tightness No 0 1 1 Muscle twitching No 0 16 16 Muscular weakness Yes 0 6 6 Myalgia No 0 2 2 Myosclerosis No 0 1 1 Myositis No 0 2 2 Nuchal rigidity No 0 2 2 Trismus No 0 1 1 Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Facial asymmetry No 0 1 1 Foot deformity No 0 1 1 Hip deformity No 0 1 1 Musculoskeletal and connective tissue disorders NEC Mastication disorder No 0 1 1 Mobility decreased No 0 5 5 Muscle contracture No 0 1 1 Musculoskeletal stiffness No 0 14 14 Pain in extremity No 0 20 20 Posture abnormal No 0 4 4 Soft tissue necrosis No 1 0 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cutaneous neoplasms benign Melanocytic naevus No 1 0 1 Haematopoietic neoplasms (excl leukaemias and lymphomas) Histiocytosis haematophagic No 1 0 1 Leukaemias B precursor type acute leukaemia No 1 0 1 Nervous system neoplasms malignant and unspecified NEC Neuroblastoma No 1 0 1 Skin neoplasms malignant and unspecified Neoplasm skin No 1 0 1 Nervous system disorders Central nervous system infections and inflammations Central nervous system inflammation No 0 1 1 Encephalitis Yes 4 0 4 CONFIDENTIAL 23 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Myelitis transverse No 1 0 1 Central nervous system vascular disorders Cerebral haemorrhage No 1 0 1 Cerebral ischaemia No 2 0 2 Cerebrovascular disorder No 1 0 1 Thalamus haemorrhage No 1 0 1 Cranial nerve disorders (excl neoplasms) Facial paresis Yes 3 0 3 Tongue paralysis Yes 1 0 1 VIIth nerve paralysis Yes 2 0 2 VIth nerve paralysis Yes 3 0 3 Demyelinating disorders Demyelination No 2 0 2 Encephalopathies Encephalopathy Yes 3 0 3 Periventricular leukomalacia No 1 0 1 Headaches Headache No 0 2 2 Increased intracranial pressure and hydrocephalus Hydrocephalus No 1 0 1 Mental impairment disorders Autism No 2 0 2 Cognitive disorder No 0 1 1 Disturbance in attention No 0 2 2 Mental impairment No 0 4 4 Mental retardation No 0 1 1 Movement disorders (incl parkinsonism) Bradykinesia No 0 1 1 Choreoathetosis No 0 1 1 Dyskinesia No 0 20 20 Dystonia No 0 1 1 Extrapyramidal disorder No 1 0 1 Head titubation No 0 1 1 Hemiparesis Yes 2 0 2 Hypokinesia No 0 7 7 Masked facies No 0 2 2 Monoparesis Yes 3 0 3 Monoplegia Yes 1 0 1 Motor developmental delay No 0 2 2 Movement disorder No 0 3 3 Opisthotonus No 0 9 9 Paresis Yes 2 0 2 Postictal paralysis Yes 1 0 1 Psychomotor hyperactivity No 0 4 4 Spastic diplegia No 1 0 1 Tremor No 0 22 22 Neurological disorders NEC Altered state of consciousness No 6 0 6 Aphasia No 1 0 1 Areflexia No 0 4 4 Ataxia No 0 3 3 Balance disorder No 0 9 9 Cerebellar ataxia No 0 2 2 CONFIDENTIAL 24 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Cerebral disorder No 0 1 1 Clonus No 0 8 8 Crying Yes 0 264 264 Depressed level of consciousness No 56 0 56 Dizziness No 0 2 2 Drooling No 0 5 5 Dysstasia No 0 2 2 Fontanelle bulging No 0 2 2 Hyperaesthesia No 0 10 10 Hyperreflexia No 0 1 1 Hypoaesthesia Yes 0 1 1 Hyporeflexia No 0 2 2 Hyporesponsive to stimuli No 0 1 1 Lethargy No 0 7 7 Loss of consciousness No 69 0 69 Meningism No 0 1 1 Motor dysfunction No 0 6 6 Myoclonus No 0 13 13 Nervous system disorder No 0 2 2 Neurological symptom No 0 1 1 Nystagmus No 0 3 3 Poor sucking reflex No 0 1 1 Postictal state No 0 3 3 Presyncope No 6 1 7 Psychomotor skills impaired No 0 3 3 Sensory loss No 0 1 1 Slow response to stimuli No 24 0 24 Somnolence Yes 0 72 72 Speech disorder No 0 1 1 Speech disorder developmental No 0 3 3 Stupor Yes 0 2 2 Subdural effusion No 0 2 2 Syncope No 9 0 9 Unresponsive to stimuli No 21 1 22 Neuromuscular disorders Autonomic nervous system imbalance No 0 1 1 Cholinergic syndrome No 0 2 2 Hypertonia No 0 27 27 Hypotonia No 0 165 165 Hypotonic-hyporesponsive episode Yes 2 100 102 Muscle contractions involuntary No 0 2 2 Muscle spasticity No 0 1 1 Sensorimotor disorder No 0 1 1 Peripheral neuropathies Demyelinating polyneuropathy No 1 0 1 Guillain-Barre syndrome Yes 2 0 2 CONFIDENTIAL 25 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Neuropathy peripheral Yes 0 2 2 Seizures (incl subtypes) Atonic seizures Yes 1 0 1 Clonic convulsion Yes 5 0 5 Complex partial seizures Yes 1 0 1 Convulsion Yes 107 0 107 Convulsions local Yes 1 0 1 Epilepsy Yes 20 0 20 Febrile convulsion Yes 98 0 98 Grand mal convulsion Yes 33 0 33 Infantile spasms Yes 8 1 9 Lennox-Gastaut syndrome No 1 0 1 Partial seizures Yes 7 0 7 Petit mal epilepsy Yes 5 0 5 Seizure like phenomena No 3 0 3 Status epilepticus No 6 0 6 Tonic clonic movements Yes 0 1 1 Tonic convulsion Yes 4 0 4 Sleep disturbances (incl subtypes) Cataplexy No 1 0 1 Circadian rhythm sleep disorder No 0 2 2 Hypersomnia No 0 5 5 Poor quality sleep No 0 2 2 Spinal cord and nerve root disorders Spinal cord compression No 0 1 1 Structural brain disorders Cerebral atrophy No 2 0 2 Cerebral ventricle dilatation No 1 0 1 Subdural hygroma No 0 1 1 Pregnancy, puerperium and perinatal conditions Neonatal and perinatal conditions Poor weight gain neonatal No 0 1 1 Pregnancy, labour, delivery and postpartum conditions Live birth No 0 1 1 Psychiatric disorders Anxiety disorders and symptoms Agitation No 0 19 19 Anxiety No 0 6 6 Anxiety disorder due to a general medical condition No 0 1 1 Fear No 0 1 1 Nervousness Yes 0 1 1 Tension No 0 1 1 Changes in physical activity Bruxism No 0 1 1 Decreased activity No 0 6 6 Restlessness Yes 0 78 78 Stereotypy No 0 1 1 Communication disorders and disturbances Mutism No 0 1 1 Phonological disorder No 0 1 1 CONFIDENTIAL 26 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Screaming No 0 31 31 Deliria (incl confusion) Disorientation No 0 2 2 Depressed mood disorders and disturbances Psychomotor retardation No 0 1 1 Tearfulness Yes 0 2 2 Dissociative disorders Dissociation No 0 1 1 Disturbances in thinking and perception Delusion No 0 1 1 Eating disorders and disturbances Eating disorder No 0 2 2 Food aversion Yes 0 5 5 Mood disorders and disturbances NEC Apathy No 0 19 19 Emotional distress No 0 1 1 Listless No 0 3 3 Moaning No 0 4 4 Personality disorders and disturbances in behaviour Indifference No 0 2 2 Personality change No 0 3 3 Psychiatric and behavioural symptoms NEC Abnormal behaviour No 0 10 10 Breath holding No 0 2 2 Decreased eye contact No 0 3 3 Staring No 0 42 42 Schizophrenia and other psychotic disorders Psychotic disorder No 1 0 1 Sleep disorders and disturbances Insomnia No 0 19 19 Middle insomnia No 0 3 3 Sleep disorder No 0 12 12 Renal and urinary disorders Renal disorders (excl nephropathies) Oliguria No 0 1 1 Pyelocaliectasis No 0 1 1 Renal impairment No 0 2 2 Ureteric disorders Ureteric stenosis No 0 1 1 Urinary tract signs and symptoms Enuresis No 0 1 1 Polyuria No 0 2 2 Reproductive system and breast disorders Reproductive tract disorders NEC Oedema genital No 0 1 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Asthma No 2 0 2 Bronchial hyperreactivity No 1 0 1 Bronchitis chronic Yes 0 1 1 Bronchospasm No 0 3 3 Obstructive airways disorder No 1 0 1 Lower respiratory tract Atelectasis No 1 0 1 CONFIDENTIAL 27 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period disorders (excl obstruction and infection) Emphysema No 0 1 1 Interstitial lung disease No 1 0 1 Pneumonia aspiration No 2 0 2 Neonatal respiratory disorders Apparent life threatening event No 10 0 10 Infantile apnoeic attack No 1 0 1 Respiratory disorders NEC Acute respiratory failure No 1 0 1 Apnoea Yes 47 0 47 Apnoeic attack Yes 0 6 6 Asphyxia No 1 1 2 Aspiration No 0 2 2 Choking No 3 0 3 Choking sensation No 0 1 1 Cough Yes 0 37 37 Cyanosis central No 1 0 1 Dry throat No 0 1 1 Dysphonia No 0 2 2 Dyspnoea No 0 30 30 Hiccups No 0 1 1 Hypopnoea Yes 0 1 1 Hypoventilation Yes 2 0 2 Hypoxia No 1 0 1 Increased upper airway secretion No 0 3 3 Lung disorder No 0 1 1 Oropharyngeal pain No 0 1 1 Productive cough Yes 0 2 2 Rales No 0 1 1 Respiration abnormal No 0 18 18 Respiratory arrest Yes 10 0 10 Respiratory depression Yes 1 0 1 Respiratory disorder No 0 12 12 Respiratory failure No 1 0 1 Respiratory tract congestion No 0 1 1 Respiratory tract inflammation No 0 1 1 Rhinorrhoea No 0 4 4 Sleep apnoea syndrome No 0 2 2 Sneezing No 0 2 2 Snoring No 0 1 1 Tachypnoea No 0 4 4 Upper respiratory tract congestion No 0 1 1 Upper respiratory tract inflammation No 0 2 2 Yawning No 0 1 1 Upper respiratory tract disorders (excl infections) Epistaxis No 0 2 2 CONFIDENTIAL 28 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Nasal congestion No 0 1 1 Pharyngeal erythema No 0 13 13 Rhinitis allergic No 0 1 1 Stridor No 3 0 3 Tonsillar disorder No 0 1 1 Tonsillar hypertrophy No 0 1 1 Skin and subcutaneous tissue disorders Angioedema and urticaria Angioedema Yes 12 0 12 Urticaria Yes 0 52 52 Urticaria papular No 0 3 3 Urticaria thermal No 0 2 2 Cornification and dystrophic skin disorders Keloid scar No 0 1 1 Skin hypertrophy No 0 1 1 Cutaneous neoplasms benign Dermal cyst No 0 1 1 Epidermal and dermal conditions Blister No 0 9 9 Decubitus ulcer No 0 1 1 Dermatitis Yes 0 2 2 Dermatitis allergic Yes 0 4 4 Dermatitis atopic Yes 0 8 8 Dermatitis diaper Yes 0 2 2 Dry skin No 0 2 2 Eczema Yes 0 16 16 Erythema Yes 0 104 104 Erythema multiforme Yes 3 0 3 Erythrosis No 0 1 1 Generalised erythema Yes 0 4 4 Granuloma skin No 0 1 1 Lichen striatus No 0 1 1 Macule Yes 0 1 1 Neurodermatitis Yes 0 4 4 Palmar erythema Yes 0 1 1 Papule Yes 0 5 5 Pemphigoid No 1 0 1 Prurigo Yes 0 2 2 Pruritus Yes 0 13 13 Rash Yes 0 83 83 Rash erythematous Yes 0 14 14 Rash generalised Yes 0 13 13 Rash macular Yes 0 19 19 Rash maculo-papular Yes 0 15 15 Rash morbilliform Yes 0 7 7 Rash papular Yes 0 4 4 Rash pruritic Yes 0 1 1 Rash vesicular Yes 0 3 3 Scab No 0 3 3 CONFIDENTIAL 29 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period Scar No 0 5 5 Seborrhoeic dermatitis Yes 0 1 1 Skin chapped No 0 1 1 Skin discolouration No 0 30 30 Skin disorder No 0 1 1 Skin exfoliation Yes 0 4 4 Skin induration No 0 1 1 Skin lesion No 0 4 4 Skin reaction No 0 2 2 Skin tightness No 0 1 1 Skin warm No 0 16 16 Stevens-Johnson syndrome Yes 1 0 1 Swelling face Yes 0 6 6 Toxic skin eruption Yes 0 1 1 Yellow skin No 2 0 2 Pigmentation disorders Schamberg’s disease No 0 1 1 Skin depigmentation No 0 4 4 Skin and subcutaneous tissue disorders NEC Erythema nodosum No 0 2 2 Lipoatrophy No 1 0 1 Skin erosion No 0 1 1 Skin ulcer No 0 2 2 Subcutaneous nodule No 0 2 2 Skin appendage conditions Acne Yes 0 1 1 Cold sweat No 0 4 4 Hair growth abnormal No 0 1 1 Hyperhidrosis No 0 14 14 Hypertrichosis No 0 2 2 Skin vascular abnormalities Acute haemorrhagic oedema of infancy No 1 0 1 Ecchymosis No 0 5 5 Henoch-Schonlein purpura No 2 0 2 Increased tendency to bruise No 0 1 1 Livedo reticularis No 0 3 3 Lividity No 0 7 7 Petechiae No 0 49 49 Purpura No 0 8 8 Skin oedema No 0 1 1 Spider naevus No 0 1 1 Social circumstances Lifestyle issues Disability No 1 0 1 Immobile No 0 3 3 Surgical and medical procedures Gastrointestinal therapeutic procedures Colectomy No 0 1 1 Ileostomy No 0 1 1 Small intestinal resection No 0 1 1 Haematological and lymphoid tissue therapeutic Haemostasis No 0 1 1 CONFIDENTIAL 30 System Organ Class (SOC) HLGT Event (PT) Listed Serious NonSerious Total Cases for BR period procedures Nervous system, skull and spine therapeutic procedures Neurosurgery No 0 1 1 Respiratory tract therapeutic procedures Endotracheal intubation No 0 1 1 Mechanical ventilation No 0 1 1 Skin and subcutaneous tissue therapeutic procedures Skin lesion excision No 0 1 1 Soft tissue therapeutic procedures Tenotomy No 0 1 1 Therapeutic procedures and supportive care NEC Abscess drainage No 0 2 2 Debridement No 0 1 1 Enteral nutrition No 0 1 1 Macrophage activation No 0 1 1 Off label use No 0 22 22 Resuscitation No 0 3 3 Surgery No 0 1 1 Vascular disorders Arteriosclerosis, stenosis, vascular insufficiency and necrosis Peripheral coldness Yes 0 5 5 Decreased and nonspecific blood pressure disorders and shock Circulatory collapse Yes 8 0 8 Hypotension Yes 0 1 1 Shock Yes 5 0 5 Embolism and thrombosis Jugular vein thrombosis No 1 0 1 Thrombosis No 1 0 1 Vascular disorders NEC Capillary disorder No 0 1 1 Flushing No 0 4 4 Hyperaemia No 0 11 11 Pallor No 0 158 158 Vasodilatation No 0 2 2 Vascular haemorrhagic disorders Haematoma No 0 16 16 Haemorrhage No 2 0 2 Vascular hypertensive disorders Hypertension No 0 2 2 Vascular inflammations Kawasaki’s disease No 0 7 7 Vasculitis Yes 1 0 1 CONFIDENTIAL 31 32 CONFIDENTIAL APPENDIX 2 : SUMMARY of CASES OF GAZE PALSY SINCE LAUNCH Summary of cases of Gaze palsy since launch Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0559034A 12 -Feb -09 Improved 12 Weeks Male Infanrix hexa 7 Hours Febrile convulsion, Gaze palsy, Musculoskeletal stiffness Poland B0564167A 06 -Mar -09 Resolved 2 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 3 Minutes Loss of consciousness, Crying, Pyrexia, Inflammation, Pain, Diarrhoea, Pallor, Gaze palsy, Hypotonia Netherlands B0566112A 20 -Mar -09 Resolved 2 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 3 Minutes Convulsion, Loss of consciousness, Gaze palsy, Depressed level of consciousness, Respiration abnormal, Injection site swelling, Pyrexia, Crying, Decreased appetite, Oligodipsia Netherlands Apnoea B0580036A 19 -Jun -09 Resolved 2 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Convulsion, Loss of consciousness, Depressed level of consciousness, Gaze palsy, Oligodipsia, Hypotonia, Pallor, Pyrexia Netherlands B0581097A 26 -Jun -09 Resolved 3 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Depressed level of consciousness, Gaze palsy, Sense of oppression, Pallor, Hypotonia, Vomiting, Pyrexia Netherlands Nasopharyngitis CONFIDENTIAL 33 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0599801A 26 -Oct -09 Resolved 2 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 3 Seconds Depressed level of consciousness, Crying, Hyperhidrosis, Vasodilatation, Gaze palsy, Pyrexia, Inflammation Netherlands B0613669A 09 -Dec -09 Resolved 2 Months Male Infanrix – polio -HIB, Infanrix hexa 2 Days Infantile spasms, Gaze palsy, Muscle spasms, Sleep disorder, Condition aggravated, Motor dysfunction, Hypertonia France B0614538A 08 -Dec -09 Resolved 2 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 5 Hours Respiration abnormal, Gaze palsy, Loss of consciousness, Pallor, Cyanosis, Hypotonia Netherlands B0642185A 19 -Mar -10 Unknown 15 Months Femal e Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 5 Days Altered state of consciousness, Gaze palsy, Tonic convulsion, Convulsion, Epilepsy, Gastroenteritis, Febrile convulsion, Hypertonia, Ear infection, Gastritis, Nasopharyngitis, Hypotonia, Body temperature increased, Vomiting, Diarrhoea, Pyrexia Czech Republic Psychomotor retardation, Psychomotor skills impaired B0646907A 09 -Apr -10 Resolved 11 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 2 Hours Convulsion, Pallor, Gaze palsy, Loss of consciousness, Hypotonia, Pyrexia, Pain, Fatigue Netherlands B0647634A 13 -Apr -10 Resolved 2 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Gaze palsy, Pyrexia, Mental impairment, Crying Netherlands CONFIDENTIAL 34 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0651462A 03 -May – 10 Resolved 2 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 6 Hours Loss of consciousness, Gaze palsy, Pallor, Cyanosis, Hypotonia, Vomiting Netherlands B0652090A 07 -May – 10 Resolved 12 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Convulsion, Gaze palsy, Loss of consciousness, Pyrexia, Otitis media, Pallor Netherlands Nasopharyngitis B0656946A 21 -May – 10 Resolved 1 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 8 Hours Febrile convulsion, Loss of consciousness, Gaze palsy, Pain, Skin warm, Respiration abnormal, Pyrexia, Crying Netherlands B0660020A 10 -Jun -10 Resolved 11 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 2 Hours Pneumonia, Loss of consciousness, Gaze palsy, Convulsion, Nasopharyngitis, Drooling, Pallor, Pyrexia Netherlands B0662920A 03 -Jun -10 Resolved 2 Years Female Infanrix hexa 5 Hours Hypotonic -hyporesponsive episode, Depressed level of consciousness, Gaze palsy, Respiration abnormal, Injection site inflammation, Vomiting, Cold sweat, Injection site pain, Pallor, Pyrexia Netherlands B0668856A 05 -Aug -10 Resolved 2 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 4 Hours Gaze palsy, Crying, Pyrexia, Myoclonus Netherlands CONFIDENTIAL 35 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0669299A 10 -Aug -10 Unknown 6 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Epilepsy, Grand mal convulsion, Loss of consciousness, Gaze palsy, Cyanosis, Pyrexia, Salivary hypersecretion, Somnolence, Hyperaemia, Escherichia urinary tract infection, Electroencephalogram abnormal, Drooling, Tremor, Muscle spasms, Partial seizures, I Italy Haemangioma, Mental impairment B0669438A 11 -Aug -10 Resolved 16 Months Male Infanrix hexa 1 Days Febrile convulsion, Gaze palsy, Unresponsive to stimuli, Pyrexia Poland B0675842A 22 -Sep -10 Unknown 12 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Cetirizine hydrochlorid e, Infanrix hexa, Pneumococc al vaccines (Non -GSK) 4 Hours Convulsion, Leukocytosis, Shock, Gaze palsy, Loss of consciousness, Pyrexia Italy Urticaria B0681967A 28 -Oct -10 Resolved 2 Months Female Infanrix hexa, Meningococ cal polysacchari de vaccine group C (Non -GSK), Pneumococ cal vaccines (Non -GSK) 2 Hours Gaze palsy, Hypotonia, Pallor Spain CONFIDENTIAL 36 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0682745A 03 -Nov -10 Unresolved 6 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Hours Convulsion, Loss of consciousness, Gaze palsy, Pallor, Pyrexia, Crying Netherlands B0683261A 05 -Nov -10 Resolved 3 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Magaldrate, Ranitidine hydrochlorid e 10 Days Gaze palsy, Hypotonia Italy B0687865A 07 -Dec -10 Resolved 11 Months Male Infanrix hexa Priorix 2 Days Loss of consciousness, Gaze palsy, Pallor, Hypotonia Italy B0690071A 17 -Dec -10 Unknown 3 Months Male Infanrix hexa, Synflorix 8 Hours Hypotonic -hyporesponsive episode, Gaze palsy, Opisthotonus, Pallor, Apathy, Fear, Agitation, Hypotonia, Crying Czech Republic Dermatitis atopic B0712712A 05 -Apr -11 Resolved 13 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Hours Loss of consciousness, Depressed level of consciousness, Convulsion, Gaze palsy, Respiration abnormal, Pallor, Hypotonia, Drooling, Cyanosis, Pyrexia, Vomiting Netherlands B0717794A 06 -May – 11 Resolved 2 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 36 Hours Loss of consciousness, Apnoea, Depressed level of consciousness, Gaze palsy, Pallor, Cyanosis, Hypotonia, Peripheral coldness, Pyrexia Netherlands B0722407A 24 -May – 11 Resolved 2 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 14 Hours Gaze palsy, Hypertonia, Pyrexia, Dyskinesia, Somnolence, Feeling hot Netherlands CONFIDENTIAL 37 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0739945A 11 -Aug -11 Unknown 5 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Convulsion, Gaze palsy, Clonus, Pyrexia Italy D0042391A 04 -Nov -03 Unresolved 2 Months Female Infanrix hexa Same day Cytomegalovirus infection, Pyrexia, Pallor, Hypotension, Tachypnoea, General physical health deterioration, Gaze palsy, Tachycardia, Hypotonia, Anuria, Transaminases increased, Disseminated intravascular coagulation, Haemolysis, Haematochezia, Hyperkalaem Germany Tobacco user, Alcohol use D0042827A 07 -Jan -04 Resolved 15 Weeks Female Infanrix hexa Infanrix hexa 4 Hours Hypotonic -hyporesponsive episode, Crying, Hypotonia, Vomiting, Pallor, Altered state of consciousness, Gaze palsy Germany D0044170A 08 -Jul -04 Resolved 3 Months Female Infanrix hexa 95 Minutes Tonic convulsion, Opisthotonus, Pallor, Gaze palsy, Muscle twitching, Salivary hypersecretion, Crying Germany D0047035A 07 -Jul -05 Unknown 4 Months Female Infanrix hexa Infanrix hexa 9 Days Nervous system disorder, Developmental delay, Abnormal behaviour, Social avoidant behaviour, Gaze palsy, Syncope, Pallor, Apathy, Extrapyramidal disorder Germany Dermatitis atopic CONFIDENTIAL 38 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0049384A 12 -Apr -06 Resolved 2 Months Male Infanrix hexa 10 Minutes Hypotonic -hyporesponsive episode, Pallor, Hypotonia, Depressed level of consciousness, Gaze palsy, Immobile, Heart rate increased, Areflexia Germany Hyperbilirubinae mia, Strabismus, Jaundice D0049670A 09 -May – 06 Unknown 5 Months Female Infanrix hexa 12 Hours Epilepsy, Convulsion, Breath sounds abnormal, Gaze palsy, Staring, Depressed level of consciousness, Muscle twitching, Salivary hypersecretion, Crying, General physical health deterioration, Diarrhoea, Gastroenteritis, Haematochezia, Bronchitis, Nausea, V Germany D0054763A 08 -Oct -07 Resolved 3 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Hypotonic -hyporesponsive episode, Febrile convulsion, Pyrexia, Urinary tract infection, Leukocyturia, Haematuria, Hypotonia, Movement disorder, Gaze palsy, Pallor, Vaccination complication Germany Familial risk factor D0056301A 27 -Feb -08 Resolved 3 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 10 Hours Hypotonic -hyporesponsive episode, Hypotonia, Retching, Vomiting, Pallor, Gaze palsy, Depressed level of consciousness, Vaccination complication, Gastroenteritis, Abnormal faeces, Diarrhoea Germany CONFIDENTIAL 39 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0056982A 21 -Apr -08 Unresolved 2 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Partial seizures, Developmental delay, Hypotonia, Plagiocephaly, Gaze palsy, Salivary hypersecretion, Daydreaming, Fatigue, Oxygen saturation decreased, Pyrexia Germany Vacuum extractor delivery, Foetal monitoring abnormal, Feeding disorder neonatal, Weight decrease neonatal D0057056A 23 -Apr -08 Unknown 4 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Zymafluor D, Paracetamol 4 Days Cerebral haemorrhage, Convulsion, Partial seizures, Status epilepticus, Rhinitis, Somnolence, Oligodipsia, Gaze palsy, Unresponsive to stimuli, Oxygen saturation decreased, Hypothermia, Apnoea, Pallor, Oedema, Pneumonia, Brain oedema, Pyrexia, Pyelonephri Germany Premature baby, Respiratory distress, Sleep apnoea syndrome, Bradycardia, Sepsis, Retinopathy congenital, Familial risk factor D0058126A 21 -Jul -08 Unknown 2 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Epilepsy, Myoclonic epilepsy, Grand mal convulsion, Status epilepticus, Pyrexia, Screaming, Hyperhidrosis, Apathy, Respiration abnormal, Use of accessory respiratory muscles, Gaze palsy, Sleep disorder, Respiratory rate increased, Musculoskeletal stiffnes Germany Microcephaly, Foetal growth restriction, Hyperbilirubinae mia, Urinary tract obstruction CONFIDENTIAL 40 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0058650A 08 -Sep -08 Unresolved 5 Months Male Infanrix hexa, DTPa – HepB -IPV – HIB (Non – GSK) 2 Months Infantile spasms, Grand mal convulsion, Developmental delay, Gaze palsy, Salivary hypersecretion, Fatigue, Skin discolouration, Unresponsive to stimuli, Febrile infection, Otitis media, Hypotonia, Illusion, Neurodermatitis, Atopy Germany Delivery, Jaundice neonatal D0058976A 09 -Oct -08 Unknown 3 Months Male Infanrix hexa 0 Days Depressed level of consciousness, Gaze palsy, Somnolence, Vomiting projectile, Pyrexia, Asthenia, Pallor Germany D0059733A 03 -Dec -08 Unknown 4 Months Unknow n Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 15 Days Vaccination complication, Injury, Fluid intake reduced, Fatigue, Listless, Body temperature increased, Vomiting, General physical health deterioration, Insomnia, Crying, Gaze palsy, Dizziness, Haemoglobin decreased, Haemorrhagic anaemia, Thrombosis, Retin Germany Premature delivery D0060368A 03 -Feb -09 Resolved with Sequelae 4 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK), Dimethicone 9 Days Epilepsy, Crying, Gaze palsy, Asthenia, Dyskinesia, Body temperature increased, Gastroenteritis adenovirus, Gastroenteritis norovirus, Dermatitis diaper, Motor developmental delay Germany Flatulence, Delivery D0060421A 06 -Feb -09 Resolved 3 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Gaze palsy, Chills, Pyrexia, Vomiting Germany CONFIDENTIAL 41 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0060869A 13 -Mar -09 Resolved 14 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK) 0 Days Febrile convulsion, Pyrexia, Opisthotonus, Gaze palsy, Tremor, Unresponsive to stimuli, Fatigue, Agitation, Crying Germany D0060889A 16 -Mar -09 Unresolved 3 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Rotavirus vaccine, Paracetamol, Ergocalcifero l, Ferrous glycine sulphate 14 Days Seizure like phenomena, Gaze palsy, Crying, Opisthotonus, Benign familial neonatal convulsions, Epilepsy, Hypertonia, Unresponsive to stimuli, Dyskinesia, Lividity, Psychomotor hyperactivity, Excessive masturbation Germany Impetigo, Iron deficiency anaemia, Coordination abnormal, Physiotherapy D0061561A 07 -May – 09 Resolved 3 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Convulsion, Cyanosis, Apnoea, Musculoskeletal stiffness, Gaze palsy Germany D0061751A 19 -May – 09 Resolved 9 Weeks Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 36 Hours Convulsion, Gaze palsy, Staring, Unresponsive to stimuli, Opisthotonus, Hypotonia, Abnormal faeces Germany Plagiocephaly D0061756A 27 -May – 09 Unknown 2 Years Male Infanrix hexa 1 Days Febrile convulsion, Pyrexia, Convulsion, Loss of consciousness, Depressed level of consciousness, Musculoskeletal stiffness, Gaze palsy, Cyanosis, Disorientation, Viral infection, Injection site erythema, Injection site swelling Germany Fall, Haematoma CONFIDENTIAL 42 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0062153A 02 -Jul -09 Resolved 2 Months Female Rotavirus vaccine, Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Febrile convulsion, Pyrexia, Gaze palsy, Muscle twitching Germany D0064655B 02 -Dec -09 Unknown 3 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Rotavirus vaccine 0 Days Apparent life threatening event, Cyanosis, Hypotonia, Gaze palsy, Fatigue, Somnolence, Sleep apnoea syndrome, Gastroenteritis rotavirus, Apnoea, Apathy Germany D0066414A 08 -Feb -10 Unresolved 5 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK), Ergocalcifero l 0 Days Convulsion, Febrile convulsion, Atonic seizures, Grand mal convulsion, Pyrexia, Diarrhoea, Gaze palsy, Cyanosis, Disturbance in attention, Staring, Pharyngeal erythema, Rhinitis, Leukocytosis, Gastroenteritis, Gastroenteritis norovirus Germany D0066491A 15 -Feb -10 Resolved 2 Months Female Synflorix, Infanrix hexa Ferrous glycine sulphate, Vitamin D 6 Hours Convulsion, Gaze palsy, Muscle spasms, Tremor Germany Premature baby D0067186A 09 -Apr -10 Resolved 14 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Febrile convulsion, Loss of consciousness, Cataplexy, Gaze palsy, Pyrexia, Vaccination complication Germany CONFIDENTIAL 43 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0067732A 25 -May – 10 Resolved 3 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Convulsion, Gaze palsy, Musculoskeletal stiffness, Cyanosis Germany D0067882A 08 -Jun -10 Resolved 5 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Hypotonic -hyporesponsive episode, Gaze palsy, Hypotonia, Mental impairment, Feeling abnormal, Neutropenia Germany Abnormal weight gain, Rhinitis, Productive cough, Vomiting, Gastrooesophag eal reflux disease, Testicular retraction D0068260A 09 -Jul -10 Resolved 23 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Febrile convulsion, Pyrexia, Diarrhoea, Gaze palsy, Grand mal convulsion, Pallor, Vomiting, Gastroenteritis Germany Febrile infection, Gastroenteritis, Vomiting D0068398A 23 -Jul -10 Resolved 8 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Febrile convulsion, Gaze palsy, Respiratory arrest, Respiratory tract infection, Pharyngeal erythema, Feeling of relaxation, Skin discolouration, Vaccination complication Germany D0068812A 09 -Sep -10 Unknown 13 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Weeks Convulsion, Gaze palsy, Depressed level of consciousness, Pyrexia, Musculoskeletal stiffness, Fall, Concussion, Contusion, Hypotonia Germany Cyanosis CONFIDENTIAL 44 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0068914A 21 -Sep -10 Resolved 14 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK) 0 Days Febrile convulsion, Pyrexia, Fatigue, Gaze palsy, Loss of consciousness, Grand mal convulsion, Oxygen saturation decreased, Disorientation, Somnolence, Tachycardia, Pharyngeal erythema Germany Therapy regimen changed D0069309A 03 -Nov -10 Unknown 4 Months Male Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 0 Days Febrile convulsion, Pyrexia, Musculoskeletal stiffness, Gaze palsy, Somnolence, Transaminases increased, Pharyngeal erythema, Tympanic membrane hyperaemia Germany Cardiac murmur D0071075A 18 -Apr – 1 1 Unknown 3 Months Male Rotavirus vaccine, Infanrix hexa, Synflorix 1 Days Thalamus haemorrhage, Convulsion, Facial paresis, Hemiparesis, Hypophagia, Restlessness, Pyrexia, Screaming, Somnolence, Pallor, Hyperaesthesia, Eyelid oedema, Abdominal distension, Hypotonia, Apnoea, Gaze palsy Germany CONFIDENTIAL 45 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071143A 26 -Apr -11 Unknown 6 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK), Intubation, Mechanical ventilation 0 Days Apnoea, Cyanosis, Febrile convulsion, Gaze palsy, Altered state of consciousness, Convulsion, Body temperature increased, Breath holding, Moaning, Erythema, Swelling, Hypokinesia, Pain, Pyrexia, Dyspnoea, Infection Germany Premature baby, Neonatal respiratory distress syndrome, Neonatal respiratory failure, Infantile apnoeic attack, Bradycardia neonatal, Hyperbilirubinae mia neonatal, Regurgitation D0071366A 13 -May – 11 Unknown 12 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 1 Days Convulsion, Depressed level of consciousness, Gaze palsy, Hypochromic anaemia, Pyrexia, Injection site erythema, Musculoskeletal stiffness, Iron deficiency Germany D0071548A 27 -May – 11 Unknown 8 Months Female Infanrix hexa, Synflorix 1 Days Convulsion, Gaze palsy, Cyanosis, Vaccination complication, Restlessness, Feeling hot, Staring, Muscle twitching, Dyspnoea, Hypotonia, Somnolence, General physical health deterioration, Body temperature increased Germany D0071728A 15 -Jun -11 Resolved 3 Months Female Infanrix hexa, Pneumococ cal vaccines (Non-GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK) 0 Days Hypotonic -hyporesponsive episode, Eye movement disorder, Convulsion, Gaze palsy, Opisthotonus, Crying Germany CONFIDENTIAL 46 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072315A 08 -Aug -11 Resolved 4 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) Salbutamol sulphate 1 Days Febrile convulsion, Muscle rigidity, Opisthotonus, Gaze palsy, Pyrexia Germany Bronchitis D0072318A 08 -Aug -11 Resolved 15 Months Female Infanrix hexa 0 Days Febrile convulsion, Pyrexia, Chills, Gaze palsy, Eye movement disorder, Cyanosis, Unresponsive to stimuli, Tremor, Grand mal convulsion, Upper respiratory tract infection Germany Familial risk factor, Febrile convulsion, Hospitalisation, Cardiac murmur, Underweight D0073004A 11 -Oct -11 Unknown 16 Months Female Infanrix hexa, Pneumococ cal vaccines (Non -GSK) 48 Hours Convulsion, Pallor, Gaze palsy, Depressed level of consciousness, Joint hyperextension Germany CONFIDENTIAL 47 48 CONFIDENTIAL APPENDIX 3 : PSUR – 23 OCTOBER 2010 to 22 OCTOBER 2011 CONFIDENTIAL 1 CONFIDENTIAL 49 EXECUTIVE SUMMARY  This is the 16th Periodic Safety Update Report (PSUR) of GSK Biologicals’ combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix™ hexa, hereafter referred to as ‘Infanrix hexa’) which covers the reporting period between 23 October 2010 to 22 October 2011.  Infanrix hexa is currently registered in 92 countries.During the period under review, no regulatory actions have been taken for safety reasons.  There have been no amendments to the Reference Safety Information (RSI) in the current reporting period.  Post-marketing exposure to Infanrix hexa during the period is estimated to be between 3 075 423 and 12 301 693 subjects. The number of subjects exposed since launch until the Data Lock Point (DLP) of this report is estimated as being between 18 232 834 and 72 931 338.  The data received during the reporting period referred to a total of 1742 reports of which 1172 cases fulfilled the ICH E2C criteria for inclusion in the main line listings and summary tabulations of this report.  No further amendment to the RSI is considered necessary at this time.  No new safety signals were identified and/or evaluated during the reporting period.  The benefit/risk profile of Infanrix hexa for active immunization of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenza type b continues to be favourable.  The Company will continue to monitor cases of anaemia haemolytic autoimmune, thrombocytopenia, thrombocytopenic purpura, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, haemolytic anemia, cyanosis, injection site nodule, abcess and injection site abscess, Kawasaki’s disease, important neurological events (including encephalitis and encephalopathy), Henoch-Schonlein purpura, petechiae, purpura, haematochezia, allergic reactions (including anaphylactic and anaphylactoid reactions), cases of lack of effectiveness as well as fatal cases. CONFIDENTIAL 2 CONFIDENTIAL 50 Table of Contents 1. INTRODUCTION 1.1. Pharmacology and Indications 1.2. Presentations 2. WORLDWIDE MARKET AUTHORISATION STATUS 3. UPDATE OF REGULATORY AUTHORITY OR MARKETING AUTHORISATION HOLDER ACTIONS TAKEN FOR SAFETY REASONS 4. CHANGES TO REFERENCE SAFETY INFORMATION 5. PATIENT EXPOSURE 5.1. Market Experience 6. INDIVIDUAL CASE HISTORIES 6.1. Definitions 6.2. Cases Presented as Line Listings 6.3. Cases Presented as Summary Tabulations 6.4. Overview 6.5. Manufacturer’s Analysis of Individual Case Histories 6.5.1. Cases with a Fatal Outcome 6.5.2. Other adverse event of interest 6.5.2.1. Blood and lymphatic system disorders 6.5.2.2. Cardiac disorders 6.5.2.3. Eye disorders 6.5.2.4. Gastrointestinal disorders 6.5.2.5. General disorders and administration site conditions 6.5.2.6. Immune system disorders 6.5.2.7. Infections and infestations 6.5.2.8. Musculoskeletal and connective tissue disorders 6.5.2.9. Nervous system disorders 6.5.2.10. Repiratory, thoracic and mediastinal disorders 6.5.2.11. Skin and subcutaneous tissue disorders 6.5.2.12. Vascular disorders 6.6. Follow-Up Data 7. STUDIES 7.1. Newly-Analysed Studies 7.2. Targeted Safety Studies 7.3. Other Safety Studies 7.4. Published Safety Studies 8. OTHER INFORMATION 8.1. Efficacy Related Information 8.1.1. Pertussis component 8.1.2. Haemophilus influenza type b component 8.1.3. Hepatitis B 8.1.4. Conclusion of cases of potential lack of efficacy 8.2. Late-breaking information 8.3. EU Risk Management Plan 7 7 7 8 8 8 8 8 9 9 10 12 14 17 17 29 29 45 54 59 63 80 87 100 102 151 157 179 184 186 186 186 186 186 187 187 187 191 191 192 193 195 CONFIDENTIAL 51 8.4. Benefit Risk Analysis 9. OVERALL SAFETY EVALUATION 9.1. Signal Management 9.2. Summary of Evaluations 9.3. Adverse events of interest 9.3.1. Cases with a fatal outcome 9.3.1.1. Cases of Sudden death 9.3.2. Other adverse events of interest 9.3.2.1. Blood and lymphatic system disorders 9.3.2.2. Cardiac disorders 9.3.2.3. Eye disorders 9.3.2.4. Gastrointestinal disorders 9.3.2.5. General disorders and administration site conditions 9.3.2.6. Immune system disorders 9.3.2.7. Infections and infestations 9.3.2.8. Musculoskeletal and connective tissue disorders 9.3.2.9. Nervous system disorders 9.3.2.10. Respiratory, thoracic and mediastinal disorders 9.3.2.11. Skin and subcutaneous tissue disorders 9.3.2.12. Vascular disorders 9.4. Areas of Regulatory Interest 9.4.1. Drug interactions 9.4.2. Overdose and Medication Errors 9.4.2.1. Overdose 9.4.2.2. Medication Errors 9.4.3. Abuse or misuse 9.4.4. Pregnancy and Lactation 9.4.4.1. Pregnancy 9.4.4.2. Lactation 9.4.5. Special Patient Groups 9.4.6. Effects of long-term treatment 9.4.7. Patient/Consumer and other non-healthcare professional reports. 10. CONCLUSION 11. REFERENCES Tables Table 1 Appended Line Listings Table 2 Appended Summary Tabulations Table 3 Reports received in Time Period of PSUR Table 4 Distribution of cases by country Table 5 Distribution of cases by source Table 6 Number of cases by SOC for all AEs received during the period Table 7 Summary of cases of Bradycardia identified during the reporting period 195 195 195 197 197 197 198 202 202 203 204 204 205 206 207 208 209 213 214 215 216 216 216 216 217 228 228 228 229 229 229 229 230 231 11 13 14 15 16 16 45 CONFIDENTIAL 52 Table 8 Concurrent diseases reported among cyanosis cases identified during the period Table 9 Summary of cases of Gaze palsy identified during the period Table 10 Summary of cases of Abscess sterile/Injection site abscess sterile identified during the period Table 11 Summary of cases of Extensive swelling of vaccinated limb identified during the period Table 12 Summary of cases of Gait disturbance identified during the period Table 13 Summary of cases of Injection site nodule identified during the period Table 14 Summary of Abscess-related cases received during the period Table 15 Summary of cases of Injection site cellulitis received during the period Table 16 Summary of cases of Muscle spasms received during the period Table 17 Summary information for complete ‘Seizures/Convulsion’ data set (n=118) Table 18 Summary information for complete ‘Epilepsy’ data set (n=19) Table 19 Summary of cases of Epilepsy and Petit mal epilepsy received during the period (n=11) Table 20 Summary of cases of Status epilepticus received during the period Table 21 Summary of cases of Complex partial seizures and Infantils spasms Table 22 Summary of cases of Depressed level of consciousness received during the period Table 23 Summary of cases of Loss of consciousness received during the period Table 24 Summary of cases of Somnolence received during the period Table 25 Summary of cases of Syncope/Presyncope received during the period Table 26 Summary of cases of Petechiae received during the period Table 27 Summary of information complete data set (n=68) Table 28 Cases of Urticaria, Urticaria papular and Urticaria thermal received during the period Table 29 Summary of cases of potential pertussis compononent-related lack of efficacy received during the period Table 30 Summary of cases of potential Hib compononent-related lack of efficacy received during the period Table 31 Summary of cases of potential Hepatits B compononent-related lack of efficacy received during the period Table 32 Reporting rate of potential lack of efficacy cases Table 33 Overview of the 10 most frequently spontaneously reported events for Infanrix hexa. Table 34 Reporting rate of sudden death since launch per PSUR period 53 54 63 65 70 74 87 92 100 105 105 106 108 109 112 127 134 145 163 170 170 188 191 192 192 196 198 CONFIDENTIAL 53 Table 35 Incidence rate of Sudden Infant Death (<1 year of age) per 1,000 live births Table 36 Cumulative number of observed and expected cases of SD following Infanrix hexa in children in their first or second year of life Table 37 Overdose cases reported with adverse events during the period Table 38 Overview of medication errors by category of maladministration Table 39 Cases of maladministration identified during the reporting period Table 40 Pregnancy Outcomes Figure 1 Reporting rate of Somnolence cases per 100 000 doses distributed and per calendar year APPENDICES APPENDIX 1 : Marketing Authorisation Status APPENDIX 2 : Global Data Sheet version 010 – 21 Oct 2010 APPENDIX 3A : All serious spontaneous cases (excluding consumer reports), all serious attributable clinical trial cases and all non-serious unlisted cases (excluding consumer and regulatory reports) APPENDIX 3B : All serious attributable clinical trial cases which were received prior to the period of this PSUR but unblinded during the reporting period (no such case was received during the period) APPENDIX 3C : All non-serious listed cases (excluding consumer and regulatory authority reports) APPENDIX 3D : All non-medically verified cases APPENDIX 3E : Cases from a previous period not included in previous PSUR APPENDIX 4A : All reported AEs for cases included in APPENDIX 3A APPENDIX 4B : All reported AEs for cases included in APPENDIX 3C APPENDIX 4C : All reported AEs from non-medically verified serious cases and non-serious unlisted cases (no such case was received during the period) APPENDIX 4D : All reported AEs from non-medically verified nonserious listed cases APPENDIX 4E : Cumulative tabulation of all unlisted events from serious unlisted spontaneous reports and all serious unlisted reactions from clinical trial cases reported since launch APPENDIX 5A : Fatal cases occurred in period APPENDIX 5B : Fatal follow-up cases APPENDIX 5C : Fatal cases – late breaking info 200 201 217 218 219 229 212 233 237 253 475 476 490 502 504 538 540 541 543 598 629 637 CONFIDENTIAL 54 1. INTRODUCTION This is the 16th Periodic Safety Update Report (PSUR) of GSK Biologicals’ combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix™ hexa, hereafter referred to as ‘Infanrix hexa’) which covers the reporting period 23 October 2010 to 22 October 2011. This PSUR covers all formulations and indications for the combination product Infanrix hexa and is prepared according to all applicable regulations [ICH, 1996; ICH, 2003; Volume 9A, 2008; CHMP/PhVWP, 2007; EMEA/CHMP, 2006]. 1.1. Pharmacology and Indications Infanrix hexa contains the following antigens adsorbed onto aluminium salts: diphtheria toxoid, tetanus toxoid, three purified pertussis antigens (pertussis toxoid [PT], filamentous haemagglutinin [FHA] and pertactin [PRN; 69 kiloDalton outer membrane protein], the purified major surface antigen (HBsAg) of the hepatitis B virus (HBV) and purified polyribosyl-ribitol-phosphate capsular polysaccharide (PRP) of Haemophilus influenzae type b (Hib), covalently bound to tetanus toxoid. It also contains three types of inactivated polio viruses (type 1: Mahoney strain; type 2: MEF-1 strain; type 3: Saukett strain). Infanrix hexa is indicated for primary and booster immunisation against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b in infants from the age of 6 weeks and may be given to infants who received a first dose of hepatitis B vaccine at birth. The primary vaccination schedule (such as 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months; 3, 5 and 11 or 12 months; 6, 10, 14 weeks) consists of three doses of 0.5 ml. An interval of at least one month should be respected between doses. If it is intended to administer Infanrix hexa according to the EPI schedule (Expanded Program on Immunisation; 6, 10, 14 weeks of age), then the vaccinee must receive a dose of hepatitis B vaccine at birth. After a vaccination with 2 doses (e.g. 3, 5 months) of Infanrix hexa a booster dose must be given at least 6 months after the last priming dose, preferably between 11 and 13 months of age. After vaccination with 3 doses (e.g. 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months) of Infanrix hexa a booster dose may be given at least 6 months after the last priming dose and preferably before 18 months of age. 1.2. Presentations A 0.5 ml dose of the vaccine contains not less than 30 IU of adsorbed diphtheria toxoid, not less than 40 IU of adsorbed tetanus toxoid, 25 µg of adsorbed PT, 25 µg of adsorbed FHA, 8 µg of adsorbed pertactin, 10 µg of adsorbed recombinant HBsAg protein, 40 Dantigen units of type 1 (Mahoney), 8 D-antigen units of type 2 (MEF-1) and 32 D-antigen units of type 3 (Saukett) of the polio virus. It also contains 10 µg of adsorbed purified capsular polysaccharide of Hib (PRP) covalently bound to 20-40 µg tetanus toxoid (T). CONFIDENTIAL 7 CONFIDENTIAL 55 2. WORLDWIDE MARKET AUTHORISATION STATUS Infanrix hexa was first approved in the European Union on 23 October 2000 (centralized procedure) and is currently licensed in 92 countries. Details of all countries where Infanrix hexa is currently approved are presented in APPENDIX 1. During the period, there was no marketing authorisation withdrawal. 3. UPDATE OF REGULATORY AUTHORITY OR MARKETING AUTHORISATION HOLDER ACTIONS TAKEN FOR SAFETY REASONS During the period under review, no actions have been taken for safety reasons concerning withdrawal, revocation, rejection, suspension or failure to obtain a renewal of a Marketing Authorisation; neither have there been any dosage modifications, changes in target population, formulation changes, restriction on distribution, or clinical trial suspension. 4. CHANGES TO REFERENCE SAFETY INFORMATION Changes to the Reference Safety Information (RSI), including rationale, are communicated to Regulatory Agencies on an ongoing basis. The RSI in effect at the beginning of the reporting period is presented in APPENDIX 2. The RSI is the Global Prescriber Information (GPI) of the Global Datasheet (GDS) version 10 dated 21 October 2010; the RSI is highlighted in this document by gray shading. There were no changes to the RSI during the time period of this report. 5. PATIENT EXPOSURE 5.1. Market Experience Information on the actual number of people exposed to Infanrix hexa in the different countries is not available to the MAH. Therefore, the total subject exposure is approximated by the number of doses distributed which is the most reliable data available with regard to exposure for a vaccine in a post-marketing setting. It is important to note that the sales database from which data are retrieved is an in-house ‘living’ database and is subject to updates and corrections depending on information provided by GSK local country subsidiaries (e.g. vaccine doses may be returned by subsidiaries to the central warehouse). These constant updates may result in discrepancies between consecutive queries of the database. For this PSUR, the database was queried at time of PSUR preparation. During the period covered by this report 12 301 693 doses of Infanrix hexa have been distributed. Since launch until the data lock point (DLP) of this PSUR, 72 931 338 doses CONFIDENTIAL 8 CONFIDENTIAL 56 have been distributed. As vaccination with Infanrix hexa can vary between 1 and 4 doses per subject in accordance with local recommendations and compliance with the vaccination schedule, post-marketing exposure to Infanrix hexa during the PSUR reporting period is estimated to be between 3 075 423 and 12 301 693 subjects. The number of subjects exposed since launch until the data lock point of this report is estimated to be between 18 232 834 and 72 931 338. Refer to Section 9.4 for pregnancy exposure figures. 6. INDIVIDUAL CASE HISTORIES 6.1. Definitions LISTEDNESS Listedness is automatically assigned by GSK at the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT) level. Listed Event: An event is only considered listed if it is included in the RSI under all circumstances. Events that are only listed in specific situations (e.g. in overdose, for a specific indication, as part of a hypersensitivity reaction or post-treatment) are assessed as ‘unlisted’. Lack of efficacy is assessed as listed. This is supported by CIOMS V which acknowledges that no vaccine can be expected to be effective in all patients. Listed Case: A case is considered listed if all Adverse Events (AEs) are covered by the RSI when it is entered onto the safety database. This may be different from the RSI used for this PSUR. Note: For clinical trials and Post-Marketing Surveillance (PMS) cases, only serious, attributable events must be in the RSI for the case to appear as listed. Unlisted Case: A case where at least one AE was not covered by the RSI at the time of case entry. SERIOUSNESS Serious Case: A case involving an untoward medical occurrence that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity or is a congenital anomaly/birth defect. Medical or scientific judgement is exercised in deciding whether other reports should also be considered serious, such as those involving important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events are also considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse. In GSK, such medically important events are termed GSK ‘medically serious AEs’ (see below). CONFIDENTIAL 9 CONFIDENTIAL 57 GSK Medically Serious AE: As proposed by CIOMS V, GSK maintains a list of all events considered to be ‘medically serious’ that is regularly reviewed and updated by the company Safety Physicians. This list of MedDRA Lower Level Terms (LLTs) is automatically applied to all spontaneous, post-marketing and literature cases as they are entered onto the safety database. Inclusion of ‘medically serious’ events makes the case serious at case level. OTHER DEFINITIONS Attributability: A clinical trial case is classified as ‘attributable’ if the investigator or the company consider there is a reasonable possibility that a serious AE was caused by the study medication. These cases may also contain individual non-serious AEs. A clinical trial case is also considered ‘attributable’ if the investigator does not specify causality for any serious AE. Primary Adverse Event: The main AE described by the reporter. If a diagnosis and associated signs/symptoms have been provided, GSK will consider the diagnosis the primary AE. Where the main AE is not clear, GSK assigns the most serious medical condition the reporter thought was associated with the drug as the primary AE. 6.2. Cases Presented as Line Listings The following type of cases received by GSK from worldwide sources during the reporting period and referenced below are considered to fulfil ICH E2C criteria for inclusion in the main line listings and/or summary tabulations of this report:  all serious adverse reactions and non-serious unlisted adverse reactions from spontaneous notifications (including published reports);  all non-serious listed adverse reactions from spontaneous reporting;  all serious adverse reactions (attributable to the vaccine by either investigator or sponsor) available from studies or named-patient/compassionate use;  all serious adverse reactions from regulatory authorities. In addition, the type of cases mentioned below is included as a line listing as well:  all serious and non-serious (listed and unlisted) adverse reactions reported by patients/consumers and other non-healthcare professionals (non-medically verified cases). The type of cases making up the PSUR line listings within Appendices 3 is summarized below and in Table 1. APPENDIX 3A contains: CONFIDENTIAL 10 CONFIDENTIAL 58  all serious cases from spontaneous notifications (including published reports and regulatory reports but excluding non-medically verified reports);  all unblinded serious cases arising from clinical trials considered related by sponsor or investigator;  all non-serious unlisted cases from spontaneous notifications (including published reports but excluding non-medically verified reports and reports received solely from regulatory authorities). APPENDIX 3B contains all serious attributable clinical trial cases unblinded during the reporting period which were not included in a previous report because they were still blinded. It is company policy that only those clinical trial reports which are expedited to regulatory authorities are unblinded on the safety database during study conduct. Clinical trial reports that are not expedited will be unblinded on study completion. Any clinical trial reports meeting ICH E2C criteria but not included in a previous PSUR, are included as follow-up information in APPENDIX 3B. In order to ensure no cases are missed, GSK uses a broad search strategy to retrieve clinical trial cases unblinded during the reporting period. Therefore, APPENDIX 3B may include some cases which have already been included in a previous PSUR (e.g. nonblinded clinical trial cases). Note that no such case was received during the period. APPENDIX 3C contains all non-serious listed cases from spontaneous notifications including published reports but excluding all non-medically verified reports and all reports received solely from regulatory authorities. APPENDIX 3D contains all non-medically verified cases, whether serious or nonserious, listed or unlisted. Table 1 Appended Line Listings Format Appendix Case Type Line Listing 3A All serious spontaneous cases (excluding consumer reports), all serious attributable clinical trial cases and all non-serious unlisted cases (excluding consumer and regulatory reports) 3B All serious attributable clinical trial cases which were received prior to the period of this PSUR but unblinded during the reporting period No such case was received during the period 3C All non-serious listed cases (excluding consumer and regulatory authority reports) 3D All non-medically verified cases 3E Cases from a previous period not included in previous PSUR CONFIDENTIAL 11 CONFIDENTIAL 59 Explanation of line listings content  Within the line listings a case is considered serious if it fulfils the ICH definition of serious (see Section 6.1). Serious cases are identified by a “#” beside the case ID.  An unlisted case contains at least one AE that is not covered by the RSI which was in place at the time of data entry.  The AEs within a case are presented at MedDRA PT level. System Organ Class (SOC) is assigned automatically according to the Primary AE.  Literature citations for all published cases are noted in the ‘Comments’ column of the line listing. 6.3. Cases Presented as Summary Tabulations An aggregate summary for each of the line-listings is presented in Appendices 4 as summarised below and in Table 2. All AEs are presented at MedDRA PT level within summary tabulations. APPENDIX 4A contains all reported AEs for cases included in APPENDIX 3A, meaning AEs from all serious spontaneous cases (excluding consumer reports), all serious attributable clinical trial cases and all non-serious unlisted cases (excluding consumer and regulatory reports). APPENDIX 4B contains all reported AEs for cases included in APPENDIX 3C, meaning AEs from all non-serious listed cases (excluding consumer and regulatory authority reports). APPENDIX 4C contains all reported AEs from non-medically verified serious cases + non-medically verified non-serious unlisted cases. APPENDIX 4D contains all reported AEs from non-medically verified non-serious listed cases. APPENDIX 4E is a cumulative tabulation of all unlisted events from serious unlisted spontaneous reports (including non-medically verified reports) and all serious unlisted reactions from clinical trial cases reported since launch. Of note, differences may appear between numbers in the previous PSUR cumulative counts of unlisted events for the following reasons: CONFIDENTIAL 12 CONFIDENTIAL 60  changes in the listedness of some AEs due to an update in the RSI;  increased consistency in the listedness assessment has been achieved following implementation of an automated listedness attribution applied to the case reports received;  in “old” cases diagnostics could have been coded with signs and symptoms. These signs and symptoms are not included in the cumulative count anymore.  in the previous tables all AEs, listed and unlisted were taken into account while in the new outputs, only the unlisted AEs are provided. Table 2 Appended Summary Tabulations Summary Tabulation 4A All reported AEs for cases included in APPENDIX 3A 4B All reported AEs for cases included in APPENDIX 3C 4C All reported AEs from non-medically verified serious cases and non-serious unlisted cases 4D All reported AEs from non-medically verified non-serious listed cases 4E Cumulative tabulation of all unlisted events from serious unlisted spontaneous reports and all serious unlisted reactions from clinical trial cases reported since launch Explanation of summary tabulations content The following information is important when evaluating the summary tabulations. Seriousness AEs from spontaneous, post-marketing or literature cases are only classified as serious within the tabulations if they are on the list of GSK medically serious terms (see Section 6.1). Therefore, although an AE may reside in a case that fulfils the ICH criteria of serious, if the event is not on the list of GSK medically serious terms it will appear within the non-serious column in the summary tabulations. GSK believes that applying the GSK medically seriousness criteria to AEs will provide a consistent and more meaningful presentation of data within the tabulations, and help with aggregation of terms for signal review activities. Counts of events are presented in the tabulations for the reporting period of the PSUR and cumulatively (APPENDIX 4E). Note: In rare situations an event may appear in both the serious and non serious columns within the summary tabulations, this may occur for the following reasons:  GSK only applies its list of medically serious terms to events reported in spontaneous reports, literature cases and post-marketing surveillance studies. Serious criteria for events originating from clinical trial cases are determined by the reporter. Therefore, as events can originate from different report sources seriousness assessments may differ.  The GSK medically serious list is compiled at the MedDRA LLT level. Summary tabulations present counts of events at the MedDRA PT level. A PT may therefore have both serious and non serious LLTs associated with it. CONFIDENTIAL 13 CONFIDENTIAL 61 6.4. Overview An overview of the 1742 reports received in the time period is presented in Table 3. Out of this grand total of 1742 cases, 1736 were reported spontaneously and six were clinical trial cases. Based on the exposure data presented in Section 5.1, a reporting rate of 14.16 cases per 100 000 doses distributed can be estimated (against 17.36 cases per 100 000 doses distributed during the previous one-year period). This corresponds to a 18.43% decrease in the overall reporting rate and was mainly driven by a decrease in the reporting rate of non-medicaly verified (‘consumer’) cases, which decreased by 81.74%. Table 3 Reports received in Time Period of PSUR NUMBER OF CASES REPORTS FULFILLING ICH E2C CRITERIA Serious Unlisted 503 Serious Listed 56 Non-serious Unlisted 545 TOTAL (Line listing) 1104 Non-Serious Listed 68 TOTAL (ICH E2C criteria) 1172 OTHER REPORTS Non-Medically Verified 54 Regulatory, non-serious 516 TOTAL (Other reports) 570 GRAND TOTAL (All reports) 1742 CONFIDENTIAL 14 CONFIDENTIAL 62 The majority of reports were received from 41 countries (Table 4), mainly Italy with 595 cases (34.2%), Germany with 382 cases (21.9%) and France with 298 cases (17.1%). Table 4 Distribution of cases by country Country of Reporter Number of Cases (%) Italy 595 (34,2) Germany 382 (21,9) France 298 (17,1) Netherlands 112 (6,4) Poland 91 (5,2) Australia 36 (2,1) Spain 25 (1,4) Czech Republic 24 (1,4) Belgium 23 (1,3) South Africa 22 (1,3) Austria 20 (1,1) Sweden 14 (0,8) Ireland 11 (0,6) Kenya 9 (0,5) Switzerland 8 (0,5) Canada 7 (0,4) Greece 7 (0,4) Latvia 7 (0,4) Argentina 5 (0,3) Romania 5 (0,3) Viet Nam 5 (0,3) Brazil 3 (0,2) Ecuador 3 (0,2) Peru 3 (0,2) Singapore 3 (0,2) Ukraine 3 (0,2) Andorra 2 (0,1) Colombia 2 (0,1) Hong Kong 2 (0,1) New Zealand 2 (0,1) Slovakia 2 (0,1) Thailand 2 (0,1) Chile 1 (0,1) Croatia 1 (0,1) Mexico 1 (0,1) Namibia 1 (0,1) Philippines 1 (0,1) Saudia Arabia 1 (0,1) Serbia 1 (0,1) Taiwan, ROC 1 (0,1) United Arab Emirates 1 (0,1) TOTAL 1742 (100,0) CONFIDENTIAL 15 CONFIDENTIAL 63 Based on the initial reporting source (Table 5), 1007 cases were received from regulatory authorities (57,8%), 667 from healthcare professionals (38.3%) and 68 cases from nonhealthcare professionals (4%). Table 5 Distribution of cases by source Source Number of Cases (%) Regulatory Authority 1007 57,8) Physician 513 (29,4) Other Health Professional 85 (4,9) Pharmacist 69 (4,0) Consumer 63 (3,6) Literature 3 (0,2) Other 1 (0,1) Representative 1 (0,1) TOTAL 1742 (100,0) Table 6 shows the numbers of cases by system organ class (SOC) for all AEs received during the period. Note that in this tabulation, seriousness and listedness are assigned at event level. Table 6 Number of cases by SOC for all AEs received during the period Event SOC Number of Cases (%) General disorders and administration site conditions 1056 30.9 Nervous system disorders 461 13.5 Skin and subcutaneous tissue disorders 358 10.5 Injury, poisoning and procedural complications 330 9.6 Infections and infestations 181 5.3 Psychiatric disorders 165 4.8 Gastrointestinal disorders 141 4.1 Vascular disorders 129 3.8 Respiratory, thoracic and mediastinal disorders 118 3.5 Investigations 82 2.4 Cardiac disorders 79 2.3 Musculoskeletal and connective tissue disorders 69 2.0 Eye disorders 60 1.8 Metabolism and nutrition disorders 59 1.7 Blood and lymphatic system disorders 46 1.3 Immune system disorders 34 1.0 Surgical and medical procedures 18 0.5 Ear and labyrinth disorders 9 0.3 Hepatobiliary disorders 6 0.2 Congenital, familial and genetic disorders 5 0.1 Renal and urinary disorders 5 0.1 Social circumstances 4 0.1 Endocrine disorders 2 0.1 Reproductive system and breast disorders 2 0.1 Neoplasms benign, malignant and unspecified (including cysts and polyps) 1 0.0 TOTAL 3420 100.0 * This number is greater than the Grand total of cases in Table 3 since each case may include AEs from multiple SOCs CONFIDENTIAL 16 CONFIDENTIAL 64 In addition to the grand total of 1742 cases, 10 cases where identified as received prior to the period of the present report, but not included in any previous PSUR (APPENDIX 3E). The reasons are as follows:  For 9 cases (B0591710A, B0631888A, B0637096A, B0674885A, D0060830A, D0061162A, D0063259A, D0066216A, D0066224A) the suspect vaccine name was changed to Infanrix hexa after the data lack point of the previous PSUR.  Case B0647987A was initially coded as Postmarketing surveillance (PMS) case. These cases types are not included in PSURs when they are non-serious (case B0647987A is non-serious). During the period, the case type was corrected to ‘Spontaneous’ and thus fulfilled the criteria for inclusion in the PSUR. These cases are described and discussed among adverse events of interest as appropriate in Sections 6.5 and 9.3. 6.5. Manufacturer’s Analysis of Individual Case Histories As a company policy, all incoming AEs are reviewed on an ongoing basis to detect any new safety signal. Once identified, all available data relating to the AEs under review are routinely evaluated in a cumulative manner for a possible causal association with the suspect product. The selection of the AEs of interest as described in this section is based on the following criteria: reporting frequency, medical significance, severity of the events, mechanisms of action, issues that are being monitored, or requests by regulatory authorities. The events of interest are described for all cases (irrespective of source, seriousness and listedness) within the PSUR review period. The events from the non-serious reports received solely from regulatory authorities are not included in the Line Listings and Summary Tabulations as per guideline E2C(R1). Separate Line Listings and Summary Tabulations are provided for consumer reports as per guideline E2C(R1). Therefore some reports may be reviewed and described in this section but will not appear in the line listing and summary tabulations of the PSUR. The events are presented by MedDRA SOCs. Reports with a fatal outcome are discussed separately, regardless of the SOC of the primary AE is classified by MedDRA. Where relevant, a company comment is provided. 6.5.1. Cases with a Fatal Outcome Thirteen (13) cases with a fatal outcome were received during the reporting period. Narratives are presented in APPENDIX 5A. Note that non-medically verified reports are included. The narratives are produced directly from the safety database using a standard search strategy. The search strategy retrieves all cases in which the patient died or which are coded with MedDRA PTs indicating that death occurred. Thus the case narratives may include reports where the AE outcome is not specified as fatal in the line listings as well as reports of intra-uterine death or stillbirth. CONFIDENTIAL 17 CONFIDENTIAL 65 Cases with a fatal outcome are reviewed on an ongoing basis, as described in Section 9.1. 1. B0683335A (Netherlands): Meningitis viral, Convulsion, Yellow skin, Cyanosis, Dehydration, Diarrhoea, Somnolence, Crying, Vomiting This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-111158) and described the occurrence of meningitis in a 2-month-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenza type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. The subject had no medical history and no concomitant medication. On 13 September 2010, the subject received 1st dose of Infanrix hexa (unknown route, unknown injection site), 1st dose of Prevenar (unknown route, unknown injection site). 3 minutes after vaccination, the subject experienced crying and sleepiness on the same day. On 18 September 2010, 5 days after vaccination, the subject was found in bed with eyes half-opened and a blue mouth. His skin was yellow/pale. He vomited pink, foaming milk. No fever was observed (37 degrees C). The boy was hospitalized, diarrhea aggravated and dehydration was diagnosed. Blood test and spinal tap were performed. The boy had several afebrile convulsions and a MRI showed severe damage of the brain. No further treatment was given. On 25 September 2010, 12 days after vaccination, the subject died from viral meningitis. The regulatory authority considered the events were unlikely to be related with vaccination with Infanrix hexa and Prevenar. Additional information has been requested but could not be obtained from regulatory authority (new regulatory number: NL-LRB-116469). It was unknown whether an autopsy was performed. Company comment: Case of death due to viral meningitis in a 2-month-old male subject 12 days after 1st combined vaccination with Infanrix hexa and Prevenar. There was severe brain damage on MRI. It is unknown whether an autopsy was performed. 2. B0700040A (Sweden): Meningitis, Sepsis, Shock, Pneumococcal infection, Renal impairment, Hepatic function abnormal, Pyrexia, Diarrhea, Vomiting This case was reported by a consumer and described the occurrence of meningitis in a 9-month-old female subject who was vaccinated with synflorix (GlaxoSmithKline) and combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. A physician or other health care professional has not verified this report. Previous and/or concurrent vaccination included Bacillus Calmette – Guerin vaccine (non-gsk) given on 28 October 2010; diphtheria and tetanus toxoids and acellular pertussis vaccine; GlaxoSmithKline given on 20 May 2010; hepatitis B vaccine recombinant; manufacturer unspecified given on 20 May 2010; synflorix; GlaxoSmithKline; given on 20 May 2010. Concurrent medications included Paracetamol for her growing teeth. On 17 August 2010, the subject received 2nd dose of Synflorix (administration site and route unknown, batch number not provided). On 26 November 2010, 101 days after vaccination with Synflorix, the subject experienced fever, vomiting and diarrhea. This continued the whole day between 11 am to 6 pm. She suddenly got better and she was not vomiting and her fever went down. She got fluid replacement and was able to urinate. On 27 CONFIDENTIAL 18 CONFIDENTIAL 66 November 2010, at 7 am, the subject was not breathing any longer. At the hospital, they tried to save her during 40 minutes. The subject died on 27 November 2010 from meningitis and sepsis. An autopsy was performed and showed abnormal renal function, hepatic function abnormal and possible pneumococcal infection. The body was in shock. Company comment: Death of a 9 month-old female subject due to meningitis and sepsis 191 days after combined vaccination with Infanrix Hexa and Synflorix. 3. B0706503A (Thailand): Shock, Respiratory arrest, Cardiac arrest, Pyrexia, Somnolence, Hypotonia, Vomiting, Crying, Apnoea. This case was reported by a physician and described the occurrence of fatal shock in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. The subject was born by C-section. Apgar score was 10 at 0 and 5 min. Birth weight was 3.2 kg and experienced a normal growth and development. Medical condition included a possible genetic abnormality due to a family history of death after vaccination (subject’s brother died 2 years ago after vaccination with DTwP). On 9 March 2011, the subject received unspecified dose of Infanrix hexa (.5 ml, unknown route of adminstration). The subject was normal before vaccination. On 10 March 2011, 24 hours after vaccination with Infanrix hexa, the subject experienced shock. She experienced low-grade fever, drowsiness and stopped breathing. The subject was floppy and had no heart rate. Cardiopulmonary resuscitation was performed during 3 hours but the subject did not respond to it. The physician considered the events were probably related to vaccination with Infanrix hexa. The subject died on 10 March 2011 from cardiorespiratory arrest. An autopsy was not performed. Follow-up received on 21 March 2011: The subject’s brother was 2 month-old when he died (11 years ago), after received DTwP which was EPI vaccine (no record available). After vaccination (no specific time available), the subject experienced vomiting (single episode) and had colicky crying at home. On 10 March 2011, the subject was taken to the clinic due to fever and crying. After massive crying, the subject experienced apnea and no heart beat was detected after stimulation. Cardiopulmonary resuscitation was performed for 10 minutes and subject responded by crying. One hour later, the subject experienced apnea again and resuscitation was continued for 3 hours without any response. Neither lab results nor autopsy results were available. Shock was the final diagnosis. Company comment: This case described a SUDI (Sudden Unexpected Death in Infancy) in a 2 month-old female subject 24 hours after vaccination with Infanrix hexa. Autopsy or lab results were not provided. There is a notion of post-vaccine death in a sibling. 4. B0712016A (Italy): Hypotonia, Hyperhidrosis, Pyrexia. This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 137473) and described the occurrence of hypotonia nos in a 11-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. CONFIDENTIAL 19 CONFIDENTIAL 67 (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. The subject was born after 41 weeks + 3 days, normal pregnancy and spontaneous delivery. Concurrent medical conditions included severe respiratory distress at birth. He was reanimated and resigned from the prenatal intensive care on 20 May 2010. He was not able to feed spontaneously (dysphagia) so a nasogastric tube was inserted with pump infusion. According to the doctor, the subject had contraindication to the vaccine. He was hospitalised from 22 May 2010 to 25 May 2010 due to respiratory distress. From 14 to 21 July 2010 due to seizures. On 18 August 2010, diagnostic results showed cerebral palsy, gastroesophageal reflux, hypoxic-ischemic encephalopathy of grade 3, microcephaly, psychomotor retardation and spastic quadriplegia (mainly the upper limbs). Concurrent medications included Paracetamol (Tachipirina), Vitamin, Vigabatrin, Topiramate, Antibiotics (Antibiotic), Bronchodilator and Steroid. On 25 March 2011, the subject received 3rd dose of Infanrix hexa (intramuscular, right thigh) and 3rd dose of Prevenar 13 (intramuscular, left thigh). On 26 March 2011, 1 day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced fever (38 to 38.5 deg.C). On 27 March 2011, 2 days after vaccination with Infanrix hexa and Prevenar 13, the subject experienced hypotonia nos and crisis of sweating. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevenar 13. The subject died on 28 March 2011, cause of death was not reported. It was unknown whether an autopsy was performed. Follow-up information received on 15 July 2011: As no additional information could be obtained, the case has been closed. Company comment: This case described death of an 11-month old male subject 48 hours after third combined vaccination with Infanrix hexa and Prevenar. The subject died in the context of severe hypoxic-ischemic encephalopathy (cerebral palsy leading to quadriplegia and microcephaly). 5. B0727175A (France): Death. This case was reported by the French regulatory authority (FR-Agence Françaiss de Sécurité Sanitaire des Produits de Santé # NT20110388) and described the occurrence of unexplained death in a 18-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. The subject had no known and relevant medical history. On 26 October 2010, the subject received an unspecified dose of Infanrix hexa (batch A21CA724A, intramuscular, injection site unknown). On 27 October 2010, 1 day after vaccination with Infanrix hexa, the subject was found dead after her nap. Autopsy did not identify any cause of death. Respiratory aspiration was assessed as not very probable. No other information was available. According to the French method of assessment, the AFSSaPS considered the causal relationship between vaccination with Infanrix hexa and unexplained death as dubious. Autopsy (2010): no identified cause of death. Company comment: This case described a SIDS in an 18 month-old female subject 1 day after vaccination with Infanrix hexa. No cause was found after autopsy. 6. B0735723A (Australia): Death. CONFIDENTIAL 20 CONFIDENTIAL 68 This case was reported by a consumer and described the occurrence of death unspecified in a 6-week-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), live attenuated human rotavirus vaccine (Rotarix) and pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. A physician or other health care professional has not verified this report. On 20 July 2011, the subject received unspecified dose of Infanrix hexa (administration site and route unknown), an unspecified dose of Rotarix (route unknown) and an unspecified dose of Prevenar 13 (unknown). On 21 July 2011, 14 hours after vaccination with Infanrix hexa, Prevenar 13 and Rotarix, the subject died for unknown reasons. The subject died on 21 July 2011, cause of death was not reported. An autopsy was performed. Autopsy results are not yet available. Further information has been expected. Company comment: This case reported a SUDI in a 6-week old male subject 14 hours after combined vaccination with Infanrix hexa, Prevenar and Rotarix. An autopsy was performed but results are not available. 7. D0071496A (Germany): Death This case was reported by a health professional via a regulatory authority (DE-PaulEhrlich-Institut # DE-PEI-PEI2011016343) and described death of a 3-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-gsk, Prevenar 13) for prophylaxis. Previous vaccinations with Infanrix hexa and Prevenar 13 (on 14 April 2011) have been well tolerated. On 16 May 2011 the subject received the second dose of Infanrix hexa (intramuscular, unknown thigh) together with the second dose of Prevenar 13 (intramuscular, unknown thigh). At this time the subject had suffered from a mild intestinal infection. In the morning of the following day, on 17 May 2011, the subject was found dead. An autopsy was performed and a preliminary autopsy report was provided. According to the autopsy protocol very early in the morning of 17 May 2011 the subject had been found “cold and lifeless” by her parents. On 05:02 an emergency physician had been called. Cardiopulmonary resuscitation by the parents and later by the emergency personal failed and death was testified. Policemen were involved at 06:20. Interrogation of the subject’s parents revealed that the subject and her four siblings had always been healthy. Follow-up information was received from the institut of legal medicine Halle (Saale) on 04 August 2011: The final autopsy report was provided. The causes and mode of death could not be clarified. The infant had been suffering from an acute unilateral otitis media at the time of death (smear from the left middle ear: proof of Haemophilus influenzae; smear from the right middle ear: no proof of microorganisms). Within the scope of additional examinations no alcohol (alcohol concentration 0.00 %) or other pharmacologic could be detected. There was neither evidence of an allergic reaction. (total IgE 5.65 kU/l, reference <20kU/l) nor of a gastrointestinal infection. Nor was there any evidence of a postvaccinal disorder.” According to the autopsy report, the onset date of the subject’s otitis media was “very recent”, but it could not be clarified whether it had been prior to or following the vaccination. Although no evidence of a relation of the event to the vaccination was found during the autopsy, the close CONFIDENTIAL 21 CONFIDENTIAL 69 temporal relation might be seen as an indication that the subject’s death was possibly related to the vaccination with Infanrix hexa and Prevenar 13. Company comment: This case described a SUDI in a 13 month-old female subject 1 day after 2nd combined vaccination with Infanrix hexa and Prevenar. A recent acute haemophilus influenzae otitis media was diagnosed on autopsy. 8. D0072663A (Germany): Death This case was reported by a German regulatory authority (DE-Paul-Ehrlich-Institut # DE-PEI-PEI2011029271) and described the occurrence of unexplained death in a 9- week-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenza type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). Pregnancy and birth had been normal. The subject’s medical history included neonatal jaundice. The subject was developing normal. Family history included no allergies. Concurrent medical conditions included suspicion of congenital hip dysplasia. Hip ultrasonography, performed on 09 August 2011, showed type IIa left and type I right. Follow-up hip ultrasonography, performed on 05 September 2011, showed type I both sides. At the time of vaccination, on 05 September 2011, the subject was well. The subject showed small white plaques in oral mucus (oropharyngeal plaques) left but most likely no oral candidiasis. Previous vaccination with Rotavirus vaccine (non-GSK) (RotaTeq; Sanofi Pasteur MSD), given orally at 2 ml on 09 August 2011, was well tolerated. Concurrent medications included colecalciferol + sodium fluoride (D-Fluoretten) and paracetamol (Ben-u-ron). On 05 September 2011 the subject received the first dose of Infanrix hexa (0.5 ml, intramuscular, unknown thigh lateral) and the first dose of Prevenar 13 (.5 ml, intramuscular, unknown thigh lateral). Approximately two days post vaccination with Infanrix hexa and Prevenar 13, on 07 September 2011, the subject died. The cause of death was unknown (death unexplained). The event had also been reported as life threatening. An autopsy was performed on 07 September 2011 at an institute for forensic pathology. At the time of reporting, on 08 September 2011, examinations had not been finished and no autopsy results have been reported. The German regulatory authority (DE-Paul-Ehrlich-Institut) has requested further information. Quality test result was received on 11 October 2011. A complete review of the batch records has been performed by Quality Assurance and Production. No deviation that could impact the quality of the product has been highlighted during the GlaxoSmithKline Biologicals investigation. At the moment no further information was available. Company comment: This case described a SUDI in a 9 week-old male subject two days after combined vaccination with Infanrix hexa and Prevenar. An autopsy was performed but results are not yet available. Since 12 September 2011, five cases linked to batch A21CB094A were reported to GSK (D0072663A, D0072852A, D0072638A, D0072908A, D0072920A). All five were serious reports and two had a fatal outcome. A complete review of the batch records was performed by Quality Assurance and Production. No deviation that could impact the quality of the product was highlighted by the GlaxoSmithKline Biologicals investigation. There is insufficient information provided in the individual CONFIDENTIAL 22 CONFIDENTIAL 70 case reports to make a thorough causality assessment. Autopsy reports of the fatalities.were pending. The three non-fatal cases were all different in nature (no cluster of any kind). These subjects all received Infanrix hexa with either Prevenar 13 or Synflorix. Allergic reactions, febrile convulsions, exanthema and fever are not unexpected to possibly occur after vaccination. 9. D0072852A (Germany): Circulatory collapse, Sepsis, Shock, Crying, Pallor This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011030856) and described the occurrence of circulatory failure in a 5- month-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccination included 13-valent pneumococcal vaccine (non-GSK) (Prevenar 13, Pfizer). First vaccination with both vaccines on 23 August 2011 was well tolerated. Information about anamnesis was provided by a hospital report from intensive care treatment after birth. The mother had been pregnant for the first time. The mother had former surgery because of false lung vein opening and received permanent treatment with bisoprolol. The subject was delivered prematurely in 31+4 weeks of gestation, by section from breech presentation after pathologic CTG. There was no premature rupture of the amnion and amniotic fluid was clear. The subject had an APGAR of 6/10/10, a weight of 1490 g, length of 39 cm, head circumference of 32.6 cm, navel artery pH was 7.16. After birth the subject had neonatal respiratory distress syndrome grade I with continuous positive airway pressure for 24 hours. The subject developed possible meconium ileus due to microcolon, transient intestinal transportation disorder, cholestatic hepatosis after parenteral nutrition, with increased transaminases (alanine aminotransferase 131 U/l, aspartate aminotransferase 100 U/l, creatine kinase 342 U/l, total bilirubin 3 mg/dl, direct bilirubin 2.75 mg/dl). Additional diagnoses after birth included neonatal anemia and iron deficiency, asymmetry from lying, small hemangioma right gluteal and dystrophic growth and weight increase. On the sixth day of life, the subject’s condition worsened and he was transferred to an intensive care unit for neonates. Intravenous antibiotics were given for seven days. The subject had abdominal distension since birth and not yet passed meconium. Acute abdomen was suspected on the seventh day of life. The subject was transferred to a pediatric chirurgic unit for further intervention, but after conservative treatment the symptoms resolved. Test results were normal for ions, blood gases, immune reactive trypsin (tested on 06 May and 06 June 2011), sonogram of head, abdomen and hip (Graf classification Ib) and hearing screening. Cytomegalovirus (CMV) and toxoplasmosis IgM and IgG antibodies were negative. Initially increased Thyroid stimulating hormone normalised on control. Bile acid was increased (74.6 mcmol/l), pancreatic kinase was decreased (68 mcg/g). Eye examination showed vascularisation limit zone III at both sides. The subject was discharged after 39 days in good condition and received rachitis prophylaxis and iron substitution. On 20 September 2011 the subject received 2nd dose of Infanrix hexa (unknown route and application site), 2nd dose of Prevenar (unknown route and application site). On 20 September 2011 in the evening, less than one day after vaccination with Infanrix hexa and Prevenar, the subject had been crying and turned grey while lying in bed. The vaccinating physician was consulted and admitted the CONFIDENTIAL 23 CONFIDENTIAL 71 infant to hospital, where the subject died on 21 September 2011, from circulatory depression or possible sepsis. Different lot numbers were reported on follow-up. Approximately 20 hours after vaccination with Infanrix hexa and Prevenar 13, the subject experienced shock with circulatory failure. An emergency physician was called and the subject was hospitalized on emergency to an intensive care unit. Approximately 10 hours after onset of symptoms the subject died despite intensive care. According to follow-up information received on 07 October 2011 via the German regulatory authority (PEI), the lot number A21CB094A was documented in vaccination certificate, while there was no documentation for the mentioned lot numbers A21CB105A and A21CB115A. Quality test result was received on 11 October 2011. A complete review of the batch records has been performed by Quality Assurance and Production. No deviation that could impact the quality of the product has been highlighted during the GlaxoSmithKline Biologicals investigation. An autopsy was performed. A duplicate case was reported by a physician, via a sales representative and no further details about the reported event were provided. Company comment: Case D0072949A was identified as a duplicate of case D0072852A that was voided. A complete review of the batch records has been performed and no deviation was evidenced during investigation process. Due to lack of relevant information the causality remains uncertain: possible circulatory or sepsis shock of unknown origin several hours after 2nd vaccination with Infanrix hexa and Prevenar. An autopsy was performed, but the results were not available (see also Section 8.2). Since 12 September 2011, five cases linked to batch A21CB094A were reported to GSK (D0072663A, D0072852A, D0072638A, D0072908A, D0072920A). All five were serious reports and two had a fatal outcome. A complete review of the batch records was performed by Quality Assurance and Production. No deviation that could impact the quality of the product was highlighted by the GlaxoSmithKline Biologicals investigation. There is insufficient information provided in the individual case reports to make a thorough causality assessment. Autopsy reports of the fatalities.were pending. The three non-fatal cases were all different in nature (no cluster of any kind). These subjects all received Infanrix hexa with either Prevenar 13 or Synflorix. Allergic reactions, febrile convulsions, exanthema and fever are not unexpected to possibly occur after vaccination. 10. B0688734A (France): Sudden infant death syndrome, Respiratory tract congestion, Cough, Nasal congestion This case was reported by the French regulatory authority (AFSSaPS reference PS20101095) and described a sudden infant death in a 10-week-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccine (Prevenar, non-gsk) for prophylaxis. The subject had mixted diet. At birth she weighed 2.99 kg and her height was 49.5 cm. She had no neonatal disorder. Medical condition included jaundice with abnormal skin reflection on 01 October 2010. On 09 November 2010, the subject received primary course of Infanrix hexa (batch A21CA777A as data entry and 121CA777A as reported, intramuscular, injection site unknown) and a CONFIDENTIAL 24 CONFIDENTIAL 72 primary course of Prevenar (batch E74711, intramuscular, injection site unknown). On 10 November 2010, the subject presented with bronchial and nasal congestions, cough, and serous fluid in tympanum (with crying at night) which was diagnosed before the administration of vaccines (medical condition). At 19:00, the subject received her last bottle (250 ml). She went to bed at 19:15 and she was layed in her parent’s bed, on a pillow. At 21:45, the father went to bed and found the subject unconscious. Mobile emergency medical unit was contacted which arrived at 22:00. At 22:23 pm, a pediatric mobile emergency medical unit arrived. Resuscitation procedure was started. The subject was intubated and received adrenaline. She was hospitalized and died at 00:00. Tracheal aspiration was positive for klebsiella pneumoniae. Causal relationship of vaccination with Infanrix hexa and Prevenar and sudden infant death was assessed as dubious, according to the French method of imputability. Company comment: Suspected case of SUDI in a 10-week old female subject 1 day after combined vaccination with Infanrix hexa and Prevenar. The subject had an upper respiratory tract infection before vaccination. It is unknown whether an autopsy was performed. 11. B0705290A (France) Sudden death, Pyrexia, Lymphadenopathy, Emphysema, Product quality issue, Cardio-respiratory arrest, Asphyxia, Febrile convulsion This case was reported by a physician and described the occurrence of death (cause unknown) in a 10-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenza type b vaccine (Infanrix Hexa, GlaxoSmithKline) for prophylaxis. The subject had no known pathology and took no concurrent medication. Vaccinal history included one dose of DTPa-IPV-Hib vaccine (Infanrixquinta, GlaxoSmithKline) administered on and one dose of tuberculosis vaccine (BCG), both administered on 31 August 2010 (information was corrected during AFFSaPS follow-up under reference TO20110471A). The vaccination schedule of the subject did not comply with French medical authority recommendations. The subject’s medical history included bronchiolitis during last winter. On 07 March 2011, the subject received a second dose of Infanrix Hexa (batch A21CA598F, route and injection site unknown). During the following night, the subject experienced fever. Mobile emergency medical unit was contacted by the parents. On their arrival, the subject was dead. No diagnostic was made, sudden infant death was suspected. An autopsy was agreed by the parents (not a complete forensic). Results were not available at the time of reporting. According to the reporter, a causal relationship between the death and Infanrix Hexa was not established. Clinical examination was normal before vaccination. Infanrix Hexa was administered intramuscularly at 11:00 on 07 March 2011. At 15:00, he presented with fever which resolved after paracetamol administration. The evening meal was taken without reportable incident. During the following night, fever recurred and the parents called the mobile emergency unit. On 08 March 2011, the subject was dead on mobile emergency medical unit arrival. He was found, by his father; laid on his stomach with face on his pillow. There were no signs of inhalation or vomiting. There was no sign of righting reflex, normally present at this age. Post mortem CONFIDENTIAL 25 CONFIDENTIAL 73 analyses were negative for C-reactive protein, blood culture and cerebrospinal fluid. Post-mortem virus tests were negative excepted positive for Respiratory Syncytial Virus in nose sample. Anatomical pathology evidenced major mesenteric adenopathy. Further information concerning autopsy report were pending. According to the French method of assessment, the AFSSaPS considered the causal relationship between vaccination with Infanrix Hexa and sudden death as dubious. Upon followup received from quality department on 31 March 2011: A product complaint has been recorded (Ref 2011-13789). QA analysis revealed the complaint to be unsubstantiated. A complete review of the batch records had been performed and no deviation that could have an impact on the product was highlighted. A search was also performed in the GSK safety database for the final bulk A21CA598 and it did not reveal a safety signal. A standard follow-up anamnesis was received from a physician on 05 April 2011: no abnormal matters during pre and post-partum conditions. Upon follow-up received from AFSSaPS on 14 April 2011: Autopsy results were provided and evidenced major lymphoid hyperplasia of mesenteric lymph nodes, of intestinal lymphoid tissu and of appendix with cellular dystrophy suggestive of viral etiology possibly subclinical. No Cytomegalovirus, Epstein-Barr virus or Herpes virus infection was found. At lung level, bilateral pseudo-emphysemateous pulmonary lesions were noticed, suggestive of suffocation phenomenon as no resuscitation was attempted. No sign suggestive of massive inhalation, no sign suggestive of infectious pneumopathy and no visceral congenital anomaly were reported. According to the AFSSAPS, based on the French method of assessment, the events were unlikely related to vaccination with Infanrix hexa. Follow-up was received on 21 April 2011 from the AFSSAPS: Psychomotor development was normal. The subject had one half-brother and one half-sister aged 6 and 5 years with medical history of convulsions. The half-brother was treated with Micropakine. On 07 March 2011, at 03:00PM, body temperature was at 39.6 Celsius degrees. On 08 March 2011, around midnight, the father still had not heard from him while he usually woke up at this time for his feed. When the father went to the bedroom, the subject was in ventral decubitus with the face on his pillow; he had cyanosis and was cold. The mobile emergency unit arrived and cardiorespiratory arrest was confirmed (the subject could not be resuscitated). His body temperature was at 35 Celsius degrees. Skull and skeleton ultrasounds were normal. Company comment: Case of SUDI in a 10-month-old male subject 1 day after a dose of Infanrix hexa (non compliant 2nd vaccination schedule following Infanrix penta + BCG). An autopsy was performed and no clear explanation was found to the subject death. Hypothesis of respiratory asphyxia as cause of death was made, due to circumstances in which the subject was found as well as the aspect of his lungs. Another hypothesis was febrile convulsion. The AFSSAPS reported that the responsibility of respiratory syncytial virus in the inflammatory lesions was unlikely. The time between vaccination with Infanrix hexa and death, was deemed too recent to provide a clear explanation for causality. 12. B0716780A (Italy): Cardiac arrest, Multi-organ failure, Pneumonia aspiration, Cerebral, ischemia, Sudden infant death syndrome, Unresponsive to stimuli, Peripheral coldness, Staring, Musculoskeletal stiffness, Pyrexia, Somnolence CONFIDENTIAL 26 CONFIDENTIAL 74 This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 139520) and described the occurrence of cardiac arrest in a 5-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. On an unspecified date, the subject received 1st dose of Infanrix hexa (unknown route of administration, unknown site of injection, batch number not provided). At an unspecified time after vaccination with 1st dose of Infanrix Hexa, the subject experienced fever. This is the reason why the second dose was not administered in the last 4 weeks. On 14 April 2011, the subject received 2nd dose of Infanrix hexa (.5 ml, intramuscular, unknown route of administration), and 2nd dose of Prevenar 13 (.5 ml, intramuscular, unknown route of administration, batch number not provided). On 14 April 2011, less than one day after vaccination with 2nd doses of Infanrix hexa and Prevenar 13, the subject experienced fever (more than 39 Deg.C). On 15 April 2011, the fever was resolved. In the afternoon of 15 April 2011, the subject did not respond to stimuli. She was admitted at the first aid with cold extremities, fixed gaze, overtone, stiff neck and normotensive fontanel. Afterwards, the subject recovered completely. At the neurological visit, the subject was alert, reactive and the state of drowsiness has been related to vaccination. Electroencephalogram was without clear anomalies irritative. On 23 April 2011 (night), the subject had a cardiac arrest. After 20 minutes of reanimation the cardiac activity resumed but with irreversible neurological sequelae. The regulatory authority reported that fever, stiff neck, fixed gaze, cold extremities, unresponsive to stimuli and cardiac arrest were possibly related to vaccination with Infanrix hexa and Prevenar 13, but almost certainly for drowsiness. On 25 April 2011, the subject died, cause of death is not specified. It was unknown whether an autopsy was performed. Follow-up information received on 19 May 2011: The parents of the subject were young, both were born in 1992. No information regarding important diseases or neonatal problems were reported. Artificial sucking from the early days due to maternal hypogalactia, was reported. The subject’s growth had always been regular, between 50 Deg and 75 Deg percentile. The first dose of the vaccines Infanrix Hexa and Prevenar 13 were administered on 10 February 2011. Within weeks of vaccination with 1st dose of Infanrix Hexa and Prevenar 13, the subject experienced fever. An autopsy was performed and there had been no element attributed to encephalitis. The histological evaluation was in course. Follow-up information received on 6 September 2011: An autopsy was performed and the results were reported on the basis of available information and histological investigations. The death occurred at 15:10 on 25 April 2011. The death was caused by multiple organ failure, ab-ingestis pneumonia, cerebral anoxia, following sudden cardiac arrest. Other significant causes were not found; therefore cardiac arrest might correspond to Sudden Infant Death Syndrome (SIDS). There was no available scientific evidence to show a causal relationship between vaccine administrations and cardiac arrest. Follow-up information received on 14 September 2011: No concomitant medication was reported. The subject was in good health before vaccination. Full report on resuscitation measures and full autopsy report were not available. Company comment: Case of SIDS in a 5-month-old female subject 1 day after a 2nd dose of combined vaccination with Infanrix hexa and Prevenar. An autopsy was CONFIDENTIAL 27 CONFIDENTIAL 75 performed and no clear explanation was found. Therefore cardiac arrest and MOF were placed within a sudden infant death syndrome. 13. D0070324A (Germany): Sudden infant death syndrome, Death, Vomiting, Cardiomyopathy This case was reported by a physician via another manufacturer and described the occurrence of possible sudden infant death syndrome (SIDS) in a 3-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). Concurrent or previous medical conditions included hyperbilirubinemia. At the time of vaccination the subject was otherwise healthy. On 18 January 2011 the subject received the first dose of Infanrix hexa (0.5 ml, intramuscular, unknown) and the first dose of Prevenar 13 (0.5 ml, intramuscular, unknown), contralaterally. Less than one week post vaccination with Infanrix hexa and Prevenar 13, In January 2011, the subject experienced possible sudden infant death syndrome (SIDS). The subject died on an unknown date between 18 January 2011 (date of vaccination) and 24 January 2011 (date when police has informed the physician) from possible sudden infant death syndrome (SIDS). It was unknown whether an autopsy was performed. The reporting physician considered that the event was unlikely related to vaccination with Infanrix hexa and/or Prevenar 13. The case was received from Pfizer Pharma GmbH, Berlin, Germany. The other manufacturer has already reported this case under international number DE-PFIZER-INC-2011025551. The same case was reported on 18 February 2011 by the same physician via a sales representative. Approximately three days post vaccination with Infanrix hexa and Prevenar 13, on an unspecified date, the subject was found dead in prone position lying in vomit. The subject was born by normal delivery at 38 weeks of pregnancy with a birth weight of 3130 g, a length of 49 cm and an Apgar score of 10/10. The subject has no underlying or concurrent medical conditions or other risk factors. On 18 January 2011 the subject received the first doses of Infanrix hexa (lot number: A21CA922C) and Prevenar 13. For the next three days following vaccination with Infanrix hexa and Prevenar 13 the subject was well. Then the subject died from at present unknown cause. The subject was found dead in prone position lying in vomit. An autopsy was performed. At the moment the result of autopsy was unknown. Follow-up information was received on 28 February 2011 from the reporting physician. The reported lot number for Prevenar 13 was E90728, not E40728. According to followup information the subject died five days post vaccination with Infanrix hexa and Prevenar 13, on 23 January 2011, and not three days post vaccination with Infanrix hexa and Prevenar 13 as reported initially. The subject has no underlying or concurrent medical conditions or other risk factors. Concurrent medications included colecalciferol + sodium fluoride (D-Fluoretten) for prophylaxis and simethicone (Espumisan) as needed for infantile colic. On 18 January 2011 the subject received the first dose of Infanrix hexa (0.5 ml, intramuscular, left thigh) and the first dose of Prevenar 13 (0.5 ml, intramuscular, right thigh), contralaterally. Approximately five days post vaccination with Infanrix hexa and Prevenar 13, on 23 January 2011, the subject died from at present unknown cause. The subject received no treatment. An CONFIDENTIAL 28 CONFIDENTIAL 76 autopsy was performed on an unknown date, but the autopsy report was not available at the moment. According to the reporting physician, in the meantime, there had been signs of possible cardiomyopathy. No further information was available. Company comment: Case of SUDI in a 3-month-old male subject less than 1 week after 1st dose of combined vaccination with Infanrix hexa and Prevenar. According to the reporting physician, there had been concerns of cardiomyopathy but no further information was available to document this. Autopsy was performed but results not available. 6.5.2. Other adverse event of interest 6.5.2.1. Blood and lymphatic system disorders 6.5.2.1.1. Anaemia haemolytic autoimmune One (1) case of Anaemia haemolytic autoimmune was reported during the period:  D0072751A (Germany): Anaemia haemolytic autoimmune, Autoantibody positive This case was reported by a physician and described the occurrence of anemia in a 7- month-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On an unknown date in 2011 the subject received the third dose of Infanrix hexa (0.5 ml, unknown). At an unspecified time post vaccination with Infanrix hexa, on an unknown date in 2011, the subject experienced anemia. This case was assessed as medically serious by GSK criteria. Follow-up was received from the physician on 26 September 2011, including a questionnaire. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer). There was no concurrent medical condition or concurrent medication or any other risk factors. On 5 July 2011 the subject received 3rd dose of Infanrix hexa (.5 ml, intramuscular, unknown thigh), together with 3rd dose of Prevenar 13 (intramuscular, the other thigh). On 2 August 2011, 28 days after vaccination with Infanrix hexa and Prevenar 13, the subject experienced autoimmune hemolytic anemia (“Waerme auto antibodies”, autoantibody positive). The subject was hospitalised. The subject was treated with blood (Blood transfusion) for several times. At the time of reporting the event was unresolved. The physician considered the event was unlikely to be related to vaccination with Infanrix hexa and and Prevenar 13. Company comment: A subject developed autoimmune haemolytic anemia within 28 days after vaccination with Infanrix Hexa.The subject was treated with several blood transfusions. 6.5.2.1.2. Autoimmune thrombocytopenia No case of Autoimmune thrombocytopenia was reported during the period. CONFIDENTIAL 29 CONFIDENTIAL 77 6.5.2.1.3. Haemolytic anaemia No case of Haemolytic anaemia was reported during the period. 6.5.2.1.4. Haemorrhagic diathesis Two (2) cases of Haemorrhagic diathesis were reported during the period:  B0737478A (Poland): Haemorrhagic diathesis, Petechiae, Pyrexia This case was reported by a regulatory authority (PL-Office of Medicinal Products # PL-URPL-OCR-20110318006) and described the occurrence of hemorrhagic diathesis in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-GSK) (Prevenar 13) for prophylaxis. On 18 February 2011, the subject received 2nd dose of Infanrix hexa (intramuscular, unknown injection site), 1st dose of Prevenar 13 (intramuscular, unknown injection site). On 18 February 2011, 8 hours after vaccination with Infanrix hexa and Prevenar 13, the subject experienced fever (38-38.6 deg. C), petechiae and manifestations of hemorrhagic diathesis: small-spot effusions all over the body. The subject was hospitalised. On 18 February 2011, lab test were performed and showed the following: C-reactive protein: 0.32; White blood cell count: 8.5; D dimer: 2184; Activated partial thromboplastin time: 33.1; Fibrynogen: 177; Thrombin time: 17.8; Prothrombin time: 130.06; Smear test from the nose: negative. The second day manifestations yielded. At the time of reporting the events were resolved. No further information can be obtained; this case has therefore been closed. Company comment: This episode relates to acute febrile petechial signs 8 hours after second dose of Infanrix hexa during combined vaccination with Prevenar. Manifestations yielded spontaneously after 24 hours.  D0070397A (Germany): Haemorrhagic diathesis, Ecchymosis, Petechiae, Upper respiratory tract infection This case was reported by a physician via a sales representative and described the occurrence of possible hemorrhagic diathesis both lower legs in a 3-month-old male subject who was vaccinated with live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline) and combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). On 08 February 2011 the subject received the first dose of Rotarix (0.5 ml, oral), the first dose of Infanrix hexa (0.5 ml, unknown) and the first dose of Prevenar 13 (0.5 ml, unknown). Approximately one day post vaccination with Rotarix, Infanrix hexa and Prevenar 13, on 09 February 2011, the subject was diagnosed with possible hemorrhagic diathesis both lower legs. On the next day, on 10 February 2011, the subject was hospitalised for an unknown period of time. Laboratory parameters for blood coagulation were normal. Inflammation parameters were normal. The subject experienced no fever. At the time of reporting the outcome of the event was CONFIDENTIAL 30 CONFIDENTIAL 78 unspecified. On 08 February 2011 the subject received the first dose of Rotarix (0.5 ml, oral), the first dose of Infanrix hexa (0.5 ml, intramuscular, right thigh, reported lot was not distributed to Germany) and the first dose of Prevenar 13 (0.5 ml, unknown). The following day, on 09 February 2011, the subject was observed with subcutaneous bleedings at both his lower legs. The subject was hospitalised. The physician considered the event was possibly related to vaccination with Rotarix and Infanrix hexa. One day after the vaccination with Rotarix, Infanrix hexa and Prevenar 13, on 10 February 2011, the subject was hospitalized. Overall diagnoses were upper respiratory tract infection, hemorrhagic diathesis, status post vaccination and persistent foramen ovale. According to anamnesis the subject developed subcutaneous bleedings in the morning of the day of hospitalization, on 10 February 2011. There was no fever or restlessness. At the time of hospitalization the subject was noticed with multiple subcutaneous bleedings at both lower thighs and possible petechiae at the knees. The remaining body surface and mucosa was free of bleedings. Gingiva, throat and tonsils were free of bleedings. Mucosa was wet and free of bleedings. Tongue was wet and without coverings. There was no struma. Eyes, ears and nose were normal and free of bleedings. Eardrums were free. Respiration was normal with mixed and equal ventilation and free of aspiratory retractions. The subject’s body temperature was 37.4 deg C. The subject was treated with inhalations of sodium chloride solution and Vitamin K. Coagulation tests resulted normally. Hemorrhagic diathesis following vaccination was suspected. The following day, on 11 February 2011, the subject was discharged from the hospital. In another examination within the following days the subject’s skin bleedings were found fading and the subject was in a good general condition. Company comment: This episode relates to acute febrile haemorragic signs (bleedings at both lower thighs and possible petechiae at the knees) one day after first dose of Infanrix hexa during combined vaccination with Prevenar and Rotarix in a 3-month-old male subject. There was a context of upper respiratory tract infection and manifestations yielded spontaneously after 24 hours. 6.5.2.1.5. Idiopathic thrombocytopenic purpura Five (5) cases of Idiopathic thrombocytopenic purpura were reported during the period and are described below. Note that four cases of Thrombocytopenic purpura were also reported during the period (see Section 6.5.2.1.7 Thrombocytopenic purpura).  B0684234A (Italy): Idiopathic thrombocytopenic purpura, Thrombocytopenia, Rhinitis, Petechiae, Pyrexia This case was reported by a physician via a regulatory authority (IT-Agenzia Italiana del Farmaco # 126680) and described the occurrence of idiopathic thrombocytopenic purpura in a 10-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. On 7 April 2010, the subject received unspecified dose of Infanrix hexa (route and injection site unknown) and unspecified dose of Prevenar (route and injection site unknown). On 17 April 2010, 10 days after vaccination with Infanrix hexa and Prevenar, the subject CONFIDENTIAL 31 CONFIDENTIAL 79 experienced thrombocytopenia. 48 hours before the admission to the hospital, he presented some petechiae on the face and then all over the body. The subject was hospitalised on 19 April 2010. During the hospitalization, the subject was treated with normal immunoglobulin (Immunoglobulin). On 25 April 2010, 18 days after vaccination with Infanrix hexa and Prevenar, the subject developed fever and serious rhinitis. The diagnosis of idiopthic thrombocytopenic purpura was made. On 7 May 2010, relevant test was performed: bone marrow aspirate showed normal results. On June 201, the subject was treated with corticosteroid due to persistent thrombocytopenia. On 16 July 2010 and on 17 September 2010, plateled counts were respectively 111.000/mm3 and 194.000/mm3 . At the time of reporting, the outcome of the events was unspecified. The regulatory authority reported that the thrombocytopenia was possibly related to vaccination with Infanrix hexa and Prevenar. Company comment: A case of ITP in a 10 month-old subject, 10 days after vaccination with Infanrix Hexa and Prevenar. Autoimmune thrombocytopenia has not been confirmed by positive antiplatelet antibodies. At the time of reporting, the outcome of the events was unknown.  B0686840A (Czech Republic): Idiopathic thrombocytopenic purpura, Febrile convulsion, clonic convulsion, Tremor, Dyskinesia, Petechiae, Platelet count decreased, Pyrexia. This case was reported by a physician via a regulatory authority (CZ-State Institute for Drug Control # CZ-CZSUKL-10001869) and described the occurrence of idiopathic thrombocytopenic purpura in a 5-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 7 May 2009, the subject received 2nd dose of Infanrix hexa (intramuscular, injection site unknown, batch number not provided). On 7 May 2009, 3-4 hours after vaccination with Infanrix hexa, the subject experienced fever (38° C). The subject was treated with antipyretics. On 8 May 2010, 1 day after vaccination with Infanrix hexa, the fever raised to 40 deg.C accompanied by shaking of hands and facial jerkings during sleep. After awaking by mother, there were no clonic convulsions yet. The subject also developed multiple petechias on skin of lower extremities and trunk. The subject was hospitalised and the regulatory authority reported that the events were clinically significant (or requiring intervention). Relevant tests were performed and showed platelet count which decreased to 7000 106 /l. The subject was treated with prednisone (Prednison) and paracetamol (Paralen). The petechias intermittently regressed and erupted during 1 month. The diagnosis was stated as febrile convulsions and idiopathic thrombocytopenic purpura. At the time of reporting, the idiopathic thrombocytopenic purpura, fever and febrile convulsions were resolved. Follow-up information received on 7 January 2011: The subject had a normal growth without serious family and personal anamnesis, but family history of cardiovascular disorder. The subject’s mother anamnesis included st. post myocardial infarction. Medical condition included CMV infection which was showed by positive CMV infection test on May 2009. During hospitalization from 13 May 2009 to 15 May 2009, relevant tests were performed: electroencephalogram examination was normal, bone marrow tap did not CONFIDENTIAL 32 CONFIDENTIAL 80 proved hemoblastosis. O2 saturation was 91.92%. Platelet count was performed several times: 10 109 /l, 10 10exp9/l, 47 109 /l and finally 210 109 /l. Blood pH was increased (7.447). Blood count and blood gases were also performed but no results were provided. Follow-up information received on 11 January 2011: The subject was hospitalised on 13 May 2009 for 2 days. The subject’s medical condition included CMV infection which was proved by following positive CMV infection test on May 2009: serology showed CMV IgG 3,1; CMV IgM 36; HSV Ig 4,3; EBV VCA IgG 0; EBV VCA IgM 0; EBV EBNA IgG 7, EBV EA IgG 0. Other relevant tests have been performed: Blood test on 13 May 2009 showed thrombocytopenia 10. Other results were in normal range. Biochemistry showed normal results. Neurological examination and psychomotorical development were also normal. At the hospital, the subject was treated with corticosteroids: methylprednisolone sodium succinate (Solumedrol), calcium carbonate (Vitacalcin) and vigantol. On 15 May 2009, the subject was discharged in good condition. On 19 May 2009, a check up showed thrombocytes which increased to 428. Petechias recovered in 1 month, fever, shaking, jerkings or convulsions were not reapeted. Then, at the time of reporting the events were resolved. Observation on neurology outpatient clinic was recommended. Company comment: A case of ITP in a 5 month-old male subject 1 day after vaccination with Infanrix Hexa in the context of concurrent CMV infection. On the basis of the information provided, the time to onset appears short to consider autoimmune thrombocytopenia (no antiplatelet antibodies test performed).  B0705987A (Ireland): Idiopathic thrombocytopenic purpura, Haemorrhage, Platelet count decreased, Petechiae, Fall, Increased tendency to bruise, Upper respiratory tract infection This case was reported by a pharmacist and described the occurrence of idiopathic thrombocytopenic purpura in a 8-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. In December 2009, the subject completed full course of Infanrix hexa (unknown route, unknown lot number). In January 2010, 1 month after vaccination with Infanrix hexa, the subject experienced idiopathic thrombocytopenic purpura, hemorrhage, platelet count decreased, petechiae, and frequent falls and bruised easily. In 2010, the subject also experienced upper respiratory tract infection treated with rituximab in June 2010. This case was assessed as medically serious by GSK. Relevant test results included: platelet count was 15 then went down to 1. A scan for leukaemia was clear. At the time of reporting, the subject was 22 months old and the outcome of the events was unspecified. The physician was not sure of what caused it. No further information was available at the time of reporting. Company comment: A case of ITP in a 8-month-old male subject 1 month after vaccination with Infanrix Hexa. A reported recent upper respiratory tract infection may have been a trigger. The outcome of the events is unknown. CONFIDENTIAL 33 CONFIDENTIAL 81  B0740099A (Netherlands): Idiopathic thrombocytopenic purpura, Petechiae, Diarrhoea, Inflammation, Pyrexia. This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-119820) and described the occurrence of idiopathic thrombocytopenic purpura in a 4-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-GSK) (Prevenar) for prophylaxis. The subject had no concomitant medication and no medical history. On 6 April 2009, the subject received 2nd dose of Infanrix hexa (unknown route, unknown injection site), 2nd dose of Prevenar (unknown route, unknown injection site). On 6 April 2009, within hours of vaccination with Infanrix hexa and Prevenar, the subject experienced fever (39deg C) for one day. In April 2009, 2 weeks after vaccination, the subject developed petechiae all over the body diagnosed as idiopathic thrombocytopenic purpura. The subject also experienced, at unspecified time after vaccination, diarrhea and inflammation localized. The subject was referred to a pediatrician. This case was assessed as medically serious by GSK. Relevant test results included: in April 2009, thrombocytes: 32. Further investigations showed no abnormalities. After 3 months, thrombocytes elevated to 130. At the time of reporting the events were resolved. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevenar. Company comment: A case of ITP in a 4-month-old female subject 2 weeks after combined vaccination with Infanrix Hexa and Prevenar. At unspecified time after vaccination, the subject experienced an infectious episode which may have been a trigger. The event resolved spontaneously.  D0071950A (Germany): Idiopathic thrombocytopenic purpura, Mouth haemorrhage, Haematoma This case was reported by a hospital physician and described the occurrence of idiopathic thrombocytopenic purpura (ITP) in a 12-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 30 June 2011 the subject received an unspecified dose of Infanrix hexa (0.5 ml, unknown). Approximately three days post vaccination with Infanrix hexa, on 03 July 2011, the subject was hospitalised for idiopathic thrombocytopenic purpura (ITP). Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). The subject has no underlying or concurrent medical conditions or other risk factors. The subject received no concomitant medication Previous vaccinations with previous doses of combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma), given on unknown dates, have been well tolerated. On 30 June 2011 the subject received a booster with the fourth dose of Infanrix hexa (0.5 ml, intramuscular, unknown thigh) and a booster with the fourth dose of Prevenar 13 (0.5 ml, intramuscular, unknown thigh). Approximately two days post CONFIDENTIAL 34 CONFIDENTIAL 82 vaccination with Infanrix hexa and Prevenar 13, on 02 July 2011, the subject experienced idiopathic thrombocytopenic purpura (ITP). The subject was hospitalised for an unknown period of time. The subject was treated with normal immunoglobulin (Immunoglobulins) and prednisolone (Prednisolon). At the time of reporting, on 14 July 2011, the events were unresolved. The reporting physician considered that the event was probably related to vaccination with Infanrix hexa and Prevenar 13. The reporter provided the answers to a GSK targeted questionnaire for the occurrence of thrombocytopenic purpura: Thrombocytopenic purpura was diagnosed. The symptoms started about two days post vaccination with Infanrix hexa and Prevenar 13. The outcome of the symptoms was unknown. Symptoms included petechiae, ecchymoses / hematoma and hemorrhage specified as hematoma of while trunk of the size of about 1 Euro, oral mucosa ecchymosis and mouth bleeding. Symptoms did not include join hematoma or joint hemorrhage. Platelet count was 6, 17 and 11 (units not specified) on 03 July 2011, 07 July 2011 and 11 July 2011, respectively (normal range was 150 – 400). Treatment included gamma globulins (Sandoglobulin 4 g; Privigen 4 g) and corticosteroids (Prednisolon 20 mg once daily from 03 July 2011 – 11 July 2011). No relevant medical history has been reported. No further information will be available. Company comment: A case of ITP in a 12 month-old male subject 2 days after combined vaccination with the 4th dose of Infanrix Hexa (all previous doses were well tolerated) and Prevenar. Treatment included gamma globulins and corticosteroids. 6.5.2.1.6. Thrombocytopenia Nine (9) cases of Thrombocytopenia were reported during the period:  B0684234A (Italy): Idiopathic thrombocytopenic purpura, Thrombocytopenia, Rhinitis, Petechiae, Pyrexia See Section 6.5.2.1.5 Idiopathic thrombocytopenic purpura.  B0693767A (France): Thrombocytopenic purpura, Petechiae, Haematoma, Epistaxis, Splenomegaly, Thrombocytopenia, Gingival bleeding See Section 6.5.2.1.7 Thrombocytopenic purpura.  B0694143A (Italy): Thrombocytopenia, Petechiae, Pyrexia This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 132290) and described the occurrence of thrombocytopenia in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. On 4 February 2010, the subject received 1st dose of Infanrix hexa (intramuscular, unknown injection site), 1st dose of Prevenar (intramuscular, unknown injection site). On 5 February 2010, 1 day after vaccination with Infanrix hexa and Prevenar, the subject experienced thrombocytopenia and diffuse petechiae. The subject was hospitalised. Relevant test results included: platelets count: 9000 CONFIDENTIAL 35 CONFIDENTIAL 83 /mm3 . The subject was treated with normal immunoglobulin (Immunoglobulin G) and cortisone. On 12 February 2010, the events were resolved. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevenar. Follow up information received on 01 April 2011: The subject also experienced fever. The subject was hospitalised from 9 to 12 February 2010. Relevant test results included: On 9 February 2010: AST:73 IU/L; Fibrin D-dimer: 2941 ng/ml; On 10 February 2010: Platelet count: 32000 /mm3; Fibrin D-dimer: 2280 ng/ml; On 12 February 2010: Platelet count: 244000 /mm3; Fibrin D-dimer: 1400 ng/ml; AST:63 IU/L; ALT: 41IU/L; LDH: 624IU/L; Urine analysis: negative The subject was treated with normal immunoglobulin (Immunoglobulin G), cortisone, paracetamol and cefixime. After discharge, the subject was given beclomethasone dipropionate (Clenil) and salbutamol sulphate (Salbutamol) for therapy at home. Company comment: Thrombocytopenia in a 2-month-old female subject 1 day after vaccination with Infanrix hexa and Prevenar. Pyrexia and elevated inflammatory parameters suggest an infectious cause. Autoimmune thrombocytopenia has not been confirmed (no antiplatelet antibodies test performed).  B0695084A (France): Thrombocytopenia, Anaemia, Haematoma, Pyrexia, Gingival bleeding, Fall, Epistaxis, Blood lactate dehydrogenase increased, Incorrect route of drug administration This case was reported by the French regulatory authority (AFSSaPS reference PS20110053) and described the occurrence of thrombocytopenia in a 2-year-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and combined measles, mumps and rubella vaccine, live and attenuated (new strain) (Priorix, GlaxoSmithKline) for prophylaxis. The subject had no relevant medical history. On 14 September 2010, the subject received unspecified doses of Infanrix hexa (intramuscular, batch and injection site unknown) and of Priorix (batch and injection site unknown). It was reported that Priorix was administered intramuscularly instead of subcutaneously (wrong route of administration). On the same day, the subject presented with a febrile episode which resolved spontaneously. On 15 September 2010, the subject experienced gingivorrhagia which resolved. On 25 September 2010, a consultation at emergency unit was made due to a fall with secondary frontal hematoma. Neurological examination was normal. The subject was not hospitalized. On the same day, she accidentally fell again. On 26 September, for the third time, she fell headlong. On 27 September 2010, she consulted at emergency unit for epistaxis. Physical examination showed a voluminous frontal and periorbital hematoma. Neurological and ENT examinations were normal. Cerebral CT-scan was normal without fracture. The subject was not hospitalized. On 28 September 2010, epistaxis recurred with worsening of frontal hematoma without new fall. Laboratory tests evidenced hemoglobin at 6.2 g/dl (anemia), reticulocytes at 71000, platelet count at 2000 /l (thrombocytopenia), neutrophils at 11000 /l, prothrombine level at 85 percent, lactate dehydrogenase at 591 (normal<480), ALAT and ASAT normal. The subject received 2 packed red blood cell transfusions and one platelet concentrate resulting in an increased of hemoglobin to 11.4 g/dl, with reticulocytes at 80000. CONFIDENTIAL 36 CONFIDENTIAL 84 Platelets remained at 2000 /l. In the evening of 28 September 2010 and on 29 September morning, she received a new platelet concentrate. Hemoglobine was at 10.5 g/dl with platelets at 13160 /l. Blood electrolytes were normal. Fever recurred. Gentamicin sulphate (Gentalline), piperacilline + tazobactam (Tazocilline) and paracetamol (Perfalgan) were started. On 29 September 2010, the subject was transfered in another hospital. Ophtalmological examination (including dilated fundus examination) was normal. Cerebral CT-scan and myelogram (no tumorous cells and good cellularity of bone marrow) were normal. Dexamethasone was started (10 mg/m2). On 01 October 2010, platelets were lower than 10000 /l, hemoglobin was at 9.7 g/dl. Lumbar puncture was sterile. Normal immunoglobulin (Tegeline) was initiated (1g / kg on two days). On 03 October 2010, platelets were at 67000 /l, hemoglobin at 10.3 g/dl. Dexamethasone was discontinued and replaced by prednisone. Antibiotics were discontinued as the subject was apyretic. On 04 October 2010, the subject was discharged from hospital. At the time of reporting, anemia, thrombocytopenia, hematoma and fever were resolved. Company comment: A case of thrombocytopenia and anaemia in a context of recurring fever of unknown cause starting 1 day after combined vaccination with Infanrix Hexa and Priorix in a 2 year-old female subject. Hematomata due to repetitive falling. The event was resolved with antibiotics, packed red blood cell transfusions, platelet concentrate and steroids.  B0699373A (Sweden): Thrombocytopenia, Contusion This case was reported by a regulatory authority (SE-Medical Products Agency # 110404) and described the occurrence of thrombocytopenia in a 12-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. The subject’s medical history included contusions after previous vaccinations. On 8 November 2010, the subject received an unspecified dose of Infanrix hexa (intramuscular, administration site unknown) and an unspecified dose of Prevenar (intramuscular, unknown). On 16 November 2010, 8 days after vaccination with Infanrix hexa and Prevenar, the subject experienced thrombocytopenia and contusions. 6 months earlier, she had normal platelets. The subject was hospitalised for observation and the platelets rose spontaneously. Lab results: On 15 November 2010: hemoglobin: 118 g/l, platelets: 6 10E9/l, white blood cells: 17.1 10E9/l. On 15 December 2010: hemoglobin: 122 g/l, platelets: 61 10E9/l, white blood cells: 8.4 10E9/l. On 28 December 2010: hemoglobin: 126 g/l, platelets: 159 10E9/l, white blood cells: 11.4 10E9/l. At the time of reporting, the events were resolved. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevenar. As no additional information could be obtained, the case has been closed. Company comment: A 12-month-old female subject experienced thrombocytopenia and contusions 8 days after vaccination with Infanrix hexa. No clear cause of this event was reported and the symptoms resolved spontaneously. CONFIDENTIAL 37 CONFIDENTIAL 85  B0724575A (France): Thrombocytopenic purpura, Thrombocytopenia, Petechiae, Injection site haematoma See Section 6.5.2.1.7 Thrombocytopenic purpura.  D0070216A (Germany): Henoch-Schonlein purpura, Thrombocytopenia, Petechiae, Pyrexia, Upper respiratory tract infection, Anaemia See Section 6.5.2.11.3 Henoch-Schonlein purpura.  D0071125A (Germany): Thrombocytopenia, Gastroenteritis rotavirus, Leukopenia, Petechiae, Haematoma, Ureteric stenosis, Pyelocaliectasis This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011012061), by a Health care Professional, and described the occurrence of thrombocytopenia in a 3-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer). Previous vaccination with Infanrix hexa and Prevenar 13 on 16 February 2011 was well tolerated. On 16 March 2011 the subject received 2nd dose of Infanrix hexa (unknown route and application site), together with 2nd dose of Prevenar 13 (unknown route and application site). On 28 March 2011, 12 days after vaccination with Infanrix hexa and Prevenar 13, the subject experienced thrombocytopenia (Platelet count was 4000 /ul). At the same time, the subject experienced rotavirus gastroenteritis. The subject was hospitalised. Repeated blood examinations were performed. “Initially, the subject additionally experienced mild leukopenia”. Hemoglobin was normal, HLA antibodies, thrombocytic allo- or auto-antibodies were negative. Follow-up was received from the regulatory authority (German Regulatory Authority (vaccines, biologicals) on 6 May 2011, including 2 hospital reports and 4 physicians’ reports. According to the 1st hospital report, provided on 11 April 2011, the subject was hospitalised due to rotavirus gastroenteritis from 28 March 2011 to 4 April 2011. A distinct thrombocytopenia was diagnosed (Platelet count was 4000 /ul). The subject was treated with platelet concentrate once. Platelet count increased to 39000. One day later platelet count decreased to 12000 again. The subject was treated with normal immunoglobulin (Immunoglobins) and platelet count increased to 60000 on 4 April 2011 and the subject was discharged from the hospital. On an ambulatory control on 7 April 2011, platelet count was 15000. On 8 April 2011 the subject was hospitalised again with a platelet count of 13000. The subject again was treated with normal immunoglobulin (Immunoglobins) with a dosage of 1 g/kg body weight. On 10 April 2011 platelet count increased to 21000. On 11 April 2011 platelet count decreased to 10000 again. Clinically the subject was in good general condition, there was no indication for infection. On 11 April 2011 the subject was transferred to another hospital. During previous hospitalization from 28 March 2011 to 4 April 2011, a stool test for Rotavirus was positive. At that time, the subject experienced petechiae and a small hematoma on the left side. Physical examination on admission on 11 April 2011 was without pathologic findings, especially there were no mucosal bleeding and no hematoma. Thrombopenia was diagnosed. Ureteric stenosis (renal pelvis dilatation) was suspected. There were no CONFIDENTIAL 38 CONFIDENTIAL 86 known allergies. Concurrent medications included D-fluoretten. Test for thrombocyt autoantibodies in eluat and for thrombocyt antibodies in plasma on 14 April 2011: In the plasma monospecific thrombocyt autoantibodies were found, which could be indication for existing autoantibodies, despite missing indication from the eluat. In case of previous thrombocyte transfusion these maybe possible thrombocyt alloantibodies. Or they may be cross-reactive antibodies within other underlying diseases like autoimmune disease, infection, CLL, monoclonal gammopathy). Another report, approximately from 18 April 2011, reported there was no splenomegaly, hepatomegaly and no lymph node enlargement. According to a pathological histological expertise from 21 April 2011, a bone marrow punch biopsy was performed. “There were sufficient megacaryocytes of all maturation stages without significant dysplastic maturation disturbances.” A bone marrow smear showed “megacaryocytes with the above described morphology.” Diagnosis: The bone marrow punch biopsy showed “tangential hit poor subcortical medullary spaces with little granulopoietic hypoplasia, little left-shift of erythropoesis, interstitial lymphocytosis and hemophagocytosis.” The bone marrow smear showed “lymphocytosis, blast cells at limit and abnormal hemophagocytosis. Left-shift of granulopoiesis with poor indication of segmented neutrophils.” Clinically thrombopenia and neutropenia were diagnosed. “The morphological changes were not characteristic for myelodysplastic syndrome. The findings point to an immunologic genesis of thrombopenia and neutropenia. Were there indications for a chronic inflammatory underlying disease, maybe Systemic Lupus erythematodes?” Immunohistochemic examinations were planned for exclusion of a blast cell excess. According to a report from 21 April 2011, from the same physician, “immunohistochemic examination showed that CD34-positive precursor cells took approximately 5 to at most 10 %. CD117-positive blast cells were not increased. CD68-positive macrophages were clearly increased, occasional with signs of hemaphagocytosis. There also was increase of CD68-positive monocytes. Only according to these histologic findings it was difficult to decide whether there was a monocytoid propagation of blast cells. The bone marrow smear showed a number of blast cells at limit and a propagation of lymphoid cells (like haematogones). An additional immunohistochemic examination in case of the CD34-positive haematogones was planned. No further information will be available. Company comment: This 3-month year old female subject experienced thrombocytopenia and neutropenia 12 days after vaccination with Infanrix hexa and Prevenar. There was a concomitant Rotavirus gastroenteritis. The thrombopenia dissolved with immunoglobins. Test for thrombocyt autoantibodies was inconclusive. After reoccurrence of the thrombocytopenia additional investigations were performed (immunohistochemistry and bone marrow smear) to exclude underlying chronic inflammatory disease.  D0072425A (Germany): Thrombocytopenia, Petechiae, Haematoma. This case was reported by a hospital physician and described the occurrence of thrombocytopenia in 24-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and combined measles, mumps and rubella vaccine, live, attenuated (new strain) (Priorix, CONFIDENTIAL 39 CONFIDENTIAL 87 GlaxoSmithKline) for prophylaxis. On an unspecified date the subject received an unspecified dose of Infanrix hexa (0.5 ml, unknown). At an unspecified time post vaccination with Infanrix hexa, on an unspecified date, the subject experienced thrombocytopenia. This case was assessed as medically serious by GSK criteria. At the time of reporting the outcome of the event was unspecified. Follow-up information was received on 14 October 2011 form the reporting hospital physician. In follow-up information the reporting hospital physician reported Infanrix hexa as Infanrix and for the first time vaccination with Priorix. The lot number had not been known. The subject has no risk factors. The subject received no permanent concomitant medication. On 18 July 2011 the subject received an unspecified dose of Priorix (0.5 ml, intramuscular, unknown). On 04 August 2011 the subject received unspecified dose of Infanrix hexa (0.5 ml, intramuscular, unknown). Approximately 24 days post vaccination with Priorix and approximately seven days after vaccination with Infanrix hexa, on 11 August 2011, the subject experienced thrombocytopenia. The subject was hospitalised for an unknown period of time. Platelet count was as low as 1 G/l. Over time platelet count was 17, 67,101, 148, 140 and 102 G/l. The exact dates of platelet count determination had not been reported. The subject was treated with normal immunoglobulin (Immunoglobulin) and prednisolone (Prednisolon). After about eight days, on 18 August 2011, the event was resolved. The reporting hospital physician considered that the event was possibly related to vaccination with Priorix and Infanrix hexa. Follow-up information was received on 24 October 2011 form the reporting hospital physician. Symptoms of thrombocytopenia included petechiae and hematoma. Platelet count was 1, 17, 67,101, 148, 140 and 102 G/l on 12 August 2011, 13 August 2011, 14 August 2011, 15 August 2011, 16 August 2011, 18 August 2011 and 20 August 2011, respectively. Follow-up information has been requested. Company comment: Thrombocytopenia in a 24 month-old subject 7 days postvaccination with Infanrix Hexa.The event resolved after 8 days of treatment with immunoglobulin and steroids. 6.5.2.1.7. Thrombocytopenic purpura Four (4) cases of Thrombocytopenic purpura were reported during the period (see Section 6.5.2.1.5 for Idiopathic thrombocytopenic purpura cases):  B0693767A (France): Thrombocytopenic purpura, Petechiae, Haematoma, Epistaxis, Splenomegaly, Thrombocytopenia, Gingival bleeding This case was reported by the French regulatory authority (AFSSaPS reference PV20100367) and described the occurrence of thrombocytopenic purpura in a 25- week-old female subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b with or without hepatitis B vaccine (unknown manufacturer) and pneumococcal vaccines (Prevenar, non-gsk) for prophylaxis. The subject was born at 39 weeks and 6 days of amenorrhea with a birth weight of 3.5 kg. The subject weighed 6.9 kg and measured 68 cm on admission. Her head circumference was 48 cm. Subject’s parents had blood relations. Her mother suffered from migraine. On 21 September 2010, the subject received unspecified doses of unspecified Infanrix (reported batch number G4046, CONFIDENTIAL 40 CONFIDENTIAL 88 which was not a GSK batch number) (coded DTPa-HBV-IPV-HIB from unknown manufacturer) and Prevenar (batch E45165). Both vaccines were administered intramuscularly in unknown sites of infjection. On 09 October 2010, 18 days after vaccination, the subject presented with palate and tongue petechiae associated with epistaxis which stopped spontaneously. On 10 October 2010, dermatologic examination showed petechiae all over the body and arch of the foot hematoma. Clinical examination showed normal ganglionic area, splenomegaly and no hepatomegaly. Other part of this examination was unremarkable. Laboratory tests evidenced thrombopenia with platelets at 1000 /mcl. Hemoglobine was at 10.3 g/dl, white blood cells were at 9400 /mcl and C-reactive protein at 1 mg/ml. The subject received a first course of normal immunoglobulin (Tegeline) at 1 mg/kg. Platelets rose to 22000 /mcl. As petechiae persisted associated with a mild gingival bleeding which stopped spontaneously, a second course of Tegeline was administered on 12 October 2010. On 14 October 2010, platelets were at 163000 /mcl, hemoglobine at 9.4 g/dl and white blood cells at 8900 /mcl. Physicians concluded to a thrombocytopenic purpura suggestive of an idiopathic thrombocytopenic purpura. On discharge from hospital the subject weighed 6.78 kg. The subject was hospitalised. At the time of reporting, petechiae and hematoma were improved. Company comment: Acase of thrombocytopenic purpura suggestive of ITP in a 25 week-old female subject 18 days after vaccination with combined diphtheria, tetanus-acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b with or without hepatitis B vaccine (unknown manufacturer) and Prevenar. The event resolved after treatment with immunoglobulin.  B0693944A (Czech Republic): Thrombocytopenic purpura, Petechiae, Haematoma This case was reported by a physician via a regulatory authority (CZ-State Institute for Drug Control # CZ-CZSUKL-10002001) and described the occurrence of thrombocytopenic purpura in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. The subject had no relevant medical history and no concomitant medication. On 10 December 2010, the subject received 2nd dose of Infanrix hexa (intramuscular, injection site unknown, batch number not provided) and 2nd dose of Prevenar 13 (intramuscular, injection site unknown, batch number not provided). On 11 December 2010, 1 day after vaccination with Infanrix hexa and Prevenar 13, the subject developed petechiae and small hematoma without any symptoms. On 13 December 2010, the subject was hospitalised for 3 days. The subject was diagnosed as having idiopathic thrombocytopenic purpura. Relevant test were performed on 13 December 2010 and showed platelets count of 4.5, APPT (activated partial prothrombine time) of 40.2, and INR (international normalized ratio) of 0.98. The subject was treated with infusion of normal immunoglobulin (Immunoglobulin). On 14 December 2010, the subject’s status remained unchanged. On 16 December 2010, the subject was discharged from the hospital, recovering and with improved laboratory data. On 4 January 2011, the subject underwent follow-up examination. Blood count was normal, platelets count was 204 (normal value). At the time of CONFIDENTIAL 41 CONFIDENTIAL 89 reporting, the events were resolved. The physician reported that the events were more likely related to vaccination with Infanrix hexa. He recommended any vaccination shouldn’t be administrated to the subject in next months. Despite attempts to obtain follow-up details, no additional information could be obtained and the case has been closed. Company comment: A case of thrombocytopenic purpura suggestive of ITP in a 4 month-old male subject one day after second combined vaccination with Infanrix Hexa and Prevenar. The haematologic status recovered after intravenous immunoglobulin.  B0695999A (Taiwan): Thrombocytopenic purpura. This case described the occurrence of thrombocytopenic purpura in a 3-month-old subject of unspecified gender who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (DTPa-HBV-IPV-HIB, manufacturer unspecified) for prophylaxis. On 10 December 2007 the subject received 2nd dose of DTPa-HBVIPV-HIB (unknown, lot number not provided). On 15 December 2007, 5 days after vaccination with DTPa-HBV-IPV-HIB, the subject experienced thrombocytopenic purpura. The subject was hospitalised. Relevant test results included platelet count: 2×103/mm3 and hemoglobin: 8 g/dl. The subject was treated with normal immunoglobulin (Immunoglobulin). The event was resolved within 6 days. The author considered the event was possibly related to vaccination with DTPa-HBVIPV-HIB. The event did not reoccur. Company comment: A case of thrombocytic purpura 5 days after 2nd dose of Infanrix hexa in a 3-month-old subject. No autoimmune cause of this event was confirmed. No clear triggers or further episodes were reported.  B0724575A (France): Thrombocytopenic purpura, Thrombocytopenia, Petechiae, Injection site haematoma This case was reported by the French regulatory authority (FR-Agence Francais de Securite Sanitaire des Produits de Sante # PO20110384) and described the occurrence of thrombocytopenic purpura in a 19-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), mmr vaccine () (M-M-RvaxPro, non-gsk) for prophylaxis. Medical history included bronchiolitis and upper respiratory tract infection (NOS). On 01 March 2011, the subject received an unspecified dose of M-M-RVaxPro (intramuscular, batch and injection site unknown). On 26 April 2011, the subject received an unspecified dose of Infanrix hexa (intramuscular, batch and injection site unknown). After this vaccination, the subject presented a severe hematoma at injection site (that could be suggestive of a decrease of platelet count at this time). On 16 May 2011, the subject was hospitalized with diffuse cutaneomucous petechial purpura. He had no fever. Lab test evidenced a severe thrombocytopenia with decrease of platelet at 3 G/l (normal 150-400). The subject was treated with normal immunoglobulin (Tegeline). In 48 hours, platelet count increased to 64 G/l. Subject’s discharge was planned for 18 May 2011. At the time of reporting, thrombocytopenia CONFIDENTIAL 42 CONFIDENTIAL 90 was improved. Outcomes of hematoma at injection site and purpura, and petechiae were unspecified. According to the French method of assessment, the AFSSaPS considered the causal relationship between vaccination with Infanrix hexa and M-MRvaxPro and the events as dubious. Company comment: A case of thrombocytopenic purpura in a 19-month-old male subject 20 days after 2nd dose of Infanrix-hexa. No autoimmune cause of this event was confirmed. No clear triggers orfurther episodes were reported. 6.5.2.1.8. Thrombocytosis Two (2) cases of Thrombocytosis were reported during the period:  B0729166A (Spain): Pemphigoid, Leukocytosis, Thrombocytosis, Blister, Scab, Skin lesion, Pruritus, Eosinophilia, Urticaria This case was reported in a literature article and described the occurrence of bullous pemphigoid in a 3-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (DTPa-HBV-IPV-HIB, manufacturer unspecified), meningococcal polysaccharide vaccine group C and unspecified Pneumococcal vaccine for prophylaxis. On an unspecified date, the subject received an unspecified dose of DTPa-HBV-IPV-HIB (administration site and route unknown, batch number not provided), an unspecified dose of Meningococcal polysaccharide vaccine group C (administration site and route unknown, batch number not provided) and an unspecified dose of Pneumococcal vaccine (administration site and route unknown, batch number not provided). 3 weeks after vaccination with DTPa-HBV-IPV-HIB, Meningococcal polysaccharide vaccine group C and Pneumococcal vaccine, the subject experienced bullous pemphigoid with blistering eruption on her palms and soles and back of the fingers, scabs and denuded areas and urticaria plaque on trunk and face. Subsequently, they were appearing lesions on the trunk, arms and andretroauricular region dominated by erythematous plaques of annular morphology. No mucosal involvement. The lesions were itchy and woke up the girl during the night. This case was assessed as medically serious by GSK. A skin biopsy was performed which showed a subepidermal blister with eosinophils and a few polymorphonuclears. In the superficial dermis, it was identified perivascular eosinophilic infiltrate. The direct immunofluorescence showed linear deposits of IgG and C3 in the epidermal basal membrane, with negativity for the markers IgA, IgM and C1q. Laboratory tests revealed leukocytosis with eosinophilia and thrombocytosis. Antibasement membrane antibodies and the rest of the profile of autoimmunity were negative. The subject was treated with antibiotics and steroid (Topical steroid) with a very good evolution and control of the lesions. After vaccination at 4 months-old, 3 to 4 days after vaccination, she presented a sudden worsening of the lesions, with involvement of palms, soles, trunk, arms and face in a generalized way. The subject was treated with deflazacort. 15 days after the start of the treatment, the lesions had completely disappeared in all locations. At the 6 months-old vaccination, in hours after vaccination, she experienced a slight outbreak, keeping the dose of corticosteroids orally. Later, there was a progressive decrease until its suppression at 3 months, no CONFIDENTIAL 43 CONFIDENTIAL 91 relapse during 12 months of follow-up. After vaccination at 15 months-old, no AEs occurred. At the time of reporting, the events were resolved. The author considered the events were related to vaccination with DTPa-HBV-IPV-HIB, Meningococcal polysaccharide vaccine group C and Pneumococcal vaccine. Company comment: A case of bullous pemphigoid 3 weeks after vaccination in a 3- month-old subject in childhood. Although there is a temporal relationship with repeat vaccinations at 4 and 6 months, it is difficult to determine a causal relationship.  D0072024A (Germany): Meningitis pneumococcal, Gastroenteritis rotavirus, Respiratory syncytial virus infection, Pneumococcal sepsis, Pharyngitis, Somnolence, Pyrexia, Fluid intake reduced, Respiration abnormal, Crying, Diarrhoea, Cardiovascular insufficiency, Pallor, Tachypnoea, Anaemia, Thrombocytosis See Section 6.5.2.7.11 Sepsis. CONFIDENTIAL 44 CONFIDENTIAL 92 6.5.2.2. Cardiac disorders 6.5.2.2.1. Bradycardia Eleven (11) cases including the event Bradycardia were identified during the period: Table 7 Summary of cases of Bradycardia identified during the reporting period Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma A0901400A 23 -Dec -10 67 Days Female Improved Infanrix hexa Tri -Vi -Sol, Ferrous sulfate Hours Apnoea, Bradycardia, Oxygen saturation decreased, Wrong technique in drug usage process Canada Anaemia neonatal, Bronchopulmonary dysplasia, Premature baby, Apnoea, Bradycardia, Oxygen saturation decreased B0691130A 28 -Dec -10 2 Months Male Resolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) Dopram 5 Hours Apnoea, Bradycardia, Oxygen saturation decreased, Blood pressure decreased, Apparent life threatening event, Urine output decreased, Cholinergic syndrome, Eye movement disorder, Gastrooesophageal reflux disease, Aspiration France Premature baby, Infantile apnoeic attack, Inguinal hernia CONFIDENTIAL 45 CONFIDENTIAL 93 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0694497A 19 -Jan -11 8 Weeks Female Resolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) Paracetamol 16 Hours Cyanosis, Acidosis, Apnoea, Inflammation, Oxygen saturation decreased, Bradycardia, Injection site pain, Injection site swelling, Injection site erythema, Bacterial infection Netherlands Premature baby, Nasopharyngitis, Small for dates baby B0698663A 08 -Feb -11 4 Months Male Resolved Infanrix hexa Respiratory syncytial virus vaccine, Palivizumab, Frusemide, Iron polymaltose, Multivitamins, Nutritional supplement, Emollient, Ibuprofen, Indomethacin, Cortisone 0 Days Anaphylactic reaction, Circulatory collapse, Slow response to stimuli, Cyanosis, Hypotonia, Hypothermia, Pallor, Bradycardia, Oxygen saturation decreased, Pyrexia Italy Premature baby, Mechanical ventilation, Patent ductus arteriosus, Bronchopulmonary dysplasia B0705098A 08 -Mar -11 2 Months Female Resolved Infanrix hexa Immediate Presyncope, Bradycardia, Hypotonia, Injection site pain, Loss of consciousness, Cyanosis France B0711289A 28 -Mar -11 6 Weeks Unknown Unknown Synflorix, Infanrix hexa Rotavirus vaccine, Infanrix hexa 8 Hours Cardiopulmonary failure, Pyrexia, Bradycardia South Africa Premature baby CONFIDENTIAL 46 CONFIDENTIAL 94 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0714363A 19 -Apr -11 2 Months Male Resolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) Ranitidine hydrochloride, Domperidone 8 Hours Hypotonic – hyporesponsive episode, Anaemia, Hypotonia, Pallor, Dyspnoea, Bradycardia, Hypopnoea, Staring Netherlands Gastrooesophageal reflux disease, Bradycardia, Vomiting, Dyspnoea B0754941A 07 -Oc t -11 2 Months Female Resolved Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) Minutes Apnoea, Bradycardia, Pallor, Foaming at mouth Belgium B0755056A 13 -Oct -11 2 Months Female Resolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) Poractant alfa, Betamethasone sodium phosphate, Whole human blood, Epoetin beta Same day Apnoea, Hypoxia, Bradycardia, Malaise, Inflammation, Respiratory disorder France Premature baby, Neonatal respiratory distress syndrome, Lung infection, Bronchopulmonary dysplasia, Anaemia neonatal, Gastrooesophageal reflux disease CONFIDENTIAL 47 CONFIDENTIAL 95 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069341A 05 -Nov -10 3 Months Male Resolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Hours Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed level of consciousness, Hypokinesia, Bronchitis Germany Atrial septal defect D0071220A 02 -May – 11 12 Weeks Male Unresolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Apnoea, Bradycardia Germany Premature baby, Neonatal respiratory distress syndrome, Bronchopulmonary dysplasia, Retinopathy CONFIDENTIAL 48 CONFIDENTIAL 96 6.5.2.2.2. Cardiac arrest Three (3) cases including the PT Cardiac arrest were reported during the period. Cases B0706503A and B0716780A are described in Section 6.5.1 Cases with a fatal outcome. The third case is described below:  D0069341A (Germany):Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed level of consciousness, Hypokinesia, Bronchitis This case was reported by a physician and described the occurrence of collapse unspecified in a 3-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 5 November 2010 the subject received 2nd dose of Infanrix hexa (unknown route and application site). Approximately less than one hour after vaccination with Infanrix hexa, while being in the office yet, the subject experienced unspecified collapse. This case was assessed as medically serious by GSK. Followup was received by the physician on 10 December 2010, including a questionnaire. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (nonGSK) (Prevenar 13, Pfizer) Previous vaccination with Infanrix hexa and Prevenar 13 was well tolerated. On 5 November 2010 the subject received 2nd dose of Infanrix hexa (intramuscular, left thigh), together with unspecified dose of Prevenar 13 (intramuscular, right thigh). At an unspecified time after vaccination with Infanrix hexa and Prevenar 13, the subject experienced “abrupt pallor and hypopnoea/apnea for 3-4 minutes, short-time bradycardia for over 1 minute, salivation and loss of consciousness for 2-3 minutes”. The subject was treated with oxygen. The subject was hospitalised for 2-4 days. At the time of reporting, on 9 November 2010, all events were resolved. The physician considered pallor, hypopnoea/apnea, short-time bradycardia, salivation and loss of consciousness were probably related to vaccination with Infanrix hexa and Prevenar 13. Follow-up was received from the reporting physician on 20 April 2011, including a questionnaire and 4 reports from other physicians. According to the questionnaire, there was no concurrent medical condition or any other risk factors. On an unspecified date the subject experienced cyanosis, apnea and bradycardia. These events were resolved after 3 minutes. The subject was treated with oxygen. At the time of reporting, all events were resolved. After the next vaccination with Infanrix hexa the events did not recur. The physician considered cyanosis, apnea and bradycardia were unrelated to vaccination with Infanrix hexa. “According to the physicians’ reports, the suspicion of adverse events was not confirmed”. According to the 1st physician’s report from 17 December 2010, “suspected beginning generalized idiopathic epilepsy with unspecific epileptic seizures (atonic seizures with myoclonia) (possible epilepsy) was diagnosed. Secondary generalized epilepsy of focal origin (focal secondary epileptic convulsions) was considered by differential diagnosis. “Six weeks ago, after a vaccination, the subject experienced collapse with pallor, blue lips (cyanosis), foaming at mouth, unresponsive episode, atonia and loss of consciousness. These CONFIDENTIAL 49 CONFIDENTIAL 97 events were resolved after 3 minutes. The subject was hospitalised and 48 hours observed. On discharge from hospital the subject was in normal condition. Electroencephalogram one week later showed normal findings. The events were interpreted as cardio-vascular phenomenon. Ultrasonic findings of heart showed small foramen ovale.” It was reported that the subject experienced asystole lasting for 3 seconds. On 17 December 2010 the subject was vomiting. There was no fever. When the subject was laid down, the subject experienced pallor and blue lips. He experienced occasional jerking in head-shoulder area, salivation with forming of vesicles, loss of consciousness, unresponsiveness and eyes rolling. These events were resolved after approximately 5 minutes. Afterwards, the subject gradually came to himself, started crying and fell asleep. At the moment, the subject suffered from cough with mucus and was teething. The patient’s family history included suspected benign infantile myoclonic epilepsy (the subject’s brother). “Pregnancy anamnesis of subject’s mother was without findings. After 40+2 weeks of pregnancy the subject was born, weighing 3750 g, with a size of 52 cm and an Apgar score of 9 / 10 / 10. The subject was healthy. Infant development was normal. There were no operations, no internal diseases, no special accidents. The subject was vaccinated only once, with the reported seizure. Despite that, there were no unusual findings.” Electroencephalogram was performed and showed “sleep electroencephalogram according to age with well pronounced sleep architecture up to sleep phase C.” “The subject now experienced his 2nd afebrile convulsive seizure with rather atypic progress. This time atonic with sprinkled myoclonia or cloni, trunk and head stressed, respectively. No relationship to a triggering situation or fever could be found, although the subject was suffering from phlegm and so suspicion of an infection associated seizure could not be ruled out completely.” According to the 2nd physician’s report from 3 January 2011, since the event on December 2010 there were no further events. Electroencephalogram was performed on 3 January 2011 and showed awake electroencephalogram according to age. Cerebral magnetic resonance tomography showed normal findings. “Immediately after electroencephalogram, the subject was atonic at trunk and extremities for 3-4 minutes, was pale and unusually calm. There was no fixed stare, but looking straight on, no indication for a focal event, no cloni. This was the 3rd event. It could possibly have been a seizure, too. Afterwards, there was no tiredness like after the former events.” According to the 3rd physician’s report from 11 April 2011, the subject visited the surgery on 17 February 2011. Sleep electroencephalogram was performed and showed normal findings. Concerning the Cerebral magnetic resonance tomography performed on 17 December 2010, “in the T2 assessed picture discrete signal increase in the area of white brain substance were conspicuous, which spread from the posterior horn rather diffuse”. A second magnetic resonance tomography was recommended. It was reported that the subject’s mother reported about mild motor retardation. According to the 4th physician’s report, when the subject was 7 months old, there was no indication for structural abnormality of the heart, no indication of clinically relevant formation of a vascular ring. Affect spasm was considered by differential diagnosis. There were repeated incidents of loss of consciousness, at the 1st time at the age of 3 months after vaccination. A 2nd time after vomiting and 2 further times when expectorating mucus during bronchitis. There never was stridor. Electrocardiogram and echocardiography showed normal findings. Foramen ovale was functionally closed. “There was no indication of structural abnormality of the heart or anomaly in CONFIDENTIAL 50 CONFIDENTIAL 98 the area of the great vessels. Especially there was no indication for pulmonal sling or arterial vascular ring, which could have been causal for such syncopal symptoms.” Company comment: Unspecified collapse in a 3 month-old female subject less than 1 hour after 2nd vaccination with Infanrix hexa, combined with Prevenar. Spontaneous recovery after 3 minutes with oxygen therapy. The event occurred 2 times more, unrelated to vaccinations. Suspicion of epileptic origin without conclusive results on EEG or MRI. 6.5.2.2.3. Cardio-respiratory arrest One (1) case including the PT Cardio-respiratory arrest was received during the period (B0705290A) and is described in Section 6.5.1 Cases with a fatal outcome. 6.5.2.2.4. Cardiogenic shock One (1) case including the PT Cardiogenic shock was reported during the period:  D0070772A (Germany): Cardiogenic shock, Cardiac failure, Congestive cardiomyopathy, Atrial tachycardia, Supraventricular tachycardia, Acidosis, Pyrexia, Gastrointestinal pain, Hypokalaemia, Fluid intake reduced, Hypertension, H1N1 influenza, Cholecystitis, Psychotic disorder, Crying This case was reported via a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011007870) and described the occurrence of cardiogenic shock in a 3- month-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa), live attenuated human rotavirus vaccine (Rotarix) and pneumococcal vaccines (non-gsk, Prevenar) for prophylaxis. Previous vaccinations were well tolerated. On 01 March 2011 the subject received a dose of Rotarix, a dose of Prevenar (right thigh) and a dose of Infanrix hexa (left thigh). According to the report Infanrix was administered, based on the provided lot number however it was evident that Infanrix hexa was administered. Twelve days after vaccination, on 13 March 2011, the subject developed atrial tachycardia and dilated cardiomyopathy. The following day, on 14 March 2011, cardiogenic shock occurred. The subject was hospitalised. Diagnosis was confirmed by means of laboratory examinations, ultra sound scan and electrocardiography (Results not specified). Meningitis was excluded. The reporter considered the events were life threatening. At the time of reporting the events were unresolved. Follow-up information was received on 26 April 2010 via the regulatory authority by means of structured information and a hospital report. On 01 March 2011 the subject received a dose of Infanrix hexa (left thigh) together with a dose of Prevenar (right thigh) and a dose of Rotarix. Twelve days after vaccination, on 13 March 2011, the subject presented at a hospital and suffered from reduced fluid intake, stomach pain and a mild increase in temperature (38.4 deg C). Cholecystitis was suspected and the subject was treated with claforan and ampicillin trihydrate. The subject’s symptoms worsened continuously, tachycardia occurred (heart rate: 220-240 bpm) and the subject was in need of oxygen. The following day, on 14 March 2011 myocarditis was suspected and the subject was transferred to another hospital by helicopter. The subject was diagnosed with cardiogenic shock (with associated acidosis and arterial hypertension), received CONFIDENTIAL 51 CONFIDENTIAL 99 artificial ventilation as well as an insertion of arterial and central venous catheters. In echocardiogram atrial enlargement and spherical ventricular dilation (left) were observed. Supraventricular tachycardia with alternating heart rates (occasionally above 220 bpm) was observed in electrocardiogram. For clarification of the origin of the subject’s cardiac insufficiency, myocarditis was excluded by means of serologic findings. The subject was negative for cardiotropic infections. Cardiac muscular enzymes were borderline but normal. Antiarrythmic therapy was started with propafenone hydrochloride (Rytmonorm), sotalol hydrochloride (Sotalex) and digoxin. Anticongestive therapy was started with enoximone (Perfan), frusemide (Furosemid), captopril and spironolactone (Aldactone). Additionally he was treated with teicoplanin (Targocid). Subsequently the subject’s cardiac function improved and in echocardiogram ventricular dilation was found regressing. As myocarditis could be excluded, the subject was suspected with pre-existing focal atrial tachycardia and resulting heart insufficiency and current cardiogenic shock. Daily dose of antiarrythmic medication was increased continuously. Heart rate was reduced significantly but continuous sine rhythm could not be established. Phases with extrasystoles were declining. At the hospital the subject was also observed with recurrent crying attacks and received treatment with sedatives (promethazine hydrochloride (Atosil) and phenobarbitone (Phenobarbital)). As there were no signs of pain or hunger, the subject’s crying attacks were considered symptoms of transitory psychotic syndrome. On 18 March 2011 artificial ventilation was removed and the subject was observed with sufficient spontaneous respiration. The subject’s general condition improved significantly and the subject could be switched to oral nutrition with supportive volume replacement. On 19 March 2011 pharyngeal swab was positive for H1N1 virus and treated with oseltamivir phosphate (Tamiflu) and meropenem (Meronem). In serologic examinations the subject was negative for Influenza A antibodies and positive for Influenza B IgG. The subject was also diagnosed with hypokalemia and received treatment with sodium fluoride (Zymafluor). After nine days the subject was discharged from the hospital. The regulatory authority reported that the subject was recovering. Company comment: Cardiogenic shock in a 3 month-old male subject, 12 days after vaccination with Infanrix hexa, combined with Rotarix and Prevenar. Diagnosis of pre-existing focal atrial tachycardia and heart insufficiency recovered with antiarritmica. 6.5.2.2.5. Cyanosis Fifty eight (58) cases including the event cyanosis were identified during the period of this report. Most cases were reported in association with a concurrent disease likely to have caused cyanosis, as shown in Table 8. Only one concurrent disease is shown per case, however more than one relevant concurrent disease may have been reported for a given case. This table also includes one case received prior to the period of this report but never included in a previous PSUR (B0591710A). This case’s ID is marked by a ‘*’ in Table 8. CONFIDENTIAL 52 CONFIDENTIAL 100 Table 8 Concurrent diseases reported among cyanosis cases identified during the period Concomitant diseases (Number of Cyanosis cases received with given concomitant disease) Case IDs Seizures (n=15) B0683335A, B0690279A, B0692681A, B0712712A, B0715581A, B0716294A, B0716693A, B0722809A, B0741792A, B0747746A, D0069341A, D0069889A, D0071143A, D0071548A, D0072318A Circulatory collapse (n=4) B0698663A, B0713106A, D0069341A, D0070901A (Pre)Syncope (n=2) B0705098A, D0072433A Hypotonia (n=18) B0683004A, B0692681A, B0698663A, B0705098A, B0706016A, B0711564A, B0712712A, B0715332A, B0716345A, B0716693A, B0717794A, B0726312A, B0734041A, D0069341A, D0070901A, D0071548A, D0072433A, B0591710A* Hypertonia (n=6) B0706228A, B0715581A, B0716294A, B0716693A, B0719722A, D0069889A Apnoea (n=9) B0694497A, B0706228A, B0713567A, B0715332A, B0717794A, D0069341A, D0071143A, D0071156A, D0072273A Dyspnoea (n=5) B0712985A, B0719722A, B0729115A, D0071143A, D0071548A Apparent life threatening event (n=0) Not Applicable Sudden Infant death Syndrome, Sudden death (n=0) Not Applicable CONFIDENTIAL 53 CONFIDENTIAL 101 6.5.2.3. Eye disorder s 6.5.2.3.1. Gaze palsy Eighteen (18) cases including the event Gaze palsy were identified during the period of this report. In 12/18 cases the event was associated to a reported convulsion (febrile in 4 cases). The event lasted between 2 hours and 10 days by mean. The outcomes had been documented in half of cases and were favourable (resolved). Cases are summarized in the table below. Table 9 Summary of cases of Gaze palsy identified during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0681967A 28 -Oct -10 Resolved 2 Months Female Infanrix hexa, Meningococcal polysaccharide vaccine group C (Non -GSK), Pneumococcal vaccines (Non – GSK) 2 Hours Gaze palsy, Hypotonia, Pallor Spain B0682745A 03 -Nov -10 Unresolved 6 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Convulsion, Loss of consciousness, Gaze palsy, Pallor, Pyrexia, Crying Netherlands B0683261A 05 -Nov -10 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Magaldrate, Ranitidine hydrochloride 10 Days Gaze palsy, Hypotonia Italy B0687865A 07 -Dec -10 Resolved 11 Months Male Infanrix hexa Priorix 2 Days Loss of consciousness, Gaze palsy, Pallor, Hypotonia Italy CONFIDENTIAL 54 CONFIDENTIAL 102 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0690071A 17 -Dec -10 Unknown 3 Months Male Infanrix hexa, Synflorix 8 Hours Hypotonic – hyporesponsive episode, Gaze palsy, Opisthotonus, Pallor, Apathy, Fear, Agitation, Hypotonia, Crying Czech Republic Dermatitis atopic B0712712A 05 -Apr -11 Resolved 13 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Loss of consciousness, Depressed level of consciousness, Convulsion, Gaze palsy, Respiration abnormal, Pallor, Hypotonia, Drooling, Cyanosis, Pyrexia, Vomiting Netherlands B0717794A 06 -May – 1 1 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 36 Hours Loss of consciousness, Apnoea, Depressed level of consciousness, Gaze palsy, Pallor, Cyanosis, Hypotonia, Peripheral coldness, Pyrexia Netherlands B0722407A 24 -May -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 14 Hours Gaze palsy, Hypertonia, Pyrexia, Dyskinesia, Somnolence, Feeling hot Netherlands B0739945A 11 -Aug -11 Unknown 5 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Convulsion, Gaze palsy, Clonus, Pyrexia Italy CONFIDENTIAL 55 CONFIDENTIAL 103 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069309A 03 -Nov -10 Unknown 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Febrile convulsion, Pyrexia, Musculoskeletal stiffness, Gaze palsy, Somnolence, Transaminases increased, Pharyngeal erythema, Tympanic membrane hyperaemia Germany Cardiac murmur D0071075A 18 -Apr -11 Unknown 3 Months Male Rotavirus vaccine, Infanrix hexa, Synflorix 1 Days Thalamus haemorrhage, Convulsion, Facial paresis, Hemiparesis, Hypophagia, Restlessness, Pyrexia, Screaming, Somnolence, Pallor, Hyperaesthesia, Eyelid oedema, Abdominal distension, Hypotonia, Apnoea, Gaze palsy Germany D0071143A 26 -Apr -11 Unknown 6 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK), Intubation, Mechanical ventilation 0 Days Apnoea, Cyanosis, Febrile convulsion, Gaze palsy, Altered state of consciousness, Convulsion, Body temperature increased, Breath holding, Moaning, Erythema, Swelling, Hypokinesia, Pain, Pyrexia, Dyspnoea, Infection Germany Premature baby, Neonatal respiratory distress syndrome, Neonatal respiratory failure, Infantile apnoeic attack, Bradycardia neonatal, Hyperbilirubinaemia neonatal, Regurgitation CONFIDENTIAL 56 CONFIDENTIAL 104 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071366A 13 -May -11 Unknown 12 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Convulsion, Depressed level of consciousness, Gaze palsy, Hypochromic anaemia, Pyrexia, Injection site erythema, Musculoskeletal stiffness, Iron deficiency Germany D0071548A 27 -May -11 Unknown 8 Months Female Infanrix hexa, Synflorix 1 Days Convulsion, Gaze palsy, Cyanosis, Vaccination complication, Restlessness, Feeling hot, Staring, Muscle twitching, Dyspnoea, Hypotonia, Somnolence, General physical health deterioration, Body temperature increased Germany D0071728A 15 -Jun -11 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Hypotonic – hyporesponsive episode, Eye movement disorder, Convulsion, Gaze palsy, Opisthotonus, Crying Germany D0072315A 08 -Aug -11 Resolved 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Salbutamol sulphate 1 Days Febrile convulsion, Muscle rigidity, Opisthotonus, Gaze palsy, Pyrexia Germany Bronchitis CONFIDENTIAL 57 CONFIDENTIAL 105 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072318A 08 -Aug -11 Resolved 15 Months Female Infanrix hexa 0 Days Febrile convulsion, Pyrexia, Chills, Gaze palsy, Eye movement disorder, Cyanosis, Unresponsive to stimuli, Tremor, Grand mal convulsion, Upper respiratory tract infection Germany Familial risk factor, Febrile convulsion, Hospitalisation, Cardiac murmur, Underweight D0073004A 11 -Oct -11 Unknown 16 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 48 Hours Convulsion, Pallor, Gaze palsy, Depressed level of consciousness, Joint hyperextension Germany CONFIDENTIAL 58 CONFIDENTIAL 106 6.5.2.4. Gastrointestinal disorders 6.5.2.4.1. Diarrhoea haemorrhagic Two (2) cases of Diarrhoea haemorrhagic were reported during the period:  B0747304A (Poland): Diarrhoea haemorrhagic, Pyrexia, Crying, Restlessness, Abnormal behaviour This case was reported by a physician via regulatory authority (PL-Office of Medicinal Products # -PL-URPL-OCR-20110905014) and described the occurrence of hemorrhagic diarrhea in a 4-month-old subject of unspecified gender who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), live attenuated human rotavirus vaccine (Rotarix) for prophylaxis. On 12 August 2011 the subject received unspecified dose of Infanrix hexa (intramuscular, unknown injection site), unspecified dose of Rotarix (oral). On 14 August 2011, 2 days after vaccination with Infanrix hexa and Rotarix, the subject experienced hemorrhagic diarrhea, fever (38 deg C) lasting for 2 days, crying, restlessness and change in behavior. Diarrhea withdrew after 11 hours. The subject was hospitalized from 14 to 18 August2011. Relevant test results included: Rotavirus test: negative; Adenovirus test: negative; Salmonella test: negative; At the time of reporting the events were resolved. No further information is expected. Company comment: The symptoms and test results confirming the diagnosis of digestive Haemorrhage (during 48 hours) after Infanrix hexa and Rotarix vaccination were not reported. Fever was associated to the episode but infectious cause could not be evidenced.  B0754698A (Poland): Diarrhoea haemorrhagic, Pyrexia, Vomiting, Faeces discoloured, Dermatitis diaper, Erythema, Dyspepsia This case was reported by a physician via a regulatory authority (PL-Office of Medicinal Products # PL-URPL-OCR-20110923001) and described the occurrence of bloody diarrhea in a 2-month-old subject of unspecified gender who was vaccinated with live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline), combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa) and pneumococcal vaccines (non-GSK) (Prevenar 13) for prophylaxis. Since the 29 July 2009, the subject experienced restlessness. On 02 August 2011, during a medical visit, the subject had abdominal pain and inflated abdomen, which was decompressed with catheter. On 04 August 2011, during another medical visit, inflated abdomen decreased and it was also decompressed with catheter. On 10 August 2011, the baby was in good general condition, ultrasonography of the abdomen and urine cultures were without abnormalities. The subject had a soft belly. On 18 August 2011, the subject received unspecified dose of Rotarix (oral), unspecified dose of Infanrix hexa (intramuscular, unknown injection site), unspecified dose of Prevenar 13 (intramuscular, unknown injection site). On 19 August 2011, 1 day after vaccination with Infanrix hexa, Prevenar 13 and Rotarix, the subject experienced bloody diarrhea, fever (37.8 deg. C) and vomiting. The CONFIDENTIAL 59 CONFIDENTIAL 107 subject was hospitalised. On 23 August 2011, at a medical control, the subject experienced dyspepsia, and still has stools with blood since a few days. On 24 August 2011, at the next medical control, the subject experienced diaper dermatitis, the stools became normal but severe reddening of skin on buttocks appeared. On 13 September 2011, the subject was hospitalised at Gastroenterological Clinic. At the time of reporting the outcome of the events was unspecified. No further information is expected, the regulatory Authority has provided GSK with all the available information for the time being, if they ever get any further information they will send it to GSK. Follow-up information received by the RAN: Hospitalisation dates were unclear so no clarification was possible. On 19 August 2011, the subject experienced green stools. On 24 August 2011, bloody diarrhea and green stools were resolved. The outcome of the rest of the events was unspecified. Company comment: Episodes of haemorragic diarrhea in a 2-month-old subject starting 1 day after combined vaccination with Infanrix hexa, Priorix and Prevenar. The subject was hospitalized but diagnostic test results are not available. The event has been resolved. 6.5.2.4.2. Haematochezia Three (3) cases of Haematochezia were reported over the period:  B0714317A (Czech Republic): Haematochezia, Gastrointestinal inflammation, Restlessness, Flatulence, Frequent bowel movements This case was reported by a physician and described the occurrence of blood streaks in stools in a 2-month-old female subject who was vaccinated with live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline), combined diphtheria, tetanusacellular pertussis, hepatitis B and inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa) for prophylaxis. The subject was healthy full term baby. On 23 March 2011, the subject received 1st dose of Rotarix (oral) and unspecified dose of Infanrix hexa (route and injection site unknown, batch number not provided). On 30 March 2011, 7 days after vaccination with Infanrix hexa and Rotarix, the subject experienced impurity of blood in stools, restlessness, flatulent belly and frequent stools. The physician considered the events were clinically significant (or requiring intervention). In April 2011, relevant test results included normal stool culture and normal sonography of abdomen which excluded intussusception. The subject was treated with symptomatic therapy. At the time of reporting, the events were unresolved. The physician considered the events were probably related to vaccination with Rotarix and the relationship between the events and Infanrix hexa was unspecified. Follow-up information received on 28 April 2011: The final diagnosis provided was unspecified gastrointestinal inflammation. The subject’s condition was improved, but not resolved. Streaks of blood in stools appeared occasionally. Despite attempts to obtain follow-up details, no additional information could be obtained and the case has been closed. Company comment: Intermittent haematochezia in a 2-month-old female subject starting 7 days after vaccination with Infanrix hexa and Rotarix. Final diagnosis of unspecified gastrointestinal inflammation after exclusion of infection and intussusception. CONFIDENTIAL 60 CONFIDENTIAL 108  B0754377A (South Africa): Intussusception, Diarrhoea, Haematochezia This case was reported by a healthcare professional (nurse) and described the occurrence of intussusception in a 4-month-old female subject who was vaccinated with live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline), combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa) and Synflorix for prophylaxis. The child was breastfeeding and was on formula. On 29 September 2011, the subject received unspecified dose of Rotarix (oral), unspecified dose of Infanrix hexa (unknown route of administration), unspecified dose of Synflorix (unknown route of administration). On 4 October 2011, 5 days after vaccination with Infanrix hexa, Rotarix and Synflorix, the subject experienced intussusception, diarrhea and blood in stools. The subject was seen by a paediatrician. This case was assessed as medically serious by GSK. On 5 October 2011, the subject was operated due to intussusception. At the time of reporting the outcome of the events was unspecified. The healthcare professional considered the events were possibly related to vaccination with Rotarix, Infanrix hexa and Synflorix. Company comment: A bowel intussusception needing surgery in a 4-month-old female subject 5 days after combined vaccination with Infanrix hexa, Synflorix and Rotarix.  D0073097A (Germany): Haematochezia, Gastrointestinal pain This case was reported by a physician via a German regulatory authority (DE-PaulEhrlich-Institut # DE-PEI-PEI2011033460) and described the occurrence of blood in stools in a 13-week-old male subject who was vaccinated with live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline) and combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). The subject’s past medical history was not provided. The subject has received no previous vaccination. On 29 September 2011 the subject received the first dose of Rotarix (0.5 ml, oral) as well as the first dose of Infanrix hexa (0.5 ml, intramuscular, left thigh) and the first dose of Prevenar 13 (0.5 ml, intramuscular, right thigh), contralaterally. Approximately two days post vaccination with Rotarix, Infanrix hexa and Prevenar 13, on 01 October 2011, the subject experienced blood in stools and gastrointestinal pain. The subject was hospitalised for an unknown period of time. Bacteria stool tests for Salmonella, Shigella, Yersinia and Campylobacter were negative. After about two days, on 02 October 2011, blood in stools was resolved. After about seven days, on 07 October 2011, gastrointestinal pain was resolved. The vaccination courses with Rotarix, Infanrix hexa and Prevenar 13 were discontinued. The German regulatory authority (DE-Paul-Ehrlich-Institut) has requested further information. At the moment no further information was available. Company comment: Haematochezia 2 days after combined vaccination with Infanrix hexa, Rotarix and Rotarix in a 13-week-old male subject Infectious causes were CONFIDENTIAL 61 CONFIDENTIAL 109 excluded and the event resolved spontaneously. Vaccination courses were discontinued. 6.5.2.4.3. Intussusception One (1) case of Intussusception was reported during the period (B0754377A) and is described in Section 6.5.2.4.2 Haematochezia. 6.5.2.4.4. Rectal haemorrhage One (1) case of Rectal haemorrhage was received during the period:  B0749250A (France): Rectal haemorrhage. This case was reported by a regulatory authority (Afssaps case ID # RS20110348) and described the occurrence of rectorrhagia in a 2-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (Prevenar 13, non-gsk) for prophylaxis. Concurrent medical conditions included cow milk protein allergy with the following symptoms vomiting and bloating. The subject was fed with Neocate (hypoallergenic, amino-acid based, nutritionally complete infant formula). On 20 March 2011 the subject received a 1st dose of Infanrix hexa (intramuscular, batch and injection site unknown) and a 1st dose of Prevenar 13 (intramuscular, batch and injection site unknown). On 21 March 2011, 12 to 24 hours after vaccination with Infanrix hexa and Prevenar 13, the subject experienced rectorrhagia which persisted for 24 to 48 hours. One month later, rectorrhagia recurred. The regulatory authority reported that the event was clinically significant (or requiring intervention). At the time of reporting, rectorrhagia was resolved. According to the French method of assessment, the AFSSaPS considered unlikely the causal relationship between vaccination with Infanrix hexa and Prevenar 13 and rectorrhagia. Company comment: 24 to 48 hours of rectorrhagia in a 2-month-old male subject1 day after vaccination with Infanrix hexa and Prevenar. No details on symptoms, physical examination, investigations and treatment were reported. Recurrence after administration of another DTP-IPV-Hib (Pentavac, non GSK) 1 month later. CONFIDENTIAL 62 CONFIDENTIAL 110 6.5.2.5. General disorders and administration site conditions 6.5.2.5.1. Abscess sterile, Injection site abscess sterile Seven (7) cases of Abscess sterile/I njection site abscess sterile were received during the period and are summarized in Table 10 . Note that case D0069239A (Germany): Soft tissue necrosis, Debridement, Incorrect route of drug administration described a sterile abscess complication indicated for surgery and is reported in Section 6.5.2.8.2 Soft tissue necrosis. Table 10 Summary of cases of Abscess sterile/Injection site abscess sterile identified during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0068815B 09 -Sep -10 Unresolved 19 Months Male Infanrix hexa Infanrix hexa 0 Years Abscess sterile, Injection site swelling, Injection site induration, Scar, Abscess drainage, Purulence, Cyst Germany Nephroplasty D0070025A 19 -Jan -11 Unknown 6 Years Male Infanrix hexa Pneumococcal vaccines (Non -GSK) 64 Days Abscess sterile, Neoplasm skin, Induration, Injection site swelling, Injection site discolouration, Granuloma skin, Scar, Surgery, Vaccination complication Germany D0070846A 30 -Mar -11 Unresolved 10 Months Male Infanrix hexa Pneumococcal vaccines (Non -GSK), Sodium Fluoride 27 Days Aspartate aminotransferase increased, Alanine aminotransferase increased, Injection site nodule, Injection site induration, Injection site erythema, Febrile convulsion, Soft tissue infection, Abscess sterile, Respiratory tract infection Germany Milk allergy D0071850A 27 -Jun -11 Unknown 8 Years Female Infanrix hexa Pneumococcal vaccines (Non -GSK) Unknown Abscess sterile Germany CONFIDENTIAL 63 CONFIDENTIAL 111 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071850B 27 -Jun -11 Unknown 8 Years Female Infanrix hexa Pneumococcal vaccines (Non -GSK) Unknown Abscess sterile Germany D0072316A 08 -Aug -11 Resolved 9 Months Female Infanrix hexa 0 Months Injection site abscess sterile, Injection site nodule, Injection site erythema, Injection site swelling Germany Hypoplastic left heart syndrome, Aortic valve atresia, Coarctation of the aorta, Atrial septal defect, Patent ductus arteriosus D0072409A 13 -Aug -11 Resolved 7 Months Male Infanrix hexa 2 Days Abscess sterile, Foreign body reaction, Allergy to metals, Lymphadenopathy, Local swelling, Induration Germany CONFIDENTIAL 64 CONFIDENTIAL 112 6.5.2.5.2. Extensive swelling of vaccinated limb Twenty -eight (28 ) cases of Extensive swelling of vaccinated limb were reported, out of which 5 serious. The reported outcome was resolved in 13 cases, improved in 3, unresolved in 8 and unknown in 4 cases. Concerning serious cases, the outcome was resolved in 4 out of 5 cases and improved in one case. These cases are summarised in Table 11. Table 11 Summary of cases of Extensive swelling of vaccinated limb identified during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0681184A 22 -Oct -10 Resolved 18 Months Male Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Injection site inflammation France B0685430A 18 -Nov -10 Unresolved 18 Months Unknown Infanrix hexa 0 Weeks Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site vesicles France B0685437A 18 -Nov -10 Resolved 18 Months Male Infanrix hexa 0 Hours Extensive swelling of vaccinated limb, Injection site warmth, Injection site pain, Pyrexia, Injection site oedema, Skin discolouration France Asthma B0692009A 04 -Jan -11 Resolved 26 Months Unknown Infanrix hexa 1 Days Injection site oedema, Injection site erythema, Injection site pain, Body temperature increased, Extensive swelling of vaccinated limb Poland CONFIDENTIAL 65 CONFIDENTIAL 113 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0700208A 16 -Feb -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Oedema, Extensive swelling of vaccinated limb, Skin warm, Pyrexia, Vomiting France B0702458A 22 -Feb -11 Unknown 11 Months Male Infanrix hexa Pneumococcal vaccines (Non – GSK) 1 Days Extensive swelling of vaccinated limb Italy B0702525A 25 -Feb -11 Unresolved 16 Months Male Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site induration, Injection site infection, Ill -defined disorder France B0703201A 22 -Feb -11 Resolved 20 Months Male Infanrix hexa MMR vaccine, strain not specified 24 Hours Extensive swelling of vaccinated limb, Injection site erythema, Injection site reaction, Injection site warmth, Pyrexia Switzerland B0703591A 03 -Mar -11 Resolved 20 Months Male Infanrix -polio – HIB, Infanrix hexa Infanrix hexa 2 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site oedema, Pyrexia, Wrong drug administered France B0705104A 09 -Mar -11 Unresolved 22 Months Male Infanrix hexa Pneumococcal vaccines (Non – GSK) 24 Hours Extensive swelling of vaccinated limb, Injection site induration, Product quality issue France CONFIDENTIAL 66 CONFIDENTIAL 114 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0705108A 09 -Mar -11 Unresolved 22 Months Male Infanrix hexa Pneumococcal vaccines (Non – GSK) 24 Hours Extensive swelling of vaccinated limb, Injection site induration, Product quality issue France B0711364A 06 -Apr -11 Improved 2 Years Female Infanrix hexa 2 Days Extensive swelling of vaccinated limb, Injection site warmth, Injection site inflammation, Injection site erythema, Incorrect route of drug administration France B0713123A 14 -Apr -11 Resolved 17 Months Male Infanrix hexa 0 Days Extensive swelling of vaccinated limb, Injection site warmth, Injection site erythema, Injection site pruritus France Coeliac disease B0715647A 26 -Apr -11 Resolved 17 Months Male Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Pyrexia, Injection site oedema, Injection site erythema, Injection site warmth, Gait disturbance France B0729084A 28 -Jun -11 Improved 2 Years Female Infanrix hexa Same day Injection site induration, Disability, Oedema, Extensive swelling of vaccinated limb France B0729737A 13 -Jun -11 Resolved 5 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Extensive swelling of vaccinated limb, Injection site erythema Italy CONFIDENTIAL 67 CONFIDENTIAL 115 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0730870A 20 -Jun -11 Resolved 18 Months Unknown Infanrix hexa Hours Injection site oedema, Injection site erythema, Injection site pain, Pyrexia, Extensive swelling of vaccinated limb Poland B0731114A 20 -Jun -11 Resolved 8 Months Unknown Infanrix hexa 1 Days Injection site oedema, Injection site erythema, Extensive swelling of vaccinated limb Poland B0734758A 18 -Jul -11 Unresolved 10 Months Male Infanrix hexa Unknown Injection site erythema, Extensive swelling of vaccinated limb, Injection site induration Italy B0735472A 27 -Jul -11 Unresolved Infant Female Infanrix hexa, Infanrix -polio – HIB DTPa -Polio – HIB (NonGSK), Pneumococcal vaccines (Non – GSK) 0 Days Extensive swelling of vaccinated limb, Injection site reaction, Injection site nodule, Injection site erythema, Injection site warmth, Injection site induration, Injection site pruritus, Hypersensitivity France B0736271A 01 -Aug -11 Unresolved 3 Months Female Infanrix hexa Synflorix 0 Days Injection site inflammation, Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site discolouration Netherlands B0741001A 18 -Aug -11 Unknown 16 Months Unknown Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site induration France CONFIDENTIAL 68 CONFIDENTIAL 116 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0741418A 19 -Aug -11 Resolved 19 Months Unknown Infanrix hexa 1 Days Injection site warmth, Injection site erythema, Injection site oedema, Extensive swelling of vaccinated limb Poland B0747623A 14 -Sep -11 Unknown 6 Months Male Infanrix hexa Unknown Injection site cellulitis, Extensive swelling of vaccinated limb, Injection site oedema Belgium Multiple allergies B0750035A 20 -Sep -11 Resolved 17 Months Unknown Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Injection site swelling, Injection site erythema, Injection site pain Poland B0750091A 20 -Sep -11 Resolved 11 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 2 Hours Injection site inflammation, Crying, Pyrexia, Hypertonia, Extensive swelling of vaccinated limb, Erythema Netherlands B0751834A 22 -Sep -11 Unresolved 25 Months Male Infanrix hexa, Varicella virus vaccine, Meningococcal polysaccharide vaccine group C (Non -GSK) 1 Days Injection site reaction, Extensive swelling of vaccinated limb, Decreased appetite, Pyrexia, Crying, Malaise, Diarrhoea, Ear pain, Injection site warmth, Injection site erythema Australia B0751948A 22 -Sep -11 Unknown 17 Months Infanrix hexa 1 Days Injection site warmth, Injection site oedema, Injection site erythema, Body temperature increased, Extensive swelling of vaccinated limb Poland CONFIDENTIAL 69 CONFIDENTIAL 117 6.5.2.5.3. Gait disturbance During the period, 1 9 cases of Gait disturbance were received , out of which 8 serious . In almost all cases (1 8/1 9) the event described was associated with at least one other adverse event. The outcome was resolved for 1 4/1 9 of these cases and for 6/8 of the serious cases. In the other cases the outcome was unknown. These cases are summarised in Table 12. Table 12 Summary of cases of Gait disturbance identified during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0686828A 30 -Nov -10 Resolved 17 Months Male Infanrix hexa, Priorix Immediate Hypotonia, Cerebellar ataxia, Gait disturbance, Pain, Hyperthermia, C – reactive protein increased France B0690264A 20 -Dec -10 Resolved 13 Months Male Infanrix hexa 0 Days Muscular weakness, Gait disturbance, Tremor, Pyrexia Italy B0691863A 29 -Dec -10 Resolved 15 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 2 Days Guillain -Barre syndrome, Neuropathy peripheral, Pyrexia, General physical health deterioration, Restlessness, Asthma, Decreased appetite, Gait disturbance, Dysstasia, Nuchal rigidity, Hyperaemia, Dysphonia, Hyporeflexia, Hypotonia, Asthenia Italy B0692411A 05 -Jan -11 Resolved 12 Months Male Infanrix hexa Pneumococcal vaccines (Non – GSK) 7 Days Gait disturbance Italy CONFIDENTIAL 70 CONFIDENTIAL 118 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0696325A 27 -Jan -11 Resolved 11 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Gait disturbance, Pyrexia Italy Pharyngeal erythema B0715647A 26 -Apr -11 Resolved 17 Months Male Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Pyrexia, Injection site oedema, Injection site erythema, Injection site warmth, Gait disturbance France B0716859A 18 -Apr -11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Gait disturbance, Stupor, Somnolence Italy B0720639A 10 -May -11 Resolved 1 Years Female Infanrix hexa, Meningococcal polysaccharide vaccine group C (Non -GSK) 0 Days Gait disturbance, Pyrexia Italy B0720709A 19 -May -11 Unknown 23 Months Female Infanrix hexa 6 Hours Insomnia, Gait disturbance, Hypotonic -hyporesponsive episode Poland Dermatitis atopic B0722375A 26 -May -11 Resolved 22 Months Unknown Infanrix hexa, Synflorix Hours Hypotonic -hyporesponsive episode, Pain in extremity, Gait disturbance, Body temperature increased, Somnolence Poland B0728126A 31 -May -11 Resolved 13 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Pyrexia, Gait disturbance, Muscular weakness Italy CONFIDENTIAL 71 CONFIDENTIAL 119 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0733393A 12 -Jul -11 Unresolved 3 Years Female Infanrix hexa 0 Days Gait disturbance, Injection site swelling, Pyrexia Viet Nam B0737089A 04 -Aug -11 Resolved 18 Months Female Infanrix hexa 1 Days Tremor, Gait disturbance, Oropharyngeal pain, Injection site reaction, Tonsillar disorder, White blood cells urine positive, Bacterial test positive, Anxiety, Upper respiratory tract congestion, Crying, Restlessness Poland B0754191A 04 -Oct -11 Unknown 26 Months Infanrix hexa, Pneumococcal vaccines (Non – GSK) 2 Days Joint swelling, Gait disturbance, Body temperature increased, Arthritis Poland B0755866A 04 -Oct -11 Unknown 11 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infection, Injection site reaction, Gait disturbance Italy D0069517A 22 -Nov -10 Resolved 13 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 2 Days Balance disorder, Vestibular neuronitis, Gait disturbance, Fall Germany D0069888A 07 -Jan -11 Resolved Female Infanrix hexa 1 Days Labyrinthitis, Gait disturbance, Balance disorder Germany D0070015A 19 -Jan -11 Resolved 16 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Ataxia, Balance disorder, Encephalitis, Gait disturbance, Pyrexia, Upper respiratory tract infection, Otitis media acute, Cerebellar ataxia Germany CONFIDENTIAL 72 CONFIDENTIAL 120 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072372A 12 -Aug -11 Unknown Female Infanrix hexa 0 Days Pain in extremity, Gait disturbance, Crying Germany CONFIDENTIAL 73 CONFIDENTIAL 121 6.5.2.5.4. Injection site nodule Twenty three (23) cases of Injection site nodule were received during the period, out of which 4 serious. The outcome was known as resolved or improved in 10/23 cases. These cases are summarised in Table 13. This table also includes one case received prior to the period of this report but never included in a previous PSUR (B0637096A). This case’s ID is marked by a ‘*’ in Table 13. Table 13 Summary of cases of Injection site nodule identified during the period Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0682340A 20 -Oct -10 12 Months Male Improved Infanrix hexa 0 Days Injection site nodule Italy B0684107A 09 -Nov -10 Infant Female Unresolved Infanrix hexa Unknown Injection site nodule, Injection site pruritus France B0686040A 24 -Nov -10 14 Months Male Improved Infanrix hexa 11 Days Injection site nodule Italy B0690263A 20 -Dec -10 1 Years Male Resolved Infanrix hexa 0 Days Injection site nodule, Pyrexia Italy B0691683A 29 -Dec -10 Infant Female Unresolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) Unknown Injection site nodule, Injection site discolouration France B0697403A 01 -Feb -11 2 Months Male Unresolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Injection site nodule France B0698664A 02 -Feb -11 5 Months Female Improved Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Injection site nodule Italy CONFIDENTIAL 74 CONFIDENTIAL 122 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0708070A 23 -Mar -11 18 Months Female Unresolved Infanrix hexa Same day Injection site oedema, Injection site nodule, Injection site induration France B0709808A 30 -Mar -11 2 Years Female Unknown Infanrix hexa 3 Weeks Injection site nodule, Injection site pruritus France Nodule B0716281A 26 -Apr -11 3 Years Male Unresolved Infanrix -polio – HIB, Infanrix hexa, Pneumococcal vaccines (Non -GSK) Unknown Injection site nodule, Injection site pruritus France Underweight B0718957A 12 -May -11 2 Months Male Resolved Infanrix hexa Unknown Injection site abscess, Injection site nodule, Injection site erythema France B0729606A 10 -Jun -11 19 Months Male Improved Infanrix hexa 0 Days Injection site warmth, Tenderness, Injection site nodule, Injection site induration, Injection site swelling, Injection site erythema, Injection site pain South Africa B0733037A 06 -Jul -11 10 Months Female Resolve d Infanrix hexa 0 Days Injection site nodule Italy B0734171A 20 -Jul -11 Infant Female Unresolved Infanrix hexa, Hepatitis B vaccine, Vaccine Unknown Injection site reaction, Injection site pruritus, Injection site nodule France CONFIDENTIAL 75 CONFIDENTIAL 123 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0735472A 27 -Jul -11 Infant Female Unresolved Infanrix hexa, Infanrix -polio – HIB DTPa -Polio -HIB (Non -GSK), Pneumococcal vaccines (Non – GSK) 0 Days Extensive swelling of vaccinated limb, Injection site reaction, Injection site nodule, Injection site erythema, Injection site warmth, Injection site induration, Injection site pruritus, Hypersensitivity France B0741005A 18 -Aug -11 Infant Female Unresolved Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Months Injection site nodule, Injection site pruritus, Hypertrichosis France B0745076A 05 -Sep -11 4 Months Male Improved Infanrix hexa Infanrix -polio – HIB 3 Weeks Subcutaneous nodule, Injection site pruritus, Injection site eczema, Injection site induration, Injection site nodule France B0746455A 12 -Sep -11 5 Months Male Unresolved Infanrix hexa, Infanrix -polio – HIB, Pneumococcal vaccines (Non -GSK) 0 Months Injection site nodule, Injection site pruritus France D0070379A 18 -Feb -11 24 Months Male Unresolved Infanrix hexa 2 Days Injection site erythema, Injection site swelling, Injection site nodule, Pyrexia Germany Heart sounds abnormal CONFIDENTIAL 76 CONFIDENTIAL 124 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0070846A 30 -Mar -11 10 Months Male Unresolved Infanrix hexa Pneumococcal vaccines (Non – GSK), Sodium Fluoride 27 Days Aspartate aminotransferase increased, Alanine aminotransferase increased, Injection site nodule, Injection site induration, Injection site erythema, Febrile convulsion, Soft tissue infection, Abscess sterile, Respiratory tract infection Germany Milk allergy D0070912A 06 -Apr -11 6 Months Male Unresolved Infanrix hexa 0 Weeks Injection site nodule, Scar Germany D0072316A 08 -Aug -11 9 Months Female Resolved Infanrix hexa 0 Years Injection site abscess sterile, Injection site nodule, Injection site erythema, Injection site swelling Germany Hypoplastic left heart syndrome, Aortic valve atresia, Coarctation of the aorta, Atrial septal defect, Patent ductus arteriosus D0072316A 08 -Aug -11 9 Months Female Resolved Infanrix hexa 0 Months Injection site abscess sterile, Injection site nodule, Injection site erythema, Injection site swelling Germany Hypoplastic left heart syndrome, Aortic valve atresia, Coarctation of the aorta, Atrial septal defect, Patent ductus arteriosus CONFIDENTIAL 77 CONFIDENTIAL 125 Case ID Initial Date Received By Dept Age Gender Case Outcome Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0637096A * 02 -Mar -10 4 Months Female Resolved Infanrix hexa 0 Days Injection site nodule, Injection site erythema Italy CONFIDENTIAL 78 CONFIDENTIAL 126 6.5.2.5.5. Injection site urticaria Three (3) cases of Injection site urticaria were received during the period (B0699204A, B0732577A and B0744335A). These cases are summarized in Section 6.5.2.11.7 Urticaria, Urticaria popular and Urticaria thermal. 6.5.2.5.6. Nodule Three (3) cases of Nodule were received during the period:  B0701338A (France): Irritability, Sleep disorder, Pyrexia, Injection site induration, Nodule, Incorrect product storage This case was reported by a pharmacist and a physician and described an incorrect product storage in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Medical conditions and concurrent medications were unspecified. On 21 February 2011, the subject received a 3rd dose of Infanrix hexa (batch, route and injection site unknown). Before administration, the vaccine was stored at room temperature during 15 days (incorrect product storage) At the time of reporting, no adverse effect was reported. Upon follow-up received on 04 March 2011 from the pharmacist: The subject weighed 6.8 kg and measured 61 cm. On the same day, he received one dose of Infanrix hexa (batch A21CA584B) and one dose of pneumococcal vaccine (Prevenar, non-gsk, batch E16268) both stored at room temperature during 15 days. One week after vaccination, the subject experienced fever at 38.5-39 degrees Celsius, irritability with sleep disorder and presented at one vaccine injection site (vaccine unspecified) an induration. At the time of reporting, Infanrix hexa was not readministered. Outcome of events and the reporter’s assessment were unspecified. Upon follow-up received from the physician on 13 May 2011: Infanrix hexa and Prevenar were administered intramuscularly in thigh. The physician noticed fever at 38 degrees Celsius, nodule and sleep disorder for 48 hours. On an unspecified date, Infanrix hexa was readministered without recurrence of events. The physician considered the causal relationship between Infanrix hexa and the reported events as almost certain. Company comment: Injection site induration 1 week after 3rd vaccination with Infanrix hexa in a 4 month-old subject. The event resolved spontaneously.  B0726560A (Sweden): Nodule, Injection site extravasation, Abscess, Erythema This case was reported by a physician and described the occurrence of nodule in a 3- month-old female subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Concurrent vaccination included pneumococcal vaccines (Prevenar 13) (non-GSK manufacturer, intramuscular, left thigh) given on 20 December 2010. In October 2010, the subject received 1st dose dose of Infanrix hexa (intramuscular, unknown injection site, lot number not provided). At an unspecified time after vaccination with Infanrix hexa, the subject experienced nodule. On 20 December 2010, the subject received 2nd CONFIDENTIAL 79 CONFIDENTIAL 127 dose of Infanrix hexa (intramuscular, right thigh). At an unspecified time after vaccination with Infanrix hexa, the subject experienced an infiltrate with a size of a rice grain, which increased. In March 2011, 3 months after vaccination with Infanrix Hexan the subject experienced redness “like an abscess” which contained one table spoon of pus. At the time of reporting the outcome of the events was unspecified. Company comment: Injection site nodule at unspecified time after vaccination with Infanrix hexa and Prevenar.  B0745840A (Italy): Injection site reaction, Nodule, Pyrexia This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 147350) and described the occurrence of injection site reaction in a 6-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. On 14 February 2011, the subject received 2nd dose of Infanrix hexa (intramuscular, site of injection unknown) and 2nd dose of Prevenar 13 (intramuscular, site of injection unknown). On 14 February 2011, less than one day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced injection site reaction, nodule (unspecified site) and fever (39.5 Deg.C.). The subject was treated with paracetamol. On 16 February 2011, the events were resolved. Follow-up received on 18 October 2011: No further informtion was expected. This case is closed. Company comment: Injection site reaction in a 6 month-old subject less than 1 day after 2nd injection with Infanrix hexa and Prevenar. 6.5.2.6. Immune system disorders 6.5.2.6.1. Anaphylactic shock Three (3) cases of Anaphylactic shock were reported over the period. These cases are described below.  B0680987A (Belgium): Anaphylactic shock, Syncope, Apnoea, Bronchospasm, Blood pressure decreased, Pallor, Respiratory rate decreased, Crying, Hypoventilation This case was reported by a physician and described the occurrence of anaphylactic shock in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), rotavirus vaccine (non-gsk) (RotaTeq) and pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. The subject had no concomitant disease and no concomitant medication. The subject had no previous reaction to drug or allergy. On 20 October 2010, the subject received first, 1st dose of RotaTeq (oral), and then unspecified dose of Infanrix hexa (intramuscular) and after unspecified dose of Prevenar (intramuscular). On 20 October 2010, 1 minute after vaccination with Prevenar, within minutes of vaccination with Infanrix hexa and Rotateq, the subject experienced anaphylactic shock, syncope, bronchospasm, decreased blood pressure, CONFIDENTIAL 80 CONFIDENTIAL 128 pallor, respiration rate decreased, hypoventilation and possible apnea. The heart sounds were good. It took quite long before she fully recovered. She experienced no rash, no urticaria, no stridor and no wheezing. When the subject arrived at hospital, she was still pale but stable at cardio-respiratory level. No test was performed. The events lasted a few minutes. On 20 October 2010, the events were resolved, the subject had fully recovered. The physician considered the events were life threatening. The subject was treated with adrenaline (1mg/ml) 0,5 ml and 4 times respiration. The child’s face brightened up and she started to cry. Her color came back and she breathed better again. But after 2 minutes, the baby became pale again. Again drowsy but recovered each time then began to cry again: was always so up and down. In the meantime ambulance was called. The subject was hospitalised for observation. At the time of reporting the events were resolved. The physician considered the events were almost certainly related to vaccination with Infanrix hexa, RotaTeq and Prevenar. This case has been identified as a duplicate of case B0685603A which was voided. This case was also reported by a physician via a sales representative. Company comment: This 2-month-old female subject experienced anaphylactic reaction 1 minute after combined vaccination with Prevenar and within a few minutes after Infanrix hexa and RotaTeq (oral). This case fulfils Level 2 of diagnostic certainty of the Brighton Collaboration Anaphylaxis Working Ggroup criteria.  B0741646A (Italy): Anaphylactic shock, Stridor, Respiratory disorder, Pulse pressure decreased, Heart rate increased, Crying This case was reported by a physician via a regulatory authority (IT-Agenzia Italiana del Farmaco # 146502) and described the occurrence of anaphylactic shock in a 2- month-old female subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. On 17 August 2011, the subject received 1st dose of Infanrix hexa (.5 ml, intramuscular, injection site unknown) and 1st dose of Prevenar 13 (.5 ml, intramuscular, injection site unknown). On 17 August 2011, less than one day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced anaphylactic shock, slight laryngeal stridor, respiratory crisis, parvus and quick pulsus and weak weeping. The subject was hospitalised and the regulatory authority reported that the events were life threatening. The subject was treated with adrenaline, cardiac massage and oxygen. At the time of reporting, the events were improved. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevenar 13. Company comment: This 2-month-old female subject experienced anaphylactic reaction less than 1 day after combined vaccination with Prevenar and Infanrix hexa. This case fulfils Level 3 of diagnostic certainty of the Brighton Collaboration Anaphylaxis Working Group criteria. CONFIDENTIAL 81 CONFIDENTIAL 129  D0071107A (Germany): Anaphylactic shock This case was reported by a physician and described the occurrence of anaphylactic shock in an 8-month-old male subject (born 20 April 2007) who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 10 January 2008 the subject received 2nd dose of Infanrix hexa (unknown route and injection site). At an unspecified time after vaccination with Infanrix hexa, the subject experienced anaphylactic shock. This case was assessed as medically serious by GSK. At the time of reporting the outcome of the event was unspecified. Despite of requests no further information will be available. Company comment: This 8-month-old male subject experienced anaphylactic shock at an unspecified time after 2nd dose of Infanrix hexa. This report lacks important information such as anaphylaxis’s symptoms, temporal sequence and treatment. This case fulfils Level 4 of diagnostic certainty of the Brighton Collaboration Anaphylaxis Working Group criteria. 6.5.2.6.2. Anaphylactic/Anaphylactoid reaction and Drug hypersensitivity Four (4) cases of Anaphylactic reaction/Anaphylactoid reaction/Drug hypersensitivity were reported over the period:  B0698663A (Italy): Anaphylactic reaction, Circulatory collapse, Slow response to stimuli, Cyanosis, Hypotonia, Hypothermia, Pallor, Bradycardia, Oxygen saturation decreased, Pyrexia. This case was reported by a physician and described the occurrence of anaphylaxis reaction in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Concurrent medical conditions included premature birth at 24 weeks (birth weight 700 g). The subject was born by cesarean section at 24 weeks + 6 days. He underwent mechanical ventilation until 2 December 2010. The persistence of the opening of the duct of Botallo was treated with cycles of ibuprofen and indomethacin, the ductus closed on 4 December 2010. The broncodisplasia of lung was treated with cortisone cycles and at the time of vaccination the subject was in good condition. Vaccinations ran the next in a protected environment. The medical family history included allergic reaction with Quincke’s oedema due to cephalosporin (mother) and allergy to Novalgina (grandfather). Concurrent vaccination included respiratory syncytial virus vaccine (manufacturer unspecified; route and injection site unknown) given on an unspecified date. In February 2011, prior to the discharged, the subject received unspecified dose of Infanrix hexa (route and injection site unknown, batch number not provided). In February 2011, less than one day after vaccination with Infanrix hexa, the subject experienced collapse, hyporesponsiveness, hypotonia nos and hypothermia. The subject was hospitalised. Tests were performed and showed normal results. At the time of reporting, the events were resolved. The physician considered the events were possibly related to vaccination with Infanrix hexa. Follow-up information reported by a physician via a CONFIDENTIAL 82 CONFIDENTIAL 130 regulatory authority (IT-Agenzia Italiana del Farmaco # 134734): Concurrent medications included Palivizumab (Synagis), Frusemide (Lasix), Iron polymaltose (Intrafer), Multivitamins (Idroplurivit), Nutritional supplement (Reuterin) and Emollient (Folium). The subject was vaccinated with Infanrix hexa on 1st February 2011 (intramuscular, injection site unknown). On 1st February 2011, less than 1 day after vaccination with Infanrix hexa, the subject also developed pallid cyanosis, bradycardia, desaturation, fever and anaphylaxis reaction. On 2 February 2011, the events were resolved. Relevant tests were performed: an electrocardiogram was performed on 1st February 2011, X-ray, X-ray of the skull and C-reactive protein were performed on 2nd February 2011 and on 3rd February 2011, an electroencephalogram was performed. All these investigations showed normal results. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa. Company comment: This 4-month-old male subject with a history of premature birth (24 weeks) experienced anaphylactic reaction less than 1 day after vaccination with Infanrix hexa. This case fulfils Level 4 of diagnostic certainty of the Brighton Collaboration Anaphylaxis Working Group criteria.  D0072050A (Germany): Anaphylactic reaction, Swelling, Erythema, Crying, Petechiae This case was reported by a physician via a sales representative and described the occurrence of anaphylactic reaction in a 3-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccination included pneumococcal vaccines (non-gsk) (Prevenar 13, Pfizer). On 12 July 2011 the subject received unspecified dose of Infanrix hexa (unknown route, unknown thigh) given contralaterally to unspecified dose of Prevenar 13 (unknown route, unknown thigh). On 12 July 2011, shortly after vaccination with Infanrix hexa and Prevenar 13, the subject experienced severe swelling with erythema on both legs up to groin. He was crying more than normal. The physician diagnosed anaphylactic reaction with swelling on both legs. The subject was hospitalised. At the time of reporting the outcome of the events was unspecified. The physician also informed German regulatory authority (Paul-Ehrlich-Institute) and public health agency. Written follow-up information was received on 22 July 2011 from physician. On 12 July 2011 the subject received 1st dose of Infanrix hexa (intramuscular, left thigh) and 1st dose of Prevenar 13 (intramuscular, right thigh). On 12 July 2011, less than one day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced extensive swelling at both extremities and erythema. He was crying more than normal. On 13 July 2011, the subject developed petechiae. Anaphylactic reaction was not mentioned anymore. The subject was hospitalised. The subject was treated with cooling and prednisone (Rectodelt). On 12 July 2011, abnormal crying was resolved. On 13 July 2011, swelling was resolved and erythema improved. No outcome for petechiae was reported, but event lasted until 18 July 2011. The vaccination course with Infanrix hexa was discontinued. The physician considered swelling; erythema and crying were almost certainly related to vaccination with Infanrix hexa and Prevenar 13. Written follow-up information was received on 08 CONFIDENTIAL 83 CONFIDENTIAL 131 August 2011 from Paul-Ehrlich-Institut (# DE-PEI-PEI2011025401) with no new medical information. No further information will be available. Company comment: This 3-month-old male subject experienced a suspect anaphylactic reaction after 1st dose of Infanrix hexa. This case fulfils Level 5 of diagnostic certainty of the Brighton Collaboration Anaphylaxis Working Group criteria.  D0072500A (Germany): Anaphylactoid reaction, Hypersensitivity, Product quality issue, Urticaria, Rash, Apathy, Anaphylactic reaction, Erythema, Petechiae, Injection site erythema. This case was initially reported by a pharmacist and described the occurrence of anaphylactoid reaction in a 13-week-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. The case was also received as pharmaceutical product complaint. On an unspecified date the subject received an unspecified dose of Infanrix hexa (0.5 ml, unknown). At an unspecified time post vaccination with Infanrix hexa, on an unknown date, the subject experienced severe allergic reaction. At the time of reporting the outcome of the event was unspecified. Follow-up information was received on 26 August 2011 from the quality assurance department. The event was now reported as anaphylactoid reaction. Follow-up information was received on 02 September 2011 from the quality assurance department. Based on all available data it was concluded that there was no evidence for a specific safety signal for the used lot of Infanrix hexa. Follow-up information was received on 16 September 2011 from the quality control department. All received returned samples conform to the description specifications. Based on QC results the pharmaceutical product complaint was considered to be unsubstantiated. Follow-up information from the reporting pharmacist has been requested. Follow-up information was received on 20 October 2011 from the vaccination responsible physician. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). On an unknown date in 2011 the subject received the first dose of Infanrix hexa (0.5 ml, unknown) and the first dose of Prevenar 13 (0.5 ml, unknown). At an unspecified time post vaccination with Infanrix hexa, on an unknown date, the subject experienced anaphylactoid reaction. The subject was hospitalised for an unknown period of time. At the time of reporting the outcome of anaphylactoid reaction was unspecified. The vaccination responsible physician considered that anaphylactoid reaction may be causally related to vaccination with Infanrix hexa and/or Prevenar 13. Follow-up information including a hospital report was received on 25 October 2011 from a physician. For the first time age and gender of the subject have been reported. The subject has no underlying or concurrent medical conditions or other risk factors. Previous vaccination with the first doses of combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma), given on 15 June 2011, was well tolerated. On 24 August 2011 at around 11:00 the subject received the second dose of Infanrix hexa (0.5 ml, unknown, unknown thigh) and the second dose of Prevenar 13 (0.5 ml, CONFIDENTIAL 84 CONFIDENTIAL 132 unknown, unknown thigh). Approximately 5 – 7 minutes post vaccination with Infanrix hexa and Prevenar 13, on 24 August 2011, the subject experienced generalized urticaria with apathy. The subject did not experience dyspnea or hypotension. According to the reporting physician these events were resolved after about four hours. The physician reported that the same batches of Infanrix hexa and Prevenar 13 had been used when the subject had received the first doses of Infanrix hexa and Prevenar 13 on 15 June 2011. On 24 August 2011 the subject was hospitalised for two days at a pediatric clinic for possible anaphylaxis post vaccination with the second doses of Infanrix hexa and Prevenar 13. According to anamnesis in the hospital the subject experienced urticaria at the head approximately 5 – 10 minutes post vaccination with Infanrix hexa and Prevenar 13, on 24 August 2011. Urticaria spread quickly over the whole body. But at the extremities the subject experienced mild exanthema (exanthema on extremities). An ambulance was called. The subject was transported to the pediatric clinic without complications. All previous vaccinations with not further specified vaccines have been well tolerated. As a neonate the subject received phototherapy for hyperbilirubinemia. One week prior to vaccination with the second doses of Infanrix hexa and Prevenar 13, on an unknown date in August 2011, the subject had suffered from rhinitis without fever. On 25 August 2011 the subject was discharged in good general condition with completely resolved urticaria for ambulatory follow-up. At the time of discharge from hospital the subject showed injection site redness. No further information will be available. Company comment: This 13-week-old male subject experienced approximately 5 – 7 minutes after 1st vaccination with Infanrix hexa and Prevenar, generalized urticaria with apathy considered causally related to the vaccination. The subject did not experience anaphylaxis (dyspnea or hypotension). The case was also received as pharmaceutical product complaint and it was concluded that there was no evidence for a specific safety signal for the used lot of Infanrix hexa. This case fulfils Level 5 of diagnostic certainty of the Brighton Collaboration Anaphylaxis Working Group criteria.  B0712429A (Czech Republic): Salmonella sepsis, Rash generalised, Pyrexia, Diarrhoea, Drug hypersensitivity, Hypersensitivity This case was reported by a physician and described the occurrence of salmonella enteritidis sepsis in a 7-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) and synflorix for prophylaxis. Since 12 December 2010, she was treated with Budesonide.Previous and/or concurrent vaccination included combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. ;GlaxoSmithKline;unknown;unknown given on 27 January 2011; synflorix ;GlaxoSmithKline;unknown;unknown given on 27 January 2011. No reactions after the 1st dose. Concurrent medications included Budesonide (Budiar). On 1 March 2011, the subject received 2nd dose of Infanrix hexa (administration site and route unknown), 2nd dose of Synflorix (administration site and route unknown). On 1 March 2011, less than one day after vaccination with Infanrix hexa and Synflorix, the subject experienced fever (39.4 deg.C). On 2 March CONFIDENTIAL 85 CONFIDENTIAL 133 2011, 1 day after vaccination with Infanrix hexa and Synflorix, the subject experienced generalised exanthema on the whole body, generalised allergic reaction and diarrhea. The subject was hospitalised for 13 days, from 2 to 14 March 2011. Blood tests were performed and showed pathological results: C-reactive protein: 8.3 mg/l and leucocytes: 27 Giga/l. The subject was treated with dimethindene maleate (Fenistil), prednisone (Prednison), and ibuprofen (Nurofen). After next dose of Nurofen, the exanthema repeated and worsened. An allergic reaction to Nurofen was diagnosed. On 6 March 2011, the diarrhea continued. She was afebrile and exanthema recovered. A microbiological cultivation of stool showed Salmonella enteritidis and on second blood tests, leucocytes was 33 Giga/l and c-reactive protein :121mg/l. The subject was admitted to Intensive Care Unit with the diagnosis of salmonelosis sepsis. She was treated with gentamicin sulphate (Gentamycin) and cefotaxime (Cefotaxim). On 14 March 2011, C-reactive protein was 6 mg/l. On 14 March 2011, salmonella enteritidis sepsis was resolved. Follow-up information received on 15 April 2011: Concurrent medical conditions included recurrent obstructive bronchitis since 3 months of age, but allergy had not been proved. As no additional information could be obtained, the case has been closed. Company comment: This 7-month-old female subject experienced generalised allergic reaction (exanthema) and diarrhea 1 day after vaccination with Infanrix hexa and Synflorix. A concomitant Salmonella enteritis infection could have play a trigger role in the drug hypersensitivity. CONFIDENTIAL 86 CONFIDENTIAL 134 6.5.2.7. Infections and infestations 6.5.2.7.1. Abscess , Abscess limb , Incision site abscess , Injection site abscess, Injecti on site infection, Streptococcal abscess During the reporting period, 25 cases were received including one of the following MedDRA Preferred Terms: Abscess (n=10), Abscess limb (n=1), Incision site abscess (n=2), Injection site abscess (n=12), Injection site infection (n=2), Streptococcal abscess (n=2). These cases are summarised in Table 14. Table 14 Summary of Abscess -related cases received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0686567A 29 -Nov -10 Resolved 9 Months Unknown Infanrix hexa 16 Days Injection site abscess, Injection site oedema, Injection site swelling Czech Republic B0696664A 28 -Jan -11 Resolved 17 Months Male Infanrix hexa, Priorix 1 Days Injection site infection, Erythema, Oedema, Feeling hot, C -reactive protein increased France B0698641A 08 -Feb -11 Resolved 3 Months Male Infanrix hexa 1 Weeks Staphylococcal abscess, Streptococcal abscess, Injection site abscess Czech Republic B0698651A 08 -Feb -11 Resolved 4 Months Male Infanrix hexa Infanrix hexa 2 Weeks Staphylococcal abscess, Streptococcal abscess, Injection site abscess Czech Republic B0702525A 25 -Feb -11 Unresolved 16 Months Male Infanrix hexa 1 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site induration, Injection site infection, Ill -defined disorder France CONFIDENTIAL 87 CONFIDENTIAL 135 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0707174A 21 -Mar -11 Resolved 21 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Weeks Staphylococcal abscess, Injection site abscess, Pyrexia, Injection site swelling, Leukocytosis, C -reactive protein increased, Injection site inflammation France Impaired selfcare B0718957A 12 -May -11 Resolved 2 Months Male Infanrix hexa Unknown Injection site abscess, Injection site nodule, Injection site erythema France B0726560A 24 -May -11 Unknown 3 Months Female Infanrix hexa Pneumococcal vaccines (Non -GSK) Unknown Nodule, Injection site extravasation, Abscess, Erythema Sweden B0728595A 06 -Jun -11 Resolved 2 Months Female Infanrix hexa Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) 14 Days Injection site mass, Injection site abscess, Discomfort South Africa B0740389A 12 -Aug -11 Improved 10 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Abscess limb, Pyrexia, Oedema peripheral, Erythema, Pain, Inflammation Italy B0740389A 12 -Aug -11 Improved 10 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Abscess limb, Pyrexia, Oedema peripheral, Erythema, Pain, Inflammation Italy B0748231A 15 -Sep -11 Unresolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK) 6 Days Groin abscess, Abscess Czech Republic CONFIDENTIAL 88 CONFIDENTIAL 136 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0748231A 15 -Sep -11 Unresolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK) 6 Days Groin abscess, Abscess Czech Republic B0756153 A 02 -Oct -11 Unknown 4 Months Female Infanrix hexa 1 Weeks Injection site abscess Ecuador D0069806A 22 -Dec -10 Unknown Infant Unknown Infanrix hexa Unknown Injection site abscess Germany D0069984A 13 -Jan -11 Resolved 6 Months Male Infanrix hexa 0 Days Injection site erythema, Injection site swelling, Abscess Germany D0070332A 17 -Feb -11 Resolved 11 Months Male Infanrix hexa 53 Days Abscess Germany D0070342A 17 -Feb -11 Resolved 6 Months Female Infanrix hexa Infanrix hexa 5 Days Abscess Germany D0071349A 12 -May -11 Unresolved 26 Months Female Infanrix hexa 6 Months Abscess, Granuloma Germany D0071422B 18 -May -11 Resolved with Sequelae 14 Months Female Infanrix hexa Pneumococcal vaccines (Non -GSK) 6 Weeks Injection site abscess, Injection site inflammation, Injection site swelling, Foreign body reaction, Incision site abscess Germany D0072015A 12 -Jul -11 Resolved with Sequelae 4 Months Female Infanrix hexa 0 Days Abscess, Induration, Erythema, Product quality issue Germany D0072769A 19 -Sep -11 Unknown 4 Months Male Infanrix hexa 2 Days Injection site abscess Germany D0072948A 19 -Sep -11 Unknown 4 Months Male Infanrix hexa 2 Days Injection site abscess Germany D0072966A 07 -Oct -11 Unresolved 17 Months Male Infanrix hexa 82 Days Abscess Germany D0073011A 12 -Oct -11 Resolved 8 Months Male Infanrix hexa 3 Days Abscess Germany CONFIDENTIAL 89 CONFIDENTIAL 137 6.5.2.7.2. Cellulitis Two (2) cases of Cellulitis were received during the period:  B0713564A (Serbia): Cellulitis, Erythema, Body temperature increased, Injection site swelling This case was reported by a physician and described the occurrence of phlegmon in a 2-year-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Previous and/or concurrent vaccination included combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (GlaxoSmithKline) given on an unspecified date. No adverse events occurred after the 2 doses. Concurrent medical conditions included weak immune system. Due to this, the administration of the 3rd dose was postponed up to date. On 8 April 2011, the subject received 3rd dose of Infanrix hexa (intramuscular, unknown thigh, batch number not provided). On 10 April 2011, 2 days after vaccination with Infanrix hexa, the subject experienced intensive erythema, increased in local temperature and swelling injection site (10 cm diameter) above skin level. The subject was hospitalised and the diagnosis of phelgmon was made. No surgery was performed. He was treated with pharmacotherapy only. The subject was treated with ceftriaxone and antibiotics (Antibiotic). At the time of reporting, the events were unresolved, he was still in hospital. At the time of reporting, no additional data were available regarding his condition. Follow-up information received on 15 July 2011: As no additional information could be obtained, the case has been closed. Commpany comment: Phlegmon in a 2 year-old male subject 2 days after 3rd vaccination with Infanrix hexa. The subject was hospitalized and treated with antibiotics. The subject had a weak immunesystem (not further specified).  B0730177A (Spain): Cellulitis, Streptococcal bacteraemia, Local reaction, Pyrexia This case was reported by a regulatory authority (ES-Agencia Esp de Medicamentos y Prod Sanitarios # ES-AGEMED-224093441) and described the occurrence of cellulitis in a 9-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 22 February 2011, the subject received an unspecified dose of Infanrix hexa (intramuscular, administration site unknown). On 1 March 2011, 7 days after vaccination with Infanrix hexa, the subject experienced fever. On 3 March 2011, 9 days after vaccination with Infanrix hexa, the subject experienced local reaction in lower limbs and cellulitis. On 5 March 2011, 11 days after vaccination with Infanrix hexa, the subject experienced streptococcal bacteremia. The subject was hospitalised from 5 to 16 March 2011 and the regulatory authority reported that the events were clinically significant (or requiring intervention). The diagnosis was cellulitis due to streptococcal bacteremia. The subject was treated with ibuprofen and antibiotics (Antibiotic). On 16 March 2011, cellulitis, streptococcal bacteremia and local reaction were resolved. In March 2011, fever was resolved. The regulatory CONFIDENTIAL 90 CONFIDENTIAL 138 authority reported that the events were probably related to vaccination with Infanrix hexa. Commpany comment: Cellulitis in lower limbs and streptococcal bacteremia 9 days after vaccination with Infanrix hexa in a 9-month-old subject. The timeframe between injection and cellulitis seems long for a causal relationship. There is no other information about other possible sources of infection. 6.5.2.7.3. Encephalic infection One (1) case of Encephalitic infection was received during the period (B0692285A) and is described in Section 6.5.2.9.5 Encephalitis, Encephalopathy and Encephalic infection. CONFIDENTIAL 91 CONFIDENTIAL 139 6.5.2.7.4. Injection site cellulitis Two (2) non -serious cases of Injection site cellulitis were receivedduring the period and are summarized in Table 15. Table 15 Summary of cases of Injection site cellulitis received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0747623A 14 -Sep -11 Unknown 6 Months Male Infanrix hexa Unknown Injection site cellulitis, Extensive swelling of vaccinated limb, Injection site oedema Belgium Multiple allergies B0748879A 16 -Sep -11 Unresolved 16 Months Male Infanrix hexa 1 Days Injection site cellulitis, Injection site warmth, Injection site pain, Inflammation, Hypersensitivity, Injection site swelling, Injection site erythema, Injection site induration Belgium CONFIDENTIAL 92 CONFIDENTIAL 140 6.5.2.7.5. Meningitis aseptic One (1) case of Meningitis aseptic was reported during the period:  B0714940A (France): Meningitis aseptic This case was reported by the French regulatory authority (AFSSaPS number MA20110871) and described the occurrence of lymphocytic meningitis in a 4- month-old female subject who was vaccinated with combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrixquinta, GlaxoSmithKline) for prophylaxis. Medical history and concurrent medications, if any, were unspecified. On 26 March 2011, the subject received 2nd dose of Infanrixquinta (intramuscular, unknown injection site, batch number “121CD021B” as reported and A21CB021B according to sales data). On 30 or 31 March 2011 (inconsistent information), four or five days days after vaccination with Infanrixquinta, the subject experienced lymphocytic meningitis. On 03 April 2011, she was transferred to the intensive care unit. Analysis of nasal sample found PCR positive for Enterovirus. After symptomatic therapy, the subject’s condition improved. Hospitalisation in intensive care unit lasted five days. The AFSSaPS reported that the event was life threatening. At the time of reporting the event was resolved without sequalae. The AFSSaPS considered the relationship between the event and the vaccination with Infanrixquinta was dubious, according to the French method of assessment. Upon follow-up received from the french center of pharmacovigilance on 09 May 2011: Suspect drug was changed to Infanrix hexa, the reporter confirmed the batch number but the name of the vaccine was unreadable on the vaccines record. Upon follow-up received from AFSSAPS on 16 May 2011: AFSSAPS had made the change from Infanrix Quinta to Infanrix Hexa on their database, as previously reported. Company comment: Lymfocytic meningitis in a 4 month-old female subject 4 or 5 days after vaccination with Infanrix hexa. The subject was hospitalized and the event recovered with symptomatic therapy. There is no additional information about investigation of other sources of infection. The AFSSaPS considered the relationship between the event and the vaccination dubious, according to the French method of assessment. 6.5.2.7.6. Meningitis pneumococcal Two (2) cases of Meningitis pneumococcal were received during the period:  D0069889A (Germany) Meningitis pneumococcal, Grand mal convulsion, Epilepsy, Hydrocephalus, Subdural hygroma, Subdural empyema, Anaemia, Generalised oedema, Ileus paralytic, Conjunctivitis, Septic shock, Pneumonia primary atypical, Neurosurgery, Pyrexia, Abdominal distension, Ill-defined disorder, Restlessness, Hyperaesthesia, Oligodipsia, Eye movement disorder, Hypertonia, Tachycardia, Oxygen saturation decreased, Ascites, Respiratory arrest, Drug ineffective, Cyanosis, Splenomegaly This case was reported by a physician and described the occurrence of pneumococcal meningitis in a 4-month-old male subject who was vaccinated with combined CONFIDENTIAL 93 CONFIDENTIAL 141 diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccines included 13-valent pneumococcal vaccines (nongsk) (Prevenar 13, Pfizer) and rotavirus vaccine (non-gsk) (RotaTeq). The subject’s medical history included premature birth at 36 weeks of gestation and congenital bacterial pneumonia (with sterile throat smear, abdominal aspirate and blood culture). The subject was healthy on the day of vaccination. On 1 October 2010 the subject received unspecified dose of Infanrix hexa (unknown route and application site), unspecified dose of Prevenar 13 (unknown route and application site) and unspecified dose of RotaTeq (oral). On 04 October 2010 the subject had increased body temperature (over 40 degC). A physician was consulted the next day, but clinical examination was without pathologic findings, except for abdominal distension. There were no neurological findings. The subject was treated with unspecified antipyretic measures. On 06 October 2010 the physician was again consulted with fever up to 40.5 degC and the patient was whining, whimpered, was restless, touch-sensitive and the drinking volume was reduced. After a short examination the subject began to seize. No drugs were administered. The subject had tonic seizures of all limbs, light-fixed pupils and open eyes with ocular deviation to top left. The subject was hospitalised on 06 October 2010 in reduced general condition with grand mal seizure and meningitis. The physician considered the events were life threatening and clinically significant (or requiring intervention). The subject showed convex, pulsating fontanel with a size of 3×4 cm, muscle hypertonus, positive meningitic signs (meningism, Laegue, Brudzinski and Kernig), tachycardia and distended abdomen. Bacterial meningitis was suspected. The patient was treated with sodium chloride and cefotaxime (Cefotaxim), phenobarbitone (Phenobarbital), oxybate sodium (Somsanit) for sedation. After the subject slept, seizures ceased. Lumbar puncture showed increased lumbar pressure and murky cerebrospinal fluid (CSF) with S. pneumoniae in rapid test. Treatment with cefotaxime (Cefotaxim), phenobarbitone (Phenobarbital), gentamicin sulphate (Gentamycin), dexamethasone and dipyrone (Metamizole sodium) was started. On 07 October 2010 the fever resolved and the patient drank well. Because of reduced stool excretion, the subject received frusemide (Lasix) for expulsion, simethicone (Sab simplex) and hyoscine butylbromide (Buscopan). Because of reduced oxygen saturation (87%) the subject received oxygen. Anemia was treated with Red blood cell concentrate. The patient’s condition improved with stable oxygen saturation and good urine expulsion. On 08 October 2010 the subject showed impaired condition, reduced drinking volume, unchanged fontanel, negative pupil reaction, sensitivity to touch, restlessness and increasing abdominal tension. Abdominal sonogram showed ascites, treated with frusemide. Because of still high readiness for seizures, lumbar puncture was performed. Lumbar pressure was normal. Cerebrospinal fluid test showed Streptococcus pneumoniae. Inflammatory parameters (C-reactive protein (CRP) and white blood cell count) were increased. Treatment was changed to vancomycin and cefotaxime. The subject drank better and became calm. On 09 October 2010 the subject received bladder catheter and intestinal tube due to intestinal paralysis. On 11 October 2010 bladder catheter was removed and the dose of Phenobarbital reduced. The subject drank normally, but had thin stool. Physiotherapy was started. Within the next days the subject’s condition improved and treatment drugs could be reduced. Additional treatment included escherichia coli (Mutaflor). On 14 October 2010 the CONFIDENTIAL 94 CONFIDENTIAL 142 subject developed conjunctivitis and was treated with benzalkonium chloride, ofloxacin (Floxal) and later with colistin and erythromycin lactobromide (Ecolicin). Restlessness was treated successfully with promethazine hydrochloride (Atosil). Because of cough, increased inflammatory parameters and increased body temperature, an X-ray was performed, which showed atypical pneumonia. On 18 October 2010 the subject had another tonic-clonic, generalised seizure with perioral fasciculation and breathing pause. Diazepam was without effect. After treatment with Phenobarbital the seizure ceased. Cranial sonogram showed extended inner and outer subarachnoid spaces. The subject was transferred to another hospital with the suspect of subdural empyema. Diagnoses in hospital included pneumococcal meningitis, symptomatic epilepsy, decreased cerebrospinal fluid resorption (hydrocephalus), generalized edema, septic shock and drug ineffectiveness. Magnetic resonance imaging (MRI) showed subdural hygroma and subdural empyema, at the right side more than at the left. The subject was treated with anti-epileptic medication and neurosurgical operation. On 18 October 2010 the subject underwent subdural-peritoneal shunt implantation. Epilepsy still required treatment. The reporting physician considered the events were probably related to Prevenar 13. Follow-up information was received on 21 January 2011 via Pfizer. The reporting physician stated that the result of serotype analysis was unknown. The following events were still unresolved: pneumococcal meningitis, epilepsy, hydrocephalus, subdural hygroma. The outcome of the following events was unknown to the physician: Grand mal attacks, subdural empyema, anaemia, edema, paralytic intestine, conjunctivitis, septic shock and pneumonia. The reporting physician considered the events were possibly related to Prevenar 13. Follow-up information was received on 16 May 2011 via Pfizer. The subject had no immunodeficiency. It was the first dose of Prevenar 13 (intramuscular) and Infanrix hexa and the third dose of RotaTeq. The reporter of this follow-up considered pneumococcal meningitis was unlikely related to Prevenar 13. A hospital report was provided, with similar information to the initial report. When admitted to hospital, the subject also showed peripheral cyanosis. Sonogram on 08 October 2010 also showed splenomegaly. According to follow-up information from 20 May 2011 pneumococcal meningitis was caused by streptococcus pneumonia serotype 19A. Company comment: Pneumococcal meningitis in a 4-month-old male subject 5 days after first dose of Infanrix hexa and Prevenar third dose of RotaTeq. The subject required subdural-peritoneal shunt implantation due to ineffective antibiotic therapy. The outcome of sequellae (grand mal attacks) is unknown.  D0072024A (Germany) Meningitis pneumococcal, Gastroenteritis rotavirus, Respiratory syncytial virus infection, Pneumococcal sepsis, Pharyngitis, Somnolence, Pyrexia, Fluid intake reduced, Respiration abnormal, Crying, Diarrhoea, Cardiovascular insufficiency, Pallor, Tachypnoea, Anaemia, Thrombocytosis This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011022521) and described the occurrence of pneumococcal meningitis with sepsis in a 3-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. CoCONFIDENTIAL 95 CONFIDENTIAL 143 suspect vaccination included 13-valent pneumococcal vaccine (non-GSK) (Prevenar 13, Pfizer). First vaccination with both vaccines was received on 13 April 2011. On 24 May 2011 the subject received 2nd dose of Infanrix hexa (intramuscular, right thigh), 2nd dose of Prevenar 13 (intramuscular, left thigh). On 25 May 2011, less than one day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced pneumococcal meningitis with pneumococcal sepsis, rotavirus gastroenteritis and respiratory syncytial viral infection. The events were resolved after 14 days. The subject was hospitalised for 15 days and the events were life threatening. A hospital report was provided. The subject was hospitalised from 25 May to 08 June 2011. According to the report, the subject developed sleepiness, high fever and fluid intake reduced on the day of admission. An ambulance was consulted, where the subject showed abnormal respiration, crying and stinky, green diarrhea. When admitted to hospital the subject additionally showed circulatory depression and pale lips, as well as enteritic bowel sounds. Oxygen saturation was good. After treatment with sodium chloride (NaCl) the condition improved, but worsened again in the evening, with tachypnea. Cerebrospinal fluid test showed bacterial meningitis and the subject was treated with cefotaxime (Cefotaxim) and gentamicin sulphate (Gentamycin). The subject was transferred to an intensive care unit. The next 24 hours of monitoring were uneventful. Additional treatment included dipyrone (Novalgin), paracetamol and further fluid. Cerebrospinal fluid, blood test and throat swab showed masses of Streptococcus pneumonia. Rotavirus in stool and respiratory syncytial virus (RSV) in swab were positive. Inflammatory parameters were transiently increased. The subject had mild anemia and thrombocytosis, which were considered to be triggered by infection. Additionally the subject was diagnosed with pharyngitis. On 27 May 2011 fever resolved and on the next day the subject was transferred back to a normal unit. Further course was without complications and with continuous improvement. On 08 June 2011 the subject was discharged in good general condition. No further information will be available. Company comment: Less than one day after combined vaccination with Infanrix hexa and Prevenar, this 3-month-old male subject experienced pneumococcal meningitis with sepsis. The subject recovered after 14 days of hospitalisation and parenteral antibiotherapy. 6.5.2.7.7. Meningitis viral One (1) case of Meningitis viral was received during the period and is described in Section 6.5.1 Cases with a fatal outcome. 6.5.2.7.8. Osteomyelitis One (1) case of Osteomyelitis was received during the period:  D0069814A (Germany): Osteomyelitis, Bone abscess. This case was reported by a physician and described the occurrence of osteomyelitis in a 9-week-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae CONFIDENTIAL 96 CONFIDENTIAL 144 type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 29 October 2010 the subject received the first dose of Infanrix hexa (0.5 ml, unknown). Approximately six days post vaccination with Infanrix hexa, on 04 November 2010, the subject experienced osteomyelitis. The event was reported by the subject’s father. The subject was hospitalised for 22 days from 12 November 2010 to 03 December 2010. At the time of reporting, on 21 December 2010, the outcome of the event was unspecified. Follow-up information was received on 04 January 2011 from the reporting physician. The subject has no underlying or concurrent medical conditions or other risk factors. The subject has received no previous vaccinations. On 29 October 2010 the subject received the first dose of Infanrix hexa (0.5 ml, intramuscular, right thigh). Approximately six days post vaccination with Infanrix hexa, on 04 November 2010, the subject experienced fractured femur left distal. Treatment included immobilising by plaster cast. Approximately 15 days post vaccination with Infanrix hexa, on 13 November 2010, the subject was diagnosed with osteomyelitis left at tibia metaphysic left medial with periosteal abscess. The subject was hospitalised on 12 November 2010 for surgery. Treatment included opening and draining of the abscess on 12 November 2010. At the time of follow-up reporting all events were resolved but control examinations have to be performed to exclude sequelae. The vaccination course with Infanrix hexa was discontinued. No further information will be available from the reporting physician. The same case was received on 21 July 2011 from the German regulatory authority (DE-PaulEhrlich-Institut # DE-PEI-PEI2010038778). Commpany comment: This 9-week-old male subject experienced osteomyelitis with bone abscess two weeks after 1st dose of Infanrix hexa. The subject had a left distal femur fracture 6 days post-vaccinaton and developed osteomyelitis at tibia metaphysic left medial with periosteal abscess (bone abscess) 14 days postvaccination. The patient was hospitalised and treated treated surgically. All events have been resolved and control examinations are performed to exclude sequelae 6.5.2.7.9. Pneumococcal sepsis One (1) case of Pneumococcal sepsis was received during the period (D0072024A) and is described in Section 6.5.2.7.6 Meningitis pneumococcal. 6.5.2.7.10. Salmonella sepsis One (1) case of Salmonella sepsis was received during the period (B0712429A) and is described in Section 6.5.2.6.2 Anaphylactic/Anaphylactoid reaction and Drug hypersensitivity. 6.5.2.7.11. Sepsis Four (4) cases of Sepsis were received during the period:  B0700040A (Sweden): Meningitis, Sepsis, Shock, Pneumococcal infection, Renal impairment, Hepatic function abnormal, Pyrexia, Diarrhea, Vomiting See Section 6.5.1 Cases with a fatal outcome. CONFIDENTIAL 97 CONFIDENTIAL 145  D0069502A (Germany): Oedema peripheral, Sepsis, Swelling, Erythema This case was reported by a physician via a sales representative and described the occurrence of bilateral leg swelling in a 20-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and 10 valent pneumococcal conjugate vaccine (Synflorix, GlaxoSmithKline) for prophylaxis. Concurrent medical conditions included ocular neoplasm. Concurrent medications included treatment with ketamine (Ketanest) three days prior to vaccination with Infanrix hexa and Synflorix, on 08 November 2010. Previous vaccinations had been performed by another paediatrician. On 11 November 2010 the subject received the fourth dose of Infanrix hexa (0.5 ml, intramuscular, unknown application site at left side) and the fourth dose of Synflorix (0.5 ml, intramuscular, unknown application site at right side), contralaterally. Less than one week post vaccination with Infanrix hexa and Synflorix, on an unknown date between 11 November 2010 and 18 November 2010, the subject experienced bilateral leg swelling. Approximately one day post vaccination with Infanrix hexa and Synflorix, on 12 November 2010, the subject experienced swelling and erythema (no site specified). On an unknown day in November 2010 the subject was hospitalised for two days for this event. Sepsis was suspected (possible sepsis). The subject was treated with amoxicillin trihydrate + potassium clavulanate (Amoxiclav) for sepsis. On the next day, on an unknown day in November 2010, the subject was discharged from hospital. At the time of reporting, on 19 November 2010, the outcome of the events was unspecified. Follow-up information was received on 06 December 2010 from the reporting physician. After about six days, on 17 November 2010, all events were resolved. The vaccination courses with Infanrix hexa and Synflorix were discontinued. No further information will be available. Company comment: Less than one week post vaccination with Infanrix hexa and Synflorix the 20 month-old subject experienced bilateral leg swelling and erythema. Sepsis was suspected but not confirmed. No etiological agent causing sepsis was reported. The subject recovered after hospitalization and antibiotherapy.  D0069690A (Germany): Injection site swelling, Injection site erythema, Sepsis This case was reported by a physician, via sales representative and described the occurrence of suspected sepsis in an 18-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. According to initial information, on 06 December 2010 the subject received the fourth dose of Infanrix hexa (left leg). Concurrently a dose of Synflorix was administered to the right leg. On an unspecified date within the following three days the subject developed swelling and redness at the injection site of Infanrix hexa. The reaction was the size of an adult’s palm. Otherwise the subject was fit. There was no whining or fever. The subject was treated with cetirizine hydrochloride and cefaclor. At the time of reporting the outcome of the events was unspecified. Follow-up information was received on 29 December 2010 from the reporting physician by means of a completed questionnaire: Previous vaccinations with Infanrix hexa were well tolerated. On 06 December 2010 the CONFIDENTIAL 98 CONFIDENTIAL 146 subject received the fourth dose of Infanrix hexa (intramuscular, left thigh). Concurrently a dose of Synflorix was administered contraleterally. The following day, on 07 December 2010, the subject developed swelling and redness at the injection site. The subject was treated with cetirizine hydrochloride and cefaclor (CEC) for suspected sepsis (not reported as an event, provided as indication of the treatment drug). On 10 December 2010 swelling and redness resolved. On an unspecified date in December 2010 the subject fully recovered. Company comment: Site injection complication within 3 days post-vaccination with Infanrix hexa and Synflorix. complication. Sepsis was suspected but not confirmed and no etiological agent was reportedThe event resolved after antibiotherapy.  D0072852A (Germany): Circulatory collapse, Sepsis, Shock, Crying, Pallor See Section 6.5.1 Cases with a fatal outcome. 6.5.2.7.12. Septic shock One case of Septic shock was received during the period (D0069889A) and is described in Section 6.5.2.7.6 Meningitis pneumococcal. CONFIDENTIAL 99 CONFIDENTIAL 147 6.5.2.8. Musculoskeletal and connective tissue disorders 6.5.2.8.1. Muscle spasms Eight (8) cases of Muscle spasms were received during the period. In one case, muscle spasms were associated with an hypotonic – hyporesponsive episode and in another case with hypertonia. The muscle spasms were resolved in 2/8 cases. These cases are summarised in Table 16. Table 16 Summary of cases of Muscle spasms received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0686677A 26 -Nov -10 Resolved 4 Months Male Infanrix hexa 0 Days Hypotonic -hyporesponsive episode, Screaming, Apathy, Unresponsive to stimuli, Sleep disorder, Muscle tightness, Abdominal pain, Decreased activity, Hypertonia, Ill – defined disorder, Hypotonia, Developmental delay, Muscle spasms, Restlessness, Crying Poland Abdominal pain B0695552A 21 -Jan -11 Unknown 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Hours Infantile spasms, Slow response to stimuli, Hypertonia, Staring, Tremor, Clonus, Muscle spasms, Joint hyperextension, Adenovirus test positive, Pyrexia, Crying Italy B0702855A 24 -Feb -11 Unknown 5 Months Female Infanrix hexa 0 Days Muscle spasms, Pyrexia, Escherichia urinary tract infection Greece B0720309A 19 -May -11 Unknown 2 Months Female Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) 0 Days Muscle contracture, Muscle spasms, Erythema, Staring, Heart rate increased Belgium CONFIDENTIAL 100 CONFIDENTIAL 148 B0745247A 06 -Sep -11 Resolved 20 Months Male Infanrix hexa 2 Days Crying, Muscle spasms, Injection site erythema Czech Republic D0070495A 04 -Mar -11 Unresolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 2 Days Restlessness, Muscle spasms, Insomnia, Crying Germany Functional gastrointestinal disorder D0070972A 11 -Apr -11 Unknown 2 Months Female Infanrix hexa 0 Days Muscle spasms, Underdose Germany D0072455A 19 -Aug -11 Unresolved 6 Months Male Infanrix hexa Pneumococcal vaccines (Non -GSK) 0 Days Restlessness, Pyrexia, Insomnia, Decreased appetite, Muscle spasms, Crying, Agitation, Fatigue, Rash, Vaccination complication, Herpes virus infection, Exanthema subitum Germany CONFIDENTIAL 101 CONFIDENTIAL 149 6.5.2.8.2. Soft tissue necrosis One (1) case of Soft tissue necrosis was reported during the period:  D0069239A (Germany): Soft tissue necrosis, Debridement, Incorrect route of drug administration This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2010030686) and described the occurrence of soft tissue necrosis in a 1- year-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On an unspecified date in 2010, approximately six month prior to initial reporting, the subject received unspecified dose of Infanrix hexa (unknown route, right thigh). In 2010, approximately 6 months after vaccination with Infanrix hexa, the subject experienced sterile necrosis in subcutis of thigh (soft tissue necrosis). The subject was hospitalised on 19 July 2010 for 5 days for local excision of necrotic tissue. In 2010, the events were resolved. The paediatrician considered that the events were related to vaccination with Infanrix hexa. The paediatrician stated that this was the second subject with necrosis in his praxis and he had increased rates of swelling post vaccination since approximately two years. According to the surgery report, the subject had abscess forming fat tissue necrosis subcutaneous on right thigh after an older subcutaneous injection (intramuscular formulation administered by other route). This was surgically removed on 20 July 2010, without any complications. The wound was treated with gentamicin sulphate (Sulmycin). When the subject was discharged, the wound was not irritated. No further information will be available. Company comment: Sterile soft tissue necrosis of the thigh in a 1-year-old male subject approximately 6 months after vaccination with Infanrix hexa. The complication recovered after adequate surgery. The surgery report states possible relation to incorrect route of drug administration (intramuscular formulation administered subcutaneously). 6.5.2.9. Nervous system disorders 6.5.2.9.1. Cerebral atrophy and Cerebral ischemia Three (3) cases of Cerebral atrophy/Cerebral ischemia were reported during the period:  B0686639A (Italy): Epilepsy, Cerebral ischaemia, Partial seizures This case was reported by a physician via a regulatory authority (IT-Agenzia Italiana del Farmaco # 128180) and described the occurrence of epileptic seizure in a 3- month-old female subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Concurrent medications included Bisolvon. On 8 November 2010, the subject received unspecified dose of Infanrix hexa (intramuscular, injection site unknown). On 18 November 2010, 10 days after vaccination with Infanrix hexa, the subject experienced epileptic seizure. The subject was hospitalised where cardiac monitoring CONFIDENTIAL 102 CONFIDENTIAL 150 was made. Relevant tests were performed: electroencephalogram showed epileptiform abnormalities in the right hemisphere and nuclear magnetic resonance with contrast liquid showed ischemic injury due to hypoxia in the right hemisphere. The subject was treated with anti-inflammatory (Anti inflammatory) and anticonvulsant (Anticonvulsants). At the time of reporting, the outcome of the event was unspecified. The regulatory authority reported that the event was possibly related to vaccination with Infanrix hexa. Follow-up information received on 2 December 2010: The vaccination performed on 8 November 2010, was 1st dose of Infanrix hexa. Nuclear magnetic resonnance resulted as hypoxic ischemic lesion in the right hemisphere. At the time of follow-up, the subject was still under control, and other clinical exams were planned little time later. Follow-up information received on 6 June 2011: On 1st June, at the clinical control, are no longer present motor focal seizures. The subject made her anticonvulsivant therapy. Company comment: This 3-month-old female subject experienced partial seizures 10 days after 1st vaccination with Infanrix hexa. Complementary exams revealed a hypoxic ischemic lesion in the right hemisphere. The time sequence before partial seizures made the possible relationship to the product dubious.  B0716780A (Italy): Cardiac arrest, Multi-organ failure, Pneumonia aspiration, Cerebral ischaemia, Sudden infant death syndrome, Unresponsive to stimuli, Peripheral coldness, Staring, Musculoskeletal stiffness, Pyrexia, Somnolence. See Section 6.5.1 Cases with a Fatal Outcome.  D0070024A (Germany): Infantile spasms, Developmental delay, Posture abnormal, Restlessness, Crying, Hypotonia, Microcephaly, Cerebral atrophy, Bone marrow failure, Vomiting, Dehydration, Hypokalaemia, Pancytopenia. This case was reported by a public department for welfare and social affairs and described the occurrence of West’s syndrome in a 4-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 8 May 2009 and 5 June 2009 the subject received 1st dose and 2nd dose of Infanrix hexa (unknown route and application site). The drug was reported as Infanrix, but the lot numbers clearly identified Infanrix hexa. At an unspecified time after vaccination with Infanrix hexa, the subject experienced convulsion disorder and developmental delay. It was unclear after which vaccination the events appeared. This case was assessed as medically serious by GSK. At the time of reporting the outcome of the events was unspecified. Co-suspect vaccination included pneumococcal vaccine (non-GSK) (Prevenar, Wyeth). On 5 June 2009 the subject received 2nd dose of Infanrix hexa (unknown route and application site), 2nd dose of Prevenar (unknown route and application site). On 09 June 2009 the subject suffered a bruise on forehead from a clay bowel falling down. Neurologic test was normal. On 17 July 2009 the subject received 3rd dose of Infanrix hexa (unknown route and application site), 3rd dose of Prevenar (unknown route and application site). Examination before vaccination was normal. The subject developed normally according to the parents. On 24 July 2009, 7 days after vaccination with Infanrix hexa and Prevenar, the parents reported about trunk bowing and feared about imperforate anus or faecal concretion. The subject was CONFIDENTIAL 103 CONFIDENTIAL 151 hospitalised on 30 July 2009. The events were disabling. The subject was diagnosed with West’s syndrome, severe developmental delay, axial hypotonia and microcephaly. During pregnancy the mother had vena-cava syndrome with a single syncope. The subject was the first and only child and was born spontaneously in 40 weeks of gestation with a weight of 3570 g, a size of 56 cm and an APGAR score of 9/10/10. The subject had a first convulsion on the day of second vaccination, on 05 June 2009 in the evening. On 30 July 2009 the subject was hospitalised with West’s syndrome. Electroencephalogram (EEG) showed hypsarrhythmia. Magnetic resonance tomogram (MRT) in August 2009 was normal. The subject was treated with clonazepam, phenobarbitone (Phenobarbital), pyridoxine hydrochloride (Vitamin B6) and folic acid, but without effect. Under treatment with sulthiame (Sultiame) and levetiracetam the convulsions improved in frequency and severity. After treatment with tetracosactrin acetate (Synacthen) and prednisolone (Prednisolon) hypsarrhythmia ceased. The subject finally received levetiracetam and valproate. After discharge in August 2009 the subject was free from convulsions, but they recurred in September 2009. Vigabatrin was given. At the age of 7 months the subject’s development was one months behind. From 30 November 2009 to 03 February 2010 the subject was treated in a specialised centre for epilepsy. In December 2009 and January 2010 the EEG results showed epileptic activity, especially posterior at both sides. Treatment with topiramate was started. Convulsions resolved under cyclic treatment with dexamethasone and omeprazole. In June 2010, at the age of 17 months, the subject had a developmental age of 7 months, with statomotor and psychomental development delay. In August 2010 the subject was hospitalised with severe vomiting (not keeping any nutrition) and exsiccation. Laboratory tests showed hypokalemia and pancytopenia. All medication was stopped. Treatment with phenobarbitone (Luminal) and antibiotics was started. MRT showed dilated subarachnoid spaces in terms of cerebral atrophy. After bone marrow puncture in another hospital drug induced bone marrow depression was suspected. This resolved in further course and blood test normalised. The last examination report was from 30 November 2010, where the physician stated that EEG again showed increased generalised epileptic activity. No further information will be available. Company comment: This 4-month-old female had a convulsion less than 1 day after 2nd dose of Infanrix hexa and Prevenar 55 days post-vaccination, she was diagnosed with West’s syndrome severe developmental delay, axial hypotonia and microcephaly. The time sequence of signs apparition remained unclear but there is a medical anamnesis of neonatal convulsion unrelated to vaccination. 6.5.2.9.2. Seizures and Epilepsy Seizures/Convulsions During the period, 118 individual case reports were received including one of the following MedDRA preferred terms: Clonic convulsion (n=4), Clonus (n=8), Convulsion (53), Febrile convulsion (n=441 ), Grand mal convulsion (n=15), 1 Including two cases received prior to this PSUR period but not included in a previous PSUR (B0674885A and B0631888A). CONFIDENTIAL 104 CONFIDENTIAL 152 Myoclonus (n=10), Partial seizures (n=3), Seizure like phenomena (2), Tonic clonic movements (2) and Tonic convulsion (n=1). In some instances more than one MedDRA preferred term was included to describe the same event. These cases are summarised in Table 17. Table 17 Summary information for complete ‘Seizures/Convulsion’ data set (n=118) Patient age (n=113) Range months 2-72 Median months 9.19 Patient gender (n=111) Male n 58 Female n 53 Report type Spontaneous n 118 Type of convulsion Febrile* n 74 Afebrile n 44 Time to onset of event (n=114) Range days 0-27 Number < 1 day n 105 Outcome (n=117) Resolved n 78 Improved n 7 Fatal n 2 Unresolved n 8 Unknown n 22 Concomitant vaccine(s) administered n 13 * Based on the presence of the following preferred terms in a seizure case:  Febrile convulsion OR  Convulsion and Pyrexia in the same case. Indeed some febrile seizures were described with the MedDRA PTs ‘Convulsion’ and ‘Pyrexia’ rather than with the PT ‘Febrile convulsion’. Epilepsy During the period, 19 individual case reports were received including at least one of the following MedDRA preferred terms: Complex partial seizures (1), Epilepsy (9), Infantile spasms (6), Petit Mal Epilepsy (3) and Status epilepticus (2). These cases are summarized in Table 18, Table 19, Table 20 and Table 21. Table 18 Summary information for complete ‘Epilepsy’ data set (n=19) Patient age (n=19) Range months 2-18 Median months 6.6 Patient gender (n=18) Male n 9 Female n 9 Report type Spontaneous n 19 Time to onset of event (n=19) Range Days 0-45 Number < 1 day n 12 Outcome (n=19) Resolved n 5 Improved n 1 Unresolved n 6 Unknown n 7 Concomitant vaccine(s) administered n 3 CONFIDENTIAL 105 CONFIDENTIAL 153 Table 19 Summary of cases of Epilepsy and Petit mal epilepsy received during the period (n=11) Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0686208A 25 -Nov -10 Unknown 3 Months Infanrix hexa 0 Months Encephalitis, Epilepsy Italy B0686639A 26 -Nov -10 Unknown 3 Months Female Infanrix hexa Bisolvon 10 Days Epilepsy, Cerebral ischaemia, Partial seizures Italy B0700168A 16 -Feb -11 Unknown 5 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Epilepsy, Petit mal epilepsy, Staring, Clonus, Dyskinesia, Pyrexia Italy B0713436A 11 -Apr -11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Petit mal epilepsy, Blepharospasm, Dyskinesia Italy B0720048A 13 -May -11 Unresolved 6 Months Female Infanrix hexa, Synflorix 1 Days Epilepsy, Infantile spasms, Tearfulness, Dyskinesia Czech Republic B0737600A 04 -Aug -11 Unknown 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 12 Days Epilepsy, Convulsion Latvia D0069341A 05 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Hours Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed Germany Atrial septal defect CONFIDENTIAL 106 CONFIDENTIAL 154 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069889A 10 -Jan -11 Unresolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 3 Days Meningitis pneumococcal, Grand mal convulsion, Epilepsy, Hydrocephalus, Subdural hygroma, Subdural empyema, Anaemia, Generalised oedema, Ileus paralytic, Conjunctivitis, Septic shock, Pneumonia primary atypical, Neurosurgery, Pyrexia, Abdominal distension Germany Premature baby, Pneumonia bacterial, Conjunctivitis infective D0070286A 12 -Feb -11 Unknown 1 Years Female Priorix Tetra, Infanrix hexa 6 Days Petit mal epilepsy, Staring, Dyskinesia Germany D0072920A 04 -Oct -11 Unknown 15 Months Male Infanrix hexa, Synflorix 6 Hours Febrile convulsion, Epilepsy, Rash, Pyrexia, Dyskinesia, Salivary hypersecretion, Eye movement disorder, Somnolence, Pallor, Tachycardia, Injection site erythema, Injection site swelling Germany R0014765A 30 -Nov -10 Improved 4 Months Male Meningitis ACWY tetanus toxoid vaccine, Infanrix hexa, Synflorix 7 Days Epilepsy Spain CONFIDENTIAL 107 CONFIDENTIAL 155 Table 20 Summary of cases of Status epilepticus received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0710868A 29 -Mar -11 Resolved 11 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Status epilepticus, Loss of consciousness, Apnoea, Convulsion, Vomiting, Skin warm, Staring, Hypotonia, Hyporesponsive to stimuli, Crying, Erythema, Upper respiratory tract infection, Pyrexia, Hypertonia, Postictal state, Malaise, Listless Netherlands D0070499A 04 -Mar -11 Resolved 18 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Synflorix 1 Days Convulsion, Endotracheal intubation, Status epilepticus, Pyrexia, Febrile convulsion Germany CONFIDENTIAL 108 CONFIDENTIAL 156 Table 21 Summary of cases of Complex partial seizures and Infantils spasms Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0684471A 10 -Nov -10 Unresolved 7 Months Female Infanrix hexa Infanrix hexa 2 Months Infantile spasms Italy B0695552A 21 -Jan -11 Unknown 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Hours Infantile spasms, Slow response to stimuli, Hypertonia, Staring, Tremor, Clonus, Muscle spasms, Joint hyperextension, Adenovirus test positive, Pyrexia, Crying Italy B0720048A 13 -May -11 Unresolved 6 Months Female Infanrix hexa, Synflorix 1 Days Epilepsy, Infantile spasms, Tearfulness, Dyskinesia Czech Republic B0728516A 24 -Jun -11 Resolved 12 Months Male Infanrix hexa, MMR vaccine (Non -GSK) 1 Days Febrile convulsion, Loss of consciousness, Tremor, Complex partial seizures, Grand mal convulsion, Pyrexia Italy D0069378A 09 -Nov -10 Unresolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 45 Days Infantile spasms, Cerebral disorder Germany CONFIDENTIAL 109 CONFIDENTIAL 157 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0070024A 19 -Jan -11 Unknown 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa 0 Days Infantile spasms, Developmental delay, Posture abnormal, Restlessness, Crying, Hypotonia, Microcephaly, Cerebral atrophy, Bone marrow failure, Vomiting, Dehydration, Hypokalaemia, Pancytopenia Germany Contusion, Ingrowing nail D0071841A 27 -Jun -11 Unresolved 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Encephalopathy, Infantile spasms, Lennox -Gastaut syndrome, Dyskinesia, Developmental delay, Eye movement disorder, Motor dysfunction, Posture abnormal, Fatigue, Hyperhidrosis, Crying, Pallor, Diarrhoea, Musculoskeletal stiffness, Depressed level of consci Germany Umbilical cord around neck, Bronchitis, Pharyngitis, Rhinitis, Klebsiella infection, Hypotonia CONFIDENTIAL 110 CONFIDENTIAL 158 6.5.2.9.3. Demyelination and Demyelinating polyneuropathy Two (2) cases of Demyelination/Demyelinating polyneuropathy were received during the period:  B0689246A (Saudia Arabia): Demyelination, Extrapyramidal disorder, Neurological symptom, Irritability, Crying, Pyrexia, Strabismus. This case was reported by a physician via a sales representative and described the occurrence of demyelination in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. On an unspecified date the subject received unspecified dose of Infanrix hexa (intramuscular, unknown injection site), unspecified dose of Prevenar (intramuscular, unknown injection site). Lot numbers not provided. The same day at night, less than one day after vaccination with Infanrix hexa and Prevenar, the subject experienced crying and fever. The 3rd day after vaccination, the baby showed irritability and acute neurological symptoms. The subject was hospitalised and the physician considered the events were disabling. An NMR was performed and showed pigmentations in the brain but no sign of infection. The subject was treated with azithromycin (Zitromax), dimethindene maleate (Fenistil) and antipyretic (Antipyretics). At the time of reporting, fever and crying were resolved but the other events were improved. The physician considered the events were possibly related to vaccination with Infanrix hexa and Prevenar. Follow up information received on 26 December 2010: Concurrent medications included Acyclovir (Zovirax) and Corticosteroid (Corticosteroids) for 3 weeks. In November 2010, the subject received 2nd dose of Infanrix hexa and 2nd dose of Prevenar. In November 2010, the subject experienced extra pyramidal symptoms, neurological symptom, irritability, crying, fever and eye squint. Relevant tests were performed (CT brain, CSF, CBC, EEG) but the results were not provided. An NMR was performed and showed patches of demyelination in the brain but no sign of infection. The final diagnosis was post vaccination acute demyelination. At the time of reporting, the events were improved. No additional information has been received. The case has been closed on 4 August 2011. Company comment: This 4-month-old male subject experienced post vaccination acute demyelination (diagnosed at MRI) with acute neurological symptoms (extra pyramidal signs, irritability, crying, fever and eye squint) starting less than one day after 2nd dose of Infanrix hexa and Prevenar  D0069554A (Germany): Guillain-Barre syndrome, Congenital neuropathy, Demyelinating polyneuropathy, Hip deformity, Foot deformity, Motor developmental delay. See Section 6.5.2.9.6 Guillain-Barré syndrome. CONFIDENTIAL 111 CONFIDENTIAL 159 6.5.2.9.4. Depressed level of consciousness Twenty four (24) cases of Depressed level of consciousness were reported during the period and are summarised in Table 22. Table 22 Summary of cases of Depressed level of consciousness received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0683333A 05 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Presyncope, Loss of consciousness, Depressed level of consciousness, Staring, Hypotonia, Pallor, Crying, Pyrexia, Pain, Mental impairment, Vomiting, Muscle contractions involuntary, Myoclonus, Abdominal abscess, Irritability, Hypotonic – hyporesponsive epis Netherlands Gastrooesop hageal reflux disease, Choking B0692285A 06 -Jan -11 Unknown 21 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Encephalitic infection, Convulsion, Dyskinesia, Fatigue, Pyrexia, Hypertonia, Depressed level of consciousness, Electroencephalogram abnormal France CONFIDENTIAL 112 CONFIDENTIAL 160 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0701374A 18 -Feb -11 Resolved 2 Months Male Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non – GSK) Rotavirus vaccine, Pneumococcal vaccines (Non – GSK) 3 Hours Hypotonic -hyporesponsive episode, Loss of consciousness, Depressed level of consciousness, Unresponsive to stimuli, Cyanosis, Cough, Ill -defined disorder, Fatigue, Adverse event, Vomiting, Eyelid disorder, Crying, Somnolence Switzerland B0707035A 15 -Mar -11 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Unknown Depressed level of consciousness, Crying, Pyrexia, Injection site inflammation, Injection site pain, Insomnia, Nasopharyngitis Netherlands B0712012A 04 -Apr -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Depressed level of consciousness, Skin warm, Staring, Hypotonia, Respiration abnormal, Crying, Pyrexia, Injection site pain Netherlands B0712712A 05 -Apr -11 Resolved 13 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Loss of consciousness, Depressed level of consciousness, Convulsion, Gaze palsy, Respiration abnormal, Pallor, Hypotonia, Drooling, Cyanosis, Pyrexia, Vomiting Netherlands B0712989A 08 -Apr -11 Resolved 3 Months Male Infanrix hexa 2 Minutes Depressed level of consciousness, Pallor, Crying, Somnolence, Malaise Netherlands CONFIDENTIAL 113 CONFIDENTIAL 161 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0717794A 06 -May -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 36 Hours Loss of consciousness, Apnoea, Depressed level of consciousness, Gaze palsy, Pallor, Cyanosis, Hypotonia, Peripheral coldness, Pyrexia Netherlands B0719423A 16 -May -11 Resolved 9 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Depressed level of consciousness, Inflammation, Pain, Injected limb mobility decreased, Pyrexia, Crying Netherlands B0727317A 17 -Jun -11 Unknown 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 2 Days Depressed level of consciousness, Hypotonic – hyporesponsive episode, Pallor, Ill -defined disorder, Feeling abnormal, Pyrexia Netherlands B0732346A 11 -Jul -11 Unknown 2 Months Female Infanrix hexa, Synflorix 4 Hours Depressed level of consciousness, Pyrexia, Somnolence Netherlands B0741007A 16 -Aug -11 Unresolved 10 Months Female Infanrix hexa Immediate Respiratory arrest, Depressed level of consciousness, Breath holding, Crying, Eye movement disorder, Skin discolouration, Pallor Netherlands Caesarean section B0746088A 08 -Sep -11 Improved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 3 Seconds Depressed level of consciousness, Crying, Injection site inflammation, Pallor, Hypotonia, Oligodipsia, Somnolence, Respiratory disorder Netherlands CONFIDENTIAL 114 CONFIDENTIAL 162 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0750040A 20 -Sep -11 Resolved 2 Months Female Infanrix hexa, Synflorix 7 Hours Presyncope, Febrile convulsion, Depressed level of consciousness, Hypertonia, Myoclonus, Pallor, Pyrexia, Musculoskeletal stiffness Netherlands B0755401A 07 -Oct -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Depressed level of consciousness, Pyrexia, Inflammation, Pain, Vomiting, Somnolence, Diarrhoea, Staring Netherland s B0756437A 18 -Oct -11 Resolved 2 Months Male Infanrix hexa, Synflorix 5 Minutes Depressed level of consciousness, Staring, Pallor Netherlands D0069325A 04 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 8 Hours Depressed level of consciousness, Hypotonic – hyporesponsive episode, Pallor, Fatigue, Eye movement disorder Germany D0069341A 05 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Hours Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed Germany Atrial septal defect CONFIDENTIAL 115 CONFIDENTIAL 163 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071099A 19 -Apr -11 Resolved 11 Weeks Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Hypotonic -hyporesponsive episode, Body temperature increased, Crying, Asthenia, Pallor, Depressed level of consciousness, Pharyngeal erythema Germany D0071366A 13 -May -11 Unknown 12 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Convulsion, Depressed level of consciousness, Gaze palsy, Hypochromic anaemia, Pyrexia, Injection site erythema, Musculoskeletal stiffness, Iron deficiency Germany D0071441A 19 – May -11 Improved 15 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Convulsion, Depressed level of consciousness, Staring, Pyrexia, Asthenia, Upper respiratory tract infection, Vaccination complication Germany D0071549A 27 -May -11 Unresolved 4 Months Male Synflorix, Infanrix hexa 0 Days Encephalitis, Bronchitis, Lactic acidosis, Hyperglycaemia, Convulsion, Injection site induration, Pyrexia, Somnolence, Hypotonia, Depressed level of consciousness, Respiration abnormal, Cough, Pallor, Lip haematoma, General physical health deterioration, Germany Pneumonia respiratory syncytial viral, Respiratory tract infection CONFIDENTIAL 116 CONFIDENTIAL 164 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071841A 27 -Jun -11 Unresolved 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Encephalopathy, Infantile spasms, Lennox-Gastaut syndrome, Dyskinesia, Developmental delay, Eye movement disorder, Motor dysfunction, Posture abnormal, Fatigue, Hyperhidrosis, Crying, Pallor, Diarrhoea, Musculoskeletal stiffness, Depressed level of consci Germany Umbilical cord around neck, Bronchitis, Pharyngitis, Rhinitis, Klebsiella infection, Hypotonia D0073004A 11 -Oct -11 Unknown 16 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 48 Hours Convulsion, Pallor, Gaze palsy, Depressed level of consciousness, Joint hyperextension Germany CONFIDENTIAL 117 CONFIDENTIAL 165 6.5.2.9.5. Encephalitis, Encephalopathy and Encephalic infection Five (5) cases of Encephalitis/Encephalopathy/Encephalic infection were received during the period:  B0686208A (Italy): Encephalitis, Epilepsy. This case was reported by a physician via a sales representative and described the occurrence of possible encephalitis in a 3-month-old subject of unspecified gender who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Subject’s medical history was negative. On 8 November 2010 the subject received 2nd dose of Infanrix hexa (unknown), lot number not provided. Less than one month after vaccination with Infanrix hexa, the subject experienced possible encephalitis and epileptic seizure. The subject was hospitalised. At the time of reporting the outcome of the events was unspecified. Company comment: A 3-month-old subject experienced encephalopathy less than one month after 2nd dose of Infanrix hexa. Due to a lack of data, this case cannot be medically assessed.  D0070015A (Germany): Ataxia, Balance disorder, Encephalitis, Gait disturbance, Pyrexia, Upper respiratory tract infection, Otitis media acute, Cerebellar ataxia. This case was reported by a German regulatory authority (DE-Paul-Ehrlich-Institut # DE-PEI-PEI2010038217) and described the occurrence of ataxia in a 16-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). Past medical history was not provided. Previous vaccinations including three doses of combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and three doses of 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma), given on 28 September 2009, 04 January 2010 and 20 April 2010, were well tolerated. On 09 December 2010 the subject received the fourth dose of Infanrix hexa (0.5 ml, subcutaneous, right thigh) and the fourth dose of Prevenar 13 (0.5 ml, subcutaneous, left thigh), contralaterally. Approximately one day post vaccination with Infanrix hexa and Prevenar 13, on 10 December 2010, the subject experienced ataxia and tendency to fall towards the right side (balance disorder). The report suspected cerebellitis and/or encephalitis. The subject was hospitalised for an unknown period of time. In hospital cerebrospinal fluid (CSF) examination, electroencephalogram (EEG), cranial magnetic resonance tomogram (cMRT) and metabolic diagnoses were performed to confirm the events but the result of these examinations have not been provided. At the time of initial reporting, on 14 December 2010, the events were unresolved. The vaccination courses with Infanrix hexa and Prevenar 13 were discontinued. The vaccine was reported as diphtheria and tetanus toxoids and acellular pertussis vaccine (Infanrix, CONFIDENTIAL 118 CONFIDENTIAL 166 GlaxoSmithKline), but according to lot number the subject was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline). Less than one day post vaccination with Infanrix hexa and Prevenar 13, on 09 December 2010, the subject experienced high fever of up to 39 degC. The following days the subject only showed subfebrile temperature of 37.5 degC. Approximately one day post vaccination with Infanrix hexa and Prevenar 13, on 10 December 2010, the subject experienced conspicuous staggering which improved over the next days. On 13 December 2010 the subject experienced conspicuous gait disturbance and was hospitalised for this event. Examinations, performed on 10 December 2010, showed upper respiratory tract infection. Cranial computed tomogram (CCT) was normal without pathogenic changes. Cerebrospinal fluid (CSF) showed increased CSF protein. CSF cell count could not be determined due to bloody and in parts coagulated CSF sample. Infection diagnostic of CSF were negative; CSF and blood cultures were sterile. Metabolic diagnostics were normal. Cranial magnetic resonance tomogram (cMRT) was normal. Electroencephalogram (EEG) showed beta superimposition due to medication and a conspicuous phase with a short group of irregular spike-slow-wave-complexes left frontocentral, control EEG was recommended. During course of hospitalisation the subject recovered and ataxia was clinically completely improved. During course of hospitalisation the subject showed high fever due to underlying respiratory tract infection. Regular laboratory examinations showed normal inflammatory parameters. Therefore the subject needed no treatment with antibiotics. The hospital physician(s) considered either post infectious cerebellar ataxia due to underlying respiratory tract infection, postvaccinal cerebellitis due to time context or otogenic ataxia associated with serous otitis media both sides (right more than left). On 18 December 2010 the subject was discharged from hospital in stable general condition against medical advice. No further information was available. At the time of follow-up reporting, on 21 December 2010, the events were resolved. Company comment: This 16-month-old male subject experienced post infectious cerebellar ataxia due to underlying respiratory tract infection in the course of Infanrix hexa vaccination. A postvaccinal cerebellitis was compatible with the time sequence (one day post-vaccination with Infanrix hexa and Prevenar) but the ataxia was associated with serous otitis media both sides and finally recovered.  D0071549A (Germany): Encephalitis, Bronchitis, Lactic acidosis, Hyperglycaemia, Convulsion, Injection site induration, Pyrexia, Somnolence, Hypotonia, Depressed level of consciousness, Respiration abnormal, Cough, Pallor, Lip haematoma, General physical health deterioration, This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011015875) and described the occurrence of viral meningoencephalitis in a 4-month-old male subject who was vaccinated with 10 valent pneumococcal conjugate vaccine (Synflorix, GlaxoSmithKline), combined diphtheria, tetanusacellular pertussis, hepatitis B and inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa) for prophylaxis. Former vaccinations included Synflorix on 04 March 2011 (same lot number), which was well tolerated. On 7 April 2011 the subject received 2nd dose of Synflorix (unknown route, right CONFIDENTIAL 119 CONFIDENTIAL 167 thigh), 1st dose of Infanrix hexa (unknown route, left thigh). On 7 April 2011, less than one day after vaccination with Infanrix hexa and Synflorix, the subject experienced injection site induration. In the evening the subject had fever. This had resolved the next day and the subject was normal. On 10 April 2011 the subject developed somnolence. The subject was hospitalised for 25 days and the events were life threatening. The subject was diagnosed with viral meningoencephalitis. On 06 May 2011 the events were still unresolved. A hospital report was provided. According to this, the subject’s medical history included respiratory syncytial virus pneumonia in January 2011. Since then there were recurrent respiratory infections. When the father wanted to give him the second baby bottle that morning, he found the subject with flaccid muscle tone and nonresponsive (could not be woken up), with rattling respiration. The subject had been lying at the side due to mild cough, but the face was not covered. When admitted, the subject was in reduced and instable general condition, with moaning, snapping breath, flaccid muscle tone, pale, nonresponsive, without reaction to pain stimuli and had prolonged recapillarisation time. There was an extended hematoma at the lip at the right, but no other signs for injury. The subject had severe pulmonary obstruction (obstructive bronchitis diagnosed), lactic acidosis and hyperglycemia. First treatment included fluid substitution. Lactic acidosis quickly normalised. Blood glucose normalised on the second day and in further course all controls of lactate, blood glucose, blood gases and metabolic screening were normal. The subject was cardio-respiratory stable. Because of suspected encephalitis treatment with ampicillin trihydrate (Ampicillin), gentamicin sulphate (Gentamicin), cefotaxime (Cefotaxim) and acyclovir (Aciclovir) was started. Imaging diagnostics and electroencephalogram (EEG) confirmed the diagnosis of meningoencephalitis. As cerebrospinal fluid test showed 41 lymphocytic cells and respiratory infection, a viral genesis was suspected. After confirmation of negative bacteriological results, antibiotic treatment was stopped after three days. Aciclovir was continued for three weeks. On the second day the subject developed cerebral seizure and was treated with phenobarbitone (Phenobarbital). In further course there were no convulsions, but daily electroencephalogram (EEG) showed epileptic potentials and general changes in terms of retardation. Before discharge, EEG was still pathologic with missing sleeping structure and discrete multifocal irritability, but without seizure potentials. The subject was discharged with improved general condition, but still abnormal EEG and multiple neurologic abnormalities, including decreased spontaneous motor movement, frequent fisting, missing head control, missing active and targeted movements and no active sounding. Company comment: This is a case of viral meningoencephalitis in a 4-month-old male subject. First symptoms occured 3 days post vaccination with Infanrix hexa and Synflorix. The subject suffered from multiple neurologic sequellae. The hospital physician did not consider that the events were a reaction to vaccination.  B0692285A (France): Encephalitic infection, Convulsion, Dyskinesia, Fatigue, Pyrexia, Hypertonia, Depressed level of consciousness, Electroencephalogram abnormal This case was reported by the French regulatory authority (AF SSPS reference LL20100605) and described the occurrence of post infectious encephalitis in a 21- CONFIDENTIAL 120 CONFIDENTIAL 168 month-old female subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (Prevenar, non-gsk) for prophylaxis. Medical condition was unspecified. On 08 December 2010, the subject received unspecified doses of Infanrix hexa (batch, route and injection site unknown) and of Prevenar (batch, route and injection site unknown). The subject experienced fever. On 09 December 2010, the subject was very tired and slept a lot. On 10 December 2010, the subject presented with convulsive status resistant to diazepam (Valium) and phenytoin (Dilantin) but effectively treated by midazolam hydrochloride (Hypnovel). Since that date, convulsion crisis recurred with abnormal movements, as pedaling, and hypertonia associated with a loss of contact (coded decreased level of consciousness). HSV1, HSV2, VZV, Epstein Barr virus and cytomegalovirus tests were negative. On 11 December 2010, an abnormal electroencephalogram was recorded with a very slow down line with a slight right hemispheric predominance without focusing suggestive of encephalitis. On 13 December 2010, HSV test was negative. Stool analysis revealed presence of campylobacter jejunii. Physicians concluded to post infectious encephalitis. The subject was hospitalised. At the time of reporting, the outcome of the events was unknown. Company comment: Post-infectious encephalitis (campylobacter jejuni) in a 21- month-old female subject. Intermittend convulsive crises starting 2 days after vaccination with Infanrix hexa and Prevenar. According to AFSSaPS, the causal relationship between Infanrix hexa and Prevenar and the reported events is dubious.  D0071841A (Germany): Encephalopathy, Infantile spasms, Lennox-Gastaut syndrome, Dyskinesia, Developmental delay, Eye movement disorder, Motor dysfunction, Posture abnormal, Fatigue, Hyperhidrosis, Crying, Pallor, Diarrhoea, Musculoskeletal stiffness, Depressed level of consciousness. This case was reported by a physician and described the occurrence of epileptic encephalopathy in a 4-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. No epilepsy was known in the family. Co-suspect vaccination included pneumococcal vaccine (non-GSK) (Prevenar, Pfizer). On 9 February 2011 the subject received 1st dose of Infanrix hexa (unknown route and application site), 1st dose of Prevenar (unknown route and application site). In the end of February or beginning of March 2011, less than one month after vaccination with Infanrix hexa and Prevenar, the subject experienced decreased contact activity, eyes rolling, smacking and motor dysfunction. The subject was hospitalised and diagnosed with epileptic encephalopathy with regressive dyskinetic movement disorder and myocloni. Electroencephalogram (EEG) showed potentials typical for epilepsy. Magnetic resonance tomogram (MRT) of head was without pathologic findings. The family consulted another hospital, where the subject was diagnosed with West syndrome / Lennox Gastaut syndrome. The hospital report was not available to the reporting physician. There were no concurrent medical conditions or concurrent medications (Prevenar was not mentioned in the case follow-up). Infanrix hexa was given intramuscular, unknown gluteal. The subject developed convulsive disease / CONFIDENTIAL 121 CONFIDENTIAL 169 West syndrome. The subject was hospitalised and the physician considered the events were disabling. The vaccination course with Infanrix hexa was discontinued. Follow-up information was received on 05 August 2011 via the German regulatory authority (PEI). The subject was born with umbilical cord around neck, but APGAR score was 10. In the evening after vaccination with Infanrix hexa and Prevenar, the subject could not keep the head straight (head posture abnormal) and had rolling eyes and restless head. The next day the subject developed sweating, tiredness and after three days high-pitched crying and regression of development (loss of known skills, speech and body control). In second week the subject was twitching and developed West syndrome. Medical stabilisation was difficult. At last (in July 2011), the subject was treated with sultiam (Ospolot). The subject had developed well until vaccination. Starting in the evening after vaccination and throughout the next three weeks, the subject developed problems holding the head with waggling the head, tiredness, pallor, diarrhea, sweating, stiff neck, was not responsive, stopped laughing, became more and more stiff, with high-pitched crying, twitching, headache and abdominal pain. The subject was hospitalised from 07 to 18 March 2011, 30 March to 09 April 2011, 16 to 18 May 2011 and 18 May to 10 June 2011. The hospital reports stated the following. The subject had two healthy siblings. After normal pregnancy, the subject was born spontaneously with a weight of 4040 g. Newborn screening and childhood examinations U1 to U3 were normal. On 31 December 2010 the subject had bronchitis, pharyngitis and purulent rhinitis. High amounts of Klebsiella pneumoniae were found in nose swab. U4 showed trunk hypotonia and physiotherapy was prescribed. On the same day vaccination was administered. After vaccination the subject’s development was regressive, with less contact, tiredness, not responsive, rolling eyes, no sounding, loss of skills. When first hospitalised, the subject had hypotonia and movement disorder, but no infection, fever or diarrhea. Diagnoses included epileptic encephalopathy with developmental regression, West syndrome, dyskinetic movement disorder and muscular hypotonia. Electroencephalogram (EEG) was pathologic with hypsarrhythmia. Several convulsions were observed in hospital. Metabolic tests were normal, except for mildly increased methylmalonic acid in urine. Tests for amino acids in urine and plasma, acylcarnitin pattern in blood and lysosomal enzymes excluded GM1/2 gangliosidosis, CLN1/2 and Morbus Krabbe and showed no signs for metabolic diseases. Glutamin in plasma was mildly increased. Echocardiogram showed no cardiac hypertrophy. Treatment with vigabatrin (Sabril) was without effect and stopped by the parents without dose reduction. Treatment with pyridoxine hydrochloride (Vitamin B6) and calcium folinate (Folinic acid) was without effect. The parents started homeopathic treatment and quantum medicine with diverting harmful substances. During these measures harmful germs were reported, including lactobacillus acidophilus, lamblia, fungi, pseudomonas aeruginosa and multiple diseases, against which vaccination was possible, like Haemophilus influenzae. The parents refused medical treatment, because the disease had been caused by vaccination and anticonvulsive treatment had not been good for the child, causing constipation, which had to be removed with treatment for “gastritis” and “reflux” by a non-medical practitioner. The hospital physician strongly advised to start medical anticonvulsive treatment. After health care for the subject had been taken over by a youth welfare office and EEG was highly pathologic, treatment with steroids was started. This was followed by sulthiame (Ospolot). Timely relation to vaccination CONFIDENTIAL 122 CONFIDENTIAL 170 was clear, but causal relation could not be assessed. Alternative causes were viral encephalitis (Cocksackie virus antibody found, which could also be maternal). A paediatrician was consulted for second assessment. The paediatrician had examined the subject on 31 December 2010 due to bacterial airways infection. At that time there were no neurologic symptoms. During examination on 22 March 2011, the subject was highly disabled, with disturbed perception, no reaction to stimuli, no contact to persons and extremely low muscle tone. The physician considered encephalitis most likely. Mercury intoxication, as suspected by the parents, was excluded. Company comment: This 4-month-old female subject was diagnosed with West Syndrome/ Lennox-Gastaut syndrome less than one month after 1st dose of Infanrix hexa and Prevenar. Causal relationship to vaccination could not be formerly assessed and other etiologies were considered (metabolic, viral encephalitis). 6.5.2.9.6. Guillain-Barré syndrome Two (2) cases of Guillain-Barré syndrome were received during the period:  B0691863A (Italy): Guillain-Barre syndrome, Neuropathy peripheral, Pyrexia, General physical health deterioration, Restlessness, Asthma, Decreased appetite, Gait disturbance, Dysstasia, Nuchal rigidity, Hyperaemia, Dysphonia, Hyporeflexia, Hypotonia, Asthenia This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 130966) and described the occurrence of Guillain Barre syndrome in a 15-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevnar) for prophylaxis. On 8 September 2010 the subject received unspecified dose of Infanrix hexa (intramuscular, unknown, lot number not provided), unspecified dose of Prevnar (intramuscular, unknown). On 10 September 2010, 2 days after vaccination with Infanrix hexa and Prevnar, the subject experienced fever (NOS). On 22 September 2010, the patient expirenced peripheral neuritis. On a date as yet unspecified, the patient experienced Guillain Barre syndrome. On 01 December 2010, he had recovered from the fever and peripheral neuritis and on a date as yet unspecified, he had recovered from Guillain Barre syndrome. The subject was hospitalised. Relevant test results included a CSF analysis and an NMR but no results were provided. The subject was treated with normal immunoglobulin (Immunoglobulin). The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevnar. Follow-up information received on 03 January 2011: The vacine lot number for Infanrix Hexa was provided (A21FA780A). Follow-up information received on 19 April 2011: The child was hospitalized for the first time from 25 September 2010 till 30 September 2010 and from 08 October 2010 till 15 October 2010. Discharge letter: hospitalization from 25 September 2010 to 30 September 2010 Diagnosis: Guillain Barre Syndrome Medical history: patient was taken to emergency room. due to ingravescent fever since 10 September 2010 (vaccination date 08 September 2010). Since the start of fever the child presented with ingravescent general condition, with restlessness, asthenia, CONFIDENTIAL 123 CONFIDENTIAL 171 decreased appetite. Since 22 September 2010 showed unsteady walk, with difficulty in maintaining erect position. On admission, the child was in a poor general condition and was unable to maintain standing position. He presented a pale-grayish complexion, decreased trophism, capillary refill inferior to 2 seconds. He presented also moderate skin hydration, hyperaemic pharynx and dysphonia as well as difficult breathing with chest wall retraction. Thorax examination showed reduced air intake, spare wheezes and rales. Clinical pattern suggestive of peripheral neuropathy with global asthenia. To be re-evaluated within 30 days. Course of hospitalization and prescribed therapy: during the first period of hospitalization the child showed clinical worsening with increased nuchal rigidity. For this reason, rachicentesis was performed. Then the child was treated with antibiotics. In the next days, marked improvement of general condition, associated with a still incomplete improvement of neurological condition, osteotendon reflexes, tone, walking and nucal rigidity. The child was discharged in moderately good condition. Advice at discharge: antibiotic therapy: amoxi-clavulanic acid (Augmentin) 2ml 3xD until 04 October 2010 inclusive. Discharge letter: hospitalization from 08 October 2010 to 15 October 2010: Diagnosis: Guillain Barre Syndrome Medical history: patient already hospitalized for peripheral neuritis. At follow up visits the child’s neurological condition had not improved. Therefore, a new hospitalization was decided in order to perform NMR of the brain and spinal cord under sedation, followed by therapy with immunoglobulins i.v. On admission: fair general condition, pale complexion, decreased trophism, capillary refill above 2 seconds, moderate skin hydration. Pink pharynx, normal breathing. Neurological visit: hypotonic child, shows difficulty in movement of upper limbs, no walking, no erect standing, no signs of meningeal irritation. Lab tests (08 October 2010): RBC 4.74 tera/L; HB 123 g/L; Ht 38%, MCV 79.2 fl/cell; PLT 476 giga/L; WBC 17.0 giga/L (neutrophils 9.9, leucocytes 5.6, monocytes 1.1 giga/L). CRP 0.7 mg/dL. Glycemia, albumin and ions normal. Lab tests (11 October 2010): RBC 9.90 tera/L; CRP< 0.5 mg/dL. Na 132 mEq/L. PT, aPTT normal. Brain/spinal chord NMR negative. Course of hospitalization and Prescribed therapy: on admission date, the child was drowsy and with leucocytosis, likely due to dehydration. He was treated with rehydrating solution; the next day therapy with immunoglobulins i.v. (400mg/Kg/die for 5 days) was started. Pretreatment with Trimeton (chlorpheniramine). No adverse reactions observed. Neurological visit: upper limbs improvement observed. Further clinical improvement can be expected, which will be monitored closely through follow up visits. Company comment: This case does not provide any supportive evidence for GBS diagnosis except for the clinical description. Rresults of diagnostic tests supportive of the diagnosis were not provided: CSF, EMG, NCS, and no investigation results of other possible etiology such as herpes infection. The febrile context 48 hours after vaccination could have triggered the occurrence of the neurologic syndrome that started 2 weeks after vaccination with Infanrix and Prevenar. Clinical neurological improvement after multiple hospitalization and therapy is reported. This case fulfils the Level 4 of diagnostic certainty of Brighton Collaboration GBS Working group criteria. CONFIDENTIAL 124 CONFIDENTIAL 172  D0069554A (Germany): Guillain-Barre syndrome, Congenital neuropathy, Demyelinating polyneuropathy, Hip deformity, Foot deformity, Motor developmental delay This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2010034653) and described the occurrence of Guillain Barre syndrome in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Later vaccinations included pneumococcal vaccine (Prevenar, Wyeth) in December 2006, January 2007 and November 2007, combined measles, mumps and rubella vaccine, live, attenuated on 27 February 2008, meningococcal vaccine (NeisVac-C, Baxter Healthcare) on 24 February 2009, hepatitis A vaccine (Havrix pediatric, GSK) in July 2009. On 22 August 2006, 26 September 2006 and 24 October 2006 the subject received 1st dose, 2nd dose and 3rd dose of Infanrix hexa (unknown route, unknown thigh). At an unspecified time after vaccination with Infanrix hexa, the subject experienced Guillain Barre syndrome (GBS). The subject developed GBS during infancy, but it was not clarified after which vaccination. The subject was hospitalised. At the time of reporting the event was unresolved. Follow-up information was received on 19 January 2011 via the German regulatory authority (PEI). Later vaccinations also included another dose of Infanrix hexa on 01 August 2007, combined measles, mumps and rubella vaccine, live, attenuated (Priorix, GSK) in June 2007 and varicella vaccine (Varivax) in June 2007. Ambulatory orthopaedic examination was performed on 23 October 2007. During early childhood the subject showed statomotor developmental delay and was diagnosed with hydrocepahalus internus. The subject had first problems, later diagnosed as coxa valga and antetorta at both sides and pes valgus. The subject received regular physiotherapy. From 09 March to 20 April 2010 the subject was hospitalised for rehabilitation measures. The following was reported for anamnesis: The subject was born in 40+5 weeks of gestation by emergency caesarean section, after complications because of unusual position. At birth the subject had a weight of 3540 g, a size of 50 cm and an Apgar score of 10/10. The subject was breast-fed for eight months and received vitamin D and fluor prophylaxis for 20 months. The subject was seldom ill, but had three-day fever once. There were no allergies. The subject had congenital hydrocephalus internus and mild Dandy-Walter disease variant, but no other malformations. The subject still received regular physiotherapy and had Swash-Orthesis at night until January 2010. During hospitalisation from 04 to 07 August 2010 a muscle conduction velocity (MLG) examination showed signs for severe polytopic demyelinating neuropathy. In a medical report from 21 October 2010 the diagnosis was polyneuropathy, differential diagnosis congenital hypomyelinating neuropathy. No further information will be available. Company comment: This case fulfils the Level 4 of diagnostic certainty of Brighton Collaboration GBS Working group criteria. The physician did not consider GBS as primary possible diagnosis and stated a chronic inflammatory demyelinating polyneuropathy (CIDP) has to be considered more likely, although the course of disease was unusual. Other differential diagnoses have been postulated (congenital hypomyelinating neuropathy). CONFIDENTIAL 125 CONFIDENTIAL 173 6.5.2.9.7. Hemiparesis One (1) case of Hemiparesis was received during the period (D0071075A) and is described in Section 6.5.2.9.12 Thalamus haemorrhage. 6.5.2.9.8. Lennox-Gastaut syndrome One (1) case of Lennox-Gastaut syndrome was received during the period (D0071841A) and is described in Section 6.5.2.9.5 Encephalitis, Encephalopathy and Encephalic infection. CONFIDENTIAL 126 CONFIDENTIAL 174 6.5.2.9.9. Loss of consciousness Thirty five (35) cases of Loss of consciousness were reported during the period and are summarized in Table 23. This table also includes one case received prior to the period of this report but never included in a previous PSUR (B0591710A). This case’s ID is marked by a ‘*’ in Table 23. Table 23 Summary of cases of Loss of consciousness received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0682745A 03 -Nov -10 Unresolved 6 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Convulsion, Loss of consciousness, Gaze palsy, Pallor, Pyrexia, Crying Netherlands B0683333A 05 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infanrix hexa, Pneumococc al vaccines (Non -GSK) Hours Presyncope, Loss of consciousness, Depressed level of consciousness, Staring, Hypotonia, Pallor, Crying, Pyrexia, Pain, Mental impairment, Vomiting, Muscle contractions involuntary, Myoclonus, Abdominal abscess, Irritability, Hypotonic -hyporesponsive epis Netherlands Gastrooesoph ageal reflux disease, Choking B0687865A 07 -Dec -10 Resolved 11 Months Male Infanrix hexa Priorix 2 Days Loss of consciousness, Gaze palsy, Pallor, Hypotonia Italy B0691167A 23 -Dec -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Apnoea, Loss of consciousness, Erythema, Hypertonia Italy CONFIDENTIAL 127 CONFIDENTIAL 175 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0692220A 04 -Jan -11 Resolved 11 Months Male Infanrix hexa 1 Days Syncope, Loss of consciousness, Febrile convulsion, Eye movement disorder, Opisthotonus, Pallor, Pyrexia Italy B0692681A 07 -Jan -11 Resolved 18 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 4 Hour s Febrile convulsion, Loss of consciousness, Pallor, Tremor, Hypotonia, Peripheral coldness, Respiratory disorder, Cyanosis, Chills, Postictal state, Pyrexia Netherlands Nasopharyngi tis, Cough, H1N1 influenza, Eczema B0695521A 19 -Jan -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 8 Hours Loss of consciousness, Pallor, Hypotonia, Feeling cold, Somnolence Netherlands B0701374A 18 -Feb -11 Resolved 2 Months Male Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non – GSK) Rotavirus vaccine, Pneumococc al vaccines (Non -GSK) 3 Hours Hypotonic -hyporesponsive episode, Loss of consciousness, Depressed level of consciousness, Unresponsive to stimuli, Cyanosis, Cough, Ill -defined disorder, Fatigue, Adverse event, Vomiting, Eyelid disorder, Crying, Somnolence Switzerland B0702744A 24 -Feb -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Loss of consciousness, Pyrexia Italy CONFIDENTIAL 128 CONFIDENTIAL 176 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0705098A 08 -Mar -11 Resolved 2 Months Female Infanrix hexa Immediate Presyncope, Bradycardia, Hypotonia, Injection site pain, Loss of consciousness, Cyanosis France B0706275A 10 -Mar -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Grand mal convulsion, Loss of consciousness, Staring, Hypertonia, Erythema, Gastrooesophageal reflux disease, Regurgitation Italy B0709210A 22 -Mar -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 8 Hours Loss of consciousness, Pallor, Pyrexia Italy B0709247A 24 -Mar -11 Resolved 6 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Hours Loss of consciousness, Pallor, Hypotonia, Hypotonic -hyporesponsive episode, Vomiting Netherlands B0710868A 29 -Mar -11 Resolved 11 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Status epilepticus, Loss of consciousness, Apnoea, Convulsion, Vomiting, Skin warm, Staring, Hypotonia, Hyporesponsive to stimuli, Crying, Erythema, Upper respiratory tract infection, Pyrexia, Hypertonia, Postictal state, Malaise, Listless Netherlands CONFIDENTIAL 129 CONFIDENTIAL 177 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0712712A 05 -Apr -11 Resolved 13 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Loss of consciousness, Depressed level of consciousness, Convulsion, Gaze palsy, Respiration abnormal, Pallor, Hypotonia, Drooling, Cyanosis, Pyrexia, Vomiting Netherlands B0715332A 21 -Apr -11 Resolved 15 Months Female Infanrix hexa, Meningococcal polysaccharide vaccine group C (Non -GSK) 0 Days Cyanosis, Loss of consciousness, Apnoea, Hypotonia, Crying Italy B0715581A 27 -Apr -11 Resolved 2 Months Female Infanrix hexa Pneumococc al vaccines (Non -GSK) Hours Hypertonia, Loss of consciousness, Cyanosis, Clonus, Eye disorder, Apathy, Convulsion France B0716232A 27 -Apr -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Syncope, Loss of consciousness, Pallor Italy B0716294A 28 -Apr -11 Resolved 13 Months Male Infanrix hexa, Meningococcal polysaccharide vaccine group C (Non -GSK) 0 Days Febrile convulsion, Cyanosis, Loss of consciousness, Clonus, Salivary hypersecretion, Hypertonia Italy B0716724A 28 -Apr -11 Resolved 2 Months Female Infanrix hexa 0 Days Loss of consciousness, Hypotonic -hyporesponsive episode, Hypotonia, Diarrhoea Poland CONFIDENTIAL 130 CONFIDENTIAL 178 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0717794A 06 -May -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 36 Hours Loss of consciousness, Apnoea, Depressed level of consciousness, Gaze palsy, Pallor, Cyanosis, Hypotonia, Peripheral coldness, Pyrexia Netherlands B0721081A 19 -May -11 Resolved 2 Months Unknown Infanrix hexa, Rotavirus vaccine (Non – GSK) 2 Days Unresponsive to stimuli, Loss of consciousness, Hypotonic -hyporesponsive episode, Apathy, Restlessness, Somnolence, Crying Poland B0722809A 27 -May -11 Resolved 3 Months Female Synflorix, Infanrix hexa 0 Days Loss of consciousness, Convulsion, Cyanosis, Somnolence, Body temperature increased, Crying Czech Republic Postmature baby, Neonatal asphyxia, Low birth weight baby, Resuscitation B0724363A 06 -Jun -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Loss of consciousness, Pyrexia, Pallor, Arrhythmia Italy Pharyngitis, Conjunctivitis B0726312A 08 -Jun -11 Resolved 10 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Cyanosis, Loss of consciousness, Hypotonia Italy B0728516A 24 -Jun -11 Resolved 12 Months Male Infanrix hexa, MMR vaccine (Non -GSK) 1 Days Febrile convulsion, Loss of consciousness, Tremor, Complex partial seizures, Grand mal convulsion, Pyrexia Italy CONFIDENTIAL 131 CONFIDENTIAL 179 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0732350A 11 -Jul -11 Resolved 3 Months Male Synflorix, Infanrix hexa Ranitidine hydrochlorid e, Domperidon e 4 Hours Loss of consciousness, Apnoea, Hypotonic – hyporesponsive episode, Pallor, Hypotonia Netherlands Hyperbilirubin aemia, Meconium stain, Gastrooesoph ageal reflux disease, Cardiac murmur B0741462A 19 -Aug -11 Resolved 3 Months Unknown Infanrix hexa Rotavirus vaccine Immediate Hypotonic -hyporesponsive episode, Loss of consciousness, Somnolence, Pallor, Hypotonia, Crying Poland B0744808A 05 -Sep -11 Resolved 5 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 19 Days Loss of consciousness, Nystagmus, Opisthotonus, Eye movement disorder, Pyrexia, Vomiting Italy Binocular eye movement disorder, Dermatitis atopic B0756155A 17 -Oct -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Sleep apnoea syndrome, Loss of consciousness, Cyanosis, Neutropenia, Salivary hypersecretion, Hyperpyrexia Italy Premature baby, Regurgitation B0757269A 18 -Oct -11 Resolved 2 Months Unknown Infanrix hexa, Pneumococcal vaccines (Non – GSK) 10 Minutes Loss of consciousness, Hypotonia, Somnolence France CONFIDENTIAL 132 CONFIDENTIAL 180 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069341A 05 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Hours Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed Germany Atrial septal defect D0070819A 28 -Mar -11 Resolved 4 Months Female Rotavirus vaccine, Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Hypotonic -hyporesponsive episode, Pyrexia, Vomiting, Loss of consciousness, Restlessness, Hyperhidrosis, Abnormal faeces, Hypotonia, Eye movement disorder, Fatigue, Abdominal distension, Pharyngeal erythema Germany D0071146A 26 -Apr -11 Resolved 12 Weeks Female Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non – GSK) 2 Hours Apparent life threatening event, Pallor, Loss of consciousness, Erythema, Respiratory arrest, Somnolence Germany CONFIDENTIAL 133 CONFIDENTIAL 181 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071516A 25 -May -11 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 30 Minutes Loss of consciousness Germany Plagiocephaly , Posture abnormal, Twin pregnancy B0591710A * 04 -Sep -09 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 6 Hours Loss of consciousness, Hypotonia, Vomiting, Pallor, Cyanosis, Drooling Netherlands 6.5.2.9.10. Somnolence Fifty nine (59) cases of Somnolence were received during the period. The outcome was favourable and the event resolved in 42 cases (including one time with sequelae). In 19 cases, the event reported was recorded in a non serious case description. These cases are summarized in Table 24. Table 24 Summary of cases of Somnolence received during the period Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0682304A 20 -Oct -10 Resolved 2 Months Male Infanrix hexa 0 Days Somnolence, Pyrexia Italy B0682373A 25 -Oct -10 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Pyrexia, Somnolence Italy CONFIDENTIAL 134 CONFIDENTIAL 182 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0683335A 05 -Nov -10 Fatal 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 3 Minutes Meningitis viral, Convulsion, Yellow skin, Cyanosis, Dehydration, Diarrhoea, Somnolence, Crying, Vomiting Netherlands B0683346A 05 -Nov -10 Unknown 4 Months Male Boostrix, Infanrix hexa Oral fluid 24 Hours Wrong drug administered, Overdose, Somnolence, Irritability Australia B0686044A 25 -Nov -10 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 4 Hours Hypotonia, Somnolence Italy B0686455A 23 -Nov -10 Unknown 2 Months Infanrix hexa, Rotavirus vaccine 3 Days Hypotonic -hyporesponsive episode, Abdominal pain, Vaccination complication, Restlessness, Crying, Somnolence Poland B0687574A 03 -Dec -10 Unknown 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Pyrexia, Somnolence Italy B0687791A 06 -Dec -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Somnolence Italy B0689223A 14 -Dec -10 Unknown 10 Weeks Unknown Infanrix hexa, Pneumococcal vaccines (Non -GSK) Immediate Pallor, Somnolence, Injection site erythema, Injection site oedema, Injection site inflammation France B0695521A 19 -Jan -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 8 Hours Loss of consciousness, Pallor, Hypotonia, Feeling cold, Somnolence Netherlands CONFIDENTIAL 135 CONFIDENTIAL 183 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0696866A 28 -Jan -11 Resolved 1 Months Infanrix hexa, Pneumococcal vaccines (Non -GSK) 3 Days Anaemia, Hypotonic – hyporesponsive episode, Apathy, Thirst decreased, Respiratory tract infection, Somnolence Poland B0701374A 18 -Feb -11 Resolved 2 Months Male Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) 3 Hours Hypotonic -hyporesponsive episode, Loss of consciousness, Depressed level of consciousness, Unresponsive to stimuli, Cyanosis, Cough, Ill – defined disorder, Fatigue, Adverse event, Vomiting, Eyelid disorder, Crying, Somnolence Switzerland B0702321A 22 -Feb -11 Resolved 10 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Euphoric mood, Somnolence Italy B0702562A 25 -Feb -11 Resolved 10 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 18 Hours Hypotonic -hyporesponsive episode, Somnolence, Pallor, Incorrect route of drug administration, Neurological examination abnormal France Anaemia B0705201A 08 -Mar -11 Resolved 2 Months Male Infanrix hexa Calcium salt 0 Days Somnolence, Urticaria, Acne Romania B0706016A 08 -Mar -11 Resolved 2 Months Female Infanrix hexa 3 Hours Hypotonic -hyporesponsive episode, Cyanosis, Somnolence, Crying, Restlessness, Pyrexia, Hypotonia, Anxiety, Lividity Poland CONFIDENTIAL 136 CONFIDENTIAL 184 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0706503A 11 -Mar -11 Fatal 2 Months Female Infanrix hexa 1 Days Shock, Respiratory arrest, Cardiac arrest, Pyrexia, Somnolence, Hypotonia, Vomiting, Crying, Apnoea Thailand Cytogenetic abnormality B0708789A 21 -Mar -11 Resolved 2 Months Male Infanrix hexa 30 Minutes Crying, Somnolence, Decreased appetite Poland B0712001A 04 -Apr -11 Resolved 7 Weeks Female Infanrix hexa 1 Days Somnolence, Injection site reaction Poland B0712989A 08 -Apr -11 Resolved 3 Months Male Infanrix hexa 2 Minutes Depressed level of consciousness, Pallor, Crying, Somnolence, Malaise Netherlands B0716780A 02 -May -11 Fatal 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Cardiac arrest, Multi -organ failure, Pneumonia aspiration, Cerebral ischaemia, Sudden infant death syndrome, Unresponsive to stimuli, Peripheral coldness, Staring, Musculoskeletal stiffness, Pyrexia, Somnolence Italy B0716859A 18 -Apr -11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Gait disturbance, Stupor, Somnolence Italy B0717816A 06 -May -11 Resolved 4 Months Unknown Infanrix hexa, Pneumococcal vaccines (Non -GSK) 13 Hours Respiration abnormal, Oligodipsia, Skin discolouration, Chills, Somnolence, Pyrexia, Injection site pain Netherlands B0719542A 16 -May -11 Unknown 1 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Decreased activity, Hypotonia, Somnolence Poland Pneumonia CONFIDENTIAL 137 CONFIDENTIAL 185 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0720694A 19 -May -11 Resolved 19 Months Unknown Infanrix hexa 0 Days Hypotonic -hyporesponsive episode, Pyrexia, Crying, Somnolence Poland B0721081A 19 -May -11 Resolved 2 Months Unknown Infanrix hexa, Rotavirus vaccine (Non – GSK) 2 Days Unresponsive to stimuli, Loss of consciousness, Hypotonic – hyporesponsive episode, Apathy, Restlessness, Somnolence, Crying Poland B0722375A 26 -May – 1 1 Resolved 22 Months Unknown Infanrix hexa, Synflorix Hours Hypotonic -hyporesponsive episode, Pain in extremity, Gait disturbance, Body temperature increased, Somnolence Poland B0722407A 24 -May -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 14 Hours Gaze palsy, Hypertonia, Pyrexia, Dyskinesia, Somnolence, Feeling hot Netherlands B0722809A 27 -May -11 Resolved 3 Months Female Synflorix, Infanrix hexa 0 Days Loss of consciousness, Convulsion, Cyanosis, Somnolence, Body temperature increased, Crying Czech Republic Postmature baby, Neonatal asphyxia, Low birth weight baby, Resuscitatio n B0727512A 16 -Jun -11 Resolved 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Malaise, Injection site inflammation, Crying, Pyrexia, Somnolence Netherlands B0728546A 23 -Jun -11 Resolved 2 Months Female Infanrix hexa Pneumococcal vaccines (Non -GSK) 7 Hours Pyrexia, Decreased appetite, Somnolence, Fatigue France Febrile convulsion, Breast feeding CONFIDENTIAL 138 CONFIDENTIAL 186 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0730356A 30 -Jun -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Hyporeflexia, Somnolence, Vomiting Italy B0731377A 16 -Jun -11 Resolved 5 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Hyperpyrexia, Erythema, Crying, Decreased appetite, Somnolence Italy B0732140A 22 -Jun -11 Unknown 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 3 Days Malaise, Fatigue, Crying, Pyrexia, Diarrhoea, Nasopharyngitis, Somnolence Netherlands B0732346A 11 -Jul -11 Unknown 2 Months Female Infanrix hexa, Synflorix 4 Hours Depressed level of consciousness, Pyrexia, Somnolence Netherlands B0732350B 02 -Sep -11 Resolved 6 Months Male Synflorix, Infanrix hexa Paracetamol, Domperidone, Esomeprazole 3 Hours Hypotonic -hyporesponsive episode, Crying, Pallor, Hypotonia, Somnolence, Unresponsive to stimuli Netherlands Gastrooesop hageal reflux disease B0734272A 20 -Jul -11 Resolved 1 Months Female Rotavirus vaccine, Infanrix hexa 0 Days Hypotonic -hyporesponsive episode, Somnolence, Hypotonia, Body temperature decreased Poland B0741462A 19 -Aug -11 Resolved 3 Months Unknown Infanrix hexa Rotavirus vaccine Immediate Hypotonic -hyporesponsive episode, Loss of consciousness, Somnolence, Pallor, Hypotonia, Crying Poland B0741965A 24 -Aug -11 Resolved 6 Months Male Infanrix hexa, Synflorix 45 Minutes Somnolence Romania CONFIDENTIAL 139 CONFIDENTIAL 187 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0746088A 08 -Sep -11 Improved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 3 Seconds Depressed level of consciousness, Crying, Injection site inflammation, Pallor, Hypotonia, Oligodipsia, Somnolence, Respiratory disorder Netherlands B0750925A 22 -Sep -11 Resolved 4 Months Female Infanrix hexa Pneumococcal vaccines (Non -GSK), Rotavirus vaccine, Domperidone, Omeprazole 0 Days Convulsion, Crying, Somnolence, Staring, Abnormal behaviour, Dyskinesia Singapore Gastrooesop hageal reflux disease B0752361A 29 -Sep -11 Resolved with Sequelae 17 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 9 Days Type 1 diabetes mellitus, Diabetic ketoacidosis, Polydipsia, Polyuria, Somnolence, Tachypnoea, Increased appetite, Vomiting, Dermal cyst, Ketosis, Lip dry, Dehydration, Lymphadenopathy Italy Growth retardation B0752371A 29 -Sep -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Cyanosis, Escherichia infection, Oxygen saturation decreased, C-reactive protein increased, Weight decreased, Decreased appetite, Hypotonic – hyporesponsive episode, Somnolence Italy Milk allergy B0754309A 22 -Sep -11 Resolved 11 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Pyrexia, Restlessness, Decreased appetite, Somnolence Italy CONFIDENTIAL 140 CONFIDENTIAL 188 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0755401A 07 -Oct -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Depressed level of consciousness, Pyrexia, Inflammation, Pain, Vomiting, Somnolence, Diarrhoea, Staring Netherlands B0756166A 14 -Oct -11 Resolved 1 Months Male Infanrix hexa 1 Days Body temperature increased, Hypotonic -hyporesponsive episode, Somnolence Poland B0756934A 06 -Oct -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Mobility decreased, Apathy, Somnolence Italy B0757269A 18 -Oct -11 Resolved 2 Months Unknown Infanrix hexa, Pneumococcal vaccines (Non -GSK) 10 Minutes Loss of consciousness, Hypotonia, Somnolence France D0069309A 03 -Nov -10 Unknow n 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Febrile convulsion, Pyrexia, Musculoskeletal stiffness, Gaze palsy, Somnolence, Transaminases increased, Pharyngeal erythema, Tympanic membrane hyperaemia Germany Cardiac murmur D0070292A 14 -Feb -11 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 3 Days Convulsion, Eye movement disorder, Dyskinesia, Pallor, Somnolence Germany Premature baby CONFIDENTIAL 141 CONFIDENTIAL 189 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0070873A 01 -Apr -11 Resolved 2 Months Femal e Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 0 Days Hypotonic -hyporesponsive episode, Pallor, Somnolence Germany D0070921A 07 -Apr -11 Resolved 2 Months Female Infanrix hexa 0 Days Kawasaki’s disease, Pyelonephritis, Pyrexia, Infection, Somnolence, Fluid intake reduced, General physical health deterioration, Pallor, Ill – defined disorder, Rash, Conjunctivitis, Erythema, Enanthema, Chapped lips, Hypertrophy of tongue papillae Germany Pyrexia, Premature baby, Haemangio ma congenital, Streptococca l infection D0071075A 18 -Apr -11 Unknown 3 Months Male Rotavirus vaccine, Infanrix hexa, Synflorix 1 Days Thalamus haemorrhage, Convulsion, Facial paresis, Hemiparesis, Hypophagia, Restlessness, Pyrexia, Screaming, Somnolence, Pallor, Hyperaesthesia, Eyelid oedema, Abdominal distension, Hypotonia, Apnoea, Gaze palsy Germany D0071096A 18 -Apr -11 Resolved 5 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Grand mal convulsion, Muscle twitching, Somnolence, Pyrexia Germany CONFIDENTIAL 142 CONFIDENTIAL 190 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0071146A 26 -Apr -11 Resolved 12 Weeks Female Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) 2 Hours Apparent life threatening event, Pallor, Loss of consciousness, Erythema, Respiratory arrest, Somnolence Germany D0071548A 27 -May -11 Unknown 8 Months Female Infanrix hexa, Synflorix 1 Days Convulsion, Gaze palsy, Cyanosis, Vaccination complication, Restlessness, Feeling hot, Staring, Muscle twitching, Dyspnoea, Hypotonia, Somnolence, General physical health deterioration, Body temperature increased Germany D0071549A 27 -May -11 Unresolved 4 Months Male Synflorix, Infanrix hexa 0 Days Encephalitis, Bronchitis, Lactic acidosis, Hyperglycaemia, Convulsion, Injection site induration, Pyrexia, Somnolence, Hypotonia, Depressed level of consciousness, Respiration abnormal, Cough, Pallor, Lip haematoma, General physical health deterioration, Germany Pneumonia respiratory syncytial viral, Respiratory tract infection CONFIDENTIAL 143 CONFIDENTIAL 191 Case ID Initial Date Received By Dept Case Outcom e Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072024A 13 -Jul -11 Unknown 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Meningitis pneumococcal, Gastroenteritis rotavirus, Respiratory syncytial virus infection, Pneumococcal sepsis, Pharyngitis, Somnolence, Pyrexia, Fluid intake reduced, Respiration abnormal, Crying, Diarrhoea, Cardiovascular insufficiency, Pallor, Tachypno Germany D0072920A 04 -Oct -11 Unknown 15 Months Male Infanrix hexa, Synflorix 6 Hours Febrile convulsion, Epilepsy, Rash, Pyrexia, Dyskinesia, Salivary hypersecretion, Eye movement disorder, Somnolence, Pallor, Tachycardia, Injection site erythema, Injection site swelling Germany CONFIDENTIAL 144 CONFIDENTIAL 192 6.5.2.9.11. Syncope and Presyncope Fifteen (15) cases of Syncope/Presyncope were received during the period and are summarised in Table 25. Table 25 Summary of cases of Syncope/Presyncope received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0680987A 22 -Oct -10 Resolved 2 Months Female Infanrix hexa, Rotavirus vaccine (Non -GSK), Pneumococcal vaccines (Non -GSK) Minutes Anaphylactic shock, Syncope, Apnoea, Bronchospasm, Blood pressure decreased, Pallor, Respiratory rate decreased, Crying, Hypoventilation Belgium B0682378A 25 -Oct -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Erythema, Pallor, Presyncope, Pyrexia Italy B0683333A 05 -Nov -10 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK) Hours Presyncope, Loss of consciousness, Depressed level of consciousness, Staring, Hypotonia, Pallor, Crying, Pyrexia, Pain, Mental impairment, Vomiting, Muscle contractions involuntary, Myoclonus, Abdominal abscess, Irritability, Hypotonic -hyporesponsive epis Netherlands Gastrooesopha geal reflux disease, Choking B0687818A 07 -Dec -10 Resolved 11 Months Female Infanrix hexa Infanrix hexa 0 Days Syncope Italy Drug hypersensitivity CONFIDENTIAL 145 CONFIDENTIAL 193 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0692220A 04 -Jan -11 Resolved 11 Months Male Infanrix hexa 1 Days Syncope, Loss of consciousness, Febrile convulsion, Eye movement disorder, Opisthotonus, Pallor, Pyrexia Italy B0699755A 14 -Feb -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Unresponsive to stimuli, Syncope, Pallor Ireland B0705098A 08 -Mar -11 Resolved 2 Months Female Infanrix hexa Immediate Presyncope, Bradycardia, Hypotonia, Injection site pain, Loss of consciousness, Cyanosis France B0716232A 27 -Apr -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Syncope, Loss of consciousness, Pallor Italy B0733127A 06 -Jul -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Presyncope, Hypotonia, Pallor, Pyrexia, Vomiting, Irritability Italy B0733860A 18 -Jul -11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Presyncope, Syncope, Pallor, Hypotonia, Vomiting Italy B0750040A 20 -Sep -11 Resolved 2 Months Female Infanrix hexa, Synflorix 7 Hours Presyncope, Febrile convulsion, Depressed level of consciousness, Hypertonia, Myoclonus, Pallor, Pyrexia, Musculoskeletal stiffness Netherlands B0756838A 17 -Oct -11 Resolved 2 Months Male Infanrix hexa, Synflorix 2 Minutes Presyncope, Pallor, Hyperhidrosis, Feeling cold, Heart rate increased Netherlands CONFIDENTIAL 146 CONFIDENTIAL 194 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069604A 02 -Dec -10 Resolved 6 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) Immediate Hypotonic -hyporesponsive episode, Syncope, Skin discolouration, Pallor, Crying, Unresponsive to stimuli, Cardiovascular disorder Germany D0069784A 20 -Dec -10 Resolved 12 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Crying, Respiratory disorder, Presyncope, Pyrexia, Fatigue, Apathy, Dyskinesia, Inappropriate affect, Decreased interest, Initial insomnia, Diarrhoea Germany D0072433A 18 -Aug -11 Resolved 6 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Synflorix, Vigantol 0 Days Syncope, Cyanosis, Restlessness, Pallor, Vomiting, Hypotonia, Unresponsive to stimuli Germany CONFIDENTIAL 147 CONFIDENTIAL 195 6.5.2.9.12. Thalamus haemorrhage One (1) case of Thalamus haemorrhage was received during the period:  D0071075A (Germany): Thalamus haemorrhage, Convulsion, Facial paresis, Hemiparesis, Hypophagia, Restlessness, Pyrexia, Screaming, Somnolence, Pallor, Hyperaesthesia, Eyelid oedema, Abdominal distension, Hypotonia, Apnoea, Gaze palsy. This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011011270) and described the occurrence of thalamic bleeding in a 3- month-old male subject who was vaccinated with live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline), combined diphtheria, tetanus-acellular pertussis, hepatitis B and inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa) for prophylaxis. On 24 March 2011 the subject received 1st dose of Rotarix (liquid, oral), 1st dose of Infanrix hexa (intramuscular, unknown injection site). On 29 March 2011, 5 days after vaccination with Infanrix hexa and Rotarix, the subject experienced thalamic bleeding of capsula interna at the right side. The subject was hospitalised. A hospital report was received on 01 June 2011 via the German regulatory authority (PEI). The subject was hospitalised from 29 March to 11 April 2011, and then transferred to another unit. Pregnancy, birth and further development of the infant had been normal. On 24 March 2011 the subject received Rotarix and Infanrix hexa. On 25 March 2011 the subject had fever up to 37.7 degC, but else no symptoms. In the night from 28 to 29 March 2011 the subject developed restlessness, screaming, reduced food intake and was hard to wake up. A paediatrician was consulted and the subject was admitted to hospital with the suspect of acute abdomen. In hospital acute abdomen was excluded. Sonogram showed recent thalamic bleeding at the right and the subject was transferred to the reporting hospital for further diagnostics. When transferred, the subject was pale with marble skin, sensitive to touch, but without hematoma or petechiae. The subject had lid edema and abdominal distension, but normal bowel sounds. There were neurological deficits. Cranial magnetic resonance tomogram (MRT) confirmed right-sided bleeding in thalamic centre region and capsula interna. A malformation of vessels was excluded. Extended hematologic diagnostics excluded factor deficiency and thrombophilia and the genesis of bleeding kept unclear. There was no sign for viral infection. Only rotavirus antigen was found in stool, which was caused by rotavirus vaccination. In further course, electroencephalogram (EEG) showed regional function disorder and increased predisposition for convulsions and the subject was treated with phenobarbitone (Phenobarbital). EEG on 06 April 2011 showed mild improvement. Initial neurologic symptoms included decreased muscle tone at the left with increased tendency for stretching of extremities at the left. The subject also had gaze palsy to the right. Additional diagnoses in hospital included cerebral convulsion, peripheral facial paresis and left-sided hemiparesis. The subject was treated with dextrose (Glucose), electrolytes, phytomenadione (Konakion), midazolam hydrochloride (Dormicum), paracetamol, chloral hydrate, and ergocalciferol (Vigantoletten). Intensive physiotherapy was started for compensation of neurologic deficits. Outstanding vaccination with Pneumococcal vaccine (unknown manufacturer) was performed stationary on 09 April 2011. After this, the subject developed solitary episodes of apnea, but without affection of other vital CONFIDENTIAL 148 CONFIDENTIAL 196 parameters. The physician stated that there will probably be mental or motor sequelae. The hospital physician did not consider a causal relation of thalamic bleeding to vaccination. No further information will be available. Company comment: This 3-month year old male subject experienced a thalamic bleeding of the right capsula interna with multiple neurological complications 5 days after 1st vaccination with Infanrix hexa and Rotarix. The treating physician did not suspect a causal relationship. 6.5.2.9.13. VIth nerve paralysis One (1) case of VIth nerve paralysis was received during the period:  B0681066A (Belgium): VIth nerve paralysis, Strabismus. This case was reported by a healthcare professional and described the occurrence of sixth nerve paralysis in a 15-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) and meningococcal polysaccharide vaccine group c (non-gsk) (Menjugate) for prophylaxis. Previous and/or concurrent vaccination included dtpapolio-hib (non-gsk) ;Sanofi Pasteur MSD;unknown;unknown given on an unspecified date. On 13 September 2010, the subject received 1st dose of Infanrix hexa (administration site and route unknown) and an unspecified dose of Menjugate (unknown). The subject had previously received 3 doses of Pentavac during his first year. The 4th dose was administered with Infanrix hexa (which contained vaccine against hepatitis B virus). On 5 October 2010, 22 days after vaccination with Infanrix hexa and Menjugate, the subject experienced paralysis of cranial nerve VI external oculomotor on left eye. No fever was experienced. On 6 and 8 October 2010, the subject was seen by the opthalmologist who decided to transfer him to the emergency department. The subject was hospitalised till 12 October 2010. On 11 October 2010, several tests were performed under general anesthesia. All the tests were negative: cerebral magnetic resonance imaging, blood test, lumbar puncture and ocular fundus. No treatment was administered. According to the neurologist, the event was not due to a problem of the brain but possibly due to Infanrix hexa and Menjugate and asked to stop vaccination against hepatits B virus. At the time of reporting, the event was unresolved. There was a paralysis of the left cranial nerve VI considered as a post viral paralysis or post vaccinal. During the hospitalisation, left paralysis of cranial nerve VI persisted without deterioration and without improvement. The subject didn’t show other sign of neurological lesions. He remained with excellent general status, the appetite was excellent. The investigation performed by him didn’t show for the moment any cause for the paralysis. He should be followed by his ophthalmologist in order to determine whether any treatment was requested. Some oligoclonal bands were noted in the cerebrospinal fluid with uncertain significance. It was advised to the parents to discontinue temporary the vaccination and to reevaluate this condition in the future. Company comment: Post-infectious or post-vaccinal paralysis of cranial nerve VI in a 15-month-old male subject 22 days after vaccination with Infanrix hexa and Menjugate. Time to onset seems long for causality. CONFIDENTIAL 149 CONFIDENTIAL 197 6.5.2.9.14. VIIth nerve paralysis Two (2) cases of VIIth nerve paralysis were received during the period:  B0728966A (France): VIIth nerve paralysis, Pain in extremity, Mobility decreased, Oedema peripheral, Erythema, Pyrexia, Facial asymmetry. This case was reported by a pediatrician, via a GSK sales representative, and described the occurrence of paralysis of mouth in a 23-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Subject’s father experienced rythm disorder after Influenza vaccination (nos) please see linked case B0728963A (same family, same reporter). In 2011, the subject received an unspecified dose of Infanrix hexa (batch, route and injection site unknown). About 48 hours after vaccination with Infanrix hexa, the subject experienced paralysis of mouth, limb pain with limb decreased mobility. This case was assessed as medically serious by GSK. At the time of reporting, the outcomes of the events were unspecified. Previous vaccination included one dose of Priorix given on 22 November 2010 and one dose of Prevenar given on 13 September 2010. The subject had a febril reaction after this vaccination with Prevenar. On 19 May 2011, the subject received a fourth dose of Infanrix hexa in thigh probably in the left side. On 20 May 2011, the subject had fever at 39 degrees Celsius wich within 24 hours and elusive lower limbs edema and redness (red plaques). On 21 May 2011, 48 hours after vaccination, the subject developped intermittent and flabby right facial asymmetry at mouth level. Several hospital consultations at pediatric unit were made (without hospitalization). Asymmetry persisted but improved and occurred mainly when the subject was tired. It was more visible when he smiled. On 23 June 2011 at consultation, asymmetry persisted. Neurological investigations were planned. On 04 July 2011, the subject was hospitalized for bilateral eyelid edema, not related to vaccination according to the physician. The reporter’s assessment was not provided. Company comment: This 23-month-old male subject experienced intermittent facial paresis starting 48 hours after combined vaccination with Infanrix hexa and Prevenar. A febrile reaction to Prevenar occurred 24 hours prior to the symptoms.  D0071922A (Germany): VIIth nerve paralysis, Facial paresis This case was reported by a physician via a sales representative and described the occurrence of central facial paresis left in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). Less than one day post vaccination with the third doses of Infanrix hexa and Prevenar 13, on 22 March 2011, the subject experienced the first episode of asymmetrical crying face (asymmetrical status facial side drooping). Approximately 49 days with the third doses of Infanrix hexa and Prevenar 13, on 10 May 2011, the subject experienced another episode of asymmetrical crying face (asymmetrical status facial side drooping). Approximately 69 days with the third doses of Infanrix hexa and Prevenar CONFIDENTIAL 150 CONFIDENTIAL 198 13, on 30 May 2011, the subject experienced a very severe episode of asymmetrical crying face (asymmetrical status facial side drooping) and was hospitalised for an unknown period of time. In hospital the subject was diagnosed with central facial paresis left of unknown origin by a neuropaediatrician. Ultrasound and cranial computed tomogram (CCT) as well as motor function tests were normal. The reporting physician considered that the event may cause permanent damage. The reporting physician considered that the event was possibly related to vaccination with Infanrix hexa. Family anamnesis included Weber’s disease (Sturge-Weber syndrome) of the mother which had already caused amputation of one leg, abnormal nodules of the 8-year-old sister which needed surgical treatment, and lipomyelomeningocele of the twin sister which needed surgical treatment followed by physiotherapy. Since the subject was two months old the subject showed reduced movement of the left side of the face when crying. The subject was diagnosed with facial paresis left. By anamnesis and differential diagnosis no involvement of the cranial branch was observed. No cause of the event could be determined. Birth anamnesis was normal. Mental and motor development was normal. The hospital physicians considered that the event was at the moment no serious neurological disease and recommended monitoring of the event. No further information will be available. Company comment: This 4-month-old male subject experienced 2 episodes of transient facial nerve palsy less than one day and 69 days after vaccination with 3rd dose of Infanrix hexa. There was no compelling evidence that the event was causally related to the combined vaccination with Infanrix hexa and Prevenar. 6.5.2.10. Repiratory, thoracic and mediastinal disorders 6.5.2.10.1. Apparent life threatening event Four (4) cases of Apparent life threatening event were received during the period:  B0691130A (France): Apnoea, Bradycardia, Oxygen saturation decreased, Blood pressure decreased, Apparent life threatening event, Urine output decreased, Cholinergic syndrome, Eye movement disorder, Gastrooesophageal reflux disease, Aspiration This case was reported by the French regulatory authority (AFSSaPS reference ST20100963) and described the occurrence of apnea in a 1-month and 29 day-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccine (Prevenar, non-gsk) for prophylaxis. Concurrent medical conditions included prematurity (born at 27 weeks of amenorrhea). The subject weighed 2.25 kg. On 15 December 2010, at about 11:00 the subject received a 1st dose of Infanrix hexa (intramuscular, batch and injection site unknown) and a 1st dose of Prevenar (intramuscular, batch and injection site unknown). On 15 December 2010 at about 16:00, approximately five hours after vaccination with Infanrix hexa and Prevenar, the subject presented with several episodes of apnea with bradycardia and oxygen desaturation which required a mechanical ventilation (Continuous positive airway pressure) and at 19:00 intubation as apnea, bradycardia and desaturation persisted. On 16 December 2010, the subject CONFIDENTIAL 151 CONFIDENTIAL 199 remained dependent on mechanical ventilation. Blood pressure and diuresis decreased. The subject was treated with dopamine at 7.5 g/kg/min. At 17:00, blood pressure and diuresis normalized. The subject remained intubated. The AFSSAPS also coded a near sudden infant death syndrome. The subject was hospitalised and the regulatory authority reported that the events were life threatening. At the time of reporting, the events were unresolved. According to the French method of assessment, the AFSSaPS considered the causal relationship between Infanrix hexa and Prevenar and the reported events as dubious. Upon follow-up received on 11 January 2011: Birth weight of the subject was 1192 g. Medical condition included neonatal apnea treated with cafeine until 30 November 2010 and with doxapram chlorhydrate (Dopram). On 15 December 2010, a possible pulmonary inhalation was considered, as the subject might had reflux. Clinical course was favourable. At the time of reporting, the events were resolved. Upon follow-up received on 17 January 2011: Contacted by phone, the intensive care pediatrician reported a severe vagal hypertonia demonstrated by oculomotor reflexes disturbance. At an unknown date, the subject had bilateral inguinal hernia surgery. At this time, he was treated with atropine. Company comment: Case of near sudden infant death syndrome in a prematurely born 2- month-old male subject 5 hours after first vaccination with Infanrix hexa and Prevenar. The subject was hospitalized and recovered completely. According to the French method of assessment, the AFSSaPS considered the causal relationship between Infanrix hexa and Prevenar and the reported events as dubious.  B0707044A (Netherlands): Anaemia, Milk allergy, Gastrooesophageal reflux disease, Body temperature increased, Gastrointestinal motility disorder This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-118313) and described the occurrence of apparent life threatening event in a 2-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-GSK) (Prevenar) for prophylaxis. Concurrent medical conditions included anemia (depth and underlying cause unspecified), recurrent elevated body temperature, defecation disorder (undulating defecation frequency), suspected cow’s milk allergy and suspected gastroesophageal reflux. Concurrent medications included Ranitidine hydrochloride (Zantac), Domperidone (Motilium) and Macrogol 4000 (Forlax). On 28 February 2011 the subject received 1st dose of Infanrix hexa (intramuscular, unknown injection site), 1st dose of Prevenar (intramuscular, unknown injection site). Lot numbers were not provided. On 1 March 2011, 8 hours after vaccination with Infanrix hexa and Prevenar, the subject experienced apparent life threatening event. The subject was hospitalised. At the time of reporting the event was improved. The regulatory authority reported that the event was possibly related to vaccination with Infanrix hexa and Prevenar. No further information is expected, the regulatory Authority has provided GSK with all the available information for the time being, if they ever get any further information they will send it to GSK. Therefore the case has been closed. CONFIDENTIAL 152 CONFIDENTIAL 200 Company comment: Apparent life threatening event in a 2-month-old male subject 8 hours after combined 1st vaccination with Infanrix hexa and Prevenar. There is insufficient information to assess this case.  D0071146A (Germany) Apparent life threatening event, Pallor, Loss of consciousness, Erythema, Respiratory arrest, Somnolence This case was reported by a physician, via Pfizer Pharma GmbH, and described the occurrence of near miss sudden infant death syndrome in a 12-week-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and live attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer Pharma). There was no relevant medical history. On 13 April 2011 the subject received the first dose of Infanrix hexa (0.5 ml, intramuscular, right thigh), the first dose of Prevenar 13 (0.5 ml, intramuscular, left thigh), contralaterally, and the first dose of Rotarix (0.5 ml, unknown formulation, oral). Post vaccination the subject was sleepy. Approximately two and a half hours post vaccination with Infanrix hexa, Prevenar 13 and Rotarix, on 13 April 2011, the subject experienced near miss sudden infant death syndrome with pallor, loss of consciousness, skin red and stopped breathing. The physician considered the events were life threatening. After measures by the grandmother with lifting up and shaking, the subject regained consciousness and the conditions normalised. Since 15 April 2011 the subject was monitored for breathing and heart sounds. Additionally the subject received supply with “vital fire”. At the time of reporting, on 19 April 2011, a events were resolved. The physician considered the events were possibly related to vaccination with Infanrix hexa, Prevenar 13 and Rotarix. Follow-up information was received on 05 May 2011 via Pfizer. Vaccination was on 13 April 2011 at 13:00. The physician considered that the events were clinically significant (or requiring intervention). Follow-up information was received on 31 October 2011 via case D0073203A received from a German regulatory authority (DE-Paul-Ehrlich-Institut). Approximately five hours post vaccination with the second dose of Rotarix, given on 26 May 2011, the subject experienced similar events (severe pallor, decreased heart and respiratory function) which have repeatedly triggered monitor alarm. For additional information please see case D0073203A. No further information will be available. Company comment: Case of near sudden death infant syndrome in a 3-month-old female subject 2 hours after first dose of Infanrix hexa, Prevenar and Rotarix. The event resolved spontaneously. A similar event was reported 5 hours after the second dose of Rotarix.  D0071421A (Germany) Apparent life threatening event, Altered state of consciousness, Hypothyroidism, Neutropenia, Staring, Hypotonia, Pallor, Respiratory arrest, Crying This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011015251) and described the occurrence of apparent life threatening event in a 4-month-old male subject who was vaccinated with synflorix (GlaxoSmithKline) for prophylaxis. Co-suspect vaccination included combined diphtheria, tetanusCONFIDENTIAL 153 CONFIDENTIAL 201 acellular pertussis, hepatitis B and inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa). Past medical history was not provided. Concurrent medications included D-fluoretten. On 29 March 2011 the subject received 1st dose of Synflorix (intramuscular, unknown gluteal) and 1st dose of Infanrix hexa (intramuscular, unknown gluteal). On 2 April 2011 in the evening, 4 days after vaccination with Infanrix hexa and Synflorix, the subject was suddenly staring, eyes did not roll back. Muscle tone was flaccid and complexion pale. The subject’s mother explained it “like dead” (consciousness disturbed). After stimulation the subject started breathing again and crying. The subject was admitted to hospital and hospitalized for 5 days. At admission to hospital the subject was in stable general condition, awake and conscious. Therapy and course The subject was admitted to hospital because of possible apparent life threatening event lasting for seconds. Monitoring was inconspicuously during stationary stay. No repeated similar event appeared. The examinations performed including metabolism diagnostics showed no pathological finding. Metabolism disturbance and central regulatory disturbance could be excluded. The subject showed latent hypothyroidism (inconspicuously peripheral thyroid parameters) and temporary neutropenia, The subject was treated with potassium iodide (Jodid). On 06 April 2011 the subject was discharged from hospital in good general condition. No further information will be available. Company comment: Case of possible apparent life threatening event lasting for a few seconds in a 4-month-old male subject 4 days after combined vaccination with Infanrix hexa and Synflorix. Extensive examinations found no pathology. The event resolved spontaneously. 6.5.2.10.2. Asphyxia One (1) case of Asphyxia was reported during the period (B0705290A) and is described in Section 6.5.1 Cases with a fatal outcome. 6.5.2.10.3. Respiratory arrest Seven (7) cases of Respiratory arrest were received during the period:  B0706503A (Thailand): Shock, Respiratory arrest, Cardiac arrest, Pyrexia, Somnolence, Hypotonia, Vomiting, Crying, Apnoea. See Section 6.5.1 Cases with a Fatal Outcome.  B0710929A (Netherlands): Hypotonic-hyporesponsive episode, Respiratory arrest, Crying This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-118929) and described the occurrence of hypotonichyporesponsive episode in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. She was born at 35.4 weeks, she grew slowly and will be examined for achalasia. On 11 March 2011, the subject received 1st dose of Infanrix hexa (intramuscular, CONFIDENTIAL 154 CONFIDENTIAL 202 administration site unknown, batch number not provided) and 1st dose of Prevenar (intramuscular, unknown). On 11 March 2011, within minutes of vaccination with Infanrix hexa and Prevenar, the subject experienced hypotonic-hyporesponsive episode. She stopped crying and seemed to fall asleep, she was white and stopped breathing. After touching her cheek, she started to cry and regained colour, but then the same happened again. These episodes repeated themselves 5 times. The subject was hospitalised for one day. In the hospital, she was well again. At the time of reporting, the events were resolved. The regulatory authority reported that the events were probably related to vaccination with Infanrix hexa and Prevenar. No further information is expected, the regulatory Authority has provided GSK with all the available information for the time being, if they ever get any further information they will send it to GSK. Company comment: Case suggestive of breath holding spells in a 2-month-old female subject minutes after vaccination with first dose of Infanrix hexa and Prevenar. The event resolved spontaneously. The subject was hospitalized for 1 day but no information on examinations was included.  B0741007A (Netherlands): Respiratory arrest, Depressed level of consciousness, Breath holding, Crying, Eye movement disorder, Skin discolouration, Pallor This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-126405) and described the occurrence of stopped breathing in a 10-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. The subject’s medical history included planned cesarean section birth with weight of 5000g. On 9 August 2011, the subject received 4th dose of Infanrix hexa (.5 ml, intramuscular, injection site unknown, batch number not provided). On 9 August 2011, immediately after vaccination with Infanrix hexa, the subject was crying for 1 minute. After 1 minute of crying, she stopped breathing and her eyes turned backwards. She did not react for 10 seconds, her face was purple, but turned white shortly after this. When she was taken on the arm, she started breathing again and cried. She was very pale and grew less pale after she was lied down. After half an hour, she went homewards, still somewhat pale. This case was assessed as medically serious by GSK. At the time of reporting, the breath holding spells, stopped breathing and not responsiveness were resolved and the outcome of other events was unspecified. Face turned white was unresloved. The regulatory authority reported that the breath holding spells was probably related to vaccination with Infanrix hexa. No further information is expected, the regulatory Authority has provided GSK with all the available information for the time being, if they ever get any further information they will send it to GSK. Company comment: Case suggestive of breath holding spells in a 10-month-old female subject minutes after vaccination with 4th dose of Infanrix hexa. The event resolved spontaneously.  D0069889A (Germany): Meningitis pneumococcal, Grand mal convulsion, Epilepsy, Hydrocephalus, Subdural hygroma, Subdural empyema, Anaemia, Generalised oedema, Ileus paralytic, Conjunctivitis, Septic shock, Pneumonia CONFIDENTIAL 155 CONFIDENTIAL 203 primary atypical, Neurosurgery, Pyrexia, Abdominal distension, Ill-defined disorder, Restlessness, Hyperaesthesia, Oligodipsia, Eye movement disorder, Hypertonia, Tachycardia, Oxygen saturation decreased, Ascites, Respiratory arrest, Drug ineffective, Cyanosis, Splenomegaly See Section 6.5.2.7.6 Meningitis pneumococcal.  D0070901A (Germany):Circulatory collapse, Respiratory arrest, Cyanosis, Hypotonic-hyporesponsive episode, Screaming, Agitation, Hypotonia, Peripheral coldness, Ill-defined disorder, Fatigue, Pyrexia This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011009758) and described the occurrence of circulatory collapse in a 12- week-old male subject who was vaccinated with combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline for prophylaxis. Co-suspect vaccinations included 13 valent pneumococcal conjugate vaccine (non-GSK) (Prevenar 13, Pfizer). Previous vaccinations were well tolerated. On 22 March 2011 the subject received 1st dose of Infanrix hexa (unknown route, left thigh), together with 1st dose of Prevenar 13 (unknown route, right thigh). On the same day, the subject experienced hypotonic-hyporesponsive episode with circulatory collapse. The event was resolved after 1 minute. The subject was hospitalised for observation. Electroencephalogram showed normal findings. A seizure was excluded. The reporting Health Professional was uncertain whether the event was life threatening. Follow-up was received from the regulatory authority on 25 August 2011, including a hospital report. The subject was hospitalised for 2 days from 22 to 23 March 2011. Possible affect spasm was diagnosed. On 22 March 2011, the subject experienced screaming and inability to calm down. On the arm of the mother, the subject suddenly experienced atonia and stopped breathing. The skin of the face was cyanotic (cyanosis). There was no clonus. The subject had cold skin. After 1-2 minutes, the events were resolved. Afterwards, the subject opened his eyes and was whining and tired. There was no vomiting. Body temperature was 37.6 degC (fever). There was no family history of chronic diseases or convulsive disorder. On admission examination, neurological examinations showed normal findings. During monitoring in the hospital there were no unusual neurological findings and no further spasm. On discharge from hospital the subject was in good general condition. Follow-up was received from the regulatory authority on 26 August 2011, including a questionnaire. There was no concurrent medical condition. There were no anamnestic characteristics. On 22 March 2011 the subject received 1st dose of Infanrix hexa (intramuscular, left thigh), together with 1st dose of Prevenar 13 (intramuscular, right thigh). On 22 March 2011, 7 hours after vaccination with Infanrix hexa and Prevenar 13, the subject experienced circulatory collapse and hypotonic-hyporesponsive episode. The event was resolved after stimulation, after approximately 1 minute. The subject was hospitalised. Blood-taking and electroencephalogram were performed and showed normal findings. The reporting physician considered that the events were related to vaccination with Infanrix hexa and Prevenar 13. The vaccination course with Infanrix hexa was discontinued. No further information will be available. CONFIDENTIAL 156 CONFIDENTIAL 204 Company comment: Case suggestive of breath holding spells in a 12-week-old male subject 7 hours after vaccination with 1st dose of Infanrix hexa and Prevenar. The event resolved after stimulation. The subject was hospitalized and no pathology was found.  D0071146A (Germany) Apparent life threatening event, Pallor, Loss of consciousness, Erythema, Respiratory arrest, Somnolence See Section 6.5.2.10.1 Apparent life threatening event.  D0071421A (Germany) Apparent life threatening event, Altered state of consciousness, Hypothyroidism, Neutropenia, Staring, Hypotonia, Pallor, Respiratory arrest, Crying See Section 6.5.2.10.1 Apparent life threatening event. 6.5.2.11. Skin and subcutaneous tissue disorders 6.5.2.11.1. Angioedema Four (4) cases of angioderma were reported over the period. These cases are described below.  B0691862A (Italy): Angioedema This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 130512) and described the occurrence of angioedema (face) in a 5-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevnar 13) for prophylaxis. On 17 December 2010 the subject received unspecified dose of Infanrix hexa (.5 ml, intramuscular, unknown), unspecified dose of Prevnar 13 (.5 ml, intramuscular, unknown). On 17 December 2010, less than one day after vaccination with Infanrix hexa and Prevnar 13, the subject experienced angioedema (face). This case was assessed as medically serious by GSK. Relevant test results included C-reactive protein (1.18 mg/dl), LDH (261 IU/L) and WBC (9590/mm3). On 18 December 2010, the event was resolved. The regulatory authority reported that the event was possibly related to vaccination with Infanrix hexa and Prevnar. No additional information could be obtained and this case has been closed. Company comment: Angioedema of the face in a 5-month-old female subject less than 1 day after combined vaccination with Infanrix hexa and Prevenar. The event resolved spontaneously within 1 day.  B0730009A (Italy): Angioedema, Urticaria This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 143398) and described the occurrence of angioedema in a 13-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. On 4 May 2011, the subject CONFIDENTIAL 157 CONFIDENTIAL 205 received 1st dose of Infanrix hexa (intramuscular, administration site unknown). On 4 May 2011, less than one day after vaccination with Infanrix hexa, the subject experienced angioedema and urticaria of right thigh. This case was assessed as medically serious by GSK. The subject was treated with ice. At the time of reporting, the outcome of the events was unspecified. Company comment: This case lacks data on the subject’s medical history and other possible diagnosis.  B0741876A (Italy): Angioedema This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 146655) and described the occurrence of giant urticaria in a 11-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Concurrent vaccination included pneumococcal vaccines (non-gsk) given on 17 August 2011. On 17 August 2011, the subject received unspecified dose of Infanrix hexa (unknown route of administration, unknown site of injection). On 17 August 2011, less than one day after vaccination with Infanrix hexa, the subject experienced giant urticaria. This case was assessed as medically serious by GSK. The subject was treated with betamethasone (Bentelan) and oxatomide (Tinset). At the time of reporting, the event was improved Company comment: This case lacks data on the subject’s medical history and other possible diagnosis.  B0749275A (Italy): Angioedema, Hyperaemia, Pyrexia This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 147929) and described the occurrence of giant urticaria in a 5-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. Concurrent vaccination included combined diphtheria, tetanusacellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. ;GlaxoSmithKline;unknown;unknown given on 20 June 2011. No adverse events occurred. On 18 August 2011, the subject received 2nd dose of Infanrix hexa (administration site and route unknown) and an unspecified dose of Prevenar 13 (unknown). On 18 August 2011, less than one day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced giant urticaria, hyperemic pharynx and fever (40 deg.C). This case was assessed as medically serious by GSK. The subject was treated with amoxicillin trihydrate (Amoxicillin) from 19 to 29 August 2011. On 28 August 2011, the events were resolved. Company comment: Case of angioedema in a 5-month-old female subject less than 1 day after vaccination with Infanrix Hexa and Prevenar. The event resolved after 10 days of antibiotherapy. The context of pyrexia might have triggered the event. In addition, one (1) case of Acute haemorrhagic oedema of infancy was received during the period: CONFIDENTIAL 158 CONFIDENTIAL 206  B0743733A (Argentina) Acute haemorrhagic oedema of infancy, Malaise, Tachycardia, Purpura, Pyrexia, Rash, Toxic skin eruption. This case was reported by a physician and described the occurrence of acute hemorrhagic edema of infancy in a 7-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Relevant medical history was not reported. Previous and/or concurrent vaccination included pneumococcal vaccines (non-gsk) given on 20 August 2011. On 20 August 2011, the subject received 3rd dose of Infanrix hexa (unknown route of administration, unknown site of injection). On 21 August 2011, within hours of vaccination with Infanrix hexa, the subject experienced high fever, exanthema and malaise. On 21 August 2011, he was taken to the emergency room where he was diagnosed with acute hemorrhagic edema of infancy. On 22 August 2011, he was examined by his pediatrician who noticed that the subject was tachychardic. He also presented a purpuric exanthema, his fever persisted and he had edema of the four limbs. The doctor assumed that the subject had a toxicodermia and treated him with corticoisteroids and antihistaminics. He controlled the subject 24 hours afterwards. He indicated evaluation by a dermatologist. The subject was not hospitalized. This case was assessed as medically serious by GSK. On 23 August 2011, the pediatrician reported that the subject responded well to the treatment. He had no fever and the edema has diminished. The purpuric lesions were fainter. Given the improvement of the subject, his mother did not consult a dermatologist. At the time of reporting, the events were improved. This case was closed since no additional information could be obtained. Company comment: Hemorrhagic edema of infancy (fever exanthema and malaise) in a 7-month-old male subject (acute less than 1 day after 3rd dose of Infanrix hexa. Due to the lack of medical data, the time sequence and assessment of causality remain dubious. 6.5.2.11.2. Erythema multiforme Two (2) cases of Erythema multiforme were received during the period:  D0069303A (Germany): Erythema multiforme This case was reported by a physician, via a web site, and described the occurrence of erythema exsudativum multiforme minor in a 9-month-old subject of unspecified gender who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccinations included pneumococcal vaccine (non-GSK) (Prevenar, Wyeth). The subject’s medical history included mild schonlein-henoch purpura after an infection when being 7 months old. On an unspecified date approximately in July 2010, the subject received 3rd dose of Infanrix hexa (unknown route and application site), together with 3rd dose of Prevenar (unknown route and application site). One day after vaccination with Infanrix hexa and Prevenar, the subject experienced erythema exsudativum multiforme minor. Laboratory values and IgE were normal. This case was assessed CONFIDENTIAL 159 CONFIDENTIAL 207 as medically serious by GSK. At the time of reporting, on 2 November 2010, the outcome of the event was unspecified. No further information will be available. Company comment: A 9-month-old subject developed minor erythema multiforme after 3rd dose of Infanrix hexa. This case lacks data on the subject’s medical history, data confirming the diagnosis (biopsy), and other possible diagnoses.  D0072847A (Germany): Erythema multiforme, Urticaria, Arthropod bite, Swelling, Erythema, Pyrexia, Hypertonia, Herpes simplex, Rash, General physical health deterioration This case was reported by a physician and described the occurrence of erythema exsudativum multiforme in a 2-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccine included rotavirus vaccine (RotaTeq). There were no concurrent medications, no concurrent medical conditions or any other risk factors. On 15 July 2011 the subject received 1st dose of Infanrix hexa (intramuscular, left gluteal). An unspecified time after vaccination the subject experienced urticaria. On 12 August 2011 the subject received 2nd dose of Infanrix hexa (intramuscular, left gluteal) and unspecified dose of RotaTeq (oral). In the evening the subject experienced fever. The subject was hospitalized from 17 August 2011 to 21 August 2011 because of parainfectious erythema exsudativum multiforme and differential diagnosis urticaria. The subject was admitted to hospital by the rescue service. The mother reported that the subject showed several mosquito bites in the morning. The subject was treated with zinc oxide and vileda. In the evening the subject’s mother used chamomile bath for the first time. At admission to hospital the subject showed swelling and erythema on whole body. There was no shortness of breath. The subject was drinking well. The subject was in good nutrient condition and showed reduced general condition. There was no itching. Ear, nose and throat were bland. Urticarial maculopapular exanthema was on whole body with maximum on trunk. Flexion tone was increased. Internal and neurological examination was age-corresponding inconspicuously. Laboratory tests showed increased IgM values for Herpes II (9 U per ml). The subject was treated with intravenous infusion, intravenously with prednisolone and with cetirizine hydrochloride drops. The exanthema was intermittent. Because of herpes II serology finding the physician suspected erythema exsudativum multiforme. The subject was discharged from hospital on 21 August 2011 with improving exathema. Latest on 24 August 2011 all events were resolved. On 20 September 2011 the subject received 3rd dose of Infanrix hexa (intramuscular, left gluteal) and unspecified dose of RotaTeq (oral). On the same day the subject experienced fever. From 24 September 2011 on the subject developed rash with increasing efflorescences. The subject was treated in emergency admission on 25 September 2011. Urticarial multiform exanthema was diagnosed as suspected vaccination reaction. The subject was treated with prednisolone acetate. In September 2011, the events were resolved. According to treating physician urticaria was unlikely related to vaccination with Infanrix hexa. No further information will be available. Company comment: A 2-month-old subject developed erythema multiforme 5 days after 2nd dose of Infanrix hexa and RotaTeq. This case lacks data confirming the CONFIDENTIAL 160 CONFIDENTIAL 208 diagnosis (biopsy), and other possible diagnosis. Conversely, a medical history of Herpes type II and recent mosquito multiple bites was noted. Causal relationship with the vaccination was unlikely. 6.5.2.11.3. Henoch-Schonlein purpura Two (2) cases of Henoch-Schonlein purpura were received during the period:  B0710915A (France): Henoch-Schonlein purpura, Contusion This case was reported by a consumer and described the occurrence of rheumatic purpura in a 5-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. A physician or other health care professional has not verified this report. Concurrent medical conditions included a cold on 10 March 2011. First dose of Infanrix hexa associated with pneumococcal vaccine (Prevenar) was well tolerated. On 22 March 2011, the subject received a 2nd dose of Infanrix hexa (batch and route unknown, unknown thigh). On 27 March 2011, 5 days after vaccination with Infanrix hexa, the subject’s mother noticed the presence of bruises on all vaccinated leg from knee to toes and on the other leg with a lower intensity (coded bruises on bilateral lower legs). At emergency service, where blood and urine analyses were performed (results not provided), the physician diagnozed a rheumatic purpura. According to the mother, the physician said that it was not very probable that rheumatic purpura was related to vaccination with Infanrix hexa and might be related to a virus infection. The subject was not hospitalized and was discharged without any treatment. On 04 April 2011, a few bruises persisted and purpura was clearly improved. This case was assessed as medically serious by GSK. At the time of reporting, the events were improved. Company comment: Case of a possible Henoch-Schonlein purpura in a 5-month-old subject 5 days after 2nd vaccination with Infanrix and Prevenar. This case lacks laboratory confirmation of the diagnosis.  D0070216A (Germany): Henoch-Schonlein purpura, Thrombocytopenia, Petechiae, Pyrexia, Upper respiratory tract infection, Anaemia This case was reported by a physician, via a sales representative, and described the occurrence of Schoenlein-Henoch purpura in a nearly 9-month-old subject of unspecified gender who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. The subject was born as hypoplastic neonate with cyanosis and hypoglycaemia, after treatment with ampicillin due to premature rupture of the amnion. The subject’s family were smokers. Former vaccinations were well tolerated. On 1 April 2010 the subject received 3rd dose of Infanrix hexa (intramuscular, left thigh). On an unspecified date in April 2010 the subject developed generalised exanthema and fever of 39 degC. On 29 April 2010 the subject was hospitalised with Schoenlein-Henoch purpura and thrombocytopenia. At the time of reporting all events were resolved. After the next vaccination with Infanrix hexa the events did not recur. The physician considered CONFIDENTIAL 161 CONFIDENTIAL 209 Schoenlein-Henoch purpura and thrombocytopenia were probably related to vaccination with Infanrix hexa. The subject was hospitalised from 29 April to 03 May 2010. According to the hospital report, the subject was diagnosed with thrombocytopenia and infection of the upper airways. When admitted to hospital the subject had petechial exanthema and mild fever. There was no previous infection. The subject had no cough, diarrhea, vomiting or denial of food. The subject had thrombocytopenia with an initial platelet count of 21 Gpt/L. This increased to 98 Gpt/l in further course without treatment. There was a mild initial anemia, but haemoglobin and hematocrit values increased in further course. Additionally a mildly increased c-reactive protein (CRP) was found. The subject was treated with ibuprofen and fluoride + Vitamin D (Zymafluor D). When the subject was discharged, the events were nearly resolved. Company comment: A nearly 9-month-old subject experienced HSP with 3rd dose of Infanrix Hexa. The subject had an upper respiratory infection prior to this event. The case lacks other laboratory data (antibody testing, plasma D-dimers, PT, etc) to confirm the diagnosis. CONFIDENTIAL 162 CONFIDENTIAL 210 6.5.2.11.4. Petechia e Twenty nine (29) cases of Petechia e were reported during the period , out of which 20 cases were quoted as serious. In 11/20 serious cases a haematologic disorder was associated: (Idiopathic or non specified) thrombocytic purpura (n=7), thrombocytopenia (n=.3), hemorrhagic diathesis (n=1). These cases are summarized in Table 26. Table 26 Summary of cases of Petechiae received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0684234A 09 -Nov -10 Unknown 10 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 10 Days Idiopathic thrombocytopenic purpura, Thrombocytopenia, Rhinitis, Petechiae, Pyrexia Italy B0686840A 3 0 -Nov -10 Resolved 5 Months Male Infanrix hexa 3 Hours Idiopathic thrombocytopenic purpura, Febrile convulsion, Clonic convulsion, Tremor, Dyskinesia, Petechiae, Platelet count decreased, Pyrexia Czech Republic Cytomegalo virus viraemia, Familial risk factor, Myocardial infarction B0693767A 07 -Jan -11 Improved 6 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 18 Days Thrombocytopenic purpura, Petechiae, Haematoma, Epistaxis, Splenomegaly, Thrombocytopenia, Gingival bleeding France B0693944A 1 3 -Jan -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Thrombocytopenic purpura, Petechiae, Haematoma Czech Republic B0694143A 18 -Jan -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Thrombocytopenia, Petechiae, Pyrexia Italy CONFIDENTIAL 163 CONFIDENTIAL 211 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0700205A 14 -Feb -11 Improved 4 Months Female Infanrix hexa 1 Days Petechiae Italy B0703972A 04 -Mar -11 Resolved 11 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non – GSK), Vitamin K 1 Days Vasodilatation, Petechiae, Erythema, Skin warm France B0705987A 09 -Mar -11 Unknown 8 Months Male Infanrix hexa 1 Months Idiopathic thrombocytopenic purpura, Haemorrhage, Platelet count decreased, Petechiae, Fall, Increased tendency to bruise, Upper respiratory tract infection Ireland B0709033A 22 -Mar -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 10 Minutes Slow response to stimuli, Hypotonia, Rash macular, Petechiae, Ecchymosis, Conjunctival haemorrhage, Rash, Joint hyperextension Italy B0714101 A 18 -Apr -11 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) 2 Hours Pyrexia, Skin warm, Petechiae Netherlan ds B0715209A 20 -Apr -11 Resolved 13 Months Female Infanrix hexa 5 Days Erythema nodosum, Arthralgia, Petechiae Netherlan ds Respiratory syncytial virus infection B0724575A 07 -Jun -11 Unknown 19 Months Male Infanrix hexa, MMR vaccine (Non -GSK) 20 Days Thrombocytopenic purpura, Thrombocytopenia, Petechiae, Injection site haematoma France Bronchiolitis , Upper respiratory tract infection CONFIDENTIAL 164 CONFIDENTIAL 212 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0727162A 16 -Jun -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Immediate Skin discolouration, Screaming, Oedema peripheral, Skin tightness, Oedema genital, Petechiae, Pyrexia, Crying, Injection site pain Netherlan ds B0728665A 24 -Jun -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 8 Hours Viral infection, Petechiae, Pyrexia, Vomiting Netherlan ds B0728714A 20 -Jun -11 Resolved 6 Months Male Infanrix hexa, Synflorix 3 Hours Lividity, Ecchymosis, Anxiety, Petechiae, Erythema, Crying, Body temperature increased, Hypersensitivity, Restlessness Poland B0729750A 13 -Jun -11 Resolved 14 Months Male Infanrix hexa, MMR vaccine (Non -GSK) Cefaclor 0 Days Petechiae Italy Otitis media acute B0731112A 05 -Jul -11 Unknown 2 Months Male Infanrix hexa, Rotavirus vaccine (Non – GSK), Pneumococcal vaccines (Non – GSK), Meningococcal vaccine Domperidone, Ranitidine hydrochloride, Carbocisteine 0 Days Apnoea, Skin discolouration, Pallor, Rash macular, Erythema, Fatigue, Pyrexia, Vomiting, Cough, Crying, Petechiae, Hyperhidrosis, Hypersensitivity, Hypotonic – hyporesponsive episode, General physical health deterioration Brazil Neonatal hypoxia, Gastrooeso phageal reflux disease B0737478A 30 -Mar -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 8 Hours Haemorrhagic diathesis, Petechiae, Pyrexia Poland B0740099A 11 -Aug -11 Resolved 4 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Hours Idiopathic thrombocytopenic purpura, Petechiae, Diarrhoea, Inflammation, Pyrexia Netherlan ds CONFIDENTIAL 165 CONFIDENTIAL 213 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0756825A 11 -Oct -11 Improved 2 Months Female Infanrix hexa, Synflorix 2 Days Petechiae, Skin discolouration Netherlan ds D0070216A 04 -Feb -11 Resolved 9 Months Male Infanrix hexa 28 Days Henoch -Schonlein purpura, Thrombocytopenia, Petechiae, Pyrexia, Upper respiratory tract infection, Anaemia Germany Respiratory fume inhalation disorder, Hypoglycae mia neonatal, Ill – defined disorder, Cyanosis neonatal D0070397A 21 -Feb -11 Resolved 3 Months Male Rotavirus vaccine, Infanrix hexa, Pneumococcal vaccines (Non – GSK) 1 Days Haemorrhagic diathesis, Ecchymosis, Petechiae, Upper respiratory tract infection Germany Ventricular septal defect, Atrial septal defect D0071125A 21 -Apr -11 Unknown 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) D -fluoretten 12 Days Thrombocytopenia, Gastroenteritis rotavirus, Leukopenia, Petechiae, Haematoma, Ureteric stenosis, Pyelocaliectasis Germany D0071437A 18 -May -11 Unknown 4 Months Female Infanrix hexa 0 Days Petechiae, Skin discolouration Germany D0072050A 14 -Jul -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) 0 Days Anaphylactic reaction, Swelling, Erythema, Crying, Petechiae Germany D0072425A 17 -Aug -11 Resolved 24 Months Male Infanrix hexa, Priorix 7 Days Thrombocytopenia, Petechiae, Haematoma Germany CONFIDENTIAL 166 CONFIDENTIAL 214 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072500A 25 -Aug -11 Unknown 13 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non – GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK), Sodium Fluoride 5 Minutes Anaphylactoid reaction, Hypersensitivity, Product quality issue, Urticaria, Rash, Apathy, Anaphylactic reaction, Erythema, Petechiae, Injection site erythema Germany Hyperbilirubi naemia, Phototherap y, Rhinitis D0072611A 06 -Sep -11 Resolved 3 Months Male Infanrix hexa 5 Hours Petechiae, Haematoma Germany D0072699A 13 -Sep -11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non – GSK) Unknown Petechiae, Oedema peripheral Germany CONFIDENTIAL 167 CONFIDENTIAL 215 6.5.2.11.5. Purpura Three (3) cases of Purpura were received during the period:  B0705315A (France): Purpura, Pyrexia, Injection site erythema, Injection site oedema, Injection site induration, Rash macular. This case was reported by a pharmacist and a physician and described the occurrence of fever in a 16-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Previous vaccinations with such type of vaccine were well tolerated. On 03 March 2011, the fourth dose of Infanrix hexa was administered intramuscularly in unknown thigh (probably the right). On 07 March 2011, the subject received a booster dose of Infanrix hexa (batch A21CA784A, route and injection site unknown). Twelve hours later, the subject experienced severe fever (40-41 degrees Celsius) during 24 hours, mild induration at injection site during 3 days and mild petechial purpura of extremities associated with erythematous macules (coded rash erythematous macular) which lasted 3 days. On 10 March 2011, platelets were at 217000/mm3. The subject was treated with paracetamol (Doliprane). The reporter considered that the events were clinically significant (or requiring intervention) and resolved. The reporter considered the events as almost certainly related to vaccination with Infanrix hexa.  B0743959A (Italy): Purpura. This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 146768) and described the occurrence of purpura in a 3-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. On 18 May 2011, the subject received unspecified dose of Infanrix hexa (unknown administration route, unspecified injection site) and unspecified dose of Prevenar 13 (unknown administration route, unspecified injection site). On 18 May 2011, less than one day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced purpura on face and extremities. At the time of reporting, the outcome of the event was unspecified. No more information was expected. Therefore, this case has been closed.  B0743733A (Argentina) Acute haemorrhagic oedema of infancy, Malaise, Tachycardia, Purpura, Pyrexia, Rash, Toxic skin eruption See Section 6.5.2.11.1 Angioderma. 6.5.2.11.6. Subcutaneous nodule Two (2) non-serious cases of Subcutaneous nodule were received during the period: CONFIDENTIAL 168 CONFIDENTIAL 216  B0740908A (Poland): Injection site reaction, Subcutaneous nodule. This case was reported by a physician and described the occurrence of injection site reaction in a 4-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. No adverse event was reported after the two previous doses of Infanrix hexa. On 21 July 2011, the subject received 3rd dose of Infanrix hexa (intramuscular, unknown injection site). On 22 July 2011, 1 day after vaccination with Infanrix hexa, the subject experienced injection site reaction (3cm diameter). On 15 August 2011, injection site reaction resolved. 3 weeks after vaccination with Infanrix hexa, a subcutaneous hard nodule (5x10cm) was perceptible on injection site. At the time of reporting the outcome of the subcutaneous hard nodule was unspecified. The physician reported that the injection site reaction was almost certainly related to vaccination with Infanrix hexa.  B0745076A (France): Subcutaneous nodule, Injection site pruritus, Injection site eczema, Injection site induration, Injection site nodule. This case was reported by a dermatologist and described the occurrence of subcutaneous nodule in a two-year-old subject of unspecified gender who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), combined diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrixquinta) for prophylaxis. Medical history and concurrent medications were unspecified. On an unspecified date, the subject received 1st dose of Infanrix Hexa (unknown batch, route and injection site). One month later, on an unspecified date, the subject received 2nd dose of Infanrix Quinta (unknown batch, route and injection site). One month later, on an unspecified date in 2011, the subject received 3rd dose of Infanrix Hexa (unknown batch, route and injection site) (inappropriate age at vaccine administration). In 2011, three weeks after vaccination with Infanrix Hexa, the subject experienced pruritus and eczematiform aspect at injection site with subcutaneous nodules. At the time of reporting, the events subcutaneous nodule, injection site pruritus and injection site eczema were unresolved. Causality assessment was not provided. Upon follow-up received on 27 September 2011: First dose of Infanrix hexa was administered on 09 November 2010 intramuscularly in left thigh. On 02 August 2011, an ultrasound scan showed an aspect of an unspecified fibrous granuloma (coded injection site granuloma) on 10 cm with scratching lesions. At the time of reporting, events were improved and Infanrix hexa was not readministered. The dermatologist considered the events were almost certainly related to vaccination with Infanrix hexa. CONFIDENTIAL 169 CONFIDENTIAL 217 6.5.2.11.7. Urticaria, Urticaria p apular and Urticaria thermal Sixty seven (67) cases of Urticaria/Urticaria p apular/Urticaria thermal were received during the period, out of which 18 were serious . Summary information for the complete set of reports is shown in Table 27 and Table 28. These tables also include one case received prior to the period of this report but never included in a previous PSUR (D0066224A). This case’s ID is marked by a ‘*’ in Table 28. Table 27 Summary of information complete data set (n=68 ) Patient age (n=65 ) Range months 2 -33 Median months 7.5 Patient gender (n=6 3 ) Male n 34 Female n 29 Report type Spontaneous n 68 Time to onset of event Range (hour) hours 0 -48 Median days less than 1 day n 47 Outcome (n=68) Resolved n 48 Improved n 5 Unresolved n 2 Unknown n 13 Concomitant vaccine administered n 5 Table 28 Cases of Urticaria , Urticaria p apular and Urticaria thermal received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0682359A 20 -Oct -10 Resolved 2 Months Female Infanrix hexa 0 Days Urticaria Italy B0682837A 29 -Oct -10 Unknown 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 2 Days Urticaria Italy CONFIDENTIAL 170 CONFIDENTIAL 218 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0684237A 09 -Nov -10 Resolved 11 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 4 Days Urticaria Italy B0684873A 16 -Nov -10 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria Italy B0686074A 25 -Nov -10 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Cyanosis, Urticaria Italy B0687294A 02 -Dec -10 Unknown 16 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Urticaria France B0689830A 17 -Dec -10 Resolved 20 Months Infanrix hexa 0 Days Injection site erythema, Body temperature increased, Urticaria Poland B0690266A 20 -Dec -10 Resolved 6 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Erythema, Urticaria, Pyrexia Italy B0692086A 30 -Dec -10 Improved 1 Years Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria, Pyrexia Italy B0692144A 04 -Jan -11 Resolved 2 Years Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria, Pyrexia Italy B0692145A 04 -Jan -11 Improved 11 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Erythema, Urticaria, Injection site pain Italy B0692425A 06 -Jan -11 Resolved 3 Months Female Infanrix hexa, EMLA 2 Days Urticaria France B0696210A 26 -Jan -11 Resolved 11 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Eyelid oedema, Localised oedema, Urticaria Italy Pyrexia, Cough CONFIDENTIAL 171 CONFIDENTIAL 219 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0696865A 28 -Jan -11 Resolved 3 Months Male Infanrix hexa 0 Days Urticaria Italy B0697023A 26 -Jan -11 Unknown 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Urticaria Italy B0697049A 26 -Jan -11 Unknown 3 Months Male Infanrix hexa, Synflorix 1 Weeks Impetigo, Urticaria papular, Rash erythematous, Rash vesicular, Rash pruritic, Rash macular Sweden B0699683A 11 -Feb -11 Unknown 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria Italy B0701038A 17 -Feb -11 Resolved 14 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Rash papular, Urticaria, Injection site oedema Italy B0701091A 18 -Feb -11 Resolved 1 Years Male Infanrix hexa, Pneumococcal vaccines (Non-GSK) 1 Days Rash maculo -papular, Urticaria, Injection site oedema, Injection site erythema Italy B0703168A 23 -Feb -11 Resolved 13 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Urticaria, Pyrexia Italy B0705201A 08 -Ma r -11 Resolved 2 Months Male Infanrix hexa Calcium salt 0 Days Somnolence, Urticaria, Acne Romania B0709029A 24 -Mar -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Pyrexia, Urticaria Netherlands B0709851A 25 -Mar -11 Resolved 3 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Lansoprazole, Arnica flower, Fluoride salt 15 Minutes Urticaria Italy CONFIDENTIAL 172 CONFIDENTIAL 220 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0709866A 25 -Mar -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) Chamomile 15 Minutes Urticaria Italy B0714105A 12 -Apr -11 Resolved 3 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria, Decreased appetite Italy B0714276A 13 -Apr -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Minutes Rash, Urticaria Italy Atopy B0714303A 13 -Apr -11 Unknown 1 Years Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Urticaria Italy B0722859A 26 -May – 11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Sodium Fluoride, Colecalciferol 0 Days Urticaria Italy B0723046A 24 -May – 11 Resolved 1 Years Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria, Pyrexia Italy B0724189A 12 -May – 11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria, Pyrexia Italy B0726175A 19 -May – 11 Resolved 20 Months Unknown Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Injection site warmth, Injection site reaction, Urticaria, Pyrexia Poland B0726356A 08 -Jun -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria Italy B0726435A 08 -Jun -11 Improved 15 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Face oedema, Urticaria, Pyrexia Italy CONFIDENTIAL 173 CONFIDENTIAL 221 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0726556A 20 -May – 11 Resolved 2 Months Male Infanrix hexa, Rotavirus vaccine 1 Days Urticaria, Rash Poland B0729166A 20 -Jun -11 Resolved 3 Months Female Infanrix hexa, Meningococcal polysaccharide vaccine group C (Non – GSK), Synflorix 3 Weeks Pemphigoid, Leukocytosis, Thrombocytosis, Blister, Scab, Skin lesion, Pruritus, Eosinophilia, Urticaria Spain B0729681A 29 -Jun -11 Unknown 16 Months Female Infanrix hexa 4 Hours Urticaria, Pyrexia, Diarrhoea France B0729732A 13 -Jun -11 Resolved 13 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Blister, Urticaria, Pyrexia Italy B0730009A 30 -Jun -11 Unknown 13 Months Female Infanrix hexa 0 Days Angioedema, Urticaria Italy B0731863A 08 -Jul -11 Resolved 6 Months Male Infanrix hexa, Meningococcal polysaccharide vaccine group C (Non – GSK), Pneumococcal vaccines (Non -GSK) 1 Days Urticaria, Tonsillitis Ireland B0732862A 30 -Jun -11 Resolved 2 Months Female Infanrix hexa, Rotavirus vaccine, Pneumococcal vaccines (Non -GSK) 3 Minutes Skin warm, Urticaria papular, Erythema, Urticaria Belgium B0733556A 13 -Jul -11 Resolved 2 Months Male Infanrix hexa 0 Days Urticaria Italy B0735456A 21 -Jul -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Allergy to vaccine, Urticaria, Pyrexia, Rash maculo – papular Italy CONFIDENTIAL 174 CONFIDENTIAL 222 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0737088A 03 -Aug -11 Resolved 2 Months Male Infanrix hexa, Infanrix – polio -HIB Pneumococcal vaccines (Non -GSK), Bacillus Calmette – Guerin Vaccine (Non – GSK) 15 Minutes Urticaria, Rash macular, Hypersensitivity France B0739944A 1 1 -Aug -11 Resolved 6 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria Italy B0742850A 25 -Aug -11 Resolved 2 Months Unknown Infanrix hexa, Infanrix – polio -HIB Pneumococcal vaccines (Non -GSK) 1 Days Urticaria France B0743870A 0 1 -Sep -11 Resolved 33 Months Male Infanrix hexa Antihistamine 0 Days Hypersensitivity, Pyrexia, Face oedema, Urticaria, Injection site inflammation France Penile oedema, Pyrexia, Bronchioliti s, Bronchitis B0744411A 02 -Sep -11 Resolved 2 Months Female Priorix, Infanrix hexa 5 Days Oedema, Diarrhoea, Vomiting, Urticaria, Transaminases increased, Drug administered to patient of inappropriate age, Papule, Crying, Pain France B0745839A 05 -Sep -11 Improved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Pyrexia, Urticaria Italy CONFIDENTIAL 175 CONFIDENTIAL 223 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0745845A 08 -Sep -11 Resolved 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria, Dyspnoea Italy B0747658A 15 -Sep -11 Unknown 27 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK ) 0 Days Urticaria Italy B0750855A 20 -Sep -11 Resolved 1 Years Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticaria Italy B0754395A 27 -Sep -11 Improved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 2 Hours Urticaria Ital y B0756170A 14 -Oct -11 Resolved 19 Months Unknown Infanrix hexa 0 Days Injection site reaction, Injection site warmth, Pyrexia, Urticaria Poland B0757243A 21 -Oct -11 Unknown 2 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Urticari a France D0066224A * 26 -Jan -10 Resolved 4 Months Female Infanrix hexa, Synflorix 3 Days Urticaria Germany D0069348A 05 -Nov -10 Resolved 4 Months Female Infanrix hexa, Synflorix Infanrix hexa, Synflorix 1 Days Urticaria Germany D0069379A 09 -Nov -10 Resolved 9 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non -GSK) 20 Hours Urticaria, Swelling, Erythema, Feeling hot Germany D0069457A 17 -Nov -10 Resolved 27 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Day s Urticaria Germany Multiple allergies CONFIDENTIAL 176 CONFIDENTIAL 224 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069610A 02 -Dec -10 Unresolved 1 Years Female Infanrix hexa, Vaccine 0 Years Urticaria, Granuloma, Injection site swelling, Injection site erythema, Injection site induration, Pyrexia Germany D0070154A 01 -Feb -11 Unknown Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Unknown Urticaria Germany D0070854A 31 -Mar -11 Resolved 3 Months Male Infanrix hexa 8 Hours Urticaria Germany Familial risk factor, Dermatitis atopic D0070920A 06 -Apr -11 Resolved 3 Months Male Infanrix hexa, Synflorix 1 Days Urticaria Germany D0071119A 20 -Apr -11 Unknown Unknown Infanrix hexa 4 Hours Urticaria Germany D0071406A 17 -May – 11 Resolved 6 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Ergocalciferol 1 Hours Urticaria, Rash, Rash erythematous, Blister, Restlessness, Cough, Skin reaction Germany Patent ductus arteriosus, Pneumonia respiratory syncytial viral D0071462A 20 -May – 11 Resolved 10 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 2 Days Urticaria Germany CONFIDENTIAL 177 CONFIDENTIAL 225 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072500A 25 -Aug -11 Unknown 13 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Infanrix hexa, Pneumococcal vaccines (Non -GSK), Sodium Fluoride 5 Minutes Anaphylactoid reaction, Hypersensitivity, Product quality issue, Urticaria, Rash, Apathy, Anaphylactic reaction, Erythema, Petechiae, Injection site erythema Germany Hyperbilirub inaemia, Photothera py, Rhinitis D0072586A 02 -Sep -11 Unresolved Male Infanrix hexa 34 Days Urticaria thermal Germany D0072847A 26 -Sep -11 Resolved 2 Months Mal e Infanrix hexa, Rotavirus vaccine (Non -GSK) 0 Days Erythema multiforme, Urticaria, Arthropod bite, Swelling, Erythema, Pyrexia, Hypertonia, Herpes simplex, Rash, General physical health deterioration Germany CONFIDENTIAL 178 CONFIDENTIAL 226 6.5.2.12. Vascular disorders 6.5.2.12.1. Circulatory collapse Seven (7) cases of Circulatory collapse were receved during the period:  B0698663A (Italy): Anaphylactic reaction, Circulatory collapse, Slow response to stimuli, Cyanosis, Hypotonia, Hypothermia, Pallor, Bradycardia, Oxygen saturation decreased, Pyrexia. See Section 6.5.2.6.2 Anaphylactic/Anaphylactoid reaction and Drug hypersensitivity.  B0713106A (Netherlands): Circulatory collapse, Cyanosis, Pallor This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-116677) and described the occurrence of circulatory collapse in a 12-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. No concomitant medication was reported. The subject had no known past drug therapy and had no known medical history. On 4 November 2010 the subject received unspecified dose of Infanrix hexa (intramuscular, unknown site of injection, batch number not provided) and unspecified dose of Prevenar (intramuscular, unknown site of injection, batch number not provided). On 4 November 2010, 22 hours after vaccination with Infanrix hexa and Prevenar, the subject experienced circulatory collapse with blue lips and pallor. When the subject was taken out of the bed, he recovered rapidly. This case was assessed as medically serious by GSK. The regulatory authority reported that the events were probably related to vaccination with Infanrix hexa and Prevenar. Further details will be provided by the Reporting Authority whenever available. Company comment: Case of near SUDI in a 12-month-old male subject 22 hours after combined vaccination with Infanrix hexa and Prevenar. The event resolved after stimulation.  D0069341A (Germany):Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed level of consciousness, Hypokinesia, Bronchitis See Section 6.5.2.2.2 Cardiac arrest.  D0069460A (Germany): Circulatory collapse, Apathy, Pallor, Asthenia, Heart rate decreased, Screaming, Staring This case was reported by a physician, via a sales representative, and described the occurrence of apathy in a 3-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated CONFIDENTIAL 179 CONFIDENTIAL 227 poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Co-suspect vaccination included pneumococcal vaccines (Prevenar 13, Pfizer). On 14 October 2010 the subject received 1st dose of Infanrix hexa (unknown route and injection site) and contralaterally Prevenar 13 (unknown route and injection site). Minutes after vaccination, after the child screamed shortly, he experienced fixed gaze, and was weak and very pale (grey face colour). The subject was breathing spontaneously. Oxygen was administered. The emergency physician admitted the subject to the hospital. The subject was observed for 24 hours with no new findings. After that the subject was feeling well. Concurrent medications included Ergocalciferol (Vigantoletten). There were no concurrent medical conditions or any other risk factors. The next vaccination with Infanrix hexa and Prevenar 13 took place in hospital with monitoring of circulation. The events did not recur. The physician considered the events were probably related to vaccination with Infanrix hexa. All events were resolved. Company comment: Case of circulatory collapse in a 3-month-old male subject minutes after 1st vaccination with Infanrix hexa and Prevenar. The event resolved after oxygen therapy. No new event after monitored 2nd vaccination.  D0070901A (Germany):Circulatory collapse, Respiratory arrest, Cyanosis, Hypotonic-hyporesponsive episode, Screaming, Agitation, Hypotonia, Peripheral coldness, Ill-defined disorder, Fatigue, Pyrexia See Section 6.5.2.10.3 Respiratory arrest.  D0071446A (Germany): Hypotonic-hyporesponsive episode, Circulatory collapse, Apathy, Pallor This case was reported by a physician and described the occurrence of hypotonichyporesponsive episode in an 8-week-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccine (non-gsk, Prevenar) for prophylaxis. On 15 April 2011 the subject received the first dose of Infanrix hexa ((batch number A21CB071A, unknown thigh) together with the first dose of Prevenar (other thigh). Six hours after vaccination, the subject fell pale, collapsed and became apathic. The subject was hospitalised. The patient had completely recovered at the time of reporting Follow-up information was received on 27 May 2011 via another manufacturer (PFIZER-INC, DE-PFIZER-INC-2011108012). The following narrative was provided: “The reporting physician was informed by the patient’s mother that after vaccination the patient has collapsed. This collapse was described as follows: When the patient’s father arrived at home he noticed that the patient was “snow-white”. When he then picked up his child the patient’s head fell to the side. The patient was still awake but seemed to be apathic. The parents immediately went to a local hospital. However, in hospital no physical examination was performed but the clinician only stated to the parents: “No wonder after receiving the vaccines”. Company comment: Case of possible circulatory collapse in an 8-week-old male subject 6 hours after 1st combined vaccination with Infanrix hexa and Prevenar. The event was resolved after stimulation. No further examinations were performed. CONFIDENTIAL 180 CONFIDENTIAL 228  D0072852A (Germany): Circulatory collapse, Sepsis, Shock, Crying, Pallor Ses Section 6.5.1 Cases with a fatal outcome. 6.5.2.12.2. Kawasaki’s disease Three (3) cases of Kawasaki’s disease were reported during the period:  B0691861A (Italy): Kawasaki’s disease, Rash maculo-papular, Diarrhoea, Pyrexia, Cheilitis, Skin exfoliation, Oedema peripheral, Erythema This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 130459) and described the occurrence of Kawasaki’s disease in a 2-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevnar) for prophylaxis. Concurrent medical conditions included G6PD deficiency, conjunctivitis and upper respiratory tract infection. On 11 November 2010 the subject received unspecified dose of Infanrix hexa (intramuscular, unknown), unspecified dose of Prevnar (intramuscular, unknown). On 13 November 2010, 2 days after vaccination with Infanrix hexa and Prevnar, the subject experienced maculo-papular exanthema on trunk, spreading to the whole body and face, diarrhea and high fever. On 14 November 2010, the baby was hospitalised due to these symptoms. After 4 days of hospitalisation, the baby presented cheilitis, perianal desquamation, pedal edema and erythema of soles of feet with persisting fever. Kawasaki disease was suspected. Relevant test results included ECG (normal), chest X-ray on 16 November 2010 and 21November 2010 (both negative), echocardiogram (mild pericardial effusion), ultrasound of the abdomen (mild fluids below liver and behind bladder as well as troponin (normal). The subject was treated with antibiotics, anti-inflammatory (Antiinflammatory), IgG (IV, 20 unt/kg) and dipyridamole (Dipiridamol). At the time of reporting the outcome of the events was unspecified. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevnar. Company comment: Kawasaki’s disease in a 2-month-old male subject 2 days after combined vaccination with Infanrix Hexa and Prevenar.  D0070921A (Germany): Kawasaki’s disease, Pyelonephritis, Pyrexia, Infection, Somnolence, Fluid intake reduced, General physical health deterioration, Pallor, Ill-defined disorder, Rash, Conjunctivitis, Erythema, Enanthema, Chapped lips, Hypertrophy of tongue papillae This case was reported by a physician via regulatory authority (DE-Paul-EhrlichInstitut # DE-PEI-PEI2011009954) and described the occurrence of Kawasaki syndrome in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. According to completed questionnaire, signed on 23 March 2011, on 28 February 2011 the subject received 1st dose of Infanrix hexa (intramuscular, left thigh). On 03 March 2011, 3 days after vaccination with Infanrix hexa, the subject CONFIDENTIAL 181 CONFIDENTIAL 229 experienced Kawasaki’s syndrome for several days. Diagnose was based on clinical symptoms and exclusion of other causes for fever after puncture of cerebrospinal fluid and urinary bladder. By differential diagnosis, sepsis, meningitis and urinary tract infection have been excluded. The subject was hospitalised and the reporter reported that the events were life threatening. In March 2011, the event was resolved. According to provided hospital report from paediatric unit, signed on 17 March 2011, the subject was hospitalised from 02 to 11 March 2011. Kawasaki’s syndrome and haemangioma were diagnosed. The subject’s medical history included premature baby (after 34th weeks of pregnancy). She was a twin. Postpartal the subject developed streptococcal infection, which was treated. Concurrent medical conditions included congenital hemangioma at back and forehead. There were no concurrent medical conditions, no continuous medications and no known allergies. On 28 February 2011 the subject received 1st dose of Infanrix hexa. On 28 February 2011 in the evening, the subject experienced fever with a body temperature up to 39.3 degC. The subject was treated with paracetamol on 28 February or 01 March 2011 in the evening and on 01 March or 02 March 2011 in the morning. Since 28 February 2011, the subject was sleeping a lot (sleepiness) and drinking less (fluid intake reduced). Blood examination showed increased value of C-reavtive protein (75 mg/L). By examination of urine via test strip, leucocytes were shown. The subject was hospitalised due to unclear highly febrile infection and suspected pyelonephritis. On admission examination, the subject was in reduced general condition. Skin coloration was mildly pale (paleness of skin). There were no signs for meningism. Values of inflammation were shown to be distinctly increased. Initially, urinary tract infection was suspected due to unusual urine test of urine bag. Puncture of bladder showed very low increased leukocyte count (15/mcl). Puncture of liquor showed also normal values. The subject was treated with cefotaxime (Cefotaxim) and mezlocillin. On the following day, the subject developed increasing exanthema on whole trunk and in further course non-purulent conjunctivitis, erythema at palmar and and plantar as well as a distinct enanthema with chapped lip and hypertrophy of tongue papillae. During treatment with antibiotics, fever remained. Due to clinical signs and fever, Kawasaki’s syndrome was suspected. The subject was treated with normal immunoglobulin (Immunoglobulin) two times (2 g/kg body weight). Treatment with antibiotics was discontinued. Symptoms improved, fever resolved. By echocardiography, no coronary aneurism could be detected. The subjected was treated with aspirin (ASS, 3-5 mg/kg body weight/d) for prophylaxis. During hospitalisation, small haemangioma at forehead and a bigger one at back were treated with cryosurgery (Cryotherapy). Symptoms resolved and subject was discharged in good general condition. Company comment: Kawasaki’s disease in a 2-month-old female subject 3 days after 1st dose of Infanrix hexa. No cardiovascular findings were reported. The subject was hospitalized and the event resolved after treatment with immunoglobulins. CONFIDENTIAL 182 CONFIDENTIAL 230  D0071621A (Germany): Kawasaki’s disease, Meningitis, Leukocytosis, Pericarditis, Mitral valve incompetence, Pyrexia, Fluid intake reduced, General physical health deterioration, Rash maculo-papular, Fungal skin infection, Cheilitis, Chapped lips, Palmar erythema, Lymphadenopa. This case was reported by a regulatory authority (DE-Paul-Ehrlich-Institut # DEPEI-PEI2011017683) and described the occurrence of atypical kawasaki disease in an nearly 12-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. Cosuspect vaccination included pneumococcal vaccines (non-gsk) (Prevenar 13, Pfizer). Previous vaccination included 1st dose of Infanrix hexa and Prevenar 13 (each unknown route and application site) given on 16 August 2011, which was well tolerated. On 2 November 2010 the subject received 2nd dose of Infanrix hexa and 2nd dose of Prevenar 13 (each unknown route and application site). At an unspecified after 2nd vaccination with Infanrix hexa and Prevenar 13, the subject experienced fever with a body temperature up to 38.2 degC. On 6 May 2011 the subject received 3rd dose of Infanrix hexa and 3rd dose of Prevenar 13 (each unknown route and application site). On 9 May 2011, 3 days after 3rd vaccination with Infanrix hexa and Prevenar 13, the subject experienced atypical Kawasaki disease. The subject developed fever with body temperatures up to 40 degC. On 11 May 2011, the subject developed exanthema on abdomen and back. Exanthema of mycotic cause was suspected. The subject was treated symptomatically with antipyretic (Antipyretics). On 12 May 2011, the subject’s fluid intake was reduced. His general condition was reduced. The subject was treated with cefpodoxime. Symptoms did not improve. On 13 May 2011 the subject was hospitalised. Atypical Kawasaki syndrome, secondary meningitis and pericarditis were diagnosed. He showed maculo-papular exanthema at trunk, arms, legs and face. His lips and palms were reddened. Cervical lymph nodes were enlarged. His body temperature was up to 40.3 degC. Initially, there were clearly increased parameters for an infection (signs of infection) as well as distinct exanthema. Culture of blood and liquor were uneventfully. Due to abnormal midstream urine, the subject was treated with cefuroxime sodium (Cefuroxim). Fever did not resolve. On 18 May 2011, the subject still suffered from fever. He showed chapped lips, palmar erythema, leukocytosis and mild cervical lymphadenopathy. Kawasaki’s disease was suspected. The subject was treated with normal immunoglobulin (Immunoglobulin) and aspirin (Acetylsalicylacid). Fever resolved and general condition improved. On 20 May 2011, echocardiography showed pericarditis and mitral insufficiency. On 24 May 2011, the subject was discharged from hospital after 12 days. At the time of reporting atypical Kawasaki disease was unresolved. The reporter reported that the events were life threatening. No further information will be available. Company comment: Kawasaki’s disease in 12-month-old male subject 3 days after 3th dose of Infanrix hexa and 2nd dose of Prevenar. The subject was hospitalizend and the event resolved after treatment with immunoglogulins and aspirin. CONFIDENTIAL 183 CONFIDENTIAL 231 6.6. Follow-Up Data Relevant follow-up information received during the period on fatal cases subsequent to their inclusion in PSUR 14 (B0580597A) and PSUR 15 (B0605003A and B0608494A) is mentioned in bold italic below. This information was taken into account for the observedto-expected analysis of sudden deaths as provided in Section 9.3.1.1. CIOMS forms are presented in APPENDIX 5B.  B0580597A (Netherlands) Sudden infant death syndrome, Depressed level of consciousness, Hypotonia, Pallor This case was reported by a healthcare professional and described the occurrence of death not otherwise specified in a 2-month-old female who was vaccinated with a 1st dose of Infanrix hexa and Prevenar. The subject had no medical history and no concomitant medication. One day after vaccination the subject was found in bed nonresponsive, floppy and pale. The subject died on 17 June 2009, cause of death was not reported. The autopsy report already received has confirmed SUDI. The regulatory authority considered the events were unlikely to be related to vaccination with Infanrix hexa and Prevenar.  B0605003A (Italy): Sudden death, Cardiac arrest, Convulsion, Hypokinesia. This case was reported by the Italian regulatory authority and described the occurrence of cardiac arrest in a 2-month-old female who was vaccinated with an unspecified dose of Infanrix hexa on 10 August 2009. Less than one day after vaccination, the subject experienced convulsions. The subject was hospitalised from 14 August until 19 August 2009. At the time of reporting, the event was resolved with sequelae. Last convulsion episode was on 18 October 2009. The baby showed a regular growth but a light motor retardation in respect of the age. Her weight was 7.10 kg. Diagnostic tests as karyotype, ultrasonography, computerized axial tomography and nuclear magnetic resonance were negative. She was treated with Luminalette. The subject died due to a cardiac arrest at an unspecified time after vaccination on 5 March 2010. After autoptic exam, the physician reported that the convulsions and cardiac arrest were unrelated to vaccination with Infanrix hexa. The autopsy report confirmed that the event was a suddenly death with no specified cause. Company comment: Case of Sudden Unexpected Death in Infancy (SUDI). The subject had a history of convulsions since 2-months of age, which started less than one day after vaccination with Infanrix hexa.  B0608494A (Netherlands): Sudden infant death syndrome, Depressed level of consciousness, Mouth haemorrhage, Nasopharyngitis This case was reported by a healthcare professional and described the occurrence of cot death in a 14-week-old male who was vaccinated with the 2nd dose of Infanrix hexa and Prevenar on 12 November 2009. The child was born at term and weighed 4120 g. The child had a history of viral infection before vaccination with the 1st dose of Infanrix hexa and Prevenar. In the beginning of November, 2 weeks before death, the subject had a common cold. The subject did not experience any adverse events CONFIDENTIAL 184 CONFIDENTIAL 232 after vaccination. Four days after vaccination with Infanrix hexa and Prevenar, the subject was brought to day care centre. He had no fever.He burped well after being fed and was put into bed at 9:25 lying on the abdomen (with permission of the mother) and he was being checked every 20 minutes. At 12:00, the subject was nonresponsive and had blood in his mouth. Reanimation was started immediately and the the child was admitted to hospital. The child died on 16 November 2009 from sudden infant death syndrome. An autopsy was performed and did not reveal any cause of death found in autopsy or on toxicological investigation. Tryptase: 4.2 mcg/l blood from heart (normal: lower than 11.5 mcg/l for adults). No indication for anaphylactic reaction. In addition, time period of 4 days considered too long to suspect an anaphylactic reaction. No indications for a relation with vaccinations. Company comment: The subject had viral infections as medical history. No cause of death found in autopsy or toxicological investigation. Anaphylactic reaction was excluded. CONFIDENTIAL 185 CONFIDENTIAL 233 7. STUDIES In line with the Addendum to ICH E2C [2], only studies with findings that have potential impact on product safety information are included in Sections 7.1, 7.3 and 7.4. 7.1. Newly-Analysed Studies No study assessing Infanrix hexa was completed during the period. No change to the RSI is warranted. 7.2. Targeted Safety Studies This section provides an update on any planned, ongoing or completed targeted safety studies involving Infanrix hexa in the reporting period. Targeted safety studies are those specifically planned or conducted to examine an actual or hypothetical safety concern (Vol 9A, Section 6.3.8.b) in a product marketed anywhere in the world. This includes any GSK-sponsored, and when applicable, GSK-supported pharmacoepidemiology study or clinical trial conducted anywhere in the world with the aim of identifying or quantifying a safety hazard. Although all clinical trials collect safety information as a matter of routine, only those initiated to examine a specific safety concern are considered a targeted safety study. No targeted safety study was planned, ongoing or completed for Infanrix hexa. 7.3. Other Safety Studies The following ongoing studies are not targeted safety studies but are also considered of interest as they may provide useful new information on the safety profile of Infanrix hexa:  103506 (DTPA-HBV-IPV-118 PRI) A phase IV, non-randomised, open-label, multi centre study with two parallel groups to assess the immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals combined DTPa-HBV-IPV/Hib vaccine administered as a three-dose primary vaccination course at 2, 4 and 6 months of age in healthy infants in Canada.  113948 (DTPA-HBV-IPV-124 PRI) A phase II, double-blind, randomized, multicentre study to evaluate the safety and immunogenicity of new formulations of GlaxoSmithKline BiologicalsDTPa-HBV-IPV/Hib vaccine when administered to healthy toddlers as a booster dose at 12 to 15 months of age.  114843 (DTPA-HBV-IPV-125 BST:124) A phase II, double-blind, randomized, multicentre study to evaluate the safety and immunogenicity of new formulations of GlaxoSmithKline BiologicalsDTPa-HBV-IPV/Hib vaccine when administered to healthy toddlers as a booster dose at 12 to 15 months of age. 7.4. Published Safety Studies A full review of the literature was conducted during the reporting period. Useful information was published during the period concerning: CONFIDENTIAL 186 CONFIDENTIAL 234 a. safety and reactogenicity of Infanrix-IPV+Hib and Infanrix hexa (Lim, 2011). Both vaccines were well tolerated and substitution of DTPa-IPV/Hib with Infanrix hexa at Month 5 reduced the number of injections required at this age by one. b. immunogenicity and safety of co-administration of Infanrix hexa with an investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine (ACWW-TT; Knuf, 2011). Pre-specified criteria for noninferiority of immunogenicity following co-administration versus separate ACWYTT and Infanrix hexa administration were reached, and the safety profile of coadministration was similar to that of Infanrix hexa alone. These studies did not highlight any safety issue. 8. OTHER INFORMATION 8.1. Efficacy Related Information Sixty two (62) cases suggesting potential lack of efficacy were received during the period and included at least one of the following MedDRA Preferred Terms: Pertussis (n=41), Bordetella test positive (n=2), Meningitis haemophilus (n=4), Haemophilus infection (3), Hepatitis B antibody negative (n=3), Therapeutic response decreased (n=1), Meningitis (3), Vaccination failure (n=48). These preferred terms were suggestive of lack of efficacy of the Pertussis, Hib and/or the Hepatitis B component. 8.1.1. Pertussis component Forty-three (43) cases including the event Pertussis (n=41) or Bordetella test positive (n=2) were identified during the reporting period. Out of 41 cases including the event Pertussis, 34 were reported with a MedDRA Preferred Terms vaccination failure. These cases are summarized in Table 29. Out of the 43 cases, there were 23 female subjects and 15 male subjects; in 5 cases gender was unknown. The age of the subjects ranged from 5 months to adult. There were 39 cases reported as serious and 4 as non-serious. In 9 cases the outcome of the event was reported as improved, resolved in 8 cases, unknown and unresolved at the time of report in 4 cases. Time to onset ranged between 5 months and 5 years. In 27 of these cases, subjects had Pertussis diagnosis confirmed by laboratory test and 16 were not laboratory confirmed. Two of the 27 laboratory-confirmed cases were asymptomatic, and the 25 symptomatic and laboratory confirmed case all received a comlete vaccination schedule. During the previous 1 year period, GSK received 13 potential lack of efficacy cases. The observed increase in the number of potential Pertussis component-related lack of efficacy reports is concurrent to the increase in number of cases received specifically from Germany (38 during the current period compared to 12 during the previous period). CONFIDENTIAL 187 CONFIDENTIAL 235 Table 29 Summary of cases of potential pertussis compononent -related lack of efficacy received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0682709A 29 -Oct -10 Unknown 9 Years Female Infanrix hexa Unknown Pertussis, Vaccination failure, Bordetella test negative Australia B0687509A 03 -Dec -10 Unknown 5 Years Female Infanrix hexa Unknown Pertussis, Vaccination failure Austria B0735430A 26 -Jul -11 Unknown 18 Months Female Infanrix hexa Unknown Pertussis, Sneezing, Post – tussive vomiting, Rhinorrhoea, Respiratory syncytial virus infection, Pyrexia, Cough, Vaccination failure South Africa B0737601A 05 -Aug -11 Unknown 18 Months Female Infanrix hexa Unknown Pertussis South Africa B0745561A 07 -Sep -11 Improved 9 Months Female Infanrix hexa 77 Days Pertussis, Cyanosis, Cough, Pyrexia, Vaccination failure Switzerland D0069221A 22 -Oct -10 Resolved 2 Years Male Infanrix hexa 21 Months Pertussis, Vaccination failure Germany D0069222A 22 -Oct -10 Resolved 11 Months Male Infanrix hexa Fluticasone propionate 8 Days Pertussis Germany Angiopathy, Tracheal stenosis, Surgery D0069277A 29 -Oct -10 Resolved 5 Years Female Infanrix hexa Varicella virus vaccine 3 Years Pertussis, Vaccination failure, Cough, Vomiting, Rhinitis, Decreased appetite, Weight decreased Germany Neurodermatitis, Food allergy, Seasonal allergy D0069673A 08 -Dec -10 Improved 1 Years Male Infanrix hexa 0 Years Pertussis, Vaccination failure Germany D0069696A 08 -Dec -10 Improved 12 Years Male Infanrix hexa, Boostrix Unknown Pertussis, Vaccination failure Germany D0069697A 08 -Dec -10 Improved 7 Years Male Infanrix hexa, Boostrix Unknown Pertussis, Vaccination failure Germany D0069698A 09 -Dec -10 Improved Adult Female Infanrix hexa Unknown Pertussis, Vaccination failure Germany CONFIDENTIAL 188 CONFIDENTIAL 236 D0069825A 23 -Dec -10 Resolved 3 Years Female Infanrix hexa 23 Months Pertussis, Vaccination failure Germany Exposure to communicable disease D0070091A 25 -Jan -11 Resolved 11 Months Female Infanrix hexa 5 Months Pertussis, Vaccination failure Germany D0070092A 25 -Jan -11 Resolved 5 Years Unknown Infanrix hexa 4 Years Pertussis, Vaccination failure Germany D0070099A 27 -Jan -11 Unknown 9 Years Female Boostrix, Infanrix hexa 19 Months Pertussis, Vaccination failure Germany D0070108A 27 -Jan -11 Unknown 4 Years Male Infanrix hexa 3 Years Pertussis, Vaccination failure Germany D0070132A 27 -Jan -11 Unknown 4 Years Male Infanrix hexa 3 Years Pertussis, Vaccination failure Germany D0070133A 27 -Jan -11 Unknown 4 Years Female Infanrix hexa 3 Years Bordetella test positive, Vaccination failure Germany D0070137A 27 -Jan -11 Unknown 5 Years Female Infanrix hexa 4 Years Bordetella test positive, Vaccination failure Germany D0070138A 27 -Jan -11 Unknown 5 Years Female Infanrix hexa 4 Years Pertussis, Vaccination failure, Inappropriate schedule of drug administration Germany D0070264A 09 -Feb -11 Unknown Child Unknown Infanrix hexa Unknown Pertussis, Vaccination failure Germany D0070268A 09 -Feb -11 Unknown Child Unknown Infanrix hexa Unknown Pertussis, Vaccination failure Germany D0070831A 28 -Mar -11 Unknown Child Unknown Infanrix hexa Unknown Pertussis Germany Cardiac operation, Mechanical ventilation D0071587A 30 -May -11 Unresolved 9 Months Female Infanrix hexa Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 5 Months Pertussis, Vaccination failure Germany Exposure to communicable disease D0071749A 17 -Jun -11 Resolved 5 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Days Pertussis Germany D0071806A 22 -Ju n -11 Resolved 8 Years Female Infanrix hexa, Boostrix 20 Months Pertussis, Vaccination failure Germany CONFIDENTIAL 189 CONFIDENTIAL 237 D0071888A 30 -Jun -11 Resolved 4 Years Male Infanrix hexa 3 Years Pertussis, Vaccination failure, Cough, Infection Germany D0071988A 08 -Jul -11 Improve d 2 Years Female Infanrix hexa 12 Months Pertussis, Cough, Vaccination failure Germany D0072007A 08 -Jul -11 Unknown 6 Months Female Infanrix hexa 29 Days Pertussis, Pyrexia, Cough, Rhinitis, Lymphadenopathy Germany D0072008A 08 -Jul -11 Improved 8 Years Female Infanrix hexa, Boostrix 2 Years Pertussis, Cough, Vaccination failure Germany D0072016A 12 -Jul -11 Unknown 31 Months Female Infanrix hexa 17 Months Pertussis, Vomiting, Rhinitis, Vaccination failure Germany D0072212A 28 -Jul -11 Improved 6 Years Male Infanrix hexa, DTPa -HepB – IPV -HIB (Non – GSK) 5 Years Pertussis, Cough, Vaccination failure Germany Lactose intolerance D0072273A 02 -Aug -11 Unresolved 5 Months Male Infanrix hexa 12 Days Pertussis, Choking, Cyanosis, Apnoea, Bronchopneumonia, Cough, Vomiting Germany D0072725A 13 -Sep -11 Improved 6 Months Male Infanrix hexa 35 Days Pertussis, Cough, Vomiting, Vaccination failure Germany Gastroenteritis norovirus D0072784A 19 -Sep -11 Resolved 5 Years Female Infanrix hexa DTPa -IPV (Non -GSK) Unknown Pertussis, Vaccination failure Germany D0072839A 23 -Sep -11 Unknown Child Male Infanrix hexa 3 Years Pertussis, Vaccination failure Germany D0072909A 30 -Sep -11 Unknown 4 Years Unknown Infanrix hexa Unknown Pertussis Germany D0072947A 28 -Sep -11 Unknown 3 Years Male Infanrix hexa 2 Years Pertussis, Cough, Vaccination failure Germany D0072968A 07 -Oct -11 Unknown 5 Months Male Infanrix hexa 57 Days Pertussis, Vaccination failure Germany D0073001A 12 -Oct -11 Unknown 6 Years Male Infanrix hexa 5 Years Pertussis, Vaccination failure Germany D0073013A 12 -Oct -11 Unresolved 5 Years Female Infanrix hexa 4 Years Pertussis, Vaccination failure Germany D0073015A 12 -Oct -11 Unresolved 27 Months Female Infanrix hexa, Pertussis vaccine 15 Months Pertussis, Vaccination failure Germany CONFIDENTIAL 190 CONFIDENTIAL 238 8.1.2. Haemophilus influenza type b component Seven (7) cases including the preffered term s Meningitis haemophilus (4) or Haemophilus infection (3) were received during the period. Four were reported from Australia. All were serious. The preferred term Vaccination failure was reported in all cases. These cases are summarized in Table 30. Table 30 Summary of cases of potential Hib compononent -related lack of efficacy received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0685610A 19 -Nov – 1 0 Resolved 10 Months Male Infanrix hexa, Infanrix -polio – HIB 5 Months Meningitis haemophilus, Vaccination failure Andorra B0711853A 05 -Apr -11 Resolved 11 Months Male Infanrix hexa 4 Months Meningitis haemophilus, Bacteraemia, Vaccination failure Australia B0711894A 05 -Apr -11 Resolved 28 Months Male Infanrix hexa 16 Months Haemophilus infection, Bacteraemia, Pharyngitis, Lethargy, Pyrexia, Dyspnoea, Vaccination failure Australia B0727262A 17 -Jun -11 Resolved 11 Months Female Infanrix hexa 4 Months Meningitis haemophilus, Pyrexia, Headache, Lethargy, Decreased appetite, Vomiting, Vaccination failure Australia B0727263A 17 -Jun -11 Resolved 10 Months Male Infanrix hexa Infanrix hexa 5 Months Haemophilus infection, Irritability, Pyrexia, Abasia Australia B0735156A 26 -Jul -11 Resolved 3 Years Female Infanrix hexa 2 Years Meningitis haemophilus, Vaccination failure South Africa D0070187A 03 -Feb -11 Unresolved 25 Months Male Infanrix hexa 7 Months Tympanic membrane perforation, Haemophilus infection, Vaccination failure Germany 8.1.3. Hepatitis B Three (3) non -serious cases of Hepatitis B antibody negative were reported over the period. These cases are summarized in Table 31. CONFIDENTIAL 191 CONFIDENTIAL 239 Table 31 Summary of cases of potential Hepatits B compononent -related lack of efficacy received during the period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0728114A 22 -Jun -11 Not Applicable Child Female Infanrix hexa Unknown Hepatitis B antibody negative France B0731677A 20 -Jun -11 Not Applicable 4 Years Male Infanrix hexa See text Corynebacterium test negative, Clostridium test negative, Hepatitis B antibody negative Austria D0072530A 29 -Aug -11 Not Applicable Unknown Infanrix hexa 1 Year Hepatitis B antibody negative Germany 8.1.4. Conclusion of cases of potential lack of efficacy During the period of this PSUR, 62 cases were identified where the MedDRA Preferred Terms could potentially correspond to a lack of effect of the Hib, pertussis or hepatitis B component. Table 32 shows the number of cases and respective reporting frequencies as reported during this PSUR and the previous PSUR periods. Table 32 Reporting rate of potential lack of efficacy cases PSUR #15 PSUR#16 Number of cases Reporting rate per 100 000 doses distributed Number of cases Reporting rate per 100 000 doses distributed Pertussis 21 0.18 43 0.35 Hib 6 0.05 7 0.06 Hepatitis B 1 0.01 3 0.02 There has been no unusual level of reports of lack of efficacy regarding the Hib and Hepatits B components. The reporting rate for potential Pertussis componenent related lack of efficacy has increased by 94%. CONFIDENTIAL 192 CONFIDENTIAL 240 8.2. Late-breaking information One new fatal case (B0762668A) was received after the data lock point as well as new follow-up data for one of the fatal cases described in Section 6.5.1 (D0072852A). The latest CIOMS forms for these cases are attached in APPENDIX 5C.  B0762668A (Belgium) Sepsis, Pyrexia, Diarrhoea This case was reported by a pharmacist and by another health professional and described the occurrence of septicemia in a 3-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), live attenuated human rotavirus vaccine (Rotarix) and pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. The subject was a premature baby. Concurrent medical conditions included cold. On 13 October 2011, the subject received 1st dose of Infanrix hexa (route and injection site unknown, batch number not provided), 1st dose of Rotarix (route unknown, batch number not provided) and 1st dose of Prevenar (route and injection site unknown, batch number not provided). On 21 October 2011, 8 days after vaccination with Infanrix hexa, Prevenar and Rotarix, the subject experienced fever and diarrhea. The subject was hospitalised. The subject died in the night 21 and 22 October 2011 from septicemia. It was unknown whether an autopsy was performed. The subject’s twin sister had received the same vaccination without problem. Information inadvertently not recorded in the initial report: The event septicemia was added. Follow-up information received on 30 November 2011 and 2 December 2011 from 2 newspapers and from a consumer via a web forum: The mother’s medical history included allergy and the family history included baby sudden death. The organisation who administered the vaccines was not aware that the subject had a cold. When the subject developed fever (39.9 deg.C) on 21 October 2011, the subject was treated by her parents with an antipyretic drug (suppository) and was taken to the hospital. At the hospital, gastroenteritis was firstly diagnosed, and after this diagnosis was changed to a pulmonary infection. The subject was treated with an antibiotic. But at 11 pm, her body was covered with purpura. The subject died at about 3 o’clock in the morning on 22 October 2011, 9 hours after she arrived at the hospital. Her body was covered with blue plaques. The diagnosis of purpura fulminans reported. The consumer also reported that rapid meningococcal meningitidis was mentioned, but no lumbar puncture and no hemoculture were performed therefore they could not conclude to this diagnosis. The subject’s parents lodged a complaint against “X” because of the lack of information provided before the vaccination about the risks and the lack of precaution taken regarding the family history. The subject’s twin sister of this case also experienced an adverse event after vaccination with same vaccines. Please see case B0767303A for details about the subject’s twin sister. Company comment: Death of a 3-month-old female subject due to septicaemia 8 days after combined 1st vaccination with Infanrix hexa, Rotarix and Prevenar. The subject’s twin sister had received the same vaccination without problem. It is unknown whether an autopsy was performed. CONFIDENTIAL 193 CONFIDENTIAL 241  D0072852A (Germany) Circulatory collapse, Sepsis, Shock, Crying, Pallor Data received after the data lock point: An autopsy was performed on 23 September 2011. Death was identified as respiratory failure with protracted shock due to interstitial pneumonia, probably of viral origin. Pathogenic microorganisms were not detected. There was no reaction at the injection site. Follow-up received on 12 December 2011 included a complete hospital report. The subject was hospitalized on 21 September 2011 at 09:30. In hospital the subject was diagnosed with death after ventricular tachycardia with hyperkaliemia and acute circulatory shock of unclear genesis with anuria and hyperkaliemia. Childhood examination U4 (performed in 3rd to 4th month of life) showed anemia (hemoglobin 8.5 g/dl). The subject’s mother had arterial hypertension and received bisoprolol. She formerly underwent surgery because of wrong lung vein ostium. After the subject had received the vaccinations, there was nothing abnormal during the day. In the night, around 01:00 o’clock the subject had been drinking about 200 ml. At 03:00 the subject started crying, which increased despite treatment with simethicone (Sab). He was vomiting twice. There was a transient improvement after receiving caraway suppository at 05:00. In the morning the subject became pale with strange breathing. When hospitalized, the subject was in bad condition, with circulatory depression, tachycardia with heart rate over 210 per min, pallor, muscle hypotonia, high irritability, moaning breathing. Green stool was excreted once. Supraventricular tachycardia could be excluded by electrocardiogram (ECG), which showed sinus tachycardia. Blood gas analysis showed acidosis with increased lactate and potassium. The subject received volume bolus via infusion on the head. After sudden worsening of condition with fall in oxygen saturation the subject received ketamine and diazepam. There was a short phase of bradycardia with the need for cardiac massage. The subject received further volume via intra-osseous access, as well as dobutamine, adrenaline (Adrenalin), claforan for suspected sepsis and hydrocortisone for circulatory support. Echocardiogram excluded dilated cardiomyopathy, but showed reduced pump function of heart. Sonogram of head excluded acute bleeding. Abdominal sonogram was normal. The subject’s body temperature had decreased to 33.1 degC rectal and exogenous warmth treatment was started. Blood test results challenged the diagnosis of sepsis, without fever and with no relevant inflammatory signs. Ammonia was increased, which was considered a possible sign for metabolic disorder. The subject received central vein catheter in V. jugularis interna and arterial catheter in V. femoralis at the right, but no stabilization could be achieved. Katecholamines were increased. The subject still had no diuresis and was treated with frusemide (Lasix). In further course the subject developed increasing potassium values, T-wave elevation, ventricular tachycardia, anuria and no improvement of the situation. Further treatment was without success. At 16:20 further cardiac problems developed, but because of the bad situation no defibrillation was started. The subject died at 16:21 in the parent’s presence. The hospital physician stated that after exclusion of cardiac, cerebral and abdominal causes, the event was most likely an atypical sepsis without fever and inflammatory signs. However, postmortal cultures of blood and cerebrospinal fluid also showed no germs. Despite of the autopsy results, the cause of death still kept unclear for the hospital physician. He stated that there were no radiologic signs for pneumonia and artificial respiration had been successful, with normalization of blood gas values. A metabolic disorder was considered possible, but CONFIDENTIAL 194 CONFIDENTIAL 242 it was more likely that lactic acidosis and hyperammonia were a secondary effect of shock. Company comment: Death was identified in the autopsy as respiratory failure with protracted shock due to interstitial pneumonia, probably of viral origin. The cause of death in the autopsy and the hospital report were not congruent. 8.3. EU Risk Management Plan There is no specific risk management plan in place for Infanrix hexa 8.4. Benefit Risk Analysis During the PSUR reporting period, no separate risk-benefit analysis has been conducted. 9. OVERALL SAFETY EVALUATION 9.1. Signal Management GSK employs a routine, pro-active process for identifying safety signals2 with three main components: 1. Ongoing awareness and review of important individual cases, including all reports with a fatal outcome. 2. Systematic, regular and proactive review of aggregate safety data. This includes trend analysis to detect increased frequency of reporting and quantitative methodologies to detect signals. 3. Systematic, regular review of the literature. A holistic approach is used so that all relevant data sources are interrogated when evaluating safety signals e.g. external sources, clinical studies, epidemiological studies, pre-clinical information. All signals identified are evaluated; however, priority is given for serious events, particularly events reported with disproportionately high frequency, DMEs3 , and events that if found to be causally related to the vaccine could significantly affect the benefitrisk profile. Following evaluation of the signal, appropriate action is agreed. The options include continuing routine proactive pharmacovigilance, defining further work to better understand the risk, or recommendation of a label change and/or amendment to the Risk Management Plan (RMP). 2 A safety signal is defined as a report or reports of an event with an unknown causal relationship to vaccination that is recognised as worthy of further exploration and continued surveillance (CIOMS VI). 3 Designated Medical Events: medically important events that are generally associated with drug toxicity. CONFIDENTIAL 195 CONFIDENTIAL 243 GSK is able to detect issues of potential concern promptly and, where appropriate, communicate them expeditiously to regulators outside the PSUR process. Actions taken on these issues are then reflected in the PSUR to ensure information is communicated appropriately to all regulatory authorities. Table 33 presents the reporting frequency of the 10 most frequently reported events for Infanrix hexa arising from spontaneous reporting including regulatory and consumer reports. For this analysis both serious and non-serious events reported were taken into account, from launch (23 October 2000) up to the data lock point of this safety update report. Listed events (according to RSI version 10) are in bold. Table 33 Overview of the 10 most frequently spontaneously reported events for Infanrix hexa. Event SOC Event PT Number Of Events1 Reporting frequency per 100,000 doses distributed General disorders and administration site conditions Pyrexia 4207 5.77 Nervous system disorders Crying 1300 1.78 General disorders and administration site conditions Injection site erythema 1124 1.54 General disorders and administration site conditions Injection site swelling 921 1.26 Nervous system disorders Hypotonia 617 0.85 Vascular disorders Pallor 558 0.77 Skin and subcutaneous tissue disorders Erythema 546 0.75 General disorders and administration site conditions Injection site induration 480 0.66 Skin and subcutaneous tissue disorders Urticaria 471 0.65 Skin and subcutaneous tissue disorders Rash 468 0.64 1. Including regulatory non-serious and consumer reports, but excluding clinical trial cases. All these events were reported with a frequency between 0.64 to 5.77 per 100 000 doses distributed. Since the last PSUR the top 10 events has not significantly changed in the reporting frequency except for ‘Inappropriate schedule of drug administration’, which is no longer part of the top 10 events. Conversely, Urticaria and Rash, which are already quoted in the GDS/RSI, appear with a relative reportive frequency of 0.65 per 100 000 doses distributed. CONFIDENTIAL 196 CONFIDENTIAL 244 9.2. Summary of Evaluations No new safety signals were identified and/or evaluated during the reporting period. 9.3. Adverse events of interest The cumulative count of an event since launch if provided in the following sections is based on the count of MedDRA PTs from cases originating from spontaneous reporting (including non-medically verified and regulatory non-serious cases). 9.3.1. Cases with a fatal outcome During the period covered by this report 13 fatal cases were identified. Ten cases suggestive of sudden deaths (sudden infant death syndrome: SIDS and sudden unexpected death in infancy: SUDI) were identified during the period covered by this PSUR. Cases remained poorly documented in the following suspected SUDI (B0706503A, B0727175A, and B0735723A) or without rationale explanation other than otitis media (D0071496A). SIDS was assessed in all other cases and autopsy confirmed the absence of causes (D0072663A, B0688734A, B0705290A, B0716780A, and D0070324A). A possible circulatory or septic shock was assessed for the last case but autopsy is still expected (D0072852A). Death occurred in a context of Viral Meningitis (B0683335A); during multi organ failure contemporary of acute meningitis (possible pneumococcus) (B0700040A), death in a context of severe hypoxic-ischemic encephalopathy (B0712016A). As shown in Table 34, 74 cases suggestive of sudden deaths have been received since launch, corresponding to a reporting frequency of 0.10 per 100 000 doses distributed (frequency of 0.08 per 100,000 doses distributed over the last one-year period). CONFIDENTIAL 197 CONFIDENTIAL 245 Table 34 Reporting rate of sudden death since launch per PSUR period PSUR # Period Time period Number of doses sold doses Number of SD as reported in the different PSURs reporting rate per 100,000 doses distributed 16 23oct10-22oct11 1Y 12301693 10 0.08 15 23oct09-22oct10 1Y 11981722 10 0.08 14 23oct08-22oct09 1Y 11496552 11 0.09 13 23oct07-22oct08 1Y 10067611 7 0.07 12 23oct06-22oct07 1Y 8621066 6 0.07 11 23oct05-22oct06 1Y 7166964 9 0.13 10 23apr05-22oct05 6M 2282686 2 0.09 9 23oct00-22apr05 4 1/2Y 9681894 18 0.19 8 23apr04-22oct04 6M 1386298 1 0.07 7 23oct03-22apr04 6M 1246906 5 0.40 6 23apr03-22oct03 6M 1247422 4 0.32 5 23oct02-22apr03 6M 1041975 1 0.10 4 23apr02-22oct02 6M 998814 0 0.00 3 23oct01-22apr02 6M 772137 1 0.13 2 23apr01-22oct01 6M 1050000 1 0.10 1 23oct00-22apr01 6M 430000 0 0.00 A cumulative review of Sudden Death since launch has been performed. Follow-up information was taken into account. 9.3.1.1. Cases of Sudden death 9.3.1.1.1. Introduction In the assessment report (dated 3 March 2010) of PSUR 14, EMA request that “The MAH should try to collect relevant and recent data of background incidence rates of sudden death in other European countries. An observed/expected analysis of sudden death should be performed in the next PSUR as well.” 9.3.1.1.2. Methods  Literature search In order to collect relevant and recent data, a literature review of sudden infant death was performed for Europe. The search of the literature was made in PubMed and Embase using simultaneously the key words “sudden infant death” or “sudden death”, “incidence rate” and “Europe”; only publications after 1990 were selected due to the effect of the “Back to Sleep‟ campaign performed in several European countries. Publications were limited to those published in French and English languages. The bibliographies of identified studies and reviews were searched to identify additional studies of interest. The German Federal Statistical Office was also consulted on line. CONFIDENTIAL 198 CONFIDENTIAL 246  Observed to Expected Analysis To estimate the expected numbers, the incidence rate of SID was considered homogenous within each age (i.e. over 1st or 2d year of life); therefore the expected number over any day was linearly extrapolated (i.e. 1/365) from the prevalence per birth cohort. The number of cases expected to occur within a predetermined risk period following vaccination (Ne) for children under 1 year of age and those between 1 and 2 years of age is derived from the following formula: where Inc = the incidence of the disease in the first or second year of life 0.454 per 1,000 live births for < 1 year olds 0.062 per 1,000 live births for 1 < 2 year olds Nbc = the number of doses of vaccine sold since launch (assumption: proportion of adverse events by age is representative for the actual age distribution at vaccination). Risk Period = adjustement from a predetermined risk period (Days/365) α = healthy vaccinee correction factor (taken here to be 0.8 based on various case-control studies of SIDS or SUID). 9.3.1.1.3. Results Table 35 present the background incidence rate of Sudden Infant Death in Europe from the selected publications. CONFIDENTIAL 199 CONFIDENTIAL 247 Table 35 Incidence rate of Sudden Infant Death (<1 year of age) per 1,000 live births Country/Population Time period Incidence Rate (/1 000 live birth) Source Data from the European Concerted Action on Sids. Case-control studies of SIDS done in 20 regions in Europe. 1992-1996 European range: 0.17 – 1.3 (median: 0.6) Carpenter, 2004 Ireland. Data from National Sudden Infant Death Register. 1993-1997 0.80 Mehanni, 2000 Austria. Prospective study. Data from autopsy records in the Tyrol. 1994-1998 0.4 Kiechl-Kohlendorfer, 2001 Italy. Data from mortality registry of the 15 health districts in the Lombardy region. 1990-2000 0.13-0.54 Montomoli, 2004 Sweden. Data from the Medical Birth Registry of Sweden. 1999 0.30 Alm, 2001 Sweden. Literature review of Scandinavian studies. 2004 0.2-0.3 Wennergren, 2004 Sweden. Data from the Medical Birth Register of Sweden from 1997-2005. 2005 0.23 Mollborg, 2010 France. National statistics from CepiDc- Inserm 2005 0.32 Aouba, 2008 Germany. Data extracted from the Federal Health Monitoring of Germany (ICD code R95). 2005 2007 0.43 0.33 Nennstiel-Ratzel, 2010 Germany. Data from the German Federal Statistical Office (ICD code R95-R99). 2007 2008 0.44 0.45 German Federal Statistical Office, 2010  Observed/Expected Analysis of Sudden Deaths (SD) Given the attention that has been given to the occurrence of sudden deaths in children in the second year of life within 14 days of the administration of hexavalent vaccines, the Company evaluated whether the number of sudden deaths reported in this age group exceeded the number one could expect to occur by coincidence, i.e. from the natural background incidence of sudden deaths. Since the distribution of the age at which subjects are vaccinated is unknown, the Company assumed that the proportion of adverse events by age is representative for the actual age distribution at vaccination. It can thus be estimated that 75% of all recipients of Infanrix hexa were in their first year of life, and 20% were in their second year of life (5% were not attributable because the age at vaccination was unknown). Therefore the number of doses (since launch) was estimated to be 54,7 and 14,6 millions respectively. Given that Germany is the main country where Infanrix hexa doses are distributed (close to 30% only in Germany), it was assumed that the incidence of sudden death observed in Germany is representative for the entire population of Infanrix hexa recipients (German Federal Bureau of Statistics, Statistisches Bundesamt; incidence rate in 1st year of life: 0.454/1,000 live births; second year: 0.062/1,000 live births, data 2008). These rates are in line with the other rates described above. A healthy vaccinee correction factor (taken here to be 0.8 based on various case-control studies of SIDS or SUID) was applied. The results of this analysis are present in Table 36 which shows the number of sudden deaths that could be expected to occur by chance within a range of days post vaccination. CONFIDENTIAL 200 CONFIDENTIAL 248 Table 36 Cumulative number of observed and expected cases of SD following Infanrix hexa in children in their first or second year of life Time since vaccination (days) Observed (1st year) Expected Observed (2d year) Expected 0 16 54.4 2 1.98 1 29 108.8 5 3.96 2 42 163.2 6 5.94 3 50 217.6 6 7.92 4 57 272 6 9.9 5 60 326.4 7 11.88 6 60 380.8 7 13.86 7 62 435.2 7 15.84 8 63 489.6 7 17.82 9 65 544 7 19.8 10 65 598.4 7 21.78 11 65 652.8 7 23.76 12 65 707.2 7 25.74 13 65 761.6 8 27.72 14 65 816 8 29.7 15 66 870.4 8 31.68 16 67 924.8 8 33.66 17 67 979.2 8 35.64 18 67 1033.6 8 37.62 19 67 1088 8 39.6 This analysis shows that the number of sudden death cases reported after vaccination with Infanrix hexa is below the number of cases expected in children in their 1st year of life; it is equal or below the number of cases expected in children between in their 2d year of life. The Company monitors these cases and their reporting frequencies on an ongoing basis. 9.3.1.1.4. Limitations There are several limitations for Observed/Expected analyses, and several levels of uncertainty. The major factors affecting O/E analyses are related to:  Underreporting, reporting biases, and incomplete case details.  Uncertainty on the number of subjects actually vaccinated.  No age stratification within the two age groups. CONFIDENTIAL 201 CONFIDENTIAL 249 9.3.2. Other adverse events of interest 9.3.2.1. Blood and lymphatic system disorders 9.3.2.1.1. Anaemia haemolytic autoimmune, Haemolytic anemia and Haemorrhagic diathesis One (1) case of Anaemia haemolytic autoimmune, no (0) case of Haemolytic anaemia and two (2) cases of Haemorrhagic diathesis were reported during the period (see Section 6.5.2.1). D0072751A described a 7-month-old male subject who experienced anemia haemolytic autoimmune within 28 days of Infanrix hexa vaccination. B0737478A described a 4- month-old male subject who experienced haemorrhagic diathesis 8 hours after second dose of Infanrix hexa and first dose of Prevenar. D0070397A described a 3-month-old male subject who experienced haemorrhagic diathesis in the context of an upper respiratory tract infection within 24 hours of receiving the first dose of Infanrix hexa, Prevenar and Rotarix. These three cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 10 spontaneous cases of Anaemia haemolytic autoimmune/Haemolytic anemia/Haemorrhagic diathesis were received, corresponding to a reporting frequency of 0.01 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors cases of Anaemia haemolytic autoimmune and Haemolytic anemia. 9.3.2.1.2. Autoimmune thrombocytopenia, Idiopathic thrombocytopenic purpura, Thrombocytopenic purpura and Thrombocytopenia No (0) case of Autoimmune thrombocytopenia, five (5) cases of Idiopathic thrombocytopenic purpura, four (4) cases of Thrombocytopenic purpura and nine (9) cases of Thrombocytopenia were reported during the period (see Section 6.5.2.1). Autoimmune thrombocytopenia was confirmed by positive antiplatelet antibodies in only one case (D0071125A). These 15 cases represent a reporting frequency of 0.12 cases per 100 000 doses distributed during the period. Since launch, 78 spontaneous cases of Autoimmune thrombocytopenia/Idiopathic thrombocytopenic purpura/Thrombocytopenic purpura, Thrombocytopenia were received, corresponding to a reporting frequency of 0.11 per 100 000 doses distributed. Thrombocytopenia is a listed event. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors Autoimmune thrombocytopenia, Idiopathic thrombocytopenic purpura, Thrombocytopenic purpura and Thrombocytopenia. CONFIDENTIAL 202 CONFIDENTIAL 250 9.3.2.1.3. Thrombocytosis Two (2) cases of Thrombocytosis were reported during the period (see Section 6.5.2.1.8). Out of these, one was associated with a pemphigoid (B0729166A). It remains difficult to determine a causal relationship between vaccination and the bullous pemphigoid. These 2 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 10 spontaneous cases of Thrombocytosis were received, corresponding to a reporting frequency of 0.01 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.2. Cardiac disorders 9.3.2.2.1. Bradycardia Eleven (11) cases including the event Bradycardia were reported over the period (see Section 6.5.2.2.1). These 11 cases represent a reporting frequency of 0.09 cases per 100 000 doses distributed during the period. Since launch, 44 spontaneous cases of Bradycardia were received, corresponding to a reporting frequency of 0.06 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.2.2. Cardiac arrest Three (3) cases including the PT Cardiac arrest were reported during the period (see Section 6.5.2.2.2). Cases B0706503A and B0716780A are discussed in Section 9.3.1 Cases with a fatal outcome. Case D0069341A described a 3-month-old female who experienced an unspecified collapse less than 1 hour after Infanrix hexa vaccination. Possible epilepsy was suspected without conclusive investigations. These 3 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 11 spontaneous cases of Cardiac arrest were received, corresponding to a reporting frequency of 0.02 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.2.3. Cardio-respiratory arrest One (1) case including the PT Cardio-respiratory arrest was received during the period (B0705290A) and is discussed in Section 9.3.1 Cases with a fatal outcome. CONFIDENTIAL 203 CONFIDENTIAL 251 9.3.2.2.4. Cardiogenic shock One (1) case including the PT Cardiogenic shock was reported during the period (see Section 6.5.2.2.4) and described a 3-month-old male who experienced cardiogenic shock 12 days after Infanrix hexa vaccination combined with Rotarix and Prevenar. Diagnosis of pre-existing focal atrial tachycardia and heart insufficiency recovered with antiarritmica. This case represents a reporting frequency of 0.01 cases per 100 000 doses distributed during the period. Itis the first spontaneous cases of Cardiogenic shock since launch. The information received with this case does not provide evidence of a specific safety signal. 9.3.2.2.5. Cyanosis Fifty eight (58) cases including the preferred term Cyanosis were identified during the period (see Section 6.5.2.2.5). Most were reported in association with a concurrent causal disease. These 58 cases represent a reporting frequency of 0.47 cases per 100 000 doses distributed during the period. Since launch, 284 spontaneous cases of Cyanosis were received, corresponding to a reporting frequency of 0.39 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors Cyanosis. 9.3.2.3. Eye disorders 9.3.2.3.1. Gaze palsy Eighteen (18) cases including the event Gaze palsy were identified during the period. In two-third of cases the event was associated to a reported convulsion. The outcomes resolved spontaneously in half of the cases. These 18 cases represent a reporting frequency of 0.18 cases per 100 000 doses distributed during the period. Since launch, 70 spontaneous cases of Gaze palsy were received, corresponding to a reporting frequency of 0.10 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.4. Gastrointestinal disorders 9.3.2.4.1. Diarrhoea haemorrhagic, Haematochezia, Intussusception, Rectal haemorrhage Six (6) cases of Diarrhoea haemorrhagic/Haematochezia/Intussusception/Rectal haemorrhage were identified during the period (see Section 6.5.2.4). CONFIDENTIAL 204 CONFIDENTIAL 252 These 6 cases represent a reporting frequency of 0.05 cases per 100 000 doses distributed during the period. Since launch, 41 spontaneous cases of Diarrhoea haemorrhagic/ Haematochezia/Intussusception/Rectal haemorrhage were received, corresponding to a reporting frequency of 0.06 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors cases of Haematochezia. 9.3.2.5. General disorders and administration site conditions 9.3.2.5.1. Abscess sterile, Injection site abscess sterile Seven (7) cases of Abscess sterile/Injection site abscess sterile were received during the period (see Section 6.5.2.5.1). These 7 cases represent a reporting frequency of 0.06 cases per 100 000 doses distributed during the period. Since launch, 38 spontaneous cases of Abscess sterile/Injection site abscess sterile were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.5.2. Extensive swelling of vaccinated limb Twenty-eight (28) cases of Extensive swelling of vaccinated limb (see Section 6.5.2.5.2), out of which 5 were quoted as serious, were received during the period. The reported outcomes resolved in 80% of cases and improved in the others. These 28 cases represent a reporting frequency of 0.23 cases per 100 000 doses distributed during the period. Since launch, 65 spontaneous cases of Extensive swelling of vaccinated limb were received, corresponding to a reporting frequency of 0.09 per 100 000 doses distributed. Extensive swelling reactions and swelling of the entire vaccinated limb is included in the current Reference Safety Information of Infanrix hexa.The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.5.3. Gait disturbance During the period, 19 cases of Gait disturbance were received (see Section 6.5.2.5.3). Out of these, 18 cases were associated with at least one other class event (pyrexia and/or nervous system). The outcome was resolved in 75% of the serious cases. These 19 cases represent a reporting frequency of 0.15 cases per 100 000 doses distributed during the period. Since launch, 71 spontaneous cases of Gait disturbance were received, corresponding to a reporting frequency of 0.10 per 100 000 doses distributed. CONFIDENTIAL 205 CONFIDENTIAL 253 The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.5.4. Injection site urticaria See Section 9.3.2.11.5 Urticaria, Urticaria popular and Urticaria thermal. 9.3.2.5.5. Nodule, Injection site nodule and Subcutaneous nodule Twenty seven (27) cases of Nodule/Injection site nodule/Subcutaneous nodule were received during the period (see Sections 6.5.2.5.4, 6.5.2.5.6 and 6.5.2.11.6). These 26 cases represent a reporting frequency of 0.21 cases per 100 000 doses distributed during the period. Since launch, 178 spontaneous cases of Nodule/Injection site nodule/Subcutaneous nodule were received, corresponding to a reporting frequency of 0.24 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors Injection site nodule. 9.3.2.6. Immune system disorders 9.3.2.6.1. Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction and Drug hypersensitivity Seven (7) cases of Anaphylactic shock/Anaphylactic reaction/Anaphylactoid reaction/Drug hypersensitivity were received during the period (see Section 6.5.2.6). The individual reports were reviewed following the case definition and diagnostic levels of certainty developed by The Brighton Collaboration Anaphylaxis Working Group. Three (3) cases of Anaphylactic shock were reported over the period. B0680987A and B0741646A were classified as Level 2 and 3 of diagnostic certainty, respectively. Case D0071107A was classified as Level 4 of diagnostic certainty. Four (4) additional cases of anaphylactic reaction and hypersensitivity were reported over the period. B0698663A was classified as Level 2 and D0072050A as Level 5 of diagnostic certainty. In case D0072500A, the subject did not experience anaphylaxis (Level 5 of diagnostic certainty). The case was also received as pharmaceutical product complaint and it was concluded that there was no evidence for a specific safety signal for the used lot of Infanrix hexa. Case B0712429A was a generalised allergic reaction (exanthema) where a Salmonella sepsis could have played a trigger role in drug hypersensitivity (Level 5 of diagnostic certainty). The 4 cases that were Level 2, 3 or 4 represent a reporting frequency of 0.03 cases per 100 000 doses distributed during the period. Since launch, 29 spontaneous cases of Anaphylactic shock/ Anaphylactic reaction/Anaphylactoid reaction/Drug hypersensitivity were received (regardless of Brighton certainty level), corresponding to a reporting frequency of 0.04 per 100 000 doses distributed. CONFIDENTIAL 206 CONFIDENTIAL 254 The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors allergic reactions (including Anaphylactic reaction and Anaphylactoid reaction). 9.3.2.7. Infections and infestations 9.3.2.7.1. Abscess, Abscess limb, Incision site abscess, Injection site abscess Injection site infection, Streptococcal abscess During the reporting period, 25 cases were received including one of the following MedDRA Preferred Terms: Abscess (n=10), Abscess limb (n=1), Incision site abscess (n=2), Injection site abscess (n=12), Injection site infection (n=2), Streptococcal abscess (n=2) (see Section 6.5.2.7.1). There was no clustering of these cases by batch, supportive of a manufacturing issue. These 25cases represent a reporting frequency of 0.20 cases per 100 000 doses distributed during the period. Since launch, 144 spontaneous cases of Abscess/Abscess limb/Incision site abscess/Injection site abscess/Injection site infection/Streptococcal abscess were received, corresponding to a reporting frequency of 0.20 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors Abscess and Injection site abscess. 9.3.2.7.2. Cellulitis and Injection site cellulitis Four (4) cases of Cellulitis/Injection site cellulitis were received during the period (see Sections 6.5.2.7.2 and 6.5.2.7.4). These 4 cases represent a reporting frequency of 0.03 cases per 100 000 doses distributed during the period. Since launch, 39 spontaneous cases of Cellulitis/Injection site cellulitis were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.7.3. Encephalic infection See Section 9.3.2.9.5 Encephalitis, Encephalopathy and Encephalic infection. 9.3.2.7.4. Meningitis aseptic, Meningitis pneumococcal, Meningitis viral Four (4) cases of Meningitis aseptic/Meningitis pneumococcal/Meningitis viral were received during the period (see Sections 6.5.2.7.5, 6.5.2.7.6 and 6.5.2.7.7). These 4 cases represent a reporting frequency of 0.03 cases per 100 000 doses distributed during the period. Since launch, 12 spontaneous cases of Meningitis aseptic/Meningitis pneumococcal/Meningitis viral were received, corresponding to a reporting frequency of 0.02 per 100 000 doses distributed. CONFIDENTIAL 207 CONFIDENTIAL 255 The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.7.5. Osteomyelitis One (1) case (D0069814A) diagnosed with Osteomyelitis at tibia metaphysic left medial with periosteal abscess (bone abscess) and treated surgically was received during the period (see Section 6.5.2.7.8). This case represents a reporting frequency of 0.01 cases per 100 000 doses distributed during the period. Since launch, 4 spontaneous cases of Osteomyelytis were received, corresponding to a reporting frequency of 0.01 per 100 000 doses distributed. The information received with this case does not provide evidence of a specific safety signal. 9.3.2.7.6. Pneumococcal sepsis, Salmonella sepsis, Sepsis, Septic shock Six (6) cases of Pneumococcal sepsis/Salmonella sepsis/Sepsis/Septic shock were received during the period (see Sections 6.5.2.7.9, 6.5.2.7.10, 6.5.2.7.11 and 6.5.2.7.12). These 6 cases represent a reporting frequency of 0.05 cases per 100 000 doses distributed during the period. Since launch, 35 spontaneous cases of Pneumococcal sepsis/ Salmonella sepsis/Sepsis/Septic shock were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.8. Musculoskeletal and connective tissue disorders 9.3.2.8.1. Muscle spasms Seventeen (17) cases of Muscle spasms were reported during the period (see Section 6.5.2.8.1). These were associated with other neurologic signs such as convulsion (n=8). These 17 cases represent a reporting frequency of 0.14 cases per 100 000 doses distributed during the period. Since launch, 53 spontaneous cases of Muscle spasms were received, corresponding to a reporting frequency of 0.07 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.8.2. Soft tissue necrosis One (1) case of Soft tissue necrosis was reported during the period (see Section 6.5.2.8.2). This case represents a reporting frequency of 0.01 cases per 100 000 doses distributed during the period. This is the second Soft tissue necrosis case received since launch. CONFIDENTIAL 208 CONFIDENTIAL 256 The information received with this case does not provide evidence of a specific safety signal. 9.3.2.9. Nervous system disorders 9.3.2.9.1. Cerebral atrophy and Cerebral ischemia Three (3) cases of Cerebral atrophy/Cerebral ischemia were reported during the period (see Section 6.5.2.9.1). Case B0716780A (Cerebral atrophy) is discussed in Section 9.3.1.1 Cases of Sudden death. Death occurred through multi organ failure. These 3 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 11 spontaneous cases of Cerebral atrophy/Cerebral ischemia were received, corresponding to a reporting frequency of 0.02 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.9.2. Seizures and Epilepsy During the period, 118 cases of Clonic convulsion/Clonus/Convulsion/Febrile convulsion/Grand mal convulsion/Myoclonus/Partial seizures/Seizure like phenomena/Tonic clonic movements/Tonic convulsion were received, as well as, 19 cases of Complex partial seizures/Epilepsy/Infantile spasms/Petit Mal Epilepsy/Status epilepticus (see Section 6.5.2.9.2). These 118 and 19 cases represent a reporting frequency of 0.96 and 0.15 cases per 100 000 doses distributed during the period, respectively. Since launch, 761 spontaneous cases of Convulsions (any kind of convulsion) were received, corresponding to a reporting frequency of 1.04 per 100 000 doses distributed. Convulsions (with or without fever) is included in the current Core Safety Information for Infanrix hexa. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.9.3. Demyelination and Demyelinating polyneuropathy Two (2) cases of Demyelination/Demyelinating polyneuropathy were received during the period (see Section 6.5.2.9.3). These 2 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 6 spontaneous cases of Demyelination/Demyelinating polyneuropathy were received, corresponding to a reporting frequency of 0.01 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. CONFIDENTIAL 209 CONFIDENTIAL 257 9.3.2.9.4. Depressed level of consciousness and Loss of consciousness Fifity four (54) cases of Depressed level of consciousness/Loss of consciousness were reported during the period (see Section 6.5.2.9.4). These 54 cases represent a reporting frequency of 0.44 cases per 100 000 doses distributed during the period. Since launch, 280 spontaneous cases of Depressed level of consciousness/Loss of consciousness were received, corresponding to a reporting frequency of 0.38 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.9.5. Encephalitis, Encephalopathy and Encephalic infection Five (5) cases of Encephalitis/Encephalopathy/Encephalic infection were received during the period (see Section 6.5.2.9.5). Postvaccinal cerebellitis was compatible with the time sequence (D0070015A). A causal relationship between Infanrix hexa and Prevenar was reported but the relationship remained dubious in two other cases (D0071549A, B0692285A). Case B0686208A lacked data on subject medical and results of investigation. These 5 cases represent a reporting frequency of 0.04 cases per 100 000 doses distributed during the period. Since launch, 34 spontaneous cases of Encephalitis/Encephalopathy/ Encephalic infection were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The company closely monitors important neurological events (including Encephalitis and Encephalopathy). 9.3.2.9.6. Guillain-Barre syndrome Two (2) cases of Guillain-Barré syndrome were reported over the period from Italy (1) and Germany (1) (see Section 6.5.2.9.6). The individual reports were reviewed following the case definition and diagnostic levels of certainty developed by The Brighton Collaboration Guillain-Barré Syndrome Working Group (Sejvar, 2011). The reports were classified to Level 4 of diagnostic certainty as the information provided was insufficient to meet the case definition of GBS according to Brighton Collaboration criteria. These 2 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 5 spontaneous cases of Guillain-Barré syndrome were received, corresponding to a reporting frequency of 0.01 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. CONFIDENTIAL 210 CONFIDENTIAL 258 9.3.2.9.7. Hemiparesis One (1) case of Hemiparesis was received during the period (see Section 6.5.2.9.7) and is discussed in Section 9.3.2.9.11 Thalamus haemorrhage. 9.3.2.9.8. Lennox Gastaut syndrome One (1) case of Lennox-Gastaut syndrome was received during the period (see Section 6.5.2.9.5 Encephalitis, Encephalopathy and Encephalic infection). This case represents a reporting frequency of 0.01 cases per 100 000 doses distributed during the period. This is the first Lennox-Gastaut syndrome case received since launch. The information received with this case does not provide evidence of a specific safety signal. 9.3.2.9.9. Somnolence Over the period 59 cases of Somnolence were reported, out of which 19 were non-serious (see Section 6.5.2.9.10). These 59 cases represent a reporting frequency of 0.48 cases per 100 000 doses distributed during the period. Since launch, 288 spontaneous cases of Somnolence were received, corresponding to a reporting frequency of 0.39 per 100 000 doses distributed. Figure 1 shows the yearly reporting rate since launch. Note that the number of Somnolence cases displayed for 2011 differs from the one in this PSUR (i.e. 39 cases in Figure 1 and 59 cases in this PSUR) for the following reasons:  The reporting rate in Figure 1 is plotted by calendar year and not by PSUR period  Vaccination date was not provided for all somnolence cases.  The date used to plot each case is the vaccination date, not the date at which the case was received by GSK Biologicals Clinical Safety and Pharmacovigilance department The rationale for having chosen to plot the vaccination date instead of the reporting date is that many of these cases were reported with a delay of approximately 100 days after event onset, which contributed to the increase in the reporting rate observed during this period. CONFIDENTIAL 211 CONFIDENTIAL 259 Figure 1 Reporting rate of Somnolence cases per 100 000 doses distributed and per calendar year The information received with these cases, as well as the data in Figure 1, do not provide evidence of a specific safety signal. 9.3.2.9.10. Syncope and Presyncope Fifteen (15) cases of Syncope/Presyncope were received during the period (see Section 6.5.2.9.11). These 15 cases represent a reporting frequency of 0.12 cases per 100 000 doses distributed during the period. Since launch, 68 spontaneous cases of Syncope/Presyncope were received, corresponding to a reporting frequency of 0.09 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.9.11. Thalamus haemorrhage One (1) case of Thalamus haemorrhage was received during the period (see Section 6.5.2.9.12). This case represents a reporting frequency of 0.01 cases per 100 000 doses distributed during the period. This is the first Thalamus haemorrhage case received since launch. CONFIDENTIAL 212 CONFIDENTIAL 260 The information received with this case does not provide evidence of a specific safety signal. 9.3.2.9.12. VIth nerve paralysis and VIIth nerve paralysis Three (3) cases of VIth nerve paralysis/VIIth nerve paralysis were received during the period (see Sections 6.5.2.9.13 and 6.5.2.9.14). These 3 cases represent a reporting frequency of 0.12 cases per 100 000 doses distributed during the period. Since launch, 7 spontaneous cases of VIth nerve paralysis/VIIth nerve paralysis were received, corresponding to a reporting frequency of 0.01 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.10. Respiratory, thoracic and mediastinal disorders 9.3.2.10.1. Apparent life threatening event Four (4) cases of Apparent life threatening event were received during the period (see Section 6.5.2.10.1). These 4 cases represent a reporting frequency of 0.03 cases per 100 000 doses distributed during the period. Since launch, 33 spontaneous cases of Apparent life threatening event were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.10.2. Asphyxia One (1) case of Asphyxia was reported during the period (see Section 6.5.2.10.2) and is discussed in Section 9.3.1 Cases with a fatal outcome. 9.3.2.10.3. Respiratory arrest Seven (7) cases of Respiratory arrest were received during the period (see Section 6.5.2.10.3). These 7 cases represent a reporting frequency of 0.06 cases per 100 000 doses distributed during the period. Since launch, 36 spontaneous cases of Respiratory arrest were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. CONFIDENTIAL 213 CONFIDENTIAL 261 9.3.2.11. Skin and subcutaneous tissue disorders 9.3.2.11.1. Angioedema Four (4) cases of Angioedema were reported over the period (see Section 6.5.2.11.1). All cases lacked data on the subject’s medical history and other possible diagnosis to provide a precise overall assessment. These 4 cases represent a reporting frequency of 0.03 cases per 100 000 doses distributed during the period. Since launch, 34 spontaneous cases of Angioedema were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.11.2. Erythema multiforme Two (2) cases of Erythema multiforme were reported during the period (see Section 6.5.2.11.2). These 2 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 15 spontaneous cases of Erythema multiforme were received, corresponding to a reporting frequency of 0.02 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.11.3. Henoch Schonlein Purpura and Purpura Five (5) cases of Henoch-Schonlein purpura/Purpura were received during the period (see Sections 6.5.2.11.3 and 6.5.2.11.5). These 5 cases represent a reporting frequency of 0.04 cases per 100 000 doses distributed during the period. Since launch, 38 spontaneous cases of Henoch-Schonlein purpura/ Purpura were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors cases of Purpura and Henoch-Schonlein purpura. 9.3.2.11.4. Petechiae Twenty nine (29) cases of Petechiae were reported during the period (see Section 6.5.2.11.4). In the majority of serious cases, haematologic disorders were associated: idiopathic / non-specified thrombocytic purpura or thrombocytopenia. These 29 cases represent a reporting frequency of 0.24 cases per 100 000 doses distributed during the period. Since launch, 161 spontaneous cases of Petechiae were received, corresponding to a reporting frequency of 0.22 per 100 000 doses distributed. CONFIDENTIAL 214 CONFIDENTIAL 262 The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors cases of Petechiae. 9.3.2.11.5. Urticaria, Urticaria popular and Urticaria thermal Sixty seven (67) cases of Urticaria/Urticaria papular/Urticaria thermal were received during the period (plus one received during a previous period but not included in a previous PSUR), out of which most resolved spontaneously (see Section 6.5.2.11.7). These 68 cases represent a reporting frequency of 0.55 cases per 100 000 doses distributed during the period. Since launch, 432 spontaneous cases of Urticaria/Urticaria papular/Urticaria thermal were received, corresponding to a reporting frequency of 0.59 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.11.6. Subcutaneous nodule Discussed in Section 9.3.2.5.5 Nodule, Injection site nodule and Subcutaneous nodule. 9.3.2.12. Vascular disorders 9.3.2.12.1. Circulatory collapse Seven (7) cases of Circulatory collapse were receved during the period (see Section 6.5.2.12.1). These 7 cases represent a reporting frequency of 0.06 cases per 100 000 doses distributed during the period. Since launch, 38 spontaneous cases of Circulatory collapse were received, corresponding to a reporting frequency of 0.05 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. 9.3.2.12.2. Kawasaki’s disease Three (3) cases of Kawasaki’s disease were reported during the period (see Section 6.5.2.12.2). In 2 out of these 3 cases, the reported information is compatible with the typical symptomatology of Kawasaki’s disease and subjects were treated with immunoglobulins. One of the subjects developed pericarditis. The etiology of Kawasaki’s disease remains unknown although in 2 of the cases the clinical history suggests an infectious disease. These 3 cases represent a reporting frequency of 0.02 cases per 100 000 doses distributed during the period. Since launch, 21 spontaneous cases of Kawasaki’s disease were received, corresponding to a reporting frequency of 0.03 per 100 000 doses distributed. The information received with these cases does not provide evidence of a specific safety signal. The Company closely monitors cases of Kawasaki’s disease. CONFIDENTIAL 215 CONFIDENTIAL 263 9.4. Areas of Regulatory Interest Areas of regulatory interest (specifically Drug Interactions, Overdose and Medication Errors, Abuse Potential, Pregnancy and Lactation, Use in Children) routinely monitored throughout the product lifecycle and during the period of the PSUR are presented below. Note that non-medically verified reports and non-serious reports received from regulatory authorities are included in these analyses. 9.4.1. Drug interactions No cases of potential drug interactions have been received during the period. Most spontaneous cases reported during the period included coadministration(s) with other vaccines (mostly pneumococcal vaccines). Vaccination with pneumococcal vaccines is standard practice in the countries where most reports originated from (Germany and Italy). No relevant findings were noticed as regarding the co-administration profile of the vaccine. No cluster of events suggestive of potential interaction was found. No new important safety information regarding drug interactions has been identified in the time period. 9.4.2. Overdose and Medication Errors There were 319 cases of potential overdose and/or reports of medication error have been received during the reporting period. Non-medically verified and regulatory non-serious cases are included in this analysis. In addition to cases of overdoses, an inappropriate drug use event has been reported 249 times over the period. An overview per category of maladministration is presented in the below table. Note that a case can contain more than one PT related to maladministration. In view of the varying ways in which reports of overdose and medication error are described and coded, there is often much overlap between these concepts. 9.4.2.1. Overdose “Overdose” is defined as more than the recommended dose of vaccine administered at the same occasion (either two vaccine doses administered too soon one after each other or two vaccines with overlapping components accidentally co-administered.) A total of 30 Overdose/Accidental overdose cases were received during the period. Out of these 30, adverse events were reported in 8 cases, including two serious. These cases are listed in Table 37. CONFIDENTIAL 216 CONFIDENTIAL 264 Table 37 Overdose cases reported with adverse events during the period Case ID Seriousness Events PT Comma Sep B0683346A Not serious Wrong drug administered, Overdose, Somnolence, Irritability B0685920A Not serious Irritability, Overdose, Wrong technique in drug usage process B0708048A Not serious Pyrexia, Overdose, Wrong drug administered B0736206A Not serious Pyrexia, Decreased appetite, Wrong drug administered, Overdose B0738500A Serious Injection site induration, Pyrexia, Wrong technique in drug usage process, Overdose B0741664A Not serious Accidental overdose, Pyrexia B0743545A Serious Injection site reaction, Wrong technique in drug usage process, Medication error, Overdose, Injection site induration, Pyrexia D0070270A Not serious Pyrexia, Restlessness, Accidental overdose The two serious Overdose cases are described below:  Case B0738500A (France): Injection site induration, Pyrexia, Wrong technique in drug usage process, Overdose. This case described an inappropriate preparation of medication in a 4-month-old infant who was vaccinated with Infanrix hexa. In August 2011, the subject received a second dose of Infanrix hexa without the Hib component (inappropriate preparation of medication). A third dose of Infanrix hexa was administered immediately (overdose). At an unspecified time after vaccination, the subject presented with mild fever and induration at injection site on 2 cm of diameter.  Case B0743545A (France): Injection site reaction, Wrong technique in drug usage process, Medication error, Overdose, Injection site induration, Pyrexia This case described the occurrence of local reaction at injection site in a 4-month-old female who was vaccinated with Infanrix hexa. On 09 August 2011 the subject received a first dose of Infanrix hexa. The vaccine used had not been properly reconstituted (wrong injection technique, medication error). As the physician thought he had only administered the solution for reconstitution of the vaccine, the physician administered on that same date an additional dose of reconstituted Infanrix hexa. The subject subsequently received two doses of diphtheria, tetanus-acellular pertussis, hepatitis B vaccine (overdose). Medication error was reported. One day after the vaccination, the subject experienced induration at injection site of 2 cm which lasted 8 days and mild febricula during 24 hours. At the time of reporting, the events were resolved without sequelae. The information received with these cases does not provide evidence of a specific safety signal. 9.4.2.2. Medication Errors In addition to Overdose and Accidental overdose cases, 301 cases involving medication errors were received during period. Out of these, 250 were reported with no adverse events and 51 with at least one adverse event. An overview per category of maladministration is presented in Table 38. Note that a case can contain more than one PT related to maladministration. CONFIDENTIAL 217 CONFIDENTIAL 265 Table 38 Overview of medication errors by category of maladministration Event PT Number Of Events Wrong technique in drug usage process 88 Incorrect product storage 47 Wrong drug administered 30 Inappropriate schedule of drug administration 28 Drug administration error 23 Incorrect dose administered 23 Underdose 20 Incorrect route of drug administration 18 Incorrect storage of drug 18 Off label use 13 Expired drug administered 10 Drug administered to patient of inappropriate age 7 Drug prescribing error 1 Medication error 1 Accidental exposure 1 CONFIDENTIAL 218 CONFIDENTIAL 266 Table 39 Cases of maladministration identified during the reporting period Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma A0901400A 23 -Dec -10 Improved 67 Days Female Infanrix hexa Tri -Vi -Sol, Ferrous sulfate Hours Apnoea, Bradycardia, Oxygen saturation decreased, Wrong technique in drug usage process Canada Anaemia neonatal, Bronchopulmonary dysplasia, Premature baby, Apnoea, Bradycardia, Oxygen saturation decreased B0683007A 04 -Nov -10 Unresolved 5 Months Female Infanrix hexa, Priorix Pneumococcal vaccines (Non – GSK), Infanrix hexa 0 Months Injection site nodule, Injection site pruritus, Hypertrichosis, Injection site discolouration, Injection site inflammation, Papule, Wrong drug administered France Gastrooesophageal reflux disease, Haemangioma, Varicella, Nasopharyngitis, Salmonellosis, Otitis media acute, Sarcoidosis B0683346A 05 -Nov -10 Unknown 4 Months Male Boostrix, Infanrix hexa Oral fluid 24 Hours Wrong drug administered, Overdose, Somnolence, Irritability Australia B0684559A 15 -Nov -10 Resolved 2 Months Unknown Infanrix hexa Same day Pyrexia, Incorrect product storage France B0685920A 24 -Nov -10 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) See text Irritability, Overdose, Wrong technique in drug usage process France B0686436A 25 -Nov -10 Not Applicable 20 Months Female Infanrix hexa See text Therapeutic response decreased, Incorrect product storage France CONFIDENTIAL 219 CONFIDENTIAL 267 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0686753A 01 – Dec -10 Improved 11 Months Female Infanrix hexa 0 Days Pyrexia, Wrong technique in drug usage process Italy B0692240A 05 -Jan -11 Unknown 3 Years Male Infanrix hexa, MMR vaccine, strain not specified 1 Years No therapeutic response, Expired drug administered Belgium B0692241A 05 -Jan -11 Not Applicable 6 Years Female Infanrix hexa, MMR vaccine, strain not specified 3 Years No therapeutic response, Expired drug administered Belgium B0695084A 20 -Jan -11 Resolved 2 Years Female Infanrix hexa, Priorix 0 Days Thrombocytopenia, Anaemia, Haematoma, Pyrexia, Gingival bleeding, Fall, Epistaxis, Blood lactate dehydrogenase increased, Incorrect route of drug administration France B0695165A 20 -Jan -11 Not Applicable 2 Months Female Infanrix hexa, Hepatitis B vaccine See text No therapeutic response, Incorrect dose administered France Viral hepatitis carrier B0695865A 25 -Jan -11 Unknown 3 Months Male Infanrix hexa 0 Days Pyrexia, Wrong technique in drug usage process Italy B0697679A 01 -Feb -11 Unknown Female Infanrix hexa Unknown Erythema, Injection site swelling, Wrong technique in drug usage process Italy CONFIDENTIAL 220 CONFIDENTIAL 268 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0697688A 01 -Feb -11 Improved Male Infanrix hexa Unknown Rash morbilliform, Injection site erythema, Injection site oedema, Wrong technique in drug usage process Italy B0701338A 21 -Feb -11 Resolved 4 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) See text Irritability, Sleep disorder, Pyrexia, Injection site induration, Nodule, Incorrect product storage France B0702562A 25 -Feb -11 Resolved 10 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 18 Hours Hypotonic – hyporesponsive episode, Somnolence, Pallor, Incorrect route of drug administration, Neurological examination abnormal France Anaemia B0702721A 28 -Feb -11 Resolved 7 Weeks Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Tonic convulsion, Apnoeic attack, Pyrexia, Hypertonia, Pallor, Hypotonia, Staring, Opisthotonus, Drug administration error France Breast feeding B0703591A 03 -Mar -11 Resolved 20 Months Male Infanrix -polio – HIB, Infanrix hexa Infanrix hexa 2 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site oedema, Pyrexia, Wrong drug administered France CONFIDENTIAL 221 CONFIDENTIAL 269 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0705706A 14 -Mar -11 Resolved 18 Months Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) Same day Arthralgia, Injection site oedema, Pain, Injected limb mobility decreased, Incorrect route of drug administration France Premature baby, Hernia, Exanthema subitum, Tonsillitis, Pharyngiti s B0705783A 14 -Mar -11 Resolved 6 Months Male Infanrix hexa, Infanrix -polio – HIB, Priorix, Pneumococcal vaccines (Non -GSK), Seasonal influenza vaccine (Non – GSK) 6 Hours Pyrexia, Diarrhoea, Nausea, Vomiting, Inappropriate schedule of drug administration France Glycogen storage disease type I, Gastrointestinal tube insertion, Hypoglycaemia B0707392A 21 -Mar -11 Unknown 2 Months Female Infanrix hexa Infanrix hexa, Pneumococcal vaccines (Non – GSK) See text Inappropriate schedule of drug administration, Decreased appetite, Weight decreased France B0708048A 23 -Mar -11 Resolved 4 Months Male Infanrix -polio – HIB, Infanrix hexa Same day Pyrexia, Overdose, Wrong drug administered France B0711364A 06 -Apr -11 Improved 2 Years Female Infanrix hexa 2 Days Extensive swelling of vaccinated limb, Injection site warmth, Injection site inflammation, Injection site erythema, Incorrect route of drug administration France CONFIDENTIAL 222 CONFIDENTIAL 270 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0716297A 29 -Apr -11 Resolved 2 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK), Rotavirus vaccine (Non – GSK) 1 Days Hypotonia, Slow response to stimuli, Pallor, Incorrect route of drug administration France Haemoglobin decreased B0718002A 06 -May – 11 Not Applicable 4 Months Unknown Infanrix hexa, Infanrix -polio – HIB See text Clostridium test negative, Underdose France B0722680A 26 -May – 11 Resolved 2 Months Female Infanrix hexa 12 Hours Pyrexia, Incorrect product storage France B0727081A 17 -Jun -11 Resolved 16 Months Female Infanrix hexa, Infanrix -polio – HIB Infanrix -polio -HIB, DTPa -Polio -HIB (Non -GSK ) 0 Months Injection site swelling, Injection site erythema, Incorrect dose administered France B0729547A 27 -Jun -11 Resolved 26 Months Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) See text Pyrexia, Expired drug administered France B0733404A 14 -Jul -11 Resolved 18 Months Male Infanrix hexa During Wrong technique in drug usage process, Oedema peripheral, Insomnia, Anxiety, Erythema Poland B0733788A 15 -Jul -11 Unknown 1 Years Male Infanrix hexa During Incorrect route of drug administration, Dyskinesia, Underdose, Injection site erythema, Injection site swelling, Injection site mass Sweden CONFIDENTIAL 223 CONFIDENTIAL 271 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0736206A 26 -Jul -11 Unknown 2 Months Male Infanrix hexa, Infanrix -polio Hours Pyrexia, Decreased appetite, Wrong drug administered, Overdose Netherla nds B0738500A 09 -Aug -11 Unknown 4 Months Unknown Infanrix hexa Infanrix -polio -HIB See text Injection site induration, Pyrexia, Wrong technique in drug usage process, Overdose France B0742113A 25 -Aug -11 Resolved 6 Months Unknown Infanrix hexa, Pneumococcal vaccines (Non -GSK) During Incorrect route of drug administration, Injection site haematoma, Injection site swelling, Injection site pain, Injection site erythema Australia B0743545A 31 -Aug -11 Resolved 4 Months Female Infanrix hexa 1 Days Injection site reaction, Wrong technique in drug usage process, Medication error, Overdose, Injection site induration, Pyrexia France B0744411A 02 -Sep -11 Resolved 2 Months Female Priorix, Infanrix hexa 5 Days Oedema, Diarrhoea, Vomiting, Urticaria, Transaminases increased, Drug administered to patient of inappropriate age, Papule, Crying, Pain France B0745305A 06 -Sep -11 Resolved 3 Months Unknown Infanrix hexa Infanrix hexa, Pneumococcal vaccines (Non – GSK) Unknown Pyrexia, Erythema, Diarrhoea, Acne, Wrong drug administere d France CONFIDENTIAL 224 CONFIDENTIAL 272 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma B0747196A 12 -Sep -11 Unknown 70 Years Male Infanrix hexa, Pneumococcal vaccines (Non -GSK) Candesartan cilexetil + hydrochlorothiazide, Clonidine hydrochloride, Torasemide, Tamsulosin hydrochloride, Pantoprazole, Simvastatin, Ticlopidine 1 Days Asthenia, Pyrexia, Drug administered to patient of inappropriate age Italy Polycythaemia vera B0747469A 14 -Sep -11 Unknown 2 Months Female Infanrix hexa Pneumococcal vaccines (Non – GSK) Same day Injection site erythema, Incorrect product storage, Incorrect route of drug administration France B0747719A 14 -Sep -11 Resolved 5 Months Male Infanrix hexa Infanrix hexa, Pneumococcal vaccines (Non – GSK), Rotavirus vaccine (Non -GSK) See text Incorrect storage of drug, Pyrexia, Irritability, Diarrhoea, Abdominal pain Belgium B0747819A 16 -Sep -11 Resolved 7 Weeks Female Infanrix hexa, Pneumococcal vaccines (Non -GSK) 0 Days Hypotonia, Hypersomnia, Feeding disorder neonatal, Drug administration error France Premature baby, Infection B0753926A 03 -Oct -11 Resolved 3 Months Male Infanrix hexa Infanrix hexa See text Crying, Inappropriate schedule of drug administration France D0069239A 27 -Oct -10 Resolved 1 Years Male Infanrix hexa During Soft tissue necrosis, Debridement, Incorrect route of drug administration Germany CONFIDENTIAL 225 CONFIDENTIAL 273 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0069721A 13 -Dec -10 Unknown 18 Months Female Infanrix hexa Infanrix hexa 0 Days Tonsillitis, Pyrexia, Incorrect dose administered Germany D0070074A 25 -Jan -11 Unknown 15 Months Male Infanrix hexa 0 Days Injection site irritation, Underdose Germany D0070138A 27 -Jan -11 Unknown 5 Years Female Infanrix hexa 5 Years Pertussis, Vaccination failure, Inappropriate schedule of drug administration Germany D0070791A 23 -Mar -11 Resolved 12 Months Female Infanrix hexa, Priorix Tetra During Injection site erythema, Injection site swelling, Wrong technique in drug usage process Germany D0070922A 07 -Apr -11 Unknown 16 Months Female Priorix Tetra, Infanrix hexa 0 Days Pyrexia, Ear infection, Bronchitis, Wrong technique in drug usage process, Incorrect route of drug administration Germany D0070972A 11 -Apr -11 Unknown 2 Months Female Infanrix hexa 0 Days Muscle spasms, Underdose Germany D0071405A 17 -May – 11 Resolved 3 Months Female Rotavirus vaccine, Infanrix hexa, Pneumococcal vaccines (Non -GSK) 1 Minutes Vomiting, Underdose Germany D0071543A 26 -May – 11 Resolved 4 Years Female Infanrix hexa 0 Days Injection site erythema, Injection site swelling, Incorrect route of drug administration, Off label use Germany CONFIDENTIAL 226 CONFIDENTIAL 274 Case ID Initial Date Received By Dept Case Outcome Age Gender Suspect Drugs PT Comma Sep Concurrent Drugs PT Comma Sep Time To Onset Since Last Dose Events PT Comma Sep Country Of Reporter Medical Conditions PT Comma D0072541A 30 -Aug -11 Unknown 40 Years Female Infanrix hexa 0 Days Injection site pain, Wrong drug administered Germany No new important safety information regarding medication errors has been identified during the time period. CONFIDENTIAL 227 CONFIDENTIAL 275 9.4.3. Abuse or misuse Not applicable to vaccines. 9.4.4. Pregnancy and Lactation 9.4.4.1. Pregnancy All cases involving a pregnant patient are included. In addition, the search strategy includes a broad selection of MedDRA PTs suggesting exposure in utero or via breast feeding or indicative of birth defects (e.g. congenital or hereditary disorders). Thus the search retrieves cases where pregnancy outcome is abnormal, normal or unknown. Cases involving females over 60 years of age and adult males (where the case was not reported as a partner pregnancy) have been excluded. Note that this search does not include the entire SMQ for ‘Adverse Pregnancy Outcome/Reproductive Toxicity (incl neonatal disorders)’; furthermore, it includes some terms that are not in the SMQ. One (1) case possibly related to administration during pregnancy or lactation was received during the reporting period:  B0681410A (France): Maternal exposure during pregnancy, Off label use This prospective case of pregnancy was reported by a gynecologist and described a vaccine exposure during pregnancy in a female subject aged between 20 and 29 years old who was vaccinated with Infanrix hexa and meningococcal polysaccharide vaccine group C (Meningitec, non-GSK) during pregnancy (3 weeks of amenorrhea). The subject’s medical history included a previous pregnancy with a delivery in July 2010. She had no concurrent pathology and took no concurrent long time treatment. Estimated date of delivery was June 2011. On 30 September 2011n the subject was lost to follow-up. No response to letters. Outcome of pregnancy was unknown. Pregnancy outcomes for the current reporting period and cumulative totals are summarised in Table 40. Changes in the numbers of the cumulative outcomes since the previous safety update reflect not only the addition of new cases but also follow-up obtained on previously received cases. CONFIDENTIAL 228 CONFIDENTIAL 276 Table 40 Pregnancy Outcomes Outcome In Period (n) Cumulative (n) Live infant, no apparent congenital anomaly1 0 1 Live infant with congenital anomaly 0 0 Elective termination, no apparent congenital anomaly1 0 0 Elective termination with congenital anomaly 0 0 Spontaneous abortion, no apparent congenital anomaly1 0 0 Spontaneous abortion with congenital anomaly 0 0 Stillbirth, no apparent congenital anomaly1 0 0 Stillbirth with congenital anomaly 0 0 Ectopic pregnancy 0 0 Molar pregnancy 0 0 Pregnancy ongoing, lost to follow-up or unknown 1 1 Total 1 2 1. Pregnancy outcome categories stating ‘no apparent congenital anomaly’ include outcomes where it is unknown whether a congenital anomaly occurred. No new important safety information regarding use in pregnancy has been identified during the time period. 9.4.4.2. Lactation No cases have been received during the reporting period where Infanrix hexa was given to lactating mothers. No new important safety information regarding administration during lactation has been identified during the time period. 9.4.5. Special Patient Groups No new important safety information related to use in children, elderly or organ impaired patients has been identified during the period. 9.4.6. Effects of long-term treatment Not applicable to vaccines. 9.4.7. Patient/Consumer and other non-healthcare professional reports. The events of interest described in Section 6.5 within the PSUR review period include all cases (irrespective of source, seriousness and listedness). Non-healthcare professional reports are therefore discussed in Section 6.5 as well. Separate Line Listings and Summary Tabulations are provided as appendices for consumer reports as per guideline E2C(R1). CONFIDENTIAL 229 CONFIDENTIAL 277 10. CONCLUSION From the review of data received during the reporting period and presented in this PSUR, it has been concluded that the safety profile of Infanrix hexa is adequately reflected in the RSI. There have been no amendments to the Reference Safety Information (RSI) in the current reporting period and no further amendments to the RSI are considered necessary at this time. The benefit/risk profile of Infanrix hexa continues to be favourable. The Company will continue to monitor cases of anaemia haemolytic autoimmune, thrombocytopenia, thrombocytopenic purpura, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, haemolytic anemia, cyanosis, injection site nodule, abcess and injection site abscess, Kawasaki’s disease, important neurological events (including encephalitis and encephalopathy), Henoch-Schonlein purpura, petechiae, purpura, haematochezia, allergic reactions (including anaphylactic and anaphylactoid reactions), cases of lack of effectiveness as well as fatal cases. CONFIDENTIAL 230 CONFIDENTIAL 278 11. REFERENCES Addendum to ICH E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs, ICH Harmonised Tripartite Guideline, 6 February 2003. Alm B et al. Changes in the epidemiology of sudden infant death syndrome in Sweden 1973-1996. Arch Dis Child. 2001; 84: 24-30. Aouba F et al. Sudden infant death syndrome : situation in 2005 and trends since 1975. BEH Thematique 3-4. 2008: 18–21. Carpenter RG et al. Sudden unexplained infant death in 20 regions in Europe: case control study. The Lancet. 2004; 364. German Federal Statistical Office. Available on line: gbe-bund.de. Consulted on: November 2010. Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population, EMEA/CHMP/PhVWP/235910/2005, effective January 2007. Guideline on the Exposure to Medicinal Products During Pregnancy: Need for PostAuthorisation Data, EMEA/CHMP/313666/2005, May 2006. ICH Harmonised Tripartite Guideline for Clinical Safety Data Management Periodic Safety Update Reports for Marketed Drugs E2C(R1), 6 November 1996. Kiechl-Kohlendorfer U et al. Epidemiology of sudden infant death syndrome (SIDS) in the Tyrol before and after an intervention campaign. Wien Klin Wochenschr. 2001; 113/1-2: 27-32. Knuf M, Pantazi-Chatzikonstantinou A, Pfletschinger U et al. An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix™ hexa is immunogenic, with an acceptable safety profile in 12-23-month-old children. Vaccine. 2011 29:25 (4264-4273). Lim FS, Phua KB, Lee BW et al. Safety and reactogenicity of DTPa-HBV-IPV/Hib and DTPa-IPV/I-Hib vaccines in a post-marketing surveillance setting. The Southeast Asian journal of tropical medicine and public health. 2011 42:1 (138-147). Mehanni M. et al. The current epidemiology of SIDS in Ireland. Irish Med J. 2000; 93:9. Mollborg P et al. Sudden infant death syndrome during low incidence in Sweden 1997- 2005. Acta Paediatrica. 2010; 99: 94-98. Montomoli C et al. Mortality due to sudden infant death syndrome in Northen Italy, 990- 2000: a baseline for the assessment of prevention campaigns. Paediatr Perinat Epidemiol. 2004; 18:336-43. Nennstiel-Ratzel U et al. Prevention of sudden infant death syndrome (SIDS) in Bavaria –Evaluation of a prevention campaign. Klin Padiatr, 2010; 222:45-50. CONFIDENTIAL 231 CONFIDENTIAL 279 Sejvar JJ, Kohl KS, Gidudu J et al. Guillain-Barré Syndrome and Fisher Syndrome: Case Definitions and Guidelines for Collection, Analysis, and Presentation of Immunization Safety Data. Vaccine. 2011;29(3):599-612. Volume 9A of the Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use, September 2008. Wennergren G et al. Prevention of sudden infant death syndrome. Pediatric Pulmonology. 2004; S26:110-11. CONFIDENTIAL 232 CONFIDENTIAL 280 233 CONFIDENTIAL APPENDIX 1 : Marketing Authorisation Status CONFIDENTIAL 281 Country * Tradename Approval Launch Removal from Market Launch comment Albania pc INFANRIX HEXA 25 -Mar -09 Planned to be launched Argentina c INFANRIX HEXA 15 -May -01 Launch could be assumed as having happened not less than 3 months after approval. Aruba INFANRIX HEXA 20 -Feb -02 Not applicable Australia c INFANRIX HEXA 26 -Nov -01 Launch could be assumed as having happened not less than 3 months after approval. Austria c INFANRIX HEXA 23 -Oct -00 22/06/2006 Launched Azerbaijan c INFANRIX HEXA 01 -Dec -08 Launch could be assumed as having happened not less than 3 months after approval. Bahrain c INFANRIX HEXA 01 -Aug -05 Launch could be assumed as having happened not less than 3 months after approval. Bangladesh c INFANRIX HEXA 09 -Sep -08 Launch could be assumed as having happened not less than 3 months after approval. Belgium c INFANRIX HEXA 23 -Oct -00 11/10/2006 Launched Bosnia INFANRIX HEXA 09 -Mar -11 Not applicable Brazil c INFANRIX HEXA 02 -Apr -01 Launch could be assumed as having happened not less than 3 months after approval. Bulgaria INFANRIX HEXA 23 -Oct -00 Not applicable Canada c INFANRIX HEXA 28 -May -04 04/12/2008 Launched Chile c INFANRIX HEXA 26 -Mar -02 Launch could be assumed as having happened not less than 3 months after approval. Colombia c INFANRIX HEXA 23 -Feb -00 Launch could be assumed as having happened not less than 3 months after approval. Costa Rica c INFANRIX HEXA 02 -Oct -01 Launch could be assumed as having happened not less than 3 months after approval. Croatia c INFANRIX HEXA 18 -Nov -04 Launch could be assumed as having happened not less than 3 months after approval. Curacao INFANRIX HEXA 28 -Sep -01 Not applicable Cyprus c INFANRIX HEXA 23 -Oct -00 31/10/2003 Launched Czech Republic c INFANRIX HEXA 23 -Oct -00 01/08/2006 Launched Denmark INFANRIX HEXA 23 -Oct -00 Not applicable Dominican Republic c INFANRIX HEXA 22 -Oct -01 Launch could be assumed as having happened not less than 3 months after approval. Ecuador c INFANRIX HEXA 07 -Feb -03 Launch could be assumed as having happened not less than 3 months after approval. El Salvador c INFANRIX HEXA 11 -Feb -03 Launch could be assumed as having happened not less than 3 months after approval. Estonia c INFANRIX HEXA 23 -Oct -00 01/03/2004 Launched Finland INFANRIX HEXA 23 -Oct -00 Not applicable France c INFANRIX HEXA 23 -Oct -00 16/08/2006 Launched Georgia c INFANRIX HEXA 04 -Mar -09 Launch could be assumed as having happened not less than 3 months after approval. Germany c INFANRIX HEXA 23 -Oct -00 21/10/2000 Launched Greece c INFANRIX HEXA 23 -Oct -00 01/09/2003 Launched Guatemala c INFANRIX HEXA 09 -Apr -02 Launch could be assumed as having happened not less than 3 months after approval. Guyana INFANRIX HEXA 11 -May -10 Not applicable CONFIDENTIAL 234 CONFIDENTIAL 282 Haiti c INFANRIX HEXA 25 -Jun -08 Launch could be assumed as having happened not less than 3 months after approval. Honduras c INFANRIX HEXA 06 -Jun -02 Launch could be assumed as having happened not less than 3 months after approval. Hong Kong c INFANRIX HEXA 26 -Nov -01 Launch could be assumed as having happened not less than 3 months after approval. Hungary INFANRIX HEXA 23 -Oct -00 Not applicable Iceland INFANRIX HEXA 23 -Oct -00 Not applicable Ireland c INFANRIX HEXA 23 -Oct -00 Launch could be assumed as having happened not less than 3 months after approval. Israel INFANRIX HEXA 01 -Aug -05 Not applicable Italy c INFANRIX HEXA 23 -Oct -00 21/02/2001 Launched Ivory Coast INFANRIX HEXA 14 -Jun -02 Not applicable Jamaica c INFANRIX HEXA 19 -Jul -01 Launch could be assumed as having happened not less than 3 months after approval. Jordan c INFANRIX HEXA 30 -Mar -05 Launch could be assumed as having happened not less than 3 months after approval. Kazakhstan c INFANRIX HEXA 16 -Jan -09 Launch could be assumed as having happened not less than 3 months after approval. Kenya c INFANRIX HEXA 06 -Dec -01 Launch could be assumed as having happened not less than 3 months after approval. Latvia pc INFANRIX HEXA 23 -Oct -00 Planned to be launched Lebanon c INFANRIX HEXA 25 -Mar -09 Launch could be assumed as having happened not less than 3 months after approval. Lithuania INFANRIX HEXA 23 -Oct -00 30/03/2005 01/01/2007 Not applicable Luxembourg INFANRIX HEXA 23 -Oct -00 Not applicable Macedonia INFANRIX HEXA 26 -Apr -10 Not applicable Madagascar c INFANRIX HEXA 11 -Feb -08 01/03/2008 Launched Malaysia c INFANRIX HEXA 06 -Jan -06 Launch could be assumed as having happened not less than 3 months after approval. Malta c INFANRIX HEXA 23 -Oct -00 01/11/2001 Launched Mauritius c INFANRIX HEXA 22 -May -06 Launch could be assumed as having happened not less than 3 months after approval. Mexico c INFANRIX HEXA 15 -Dec -00 Launch could be assumed as having happened not less than 3 months after approval. Moldova c INFANRIX HEXA 12 -May -03 Launch could be assumed as having happened not less than 3 months after approval. Morocco c INFANRIX HEXA 06 -Oct -03 Launch could be assumed as having happened not less than 3 months after approval. Myanmar c INFANRIX HEXA 26 -May -10 07/09/2011 Launched Namibia c INFANRIX HEXA 07 -Apr -06 Launch could be assumed as having happened not less than 3 months after approval. Netherlands c INFANRIX HEXA 23 -Oct -00 30/01/2005 Launched New Zealand c INFANRIX HEXA 24 -Apr -01 Launch could be assumed as having happened not less than 3 months after approval. Nicaragua c INFANRIX HEXA 02 -Apr -02 Launch could be assumed as having happened not less than 3 months after approval. Norway INFANRIX HEXA 13 -Aug -01 Not applicable Pakistan c INFANRIX HEXA 22 -Nov -02 Launch could be assumed as having happened not less than 3 months after approval. Panama c INFANRIX HEXA 22 -Apr -02 Launch could be assumed as having happened not less than 3 months after approval. Peru c INFANRIX HEXA 06 -May -03 Launch could be assumed as having happened not less than 3 months after approval. Philippines c INFANRIX HEXA 03 -Oct -02 Launch could be assumed as having happened not less than 3 months after approval. Poland c INFANRIX HEXA 23 -Oct -00 06/02/2004 Launched CONFIDENTIAL 235 CONFIDENTIAL 283 Portugal INFANRIX HEXA 23 -Oct -00 Not applicable Qatar pc INFANRIX HEXA 07 -Oct -10 Planned to be launched Romania c INFANRIX HEXA 23 -Oct -00 31/01/2007 Launched Saudi Arabia c INFANRIX HEXA 03 -Oct -05 Launch could be assumed as having happened not less than 3 months after approval. Serbia pc INFANRIX HEXA® 20 -Mar -09 Planned to be launched Singapore c INFANRIX HEXA 07 -May -03 Launch could be assumed as having happened not less than 3 months after approval. Slovakia c INFANRIX HEXA 23 -Oct -00 01/01/2008 Launched Slovenia INFANRIX HEXA 23 -Oct -00 Not applicable South Africa c INFANRIX HEXA 07 -Apr -06 Launch could be assumed as having happened not less than 3 months after approval. Spain c INFANRIX HEXA 23 -Oct -00 01/06/2001 Launched Sri Lanka c INFANRIX HEXA 04 -Jul -05 Launch could be assumed as having happened not less than 3 months after approval. Sweden c INFANRIX HEXA 23 -Oct -00 01/12/2001 Launched Switzerland c INFANRIX HEXA 02 -Oct -00 Launch could be assumed as having happened not less than 3 months after approval. Syria INFANRIX HEXA 26 -Nov -06 Not applicable Taiwan c INFANRIX HEXA 14 -Oct -04 Launch could be assumed as having happened not less than 3 months after approval. Thailand c INFANRIX HEXA 13 -Sep -02 10/01/2003 Launched Trinidad and Tobago c INFANRIX HEXA 24 -Sep -01 Launch could be assumed as having happened not less than 3 months after approval. Tunisia INFANRIX HEXA 20 -Aug -05 Not applicable UK INFANRIX HEXA 23 -Oct -00 Not applicable Ukraine c INFANRIX HEXA 12 -Nov -02 Launch could be assumed as having happened not less than 3 months after approval. United Arab Emirates c INFANRIX HEXA 18 -Sep -06 Launch could be assumed as having happened not less than 3 months after approval. Venezuela c INFANRIX HEXA 11 -Jul -02 Launch could be assumed as having happened not less than 3 months after approval. Vietnam c INFANRIX HEXA 19 -Sep -05 Launch could be assumed as having happened not less than 3 months after approval. Yemen INFANRIX HEXA 11 -Aug -08 Not applicable *c, commercialized; pc, planned commercialized; empty, not commercialized and not planned CONFIDENTIAL 236 CONFIDENTIAL 284 237 CONFIDENTIAL APPENDIX 2 : Global Data Sheet version 010 – 21 Oct 2010 CONFIDENTIAL 285 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 1 of 15 CONFIDENTIAL GLOBAL DATASHEET Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine CONFIDENTIAL 238 CONFIDENTIAL 286 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 2 of 15 CONFIDENTIAL GLOBAL PRESCRIBER INFORMATION TITLE Combined diphtheria-tetanus-acellular pertussis, hepatitis B, enhanced inactivated polio vaccine and Haemophilus influenzae type b vaccine. SCOPE Trade Name(s) Infanrix hexa Formulation and Strength Powder and suspension for suspension for injection. 1 dose (0.5 ml) contains: Diphtheria toxoid1 not less than 30 International units Tetanus toxoid1 not less than 40 International units Bordetella pertussis antigens Pertussis toxoid1 25 micrograms Filamentous Haemagglutinin1 25 micrograms Pertactin1 8 micrograms Hepatitis B surface antigen2,3 10 micrograms Poliovirus (inactivated) type 1 (Mahoney strain)4 40 D-antigen unit type 2 (MEF-1 strain)4 8 D-antigen unit type 3 (Saukett strain)4 32 D-antigen unit Haemophilus influenzae type b polysaccharide 10 micrograms (polyribosylribitol phosphate)3 conjugated to tetanus toxoid as carrier protein 20 – 40 micrograms 1 adsorbed on aluminium hydroxide, hydrated (Al(OH)3) 0.5 milligrams Al3+ 2 produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology 3 adsorbed on aluminium phosphate (AlPO4) 0.32 milligrams Al3+ 4 propagated in VERO cells The DTPa-HBV-IPV component is presented as a turbid white suspension. Upon storage, a white deposit and clear supernatant can be observed. CONFIDENTIAL 239 CONFIDENTIAL 287 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 3 of 15 CONFIDENTIAL The Hib component is presented as a white powder. Excipients It is mandatory for country product information to include both the complete list of excipients for all locally marketed presentations, and any locally imposed excipient warning statements. Lactose Sodium chloride (NaCl) Medium 199 (as stabilizer including amino acids, mineral salts and vitamins) Water for injections Residues Potassium chloride Disodium phosphate Monopotassium phosphate Polysorbate 20 and 80 Glycine Formaldehyde Neomycin sulphate Polymyxin B sulphate CLINICAL INFORMATION Indications Infanrix hexa is indicated for primary and booster vaccination of infants against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenza type b. Dosage and Administration Posology Primary vaccination The primary vaccination schedule consists of three doses of 0.5 ml (e.g. 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months) or two doses (e.g. 3, 5 months). There should be an interval CONFIDENTIAL 240 CONFIDENTIAL 288 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 4 of 15 CONFIDENTIAL of at least 1 month between doses. The Expanded Program on Immunisation schedule (at 6, 10, 14 weeks of age) may only be used if a dose of hepatitis B vaccine has been given at birth. Locally established immunoprophylactic measures against hepatitis B should be maintained. Where a dose of hepatitis B vaccine is given at birth, Infanrix hexa can be used as a replacement for supplementary doses of hepatitis B vaccine from the age of 6 weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used. Booster vaccination After a vaccination with 2 doses (e.g. 3, 5 months) of Infanrix hexa a booster dose must be given at least 6 months after the last priming dose, preferably between 11 and 13 months of age. After vaccination with 3 doses (e.g. 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months) of Infanrix hexa a booster dose may be given at least 6 months after the last priming dose and preferably before 18 months of age. Booster doses should be given in accordance with the official recommendations. Infanrix hexa can be considered for the booster if the composition is in accordance with the official recommendations. Other combinations of antigens have been studied in clinical trials following primary vaccination with Infanrix hexa and may be used for a booster dose: diphtheria, tetanus, acellular pertussis (DTPa), diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b (DTPa+Hib), diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, Haemophilus influenzae type b (DTPa-IPV+Hib) and diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis, Haemophilus influenzae type b (DTPa-HBV-IPV+Hib). Method of administration Infanrix hexa is for deep intramuscular injection. Contraindications Hypersensitivity to the active substances or to any of the excipients or residues (see Formulation and Strength, Excipients and Residues). Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccines. Infanrix hexa is contraindicated if the child has experienced an encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with CONFIDENTIAL 241 CONFIDENTIAL 289 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 5 of 15 CONFIDENTIAL pertussis containing vaccine. In these circumstances pertussis vaccination should be discontinued and the vaccination course should be continued with diphtheria-tetanus, hepatitis B, inactivated polio and Hib vaccines. Warnings and Precautions As with other vaccines, administration of Infanrix hexa should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection is not a contra-indication. Vaccination should be preceded by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination. If any of the following events are known to have occurred in temporal relation to receipt of pertussis-containing vaccine, the decision to give further doses of pertussis-containing vaccines should be carefully considered: – Temperature of 40.0°C within 48 hours, not due to another identifiable cause. – Collapse or shock-like state (hypotonic-hyporesponsiveness episode) within 48 hours of vaccination. – Persistent, inconsolable crying lasting 3 hours, occurring within 48 hours of vaccination. – Convulsions with or without fever, occurring within 3 days of vaccination. There may be circumstances, such as a high incidence of pertussis, when the potential benefits outweigh possible risks. In children with progressive neurological disorders, including infantile spasms, uncontrolled epilepsy or progressive encephalopathy, it is better to defer pertussis (Pa or Pw) immunization until the condition is corrected or stable. However, the decision to give pertussis vaccine must be made on an individual basis after careful consideration of the risks and benefits. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine. Infanrix hexa should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects. Infanrix hexa should under no circumstances be administered intravascularly or intradermally. Infanrix hexa contains traces of neomycin and polymyxin. The vaccine should be used with caution in patients with known hypersensitivity to one of these antibiotics. CONFIDENTIAL 242 CONFIDENTIAL 290 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 6 of 15 CONFIDENTIAL Infanrix hexa will not prevent disease caused by pathogens other than Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzae type b. However, it can be expected that hepatitis D will be prevented by immunisation as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection. A protective immune response may not be elicited in all vaccinees (see Pharmacodynamic Effects). A history of febrile convulsions, a family history of convulsions or Sudden Infant Death Syndrome (SIDS) do not constitute contraindications for the use of Infanrix hexa. Vaccinees with a history of febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination. Human Immunodeficiency Virus (HIV) infection is not considered as a contra-indication. The expected immunological response may not be obtained after vaccination of immunosuppressed patients. Since the Hib capsular polysaccharide antigen is excreted in the urine a positive urine test can be observed within 1-2 weeks following vaccination. Other tests should be performed in order to confirm Hib infection during this period. Limited data in 169 premature infants indicate that Infanrix hexa can be given to premature children. However, a lower immune response may be observed and the level of clinical protection remains unknown. The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunization series to very premature infants (born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed. Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints. Interactions There are insufficient data with regard to the efficacy and safety of simultaneous administration of Infanrix hexa and Measles-Mumps-Rubella vaccine to allow any recommendation to be made. Data on concomitant administration of Infanrix hexa with Prevenar (pneumococcal saccharide conjugated vaccine, adsorbed) have shown no clinically relevant interference in the antibody response to each of the individual antigens when given as a 3 dose primary vaccination. However, high incidence of fever (> 39.5°C) was reported in infants receiving Infanrix hexa and Prevenar compared to infants receiving the hexavalent vaccine alone. Antipyretic treatment should be initiated according to local treatment guidelines. CONFIDENTIAL 243 CONFIDENTIAL 291 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 7 of 15 CONFIDENTIAL As with other vaccines, it may be expected that in patients receiving immunosuppressive therapy, an adequate response may not be achieved. Pregnancy and Lactation Pregnancy As Infanrix hexa is not intended for use in adults, information on the safety of the vaccine when used during pregnancy is not available. Lactation As Infanrix hexa is not intended for use in adults, information on the safety of the vaccine when used during lactation is not available. Ability to perform tasks that require judgement, motor or cognitive skills Not relevant. Adverse Reactions Clinical Trial Data The safety profile presented below is based on data from more than 16,000 subjects. As has been observed for DTPa and DTPa-containing combinations, an increase in local reactogenicity and fever was reported after booster vaccination with Infanrix hexa with respect to the primary course. Adverse reactions reported are listed according to the following frequency: Very common: 1/10 Common: 1/100 to < 1/10 Uncommon: 1/1000 to < 1/100 Rare: 1/10000 to < 1/1000 Very rare: < 1/10000 Infections and infestations Uncommon: upper respiratory tract infection Metabolism and nutrition disorders Very common: appetite lost Psychiatric disorders CONFIDENTIAL 244 CONFIDENTIAL 292 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 8 of 15 CONFIDENTIAL Very common: irritability, crying abnormal, restlessness Common: nervousness Nervous system disorders Uncommon: somnolence Very rare: convulsions (with or without fever) Respiratory, thoracic and mediastinal disorders Uncommon: cough* Rare: bronchitis Gastrointestinal disorders Common: vomiting, diarrhoea Skin and subcutaneous tissue disorders Common: pruritus* Rare: rash Very rare: dermatitis, urticaria* General disorders and administration site conditions Very common: pain, redness, local swelling at the injection site (≤ 50 mm), fever 38°C, fatigue Common: local swelling at the injection site (> 50 mm)**, fever >39.5°C, injection site reactions, including induration Uncommon: diffuse swelling of the injected limb, sometimes involving the adjacent joint** Post Marketing Data Blood and lymphatic system disorders Lymphadenopathy, thrombocytopenia Immune system disorders Allergic reactions (including anaphylactic and anaphylactoid reactions) Nervous system disorders Collapse or shock-like state (hypotonic-hyporesponsiveness episode) Respiratory, thoracic and mediastinal disorders Apnoea* [see Warnings and Precautions for apnoea in very premature infants (≤ 28 weeks of gestation)] Skin and subcutaneous tissue disorders CONFIDENTIAL 245 CONFIDENTIAL 293 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 9 of 15 CONFIDENTIAL Angioneurotic oedema* General disorders and administration site conditions Extensive swelling reactions, swelling of the entire injected limb**, vesicles at the injection site * observed with other GSK DTPa-containing vaccines ** Children primed with acellular pertussis vaccines are more likely to experience swelling reactions after booster administration in comparison with children primed with whole cell vaccines. These reactions resolve over an average of 4 days. Experience with hepatitis B vaccine: Meningitis, mimicking serum sickness, paralysis, encephalitis, encephalopathy, neuropathy, neuritis, hypotension, vasculitis, lichen planus, erythema multiforme, arthritis, muscular weakness have been reported during post-marketing surveillance following GlaxoSmithKline Biologicals’ hepatitis B vaccine in infants < 2 years old. The causal relationship to the vaccine has not been established. Overdosage Insufficient data are available. Clinical Pharmacology Pharmacodynamics ATC Code Pharmaco-therapeutic group: Bacterial and viral vaccines combined, ATC code J07CA09 Pharmacodynamic Effects Result obtained in the clinical studies for each of the components are summarised in the tables below: CONFIDENTIAL 246 CONFIDENTIAL 294 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 10 of 15 CONFIDENTIAL Percentage of subjects with antibody titres ≥ assay cut-off one month after primary vaccination with Infanrix hexa Antibody (cut-off) Two doses Three doses 3-5 months N= 530 (4 studies) 2-3-4 months N= 196 ( 2 studies) 2-4-6 months N= 1693 (6 studies) 3-4-5 months N= 1055 (6 studies) 6-10-14 weeks N= 265 ( 1 study) % % % % % Anti-diphtheria (0.1 IU/ml) † 98.0 100.0 99.8 99.7 99.2 Anti-tetanus (0.1 IU/ml) † 100.0 100.0 100.0 100.0 99.6 Anti-PT (5 EL.U/ml) 99.5 100.0 100.0 99.8 99.6 Anti-FHA (5 EL.U/ml) 99.7 100.0 100.0 100.0 100.0 Anti-PRN (5 EL.U/ml) 99.0 100.0 100.0 99.7 98.9 Anti-HBs (10 mIU/ml) † 96.8 99.5 98.9 98.0 98.5* Anti-Polio type 1 (1/8 dilution) † 99.4 100.0 99.9 99.7 99.6 Anti-Polio type 2 (1/8 dilution) † 96.3 97.8 99.3 98.9 95.7 Anti-Polio type 3 (1/8 dilution) † 98.8 100.0 99.7 99.7 99.6 Anti-PRP (0.15 g/ml) † 91.7 96.4 96.6 96.8 97.4 N=number of subjects * in a subgroup of infants not administered hepatitis B vaccine at birth, 77.7% of subjects had anti-HBs titres 10 mIU/ml † cut-off accepted as indicative of protection CONFIDENTIAL 247 CONFIDENTIAL 295 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 11 of 15 CONFIDENTIAL Percentage of subjects with antibody titres ≥ assay cut-off one month after booster vaccination with Infanrix hexa Antibody (cut-off) Booster vaccination at 11 months of age following a 3-5 month primary course N=532 (3 studies) Booster vaccination during the second year of life following a three dose primary course N= 2009 (12 studies) % % Anti-diphtheria (0.1 IU/ml) † 100.0 99.9 Anti-tetanus (0.1 IU/ml) † 100.0 99.9 Anti-PT (5 EL.U/ml) 100.0 99.9 Anti-FHA (5 EL.U/ml) 100.0 99.9 Anti-PRN (5 EL.U/ml) 99.2 99.5 Anti-HBs (10 mIU/ml) † 98.9 98.4 Anti-Polio type 1 (1/8 dilution) † 99.8 99.9 Anti-Polio type 2 (1/8 dilution) † 99.4 99.9 Anti-Polio type 3 (1/8 dilution) † 99.2 99.9 Anti-PRP (0.15 g/ml) † 99.6 99.7 N= Number of subjects † cut-off accepted as indicative of protection As the immune response to pertussis antigens following Infanrix hexa administration is equivalent to that of Infanrix, the protective efficacy of the two vaccines is expected to be equivalent. The protective efficacy of the pertussis component of Infanrix against WHO-defined typical pertussis ( 21 days of paroxysmal cough) was demonstrated in: – a prospective blinded household contact study performed in Germany (3, 4, 5 months schedule). Based on data collected from secondary contacts in households where there was an index case with typical pertussis, the protective efficacy of the vaccine was 88.7%. – a NIH sponsored efficacy study performed in Italy (2, 4, 6 months schedule). The vaccine efficacy was found to be 84%. In a follow-up of the same cohort, the efficacy CONFIDENTIAL 248 CONFIDENTIAL 296 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 12 of 15 CONFIDENTIAL was confirmed up to 60 months after completion of primary vaccination without administration of a booster dose of pertussis. Results of long term follow-up in Sweden demonstrate that acellular pertussis vaccines are highly efficacious in infants when administered according to the 3 and 5 months primary vaccination schedule, with a booster dose administered at approximately 12 months. However, data indicate that protection against pertussis may be waning at 7-8 years of age. This suggests that a second booster dose of pertussis vaccine is warranted in children aged 5-7 years who have previously been vaccinated following this schedule. Protective immunity against hepatitis B has been shown to persist for at least 3.5 years in more than 90% of children administered four doses of Infanrix hexa. Antibody levels were not different from what was observed in a parallel cohort administered monovalent hepatitis B vaccine. The effectiveness of the Hib component of Infanrix hexa was investigated via an extensive post-marketing surveillance study conducted in Germany. Over a seven year follow-up period, the effectiveness of the Hib components of two hexavalent vaccines, of which one was Infanrix hexa, was 89.6% for a full primary series and 100% for a full primary series plus booster dose (irrespective of the Hib vaccine used for priming). Pharmacokinetics Evaluation of pharmacokinetic properties is not required for vaccines. Clinical Studies See Pharmacodynamic Effects. NON-CLINICAL INFORMATION Preclinical data reveal no special hazard for humans based on conventional studies of safety, specific toxicity, repeated dose toxicity and compatibility of ingredients. PHARMACEUTICAL INFORMATION Shelf-Life The expiry date of the vaccine is indicated on the label and packaging. The expiry date refers to the last day of the month mentioned. The shelf-life is 3 years. CONFIDENTIAL 249 CONFIDENTIAL 297 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 13 of 15 CONFIDENTIAL Storage Infanrix hexa should be stored at +2°C to +8°C. Protect from light. During transport, recommended conditions of storage must be respected. The DTPa-HBV-IPV suspension and the reconstituted vaccine must not be frozen. Discard if it has been frozen. Nature and Contents of Container The DTPa-HBV-IPV component is presented in a pre-filled syringe or vial. The Hib component is presented as a white pellet in a glass vial. The vials and pre-filled syringes are made of neutral glass type I, which conforms to European Pharmacopoeia Requirements. Vial and pre-filled syringe presentations (with or without needles) are available in packs of 1, 10, 20 and 50. Vial and vial presentation is available in pack sizes of 1 and 50. Incompatibilities Infanrix hexa should not be mixed with other vaccines in the same syringe. Use and Handling 1. Wording for vial and pre-filled syringe presentation The DTPa-HBV-IPV suspension should be well shaken in order to obtain a homogeneous turbid white suspension. The DTPa-HBV-IPV suspension and the Hib powder should be inspected visually for any foreign particulate matter and/or variation of physical aspect. In the event of either being observed, discard the vaccine. Infanrix hexa must be reconstituted by adding the entire content of the pre-filled syringe to the vial containing the Hib powder. It is good clinical practice to only inject a vaccine when it has reached room temperature. In addition, a vial at room temperature ensures sufficient elasticity of the rubber closure to minimise any coring of rubber particles. To achieve this, the vial should be kept at room temperature (25 3 °C) for at least five minutes before connecting the pre-filled syringe and reconstituting the vaccine. The reconstituted vaccine presents as a slightly more cloudy suspension than the liquid component alone. This is normal and does not impair the performance of the vaccine. In the event of other variation being observed, discard the vaccine. After reconstitution, the vaccine should be injected immediately. However the vaccine may be kept for up to 8 hours at room temperature (21°C). CONFIDENTIAL 250 CONFIDENTIAL 298 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 14 of 15 CONFIDENTIAL Withdraw the entire contents of the vial. Specific instructions for the pre-filled syringe with a luer lock adaptor (PRTC) Needle Syringe 1. Holding the syringe barrel in one hand (avoid holding the syringe plunger), unscrew the syringe cap by twisting it anticlockwise. 2. To attach the needle to the syringe, twist the needle clockwise into the syringe until you feel it lock (see picture). 3. Remove the needle protector, which on occasion can be a little stiff. 4. Administer the vaccine. 2. Wording for vial and vial presentation Upon storage, a white deposit and clear supernatant may be observed in the vial containing the DTPa-HBV-IPV suspension. This does not constitute a sign of deterioration. Infanrix hexa must be reconstituted by adding the entire content of the vial containing the DTPa-HBV-IPV suspension to the vial containing the Hib powder. To do so, draw up the suspension with a syringe and add the suspension to the powder. The mixture should be well shaken until the powder is completely dissolved in the suspension. The reconstituted vaccine presents as a slightly more cloudy suspension than the liquid component alone. This is normal and does not impair the performance of the vaccine. The reconstituted vaccine should be inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vaccine. A new needle should be used to administer the vaccine. Needle protector Syringe plunger Syringe barrel Syringe cap CONFIDENTIAL 251 CONFIDENTIAL 299 Active Name: Combined diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis (inactivated) and Haemophilus influenzae type b vaccine Version Number: 010 Version Date: 21 Oct 2010 Page 15 of 15 CONFIDENTIAL After reconstitution, the vaccine should be used immediately. Withdraw the entire contents of the vial. Any unused product or waste material should be disposed of in accordance with local requirements. CONFIDENTIAL 252 CONFIDENTIAL 300 253 CONFIDENTIAL APPENDIX 3A : All serious spontaneous cases (excluding consumer reports), all serious attributable clinical trial cases and all non-serious unlisted cases (excluding consumer and regulatory reports) CONFIDENTIAL 301 Appendix 3A: Individual Case Histories Received in Time Period of PSUR for: Infanrix hexa Case No. Country Report Source Age/Sex Form’n or Route TDD Treatment Dates† Event Onset TTO / TTOSLD Events Outcome Comments Blood and lymphatic system disorders #B0740907A France PH,MD,RA 4 Months/M INJ U 10Aug2011-10Aug2011 11Aug2011 U/1 Days Agranulocytosis, Pyrexia, Rash R #D0072751A Germany MD 7 Months/M INJ .5ML 05Jul2011-05Jul2011 02Aug2011 U/28 Days Anaemia haemolytic autoimmune*, Autoantibody positive N #B0696866A Poland MD,RA 1 Months/U INJ U 20Dec2010-20Dec2010 23Dec2010 U/3 Days Anaemia, Hypotonic-hypore sponsive episode, Apathy, Thirst decreased, Respiratory tract infection, Somnolence R CONFIDENTIAL 254 CONFIDENTIAL 302 #D0070397A Germany MD,RP 3 Months/M INJ .5ML 08Feb2011-08Feb2011 09Feb2011 U/1 Days Haemorrhagic diathesis*, Ecchymosis, Petechiae, Upper respiratory tract infection R #B0737478A Poland MD,RA 4 Months/M INJ U 18Feb2011-18Feb2011 18Feb2011 U/8 Hours Haemorrhagic diathesis, Petechiae, Pyrexia R #B0686840A Czech Republic MD,RA 5 Months/M INJ U 07May2009-07May2009 07May2009 U/3 Hours Idiopathic thrombocytopenic purpura, Febrile convulsion, Clonic convulsion, Tremor, Dyskinesia, Petechiae, Platelet count decreased, Pyrexia R #B0705987A Ireland PH 8 Months/M INJ U 01Dec2009-01Dec2009 01Jan2010 U/1 Months Idiopathic thrombocytopenic purpura, Haemorrhage, Platelet count decreased, Petechiae, Fall, Increased tendency to bruise, Upper respiratory tract infection U CONFIDENTIAL 255 CONFIDENTIAL 303 #D0071950A Germany MD 12 Months/M INJ .5ML 30Jun2011-30Jun2011 02Jul2011 U/2 Days Idiopathic thrombocytopenic purpura*, Mouth haemorrhage*, Mouth haemorrhage*, Haematoma* N #B0740099A Netherlands MD,RA 4 Months/F INJ U 06Apr2009-06Apr2009 06Apr2009 U/Hours Idiopathic thrombocytopenic purpura, Petechiae, Diarrhoea, Inflammation, Pyrexia R #B0684234A Italy MD,RA 10 Months/M INJ U 07Apr2010-07Apr2010 17Apr2010 U/10 Days Idiopathic thrombocytopenic purpura, Thrombocytopeni a, Rhinitis, Petechiae, Petechiae, Pyrexia U #B0715203A Italy MD,RA 5 Months/F INJ U 14Apr2009-14Apr2009 17Apr2009 U/3 Days Leukocytosis, Inflammatory marker increased, Hyperaemia, Rhinitis, Injection site reaction, Nuchal rigidity, Irritability, Pyrexia, Crying U B0686750A Poland MD,RA 19 Months/U INJ U 25Aug2010-25Aug2010 27Aug2010 U/2 Days Lymphadenopath y, Injection site oedema, Injection site erythema, Lymphadenopath y U CONFIDENTIAL 256 CONFIDENTIAL 304 #B0691905A Poland RA 17 Months/U INJ U 02Dec2010-02Dec2010 03Dec2010 U/Hours Lymphadenopath y, Oedema, Erythema, Lymph node palpable, Pyrexia, Restlessness, Insomnia U #B0695084A France RA 2 Years/F INJ U 14Sep2010-14Sep2010 14Sep2010 U/0 Days Thrombocytopeni a, Anaemia, Haematoma, Pyrexia, Gingival bleeding, Fall, Epistaxis, Blood lactate dehydrogenase increased, Incorrect route of drug administration R #B0699373A Sweden HP,RA 12 Months/F INJ U 08Nov2010-08Nov2010 16Nov2010 U/8 Days Thrombocytopeni a, Contusion R #D0071125A Germany HP,RA 3 Months/F INJ U 16Mar2011-16Mar2011 28Mar2011 U/12 Days Thrombocytopeni a, Gastroenteritis rotavirus, Leukopenia, Petechiae, Haematoma, Ureteric stenosis, Pyelocaliectasis U CONFIDENTIAL 257 CONFIDENTIAL 305 #D0072425A Germany MD 24 Months/M INJ .5ML 04Aug2011-04Aug2011 11Aug2011 U/7 Days Thrombocytopeni a*, Petechiae*, Haematoma* R #B0694143A Italy MD,RA 2 Months/F INJ U 04Feb2010-04Feb2010 05Feb2010 U/1 Days Thrombocytopeni a, Petechiae, Pyrexia R #B0695999A Taiwan, ROC LI 3 Months/U INJ U 10Dec2007-10Dec2007 15Dec2007 U/5 Days Thrombocytopeni c purpura* R Thrombocytopenic Purpura Following Vaccination in Early Childhood: Experience of a Medical Centre in the Past 2 Decades. J Clin Med Assoc. Dec2010; Vol 73: n°12 #B0693944A Czech Republic MD,RA 4 Months/M INJ U 10Dec2010-10Dec2010 11Dec2010 U/1 Days Thrombocytopeni c purpura, Petechiae, Haematoma R #B0693767A France RA 6 Months/F INJ U 21Sep2010-21Sep2010 09Oct2010 U/18 Days Thrombocytopeni c purpura, Petechiae, Haematoma, Epistaxis, Splenomegaly, Thrombocytopeni a, Gingival bleeding I CONFIDENTIAL 258 CONFIDENTIAL 306 #B0724575A France RA 19 Months/M INJ U 26Apr2011-26Apr2011 01Jan2011 U/20 Days Thrombocytopeni c purpura, Thrombocytopeni a, Petechiae, Injection site haematoma U Cardiac disorders #B0716780A Italy MD,RA 5 Months/F INJ, INJ U, .5ML 10Feb2011-10Feb2011, 14Apr2011-14Apr2011 U/63 Days, U/0 Days Cardiac arrest, Multi-organ failure, Pneumonia aspiration, Cerebral ischaemia, Sudden infant death syndrome, Unresponsive to stimuli, Peripheral coldness, Staring, Musculoskeletal stiffness, Pyrexia, Pyrexia, Somnolence F #D0070772A Germany RA 3 Months/M INJ U 01Mar2011-01Mar2011 13Mar2011 U/12 Days Cardiogenic shock, Cardiac failure, Congestive cardiomyopathy, Atrial tachycardia, Supraventricular tachycardia, Acidosis, Pyrexia, Gastrointestinal pain, Hypokalaemia, Fluid intake reduced, R CONFIDENTIAL 259 CONFIDENTIAL 307 Hypertension, H1N1 influenza, Cholecystitis, Psychotic disorder, Crying #B0711289A South Africa HP,MD 6 Weeks/U INJ U 20Mar2011-20Mar2011, 21Apr2011-21Apr2011 20Mar2011 U/0 Years, U/U Cardiopulmonary failure, Pyrexia, Bradycardia, Pyrexia U Possible HHE in an infant born prematurely #B0693461A Austria MD,RA 3 Months/M INJ U 01Jan2010-01Jan2010 14Dec2010 U/Unknown Cardiovascular disorder* R #D0071453A Germany MD,RA 6 Months/M INJ U 12May2011-12May2011 12May2011 U/0 Days Cardiovascular disorder, Apathy, Hyperpyrexia, Respiratory tract infection, Chills, Cyanosis, Pallor, Hypoventilation R #D0072089A Germany MD,RA 11 Weeks/M INJ U 23May2011-23May2011 01May2011 U/7 Hours Cardiovascular disorder, Crying, Hypotonia, Dyskinesia, Pallor R CONFIDENTIAL 260 CONFIDENTIAL 308 #B0694497A Netherlands HP,RA 8 Weeks/F INJ U 05Jan2011-05Jan2011 05Jan2011 U/0 Days Cyanosis, Acidosis, Apnoea, Inflammation, Oxygen saturation decreased, Bradycardia, Injection site pain, Injection site swelling, Injection site erythema, Bacterial infection R #B0713567A Poland MD,RA 2 Months/M INJ U 15Mar2011-15Mar2011 15Mar2011 U/Minutes Cyanosis, Apnoea, Hypotonic-hypore sponsive episode R #B0712985A Netherlands MD,RA 1 Months/M INJ .5ML 21Dec2010-21Dec2010 21Dec2010 U/4 Hours Cyanosis, Cyanosis, Hypotonic-hypore sponsive episode, Dyspnoea, Foaming at mouth U #B0743683A Netherlands HP,MD,RA 3 Months/M INJ, INJ U, .5ML 07Jul2011-07Jul2011, 1 Days U/Hours, U/Hours Cyanosis, Cyanosis, Skin discolouration, Erythema, Gastrointestinal disorder, Injection site inflammation, Pyrexia, Erythema, Skin discolouration R CONFIDENTIAL 261 CONFIDENTIAL 309 #B0719722A Italy MD,RA 11 Months/F INJ U 11May2011-11May2011 11May2011 U/0 Days Cyanosis, Dyspnoea, Hypertonia I #B0752371A Italy MD,RA 2 Months/M INJ U 01Jun2011-01Jun2011 01Jun2011 U/0 Days Cyanosis, Escherichia infection, Oxygen saturation decreased, C-reactive protein increased, Weight decreased, Decreased appetite, Hypotonic-hypore sponsive episode, Somnolence R #B0728501A Thailand HP 5 Months/F INJ U 23Jun2011-23Jun2011 23Jun2011 U/2 Hours Cyanosis, Fatigue, Cold sweat, Pyrexia, Irritability R #B0683004A Italy RA 4 Months/M INJ U 28Jan2009-28Jan2009 28Jan2009 U/0 Days Cyanosis, Hypotonia, Pallor R #B0741415A Poland MD,RA 5 Months/U INJ U 01Aug2011-01Aug2011 01Aug2011 U/0 Days Cyanosis, Hypotonic-hypore sponsive episode, Crying R CONFIDENTIAL 262 CONFIDENTIAL 310 #B0681642A Switzerland MD,RA 4 Months/F INJ U 13Sep2010-13Sep2010 13Sep2010 U/6 Hours Cyanosis, Hypotonic-hypore sponsive episode, Pallor, Vomiting, Pyrexia R #B0744335A Italy MD,RA 2 Months/F INJ .5ML 09Aug2011-09Aug2011 09Aug2011 U/0 Days Cyanosis, Injection site urticaria, Crying, Irritability R #B0715332A Italy RA 15 Months/F INJ U 04Apr2011-04Apr2011 04Apr2011 U/0 Days Cyanosis, Loss of consciousness, Apnoea, Hypotonia, Crying R #B0726312A Italy RA 10 Months/F INJ U 26May2011-26May2011 26May2011 U/0 Days Cyanosis, Loss of consciousness, Hypotonia R #B0690279A Italy MD,RA 3 Months/M INJ U 20May2010-20May2010 20May2010 U/0 Days Cyanosis, Oculogyric crisis, Myoclonus, Pyrexia R #B0711564A Italy RA 2 Months/F INJ U 29Mar2011-29Mar2011 29Mar2011 U/0 Days Cyanosis, Pallor, Hypotonia R CONFIDENTIAL 263 CONFIDENTIAL 311 #B0712499A Italy MD,RA 5 Months/M INJ U 04Apr2011-04Apr2011 04Apr2011 U/0 Days Cyanosis, Pallor, Hypotonic-hypore sponsive episode, Crying R #B0730016A Italy RA 19 Months/M INJ U 18May2011-18May2011 19May2011 U/1 Days Cyanosis, Pyrexia R #D0072994A Germany MD,RA 12 Weeks/M INJ U 19Apr2011-19Apr2011 19Apr2011 U/5 Hours Cyanosis, Rash macular, Crying, Pain R D0071925A Germany CO,MD 11 Weeks/F INJ U 28Jun2011-28Jun2011 28Jun2011 U/Immediate Cyanosis, Rash macular, Screaming R #D0071602A Germany P 3 Months/M INJ .5ML 21Jan2011-21Jan2011 22Jan2011 U/12 Hours Cyanosis, Screaming, Flushing, Cyanosis*, Crying* R #B0729115A Italy MD,RA 6 Months/M INJ U 20Jul2010-20Jul2010 20Jul2010 U/Hours Cyanosis, Unresponsive to stimuli, Dyspnoea, Glossoptosis, Staring R CONFIDENTIAL 264 CONFIDENTIAL 312 Congenital, familial and genetic disorders #D0071554A Germany MD,RA 8 Months/F INJ U 1 Days 01Jul2010 U/Unknown Talipes, Posture abnormal, Decubitus ulcer, Developmental delay, Balance disorder I Ear and labyrinth disorders #D0070187A Germany RA 25 Months/M INJ, INJ, INJ, INJ .5ML, .5ML, .5ML, .5ML 18Jun2010-18Jun2010, 18Mar2009-18Mar2009, 02Apr2009-02Apr2009, 05May2009-05May2009 21Jan2011 U/7 Months, U/22 Months, U/22 Months, U/21 Months Tympanic membrane perforation*, Haemophilus infection*, Vaccination failure* N #D0070501A Germany RA 21 Months/F INJ, INJ, INJ, INJ U, U, U, U 01Sep2009-01Sep2009, 10Nov2010-10Nov2010, 06Oct2009-06Oct2009, 12Nov2009-12Nov2009 17Feb2011 U/18 Months, U/16 Months, U/15 Months, U/99 Days Tympanic membrane perforation, Vaccination failure R Eye disorders #B0696210A Italy MD,RA 11 Months/M INJ U 19Jan2011-19Jan2011 19Jan2011 U/0 Days Eyelid oedema, Localised oedema, Urticaria, Urticaria R #B0722407A Netherlands MD,RA 2 Months/M INJ U 03Feb2011-03Feb2011 03Feb2011 U/14 Hours Gaze palsy, Hypertonia, Pyrexia, Dyskinesia, Somnolence, Feeling hot R CONFIDENTIAL 265 CONFIDENTIAL 313 #B0683261A Italy MD,RA 3 Months/F INJ U 21Sep2010-21Sep2010 01Oct2010 U/10 Days Gaze palsy, Hypotonia R #B0681967A Spain MD,RA 2 Months/F INJ U 27Sep2010-27Sep2010 27Sep2010 U/2 Hours Gaze palsy, Hypotonia, Pallor R #B0700213A Italy RA 5 Months/M INJ U 19Jan2011-19Jan2011 22Jan2011 U/3 Days Oculogyric crisis U D0069798A Germany MD 2 Months/M INJ U 25Oct2010-25Oct2010 27Oct2010 U/2 Days Pupils unequal N Gastrointestinal disorders D0070465A Germany MD,RA 3 Months/M INJ U 05Jan2011-05Jan2011 05Jan2011 U/0 Days Abdominal distension, Pyrexia, Hypotonia, Pallor, Restlessness, Vomiting R CONFIDENTIAL 266 CONFIDENTIAL 314 B0736768A Poland MD 2 Months/F INJ U 14Jun2011-14Jun2011 14Jun2011 U/0 Days Abdominal pain, Anxiety, Crying R B0681732A South Africa HP 8 Weeks/U INJ U 20Oct2010-20Oct2010 20Oct2010 U/0 Days Abdominal pain, Irritability, Pyrexia W B0743702A Netherlands MD,RA 2 Months/M INJ U 15Jul2011-15Jul2011 15Jul2011 U/Hours Abnormal faeces R #B0701523A Italy RA 5 Months/M INJ U 10Jan2011-10Jan2011 10Jan2011 U/0 Days Colitis, Pyrexia I #B0747304A Poland MD,RA 4 Months/U INJ U 12Aug2011-12Aug2011 14Aug2011 U/2 Days Diarrhoea haemorrhagic, Pyrexia, Crying, Restlessness, Abnormal behaviour R #B0754698A Poland MD,RA 2 Months/U INJ U 18Aug2011-18Aug2011 19Aug2011 U/1 Days Diarrhoea haemorrhagic, Pyrexia, Vomiting, Faeces discoloured, Dermatitis diaper, U CONFIDENTIAL 267 CONFIDENTIAL 315 Erythema, Dyspepsia #B0747625A France MD,RP 2 Months/F INJ U 23Aug2011-23Aug2011 23Aug2011 U/Same day Diarrhoea, Vomiting, Gastroenteritis R #B0694325A Spain P 3 Months/M INJ U 18Nov2010-18Nov2010 20Nov2010 U/2 Days Gastrooesophage al reflux disease*, Bronchial hyperreactivity* R #B0714317A Czech Republic MD 2 Months/F INJ U 23Mar2011-23Mar2011 30Mar2011 U/7 Days Haematochezia, Gastrointestinal inflammation, Restlessness, Flatulence, Frequent bowel movements I #D0073097A Germany MD,RA 13 Weeks/M INJ .5ML 29Sep2011-29Sep2011 01Oct2011 U/2 Days Haematochezia*, Gastrointestinal pain* R CONFIDENTIAL 268 CONFIDENTIAL 316 #B0754377A South Africa HP 4 Months/F INJ U 29Sep2011-29Sep2011 04Oct2011 U/5 Days Intussusception, Diarrhoea, Haematochezia U D0072360A Germany MD,RP 3 Years/F INJ U 21Jun2011-21Jun2011 21Jun2011 U/0 Days Lip swelling, Dyspnoea R #B0749250A France RA 2 Months/M INJ U 20Mar2011-20Mar2011 21Mar2011 U/0 Days Rectal haemorrhage R #B0747231A Poland MD,RA 1 Months/U INJ U 10Aug2011-10Aug2011 10Aug2011 U/0 Days Vomiting, Pyrexia, Diarrhoea, Rash macular, Rash generalised R D0071405A Germany MD 3 Months/F INJ U 16May2011-16May2011 16May2011 U/0 Days Vomiting, Underdose R General disorders and administration site conditions CONFIDENTIAL 269 CONFIDENTIAL 317 #D0071850A Germany MD,RP 8 Years/F INJ U 1 Days U/Unknown Abscess sterile U #D0071850B Germany MD,RP 8 Years/F INJ U 1 Days U/Unknown Abscess sterile U #D0072409A Germany MD,RP 7 Months/M INJ, INJ .5ML, .5ML 29Oct2010-29Oct2010, 1 Days 31Oct2010 U/2 Days, U/Unknown Abscess sterile, Foreign body reaction, Allergy to metals, Lymphadenopath y, Local swelling, Induration, Local swelling, Induration R #D0068815B Germany MD,RA 19 Months/M INJ U 23Feb2010-23Feb2010, 11Jan2010-11Jan2010, 1 Days 01Jan2010 U/0 Years, U/Unknown, U/U Abscess sterile*, Injection site swelling*, Injection site induration*, Scar*, Abscess drainage, Purulence, Cyst N #D0070025A Germany MD,RP 6 Years/M INJ U 07Oct2010-07Oct2010 10Dec2010 U/64 Days Abscess sterile, Neoplasm skin, Induration, Injection site swelling, Injection site discolouration, Granuloma skin, U CONFIDENTIAL 270 CONFIDENTIAL 318 Scar, Surgery, Vaccination complication D0069774A Germany MD,RP U/U INJ U 1 Days U/Unknown Adverse event U #B0726474A Italy MD U/F INJ U 1 Days U/Unknown Condition aggravated U #B0727175A France RA 18 Months/F INJ U 26Oct2010-26Oct2010 27Oct2010 U/1 Days Death F #D0071496A Germany HP,RA 3 Months/F INJ U 16May2011-16May2011 17May2011 U/1 Days Death F #D0072663A Germany RA 9 Weeks/M INJ .5ML 05Sep2011-05Sep2011 07Sep2011 U/2 Days Death* F CONFIDENTIAL 271 CONFIDENTIAL 319 #D0070336A Germany HP,RA 4 Months/M INJ U 01Jul2009-01Jul2009 15Jul2009 U/14 Days Developmental delay, Hypotonia, Nystagmus, Speech disorder, Transaminases increased, Hypoaesthesia, Dizziness, Visual acuity reduced N #D0070043A Germany MD,RA 3 Months/M INJ U 12Jan2010-12Jan2010, 12Feb2010-12Feb2010, 12Mar2010-12Mar2010 01Jan2010 U/10 Days, U/U, U/U Developmental delay*, Movement disorder*, Stereotypy*, Motor dysfunction*, Hypotonia*, Muscle twitching*, Areflexia*, Reflex test normal*, Ill-defined disorder*, Pyrexia*, Hypersensitivity*, Lip swelling*, Rash*, Cytomegalovirus test positive*, Iodine deficiency*, Hydrocele*, Convulsion*, Hypothyroidism* N CONFIDENTIAL 272 CONFIDENTIAL 320 D0069358C Germany HP,RA 2 Months/M INJ U 13Nov2009-13Nov2009 13Nov2009 U/0 Days Developmental delay, Psychomotor hyperactivity, Sleep disorder, Hyperhidrosis, Restlessness, Ill-defined disorder U #D0069358A Germany HP,RA 7 Months/M INJ U 12Apr2010-12Apr2010 12Apr2010 U/1 Hours Developmental delay, Weight gain poor, Psychomotor hyperactivity, Hyperhidrosis, Tremor, Injection site erythema, Injection site swelling, Sleep disorder N B0703201A Switzerland LI 20 Months/M INJ U 1 Days U/24 Hours Extensive swelling of vaccinated limb, Injection site erythema, Injection site reaction, Injection site warmth, Pyrexia R B.M. Huber MD : Extensive limb swelling after vaccination : 1 case. The journal of Pediatrics 2011 Feb. http://www.jpeds.com/ B0741001A France MD 16 Months/U INJ U 01Aug2011-01Aug2011 01Aug2011 U/1 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site induration U CONFIDENTIAL 273 CONFIDENTIAL 321 B0702525A France PH 16 Months/M INJ U 23Feb2011-23Feb2011 24Feb2011 U/1 Days Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site induration, Injection site infection, Ill-defined disorder N #B0703591A France PH 20 Months/M INJ U 1 Days, 1 Days, 1 Days 25Feb2011 U/See text, U/U, U/U Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site oedema, Pyrexia, Wrong drug administered R B0685430A France MD 18 Months/U INJ U 16Nov2010-16Nov2010 01Nov2010 U/0 Weeks Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site vesicles N B0705104A France MD 22 Months/M INJ U 01Mar2011-01Mar2011 01Mar2011 U/24 Hours Extensive swelling of vaccinated limb, Injection site induration, Product quality issue N CONFIDENTIAL 274 CONFIDENTIAL 322 B0705108A France MD 22 Months/M INJ U 01Mar2011-01Mar2011 01Mar2011 U/24 Hours Extensive swelling of vaccinated limb, Injection site induration, Product quality issue N B0681184A France MD 18 Months/M INJ U 25Aug2010-25Aug2010 26Aug2010 U/1 Days Extensive swelling of vaccinated limb, Injection site inflammation R #B0750035A Poland MD,RA 17 Months/U INJ U 17Aug2011-17Aug2011 18Aug2011 U/1 Days Extensive swelling of vaccinated limb, Injection site swelling, Injection site erythema, Injection site pain R B0713123A France CO,MD 17 Months/M INJ U 12Apr2011-12Apr2011 13Apr2011 U/0 Days Extensive swelling of vaccinated limb, Injection site warmth, Injection site erythema, Injection site pruritus I B0711364A France MD 2 Years/F INJ U 04Apr2011-04Apr2011 06Apr2011 U/2 Days Extensive swelling of vaccinated limb, Injection site warmth, Injection site inflammation, Injection site erythema, Incorrect route of I CONFIDENTIAL 275 CONFIDENTIAL 323 drug administration B0685437A France MD 18 Months/M INJ U 17Nov2010-17Nov2010 17Nov2010 U/0 Hours Extensive swelling of vaccinated limb, Injection site warmth, Injection site pain, Pyrexia, Injection site oedema, Skin discolouration R #B0751956A Czech Republic MD,RA 3 Months/F INJ U 23Aug2011-23Aug2011 U/0 Months Fatigue, Hypotonia, Hypersomnia U B0709060A Netherlands HP,RA 10 Months/F INJ U 20Aug2010-20Aug2010 U/Unknown Fibrosis, Inflammation, Pyrexia R #B0692411A Italy RA 12 Months/M INJ U 21Oct2010-21Oct2010 28Oct2010 U/7 Days Gait disturbance* R CONFIDENTIAL 276 CONFIDENTIAL 324 B0733393A Viet Nam MD 3 Years/F INJ U 04Jul2011-04Jul2011 04Jul2011 U/0 Days Gait disturbance, Injection site swelling, Pyrexia N D0071920A Germany MD Infant/U INJ U 1 Days U/Unknown Granuloma U #D0072470A Germany RA 20 Months/M INJ .5ML 22Jul2011-22Jul2011, 20May2010-20May2010 22Jul2011 U/0 Days, U/U Hyperpyrexia* R #B0742490A Greece MD,RP 2 Months/F INJ U 01Feb2010-01Feb2010 01Feb2010 U/Hours Hyperpyrexia, Rash morbilliform R B0742514A Greece MD,RP 2 Months/F INJ U 01Jan2011-01Jan2011 01Jan2011 U/Hours Hyperpyrexia, Rash morbilliform R B0742521A Greece MD,RP 2 Months/F INJ U 08Aug2011-08Aug2011 08Aug2011 U/Hours Hyperpyrexia, Rash morbilliform R CONFIDENTIAL 277 CONFIDENTIAL 325 B0707224A Argentina MD 4 Months/F INJ U 01Feb2011-01Feb2011 01Feb2011 U/1 Days Hypothermia R B0735139A Netherlands MD,RA 4 Months/F INJ, INJ, INJ U, U, .5ML U, 13May2011-13May2011, U 13May2011 U/Unknown, U/Unknown, U/4 Hours Ill-defined disorder, Eating disorder, Gastrointestinal disorder, Pyrexia, Vomiting, Pyrexia, Diarrhoea, Vomiting R #B0715306A Romania MD,RP 6 Months/M INJ U 14Apr2011-14Apr2011 15Apr2011 U/1 Days Ill-defined disorder, Inflammation, Agitation, Pyrexia R B0705049A Colombia HP,MD 4 Months/M INJ, INJ U, U 03Mar2011-03Mar2011, 03Jan2011-03Jan2011, 17May2011-17May2011 03Mar2011 U/0 Days, U/0 Days, U/U Ill-defined disorder, Pyrexia, Pyrexia, Irritability U B0756832A Netherlands HP,RA 2 Months/M INJ .5ML 07Jul2011-07Jul2011 07Jul2011 U/13 Hours Ill-defined disorder, Pyrexia, Respiration abnormal, Hypotonic-hypore sponsive episode R CONFIDENTIAL 278 CONFIDENTIAL 326 B0718374A Belgium MD 15 Months/M INJ U 19Apr2011-19Apr2011 U/See text Incorrect product storage X B0718379A Belgium MD 15 Months/M INJ U 19Apr2011-19Apr2011 U/See text Incorrect product storage X B0718380A Belgium MD 15 Months/F INJ U 19Apr2011-19Apr2011 U/See text Incorrect product storage X B0681225A France PH 3 Months/M INJ U 01Sep2010-01Sep2010 01Sep2010 U/See text Incorrect product storage X B0681900A France MD 19 Months/F INJ U 18Oct2010-18Oct2010 18Oct2010 U/See text Incorrect product storage X B0683002A France MD Infant/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/See text Incorrect product storage X CONFIDENTIAL 279 CONFIDENTIAL 327 B0683003A France MD Infant/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/See text Incorrect product storage X B0685438A France MD 2 Months/U INJ U 01Oct2010-01Oct2010 01Oct2010 U/See text Incorrect product storage X B0685922A France PH Infant/U INJ U 01Nov2010-01Nov2010 01Nov2010 U/See text Incorrect product storage X B0686441A France PH 2 Months/F INJ U 24Nov2010-24Nov2010 24Nov2010 U/See text Incorrect product storage X B0688412A France MD U/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/See text Incorrect product storage X B0688724A France MD 3 Months/M INJ U 01Oct2010-01Oct2010 01Oct2010 U/See text Incorrect product storage X CONFIDENTIAL 280 CONFIDENTIAL 328 B0689227A France PH 1 Years/U INJ U 08Dec2010-08Dec2010 08Dec2010 U/See text Incorrect product storage X B0689746A France HP,PH 2 Months/M INJ U 14Dec2010-14Dec2010 14Dec2010 U/See text Incorrect product storage X B0691868A France PH 2 Months/U INJ U 01Dec2010-01Dec2010 01Dec2010 U/See text Incorrect product storage X B0692725A France MD 4 Months/M INJ U 19Oct2010-19Oct2010 19Oct2010 U/See text Incorrect product storage X B0692728A France MD 6 Months/M INJ U 18Oct2010-18Oct2010 18Oct2010 U/See text Incorrect product storage X B0692729A France MD 9 Months/M INJ U 19Oct2010-19Oct2010 19Oct2010 U/See text Incorrect product storage X CONFIDENTIAL 281 CONFIDENTIAL 329 B0692906A France MD,RP 2 Months/F INJ U 1 Days U/See text Incorrect product storage X B0693355A France MD Neonate/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/See text Incorrect product storage X B0694120A France PH 3 Months/M INJ U 17Jan2011-17Jan2011 17Jan2011 U/See text Incorrect product storage X B0695156A France PH 2 Months/U INJ U 1 Days U/See text Incorrect product storage X B0700350A France CO,PH 2 Months/F INJ U 16Feb2011-16Feb2011 01Feb2011 U/See text Incorrect product storage X B0701361A France PH 2 Months/F INJ U 17Feb2011-17Feb2011 17Feb2011 U/See text Incorrect product storage X CONFIDENTIAL 282 CONFIDENTIAL 330 B0705083A France MD Infant/U INJ U 1 Days U/See text Incorrect product storage X B0707186A France PH 2 Months/F INJ U 18Mar2011-18Mar2011 18Mar2011 U/See text Incorrect product storage X B0712971A France PH 2 Months/M INJ U 01Apr2011-01Apr2011 01Apr2011 U/See text Incorrect product storage X B0724552A France MD 2 Months/U INJ U 26May2011-26May2011 26May2011 U/See text Incorrect product storage X B0725917A France PH 6 Months/F INJ U 01Jun2011-01Jun2011 01Jun2011 U/See text Incorrect product storage X B0729492A France PH 2 Months/F INJ U 01Jun2011-01Jun2011 01Jun2011 U/See text Incorrect product storage X CONFIDENTIAL 283 CONFIDENTIAL 331 B0729515A France PH 2 Months/U INJ U 01Jun2011-01Jun2011 01Jun2011 U/See text Incorrect product storage X B0731763A France PH U/U U U 1 Days U/See text Incorrect product storage X B0737084A France MD 2 Months/F INJ U 03Aug2011-03Aug2011 03Aug2011 U/See text Incorrect product storage X B0746698A France MD U/U INJ U 1 Days U/See text Incorrect product storage X B0750069A France PH U/U INJ U U 09Sep2011 U/See text Incorrect product storage X B0756736A France PH 3 Months/U INJ U 19Oct2011-19Oct2011 19Oct2011 U/See text Incorrect product storage X CONFIDENTIAL 284 CONFIDENTIAL 332 B0684837A France PH,MD 2 Months/M INJ U 15Nov2010-15Nov2010 15Nov2010 U/See text Incorrect product storage* X B0683276A France MD,RP 2 Months/M INJ U 26Oct2010-26Oct2010 26Oct2010 U/See text Incorrect product storage, Drug administered to patient of inappropriate age X B0711998A Ethiopia MD 5 Weeks/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Incorrect product storage, Drug administration error X #B0702823A Spain HP,RA 2 Months/M INJ U 18Feb2011-18Feb2011 18Feb2011 U/Immediate Induration, Erythema R D0069932A Germany MD,RA 4 Months/M INJ U 03Jan2011-03Jan2011 03Jan2011 U/0 Days Induration*, Erythema*, Oedema peripheral* U B0719482A Netherlands HP,RA 1 Years/F INJ U 29Jul2010-29Jul2010 U/Unknown Inflammation U CONFIDENTIAL 285 CONFIDENTIAL 333 #B0683274A Italy MD 4 Months/F INJ U 25Oct2010-25Oct2010 28Oct2010 U/3 Days Inflammation, Inflammatory marker increased, Pyrexia R B0698816A Netherlands HP,RA 11 Months/M INJ U 28Jul2010-28Jul2010 01Jul2010 U/Hours Inflammation, Pyrexia, Otitis media, Skin discolouration R B0698798A Netherlands HP,RA 4 Months/F INJ U 07Dec2009-07Dec2009 17Dec2009 U/10 Days Inflammation, Skin ulcer, Injection site discolouration, Injection site pruritus N #D0072316A Germany RA 9 Months/F INJ, INJ .5ML, U 30May2011-30May2011, 07Apr2011-07Apr2011 01Apr2011 U/0 Years, U/0 Months Injection site abscess sterile*, Injection site nodule*, Injection site erythema*, Injection site swelling*, Injection site nodule R B0718962A France MD 2 Months/M INJ U 1 Days U/Unknown Injection site cyst, Injection site pruritus U CONFIDENTIAL 286 CONFIDENTIAL 334 D0072257A Germany MD,RA 4 Months/F INJ U 25Mar2011-25Mar2011 01Apr2011 U/4 Weeks Injection site discolouration N D0072258A Germany MD,RA 3 Months/M INJ U 28Mar2011-28Mar2011 01Apr2011 U/4 Weeks Injection site discolouration N D0071052A Germany MD,RP 2 Months/M INJ, INJ, INJ U, U, U 17Dec2010-17Dec2010, 07Feb2011-07Feb2011, 08Mar2011-08Mar2011 U/Unknown, U/Unknown, U/Unknown Injection site discolouration*, Injection site discolouration*, Injection site discolouration*, Product quality issue* N D0071085A Germany CO,MD,RA, RP 3 Months/M INJ, INJ U, U 14Mar2011-14Mar2011, 01Apr2011-01Apr2011 01Jan2011 U/0 Months, U/0 Months Injection site discolouration*, Injection site discolouration*, Product quality issue* U D0071231A Germany MD,RA 3 Months/F INJ, INJ U, U 24Jan2011-24Jan2011, 04Mar2011-04Mar2011 01Jan2011 U/0 Years, U/0 Years Injection site discolouration*, Injection site discolouration*, Product quality issue* N CONFIDENTIAL 287 CONFIDENTIAL 335 B0743118A Netherlands MD,RA 2 Months/M INJ .5ML 16Aug2011-16Aug2011 16Aug2011 U/Seconds Injection site discolouration, Injection site erythema, Malaise, Pyrexia R D0069323A Germany MD 9 Months/M INJ U 20Sep2010-20Sep2010 U/0 Days Injection site discolouration*, Injection site induration*, Injection site erythema* I D0071009A Germany MD,RA,RP 4 Months/M INJ U 17Mar2011-17Mar2011 01Jan2011 U/0 Months Injection site discolouration*, Product quality issue* N D0071086A Germany MD,RA,RP 4 Months/F INJ U 11Mar2011-11Mar2011 01Jan2011 U/0 Years Injection site discolouration*, Product quality issue* N D0071128A Germany MD,RA 4 Months/M INJ U 17Mar2011-17Mar2011 01Apr2011 U/4 Weeks Injection site discolouration*, Product quality issue* N D0071129A Germany MD,RA 4 Months/F INJ U 22Mar2011-22Mar2011 01Apr2011 U/4 Weeks Injection site discolouration*, Product quality issue* N CONFIDENTIAL 288 CONFIDENTIAL 336 D0071218A Germany MD,RA 4 Months/M INJ U 02Mar2011-02Mar2011 01Apr2011 U/4 Weeks Injection site discolouration*, Product quality issue* N D0071219A Germany MD,RA 4 Months/F INJ U 02Mar2011-02Mar2011 01Apr2011 U/4 Weeks Injection site discolouration*, Product quality issue* N B0710275A France MD 3 Months/F INJ U 1 Days U/Unknown Injection site erythema, Generalised erythema, Hypersensitivity R B0747469A France MD 2 Months/F INJ U 14Sep2011-14Sep2011 14Sep2011 U/Same day Injection site erythema, Incorrect product storage, Incorrect route of drug administration U B0695756A France MD 34 Months/U INJ U 21Jan2011-21Jan2011 22Jan2011 U/1 Days Injection site erythema, Injection site induration, Injection site swelling, Lymphadenopath y N CONFIDENTIAL 289 CONFIDENTIAL 337 #B0716747A Poland MD,RA 1 Months/U INJ U 08Feb2011-08Feb2011 08Feb2011 U/0 Days Injection site erythema, Injection site oedema, Crying, Pyrexia R B0725393A France MD 2 Months/F INJ U 01May2011-01May2011 01May2011 U/0 Days Injection site erythema, Injection site pain, Injection site oedema, Injection site warmth R B0702448A France MD 17 Months/M INJ U 23Feb2011-23Feb2011 24Feb2011 U/1 Days Injection site erythema, Injection site reaction, Injection site warmth, Injection site pain, Injection site swelling, Injection site induration, Injection site pruritus R D0069984A Germany MD 6 Months/M INJ U 10Jan2011-10Jan2011 10Jan2011 U/0 Days Injection site erythema*, Injection site swelling*, Abscess* R D0071543A Germany MD 4 Years/F INJ U 14Apr2011-14Apr2011 14Apr2011 U/0 Days Injection site erythema, Injection site swelling, Incorrect route of drug administration, Off label use R CONFIDENTIAL 290 CONFIDENTIAL 338 B0701152A South Africa HP 14 Weeks/F INJ U 15Feb2011-15Feb2011 01Feb2011 U/Days Injection site erythema, Injection site swelling, Injection site induration U B0701172A South Africa HP 18 Months/F INJ U 16Feb2011-16Feb2011 17Feb2011 U/1 Days Injection site erythema, Injection site swelling, Injection site induration U B0701171A South Africa HP 18 Months/F INJ U 16Feb2011-16Feb2011 17Feb2011 U/1 Days Injection site erythema, Injection site swelling, Injection site induration, Injection site vesicles U D0070379A Germany MD 24 Months/M INJ U 14Feb2011-14Feb2011 16Feb2011 U/2 Days Injection site erythema, Injection site swelling, Injection site nodule, Pyrexia N D0070791A Germany MD 12 Months/F INJ U 22Mar2011-U 22Mar2011 U/During Injection site erythema, Injection site swelling, Wrong technique in drug usage process R CONFIDENTIAL 291 CONFIDENTIAL 339 B0736298A South Africa HP 19 Months/M INJ U 27Jul2011-27Jul2011 29Jul2011 U/2 Days Injection site erythema, Injection site warmth N D0070442A Germany MD,RG,RA 22 Months/F INJ .5ML 18Feb2011-18Feb2011 19Feb2011 U/1 Days Injection site erythema*, Injection site warmth* U B0710891A France MD 2 Years/M INJ U 29Mar2011-29Mar2011 29Mar2011 U/3 Hours Injection site erythema, Injection site warmth, Injection site induration, Pyrexia, Inflammation U B0720201A France CO,MD 16 Months/M INJ U 04May2011-04May2011 01May2011 U/0 Weeks Injection site erythema, Injection site warmth, Injection site swelling, Injection site haematoma, Injection site vesicles I D0070872A Germany HP,RA 16 Months/F INJ U 09Dec2010-09Dec2010 01Jan2011 U/0 Months Injection site extravasation, Injection site scar N CONFIDENTIAL 292 CONFIDENTIAL 340 B0750616A France MD 1 Years/M INJ U 15Oct2010-15Oct2010 22Oct2010 U/7 Days Injection site haematoma, Injection site pruritus, Injection site dermatitis, Injection site induration N #B0717663A South Africa HP 3 Months/M INJ .5ML 26Apr2011-26Apr2011 26Apr2011 U/0 Days Injection site haemorrhage, Injection site rash, Injection site swelling, Injection site erythema, Irritability, Crying U B0709384A Belgium MD,RP Infant/U INJ U 1 Days U/Unknown Injection site induration R B0718963A France MD 3 Months/F INJ U 1 Days U/Unknown Injection site induration U B0718964A France MD Infant/M INJ U 1 Days U/Unknown Injection site induration U CONFIDENTIAL 293 CONFIDENTIAL 341 D0071088A Germany MD,RP 5 Months/F INJ U 04Mar2011-04Mar2011 01Mar2011 U/0 Weeks Injection site induration N D0071420A Germany MD,RP U/U INJ U 1 Days U/Unknown Injection site induration U #B0729084A France RA 2 Years/F INJ U 12Apr2011-12Apr2011 12Apr2011 U/Same day Injection site induration, Disability, Oedema, Extensive swelling of vaccinated limb I B0719704A France MD 20 Months/F INJ U 11May2011-11May2011 12May2011 U/1 Days Injection site induration, Injection site erythema, Injection site pruritus N #B0727606A Poland MD,RA 18 Months/U INJ U 20May2011-20May2011 21May2011 U/1 Days Injection site induration, Injection site erythema, Pyrexia R CONFIDENTIAL 294 CONFIDENTIAL 342 B0727001A France MD 18 Months/F INJ U 01Jun2011-01Jun2011 01Jun2011 U/0 Months Injection site induration, Injection site inflammation, Injection site warmth, Injection site pain, Product quality issue U B0727004A France MD 2 Years/F INJ U 01Jun2011-01Jun2011 01Jun2011 U/0 Months Injection site induration, Injection site inflammation, Injection site warmth, Injection site pain, Product quality issue U B0750870A France PH Infant/F INJ U 09Sep2011-09Sep2011 01Jan2010 U/0 Months Injection site induration, Injection site swelling, Injection site warmth, Injection site erythema, Rash I B0753352A France PH 17 Months/F INJ U 15Sep2011-15Sep2011 15Sep2011 U/0 Days Injection site induration, Injection site warmth, Injection site erythema, Injection site pain, Injection site oedema I #B0738500A France RA 4 Months/U INJ, INJ U, U 01Aug2011-01Aug2011, 01Aug2011-01Aug2011 01Aug2011 U/See text, U/See text Injection site induration, Pyrexia, Wrong technique in drug usage process, Overdose U CONFIDENTIAL 295 CONFIDENTIAL 343 B0683368A Netherlands HP,RA 12 Months/M INJ U 08Apr2010-08Apr2010 08Apr2010 U/0 Days Injection site inflammation R B0736271A Netherlands MD,RA 3 Months/F INJ .5ML 11Jul2011-11Jul2011 13Jul2011 U/0 Days Injection site inflammation, Extensive swelling of vaccinated limb, Injection site erythema, Injection site warmth, Injection site discolouration N B0735199A Netherlands HP,RA 3 Months/F INJ U 10Mar2010-10Mar2010 U/3 Days Injection site inflammation, Injection site discolouration N B0726647A Poland MD,RA 16 Months/U INJ U 16Apr2011-16Apr2011 27Apr2011 U/11 Days Injection site inflammation, Injection site erythema, Injection site oedema R B0755890A Netherlands MD,RA 12 Months/F INJ U 19Jan2010-19Jan2010 19Jan2010 U/0 Days Injection site inflammation, Injection site pain, Fibrosis, Injection site haematoma, Injection site swelling, Injection site haemorrhage, Dermatitis U CONFIDENTIAL 296 CONFIDENTIAL 344 #B0757275A France RA 21 Months/M INJ U 24Aug2011-24Aug2011 U/0 Days Injection site inflammation, Injection site rash, Injection site warmth, Injection site induration, Injection site pain, Injection site erythema, Eczema, Impetigo I B0681516A France MD 2 Months/U INJ U 01Sep2010-01Sep2010 01Sep2010 U/0 Days Injection site inflammation*, Injection site warmth*, Injection site erythema*, Injection site pain*, Pyrexia* R B0707830A Netherlands HP,RA 2 Months/M INJ .5ML 01Dec2010-01Dec2010 01Dec2010 U/Hours Injection site inflammation, Pyrexia R B0727488A Netherlands MD,RA 3 Months/F INJ U 12Oct2010-12Oct2010 12Oct2010 U/2 Hours Injection site inflammation, Pyrexia, Crying, Injection site pain R B0733456A Netherlands HP,RA 2 Months/F INJ U 04Oct2010-04Oct2010 04Oct2010 U/3 Minutes Injection site inflammation, Pyrexia, Crying, Injection site pain, Crying R CONFIDENTIAL 297 CONFIDENTIAL 345 B0737614A Netherlands HP,RA 11 Months/M INJ U 12Nov2010-12Nov2010 13Nov2010 U/1 Days Injection site inflammation, Pyrexia, Crying, Injection site pain, Fibrosis, Malaise, Nasopharyngitis R B0751103A Netherlands HP,RA 4 Months/F INJ U 15Oct2010-15Oct2010 15Oct2010 U/0 Days Injection site inflammation, Pyrexia, Crying, Injection site pain, Listless, Malaise R B0756895A Netherlands HP,RA 2 Months/F INJ U 09Nov2010-09Nov2010 09Nov2010 U/2 Hours Injection site inflammation, Pyrexia, Crying, Injection site pain, Skin discolouration, Respiration abnormal, Hypotonia, Malaise U B0731185A Netherlands HP,RA 12 Months/M INJ U 31May2011-31May2011 31May2011 U/0 Days Injection site inflammation, Rash generalised, Pyrexia I B0697403A France HP 2 Months/M INJ U 19Jan2011-19Jan2011 19Jan2011 U/0 Days Injection site nodule N CONFIDENTIAL 298 CONFIDENTIAL 346 B0691683A France MD Infant/F INJ, INJ U, U 01Sep2009-01Sep2009, 01Sep2010-01Sep2010 01Jan2009 U/Unknown, U/Unknown Injection site nodule, Injection site discolouration N B0684107A France MD,RP Infant/F INJ U 1 Days U/Unknown Injection site nodule, Injection site pruritus N B0709808A France MD 2 Years/F INJ U 01Jun2010-01Jun2010 01Jan2010 U/3 Weeks Injection site nodule, Injection site pruritus U B0716281A France MD,RP 3 Years/M INJ U 1 Days U/Unknown Injection site nodule, Injection site pruritus N #B0746455A France RA 5 Months/M INJ, INJ U, U 13Nov2010-13Nov2010, 14Jan2011-14Jan2011 01Jan2011 U/2 Months, U/0 Months Injection site nodule, Injection site pruritus N B0741005A France MD Infant/F INJ U 01Sep2010-01Sep2010 01Sep2010 U/0 Months Injection site nodule, Injection site pruritus, Hypertrichosis N CONFIDENTIAL 299 CONFIDENTIAL 347 #B0683007A France HP,MD 5 Months/F INJ U 01Feb2009-01Feb2009, 01May2009-01May2009, 01Mar2009-01Mar2009 01May2009 U/0 Months, U/U, U/U Injection site nodule, Injection site pruritus, Hypertrichosis, Injection site discolouration, Injection site nodule, Injection site inflammation, Papule, Wrong drug administered N D0070912A Germany HP,RA 6 Months/M INJ, INJ U, U 26Jan2011-26Jan2011, 22Dec2010-22Dec2010 01Dec2010 U/0 Months, U/0 Weeks Injection site nodule, Scar, Injection site nodule, Scar N B0708070A France MD 18 Months/F INJ U 10Mar2011-10Mar2011 10Mar2011 U/Same day Injection site oedema, Injection site nodule, Injection site induration N B0756102A Ecuador MD,RP 9 Months/F INJ U 01Sep2011-01Sep2011, 01Jan2011-01Jan2011, 1 Days 27Sep2011 U/3 Weeks, U/0 Months, U/U Injection site papule N B0708548A Peru MD 18 Months/M INJ U 18Feb2011-18Feb2011 18Feb2011 U/Hours Injection site rash, Injection site erythema, Injection site oedema, Injection site swelling R CONFIDENTIAL 300 CONFIDENTIAL 348 D0071230A Germany MD U/U INJ U 27Aug2010-27Aug2010 U/0 Years Injection site reaction U B0685692A Ukraine CO,MD 6 Months/F INJ U 09Nov2010-09Nov2010 09Nov2010 U/0 Days Injection site reaction N D0071777A Germany MD 19 Months/M INJ .5ML 20Sep2010-20Sep2010 20Sep2010 U/Unknown Injection site reaction* N B0734425A France MD 8 Weeks/F INJ U 08Jul2011-08Jul2011 08Jul2011 U/Immediate Injection site reaction, Injection site erythema, Injection site swelling, Injection site induration, Pyrexia, Injection site oedema R #B0747299A Poland MD,RA 19 Months/U INJ U 16Aug2011-16Aug2011 16Aug2011 U/0 Days Injection site reaction, Injection site extravasation, Injection site erythema, Pharyngeal erythema R CONFIDENTIAL 301 CONFIDENTIAL 349 B0734171A France MD Infant/F INJ U 01Nov2010-01Nov2010 U/Unknown Injection site reaction, Injection site pruritus, Injection site nodule N #B0727676A Poland MD,RA 18 Months/U INJ U 21May2011-21May2011 22May2011 U/1 Days Injection site reaction, Injection site swelling, Injection site erythema, Injection site warmth, Body temperature increased R B0714712A Poland MD,RA 6 Months/U INJ U 08Feb2011-08Feb2011 08Feb2011 U/0 Days Injection site reaction, Injection site warmth, Body temperature, Injection site erythema, Injection site pain R #B0756170A Poland MD,RA 19 Months/U INJ U 15Sep2011-15Sep2011 15Sep2011 U/0 Days Injection site reaction, Injection site warmth, Pyrexia, Urticaria R B0743179A Netherlands MD,RA 10 Months/M INJ .5ML 16Aug2011-16Aug2011 16Aug2011 U/4 Hours Injection site reaction, Pyrexia, Crying, Rash N CONFIDENTIAL 302 CONFIDENTIAL 350 B0740908A Poland MD 4 Months/M INJ U 21Jul2011-21Jul2011 22Jul2011 U/1 Days Injection site reaction, Subcutaneous nodule U #B0743545A France RA 4 Months/F INJ, INJ U, U 09Aug2011-09Aug2011, 09Aug2011-09Aug2011 10Aug2011 U/1 Days, U/1 Days Injection site reaction, Wrong technique in drug usage process, Medication error, Overdose, Injection site induration, Pyrexia R B0728595A South Africa HP,MD 2 Months/F INJ U 12Apr2011-12Apr2011 26Apr2011 U/14 Days Injection site swelling, Injection site abscess, Discomfort R D0070911A Germany MD,RA 17 Months/M INJ U 01Jul2009-01Jul2009 01Jul2009 U/0 Days Injection site swelling, Injection site erythema, Injection site warmth U #D0069419A Germany RA 2 Years/M INJ U 01Jan2006-01Jan2006 01Jan2006 U/Unknown Injection site swelling*, Injection site erythema*, Injection site warmth*, Injection site pain*, Lymphadenopath y*, Injection site reaction* N CONFIDENTIAL 303 CONFIDENTIAL 351 #D0069690A Germany MD,RP 18 Months/M INJ U 06Dec2010-06Dec2010 07Dec2010 U/1 Days Injection site swelling, Injection site erythema, Sepsis R D0071985A Germany MD,RP 4 Months/M INJ U 07Jul2011-07Jul2011 U/Unknown Injection site swelling, Injection site warmth, Injection site erythema, Injection site pain R D0072079A Germany MD,RP 30 Months/M INJ U 05Jul2011-05Jul2011 U/Unknown Injection site swelling, Injection site warmth, Injection site erythema, Injection site pain R D0072080A Germany MD,RP 24 Months/M INJ U 04Jul2011-04Jul2011 U/Unknown Injection site swelling, Injection site warmth, Injection site erythema, Injection site pain R D0072081A Germany MD,RP 3 Months/F INJ U 16Jun2011-16Jun2011 U/Unknown Injection site swelling, Injection site warmth, Injection site erythema, Injection site pain R #B0741418A Poland MD,RA 19 Months/U INJ U 13Jul2011-13Jul2011 14Jul2011 U/1 Days Injection site warmth, Injection site erythema, Injection site oedema, Extensive R CONFIDENTIAL 304 CONFIDENTIAL 352 swelling of vaccinated limb #B0709244A Poland MD,RA 26 Months/U INJ U 07Feb2011-07Feb2011 08Feb2011 U/1 Days Injection site warmth, Injection site oedema, Injection site erythema U B0751948A Poland MD,RA 17 Months/U SUS U 13Jul2011-13Jul2011 14Jul2011 U/1 Days Injection site warmth, Injection site oedema, Injection site erythema, Body temperature increased, Extensive swelling of vaccinated limb U #B0713570A Poland MD,RA 18 Months/U INJ U 01Mar2011-01Mar2011 02Mar2011 U/1 Days Injection site warmth, Injection site oedema, Injection site erythema, Injection site pain, Restlessness, Body temperature increased R B0726162A Poland MD,RA 18 Months/M INJ U 23Mar2011-23Mar2011 24Mar2011 U/1 Days Injection site warmth, Injection site reaction R CONFIDENTIAL 305 CONFIDENTIAL 353 B0726175A Poland MD,RA 20 Months/U INJ U 22Mar2011-22Mar2011 22Mar2011 U/0 Days Injection site warmth, Injection site reaction, Urticaria, Pyrexia R B0729606A South Africa HP 19 Months/M INJ U 08Jun2011-08Jun2011 08Jun2011 U/0 Days Injection site warmth, Tenderness, Injection site nodule, Injection site induration, Injection site swelling, Injection site erythema, Injection site pain I B0729497A France MD 2 Months/M INJ U 27May2011-27May2011 29May2011 U/2 Days Irritability, Crying, Middle insomnia R B0685920A France MD 4 Months/M INJ, INJ U, U 23Nov2010-23Nov2010, 23Nov2010-23Nov2010 23Nov2010 U/See text, U/See text Irritability, Overdose, Wrong technique in drug usage process R #B0730845A Italy MD,RA 5 Months/F INJ U 16Jun2011-16Jun2011 16Jun2011 U/0 Days Irritability, Pyrexia R CONFIDENTIAL 306 CONFIDENTIAL 354 B0701338A France PH,MD 4 Months/M INJ U 21Feb2011-21Feb2011 21Feb2011 U/See text Irritability, Sleep disorder, Pyrexia, Injection site induration, Nodule, Incorrect product storage R B0690212A Netherlands MD,RA 11 Months/F INJ U 12Apr2010-12Apr2010 01Apr2010 U/0 Days Malaise, Abnormal behaviour, Pyrexia R B0708970A Netherlands HP,RA 4 Months/F INJ U 19Mar2009-19Mar2009 01Mar2009 U/1 Days Malaise, Faeces discoloured, Crying, Pyrexia U B0732140A Netherlands HP,RA 4 Months/F INJ U 22Sep2010-22Sep2010 01Sep2010 U/3 Days Malaise, Fatigue, Crying, Pyrexia, Diarrhoea, Nasopharyngitis, Somnolence U #B0689818A France RA 10 Weeks/F INJ U 23Nov2010-23Nov2010 23Nov2010 U/5 Hours Malaise, Hypotonia R #B0716345A France RA 2 Months/F INJ U 22Feb2011-22Feb2011 22Feb2011 U/7 Hours Malaise, Hypotonia, Cyanosis R CONFIDENTIAL 307 CONFIDENTIAL 355 B0731042A Netherlands MD,RA 2 Months/M INJ U 12May2011-12May2011 12May2011 U/0 Days Malaise, Ill-defined disorder R B0727512A Netherlands MD,RA 4 Months/F INJ U 18Aug2010-18Aug2010 18Aug2010 U/0 Days Malaise, Injection site inflammation, Crying, Pyrexia, Somnolence R B0707085A Netherlands MD,RA 2 Months/M INJ U 03Nov2010-03Nov2010 U/Unknown Malaise, Pallor, Insomnia, Pyrexia, Crying R B0711155A Netherlands HP,RA 5 Months/M INJ U 17Aug2010-17Aug2010 01Aug2010 U/4 Days Malaise, Rash, Crying, Pyrexia R B0726560A Sweden HP,MD 3 Months/F INJ, INJ U, U 20Dec2010-20Dec2010, 01Oct2010-01Oct2010 U/Unknown, U/Unknown Nodule, Injection site extravasation, Abscess, Erythema U B0692240A Belgium MD 3 Years/M INJ, INJ U, U 01Jan2008-01Jan2008, 1 Days U/1 Years, U/During No therapeutic response, Expired drug administered U CONFIDENTIAL 308 CONFIDENTIAL 356 B0692241A Belgium MD 6 Years/F INJ U 22Jun2005-22Jun2005 U/3 Years No therapeutic response, Expired drug administered X B0695165A France MD 2 Months/F INJ, INJ U, U 01Jan2010-01Jan2010, 01Jan2009-01Jan2009 01Jan2009 U/See text, U/9 Months No therapeutic response, Incorrect dose administered X #B0744411A France PH,MD,RA 2 Months/F INJ U 25Aug2011-25Aug2011 25Aug2011 U/5 Days Oedema, Diarrhoea, Vomiting, Urticaria, Transaminases increased, Drug administered to patient of inappropriate age, Papule, Crying, Pain R #B0700208A France RA 4 Months/M INJ U 24Sep2010-24Sep2010 25Sep2010 U/1 Days Oedema, Extensive swelling of vaccinated limb, Skin warm, Pyrexia, Vomiting R D0072570A Germany MD,RA 30 Months/F INJ U 17Feb2011-17Feb2011 18Feb2011 U/1 Days Oedema peripheral R CONFIDENTIAL 309 CONFIDENTIAL 357 #B0755892A Czech Republic MD,RA 3 Months/M INJ U 06Oct2011-06Oct2011 06Oct2011 U/10 Minutes Oedema peripheral, Crying, Erythema, Skin discolouration R D0072932A Germany MD 2 Months/M INJ U 20Sep2011-20Sep2011 20Sep2011 U/2 Hours Oedema peripheral, Erythema R #B0688647A Slovakia MD 5 Months/F INJ U 01Dec2010-01Dec2010 01Dec2010 U/2 Minutes Oedema peripheral*, Erythema* R D0072448A Germany MD 2 Months/M INJ, INJ U, U 11Sep2009-11Sep2009, 27Oct2009-27Oct2009 U/Unknown, U/Unknown Oedema peripheral, Erythema, Screaming R D0072142A Germany CO,MD 13 Months/F INJ U 20Jul2011-20Jul2011 21Jul2011 U/1 Days Oedema peripheral, Haematoma R #B0691164A Netherlands HP,RA 7 Weeks/M INJ U 30Aug2010-30Aug2010 31Aug2010 U/25 Hours Oedema peripheral*, Oedema peripheral*, Cardiac murmur* R CONFIDENTIAL 310 CONFIDENTIAL 358 B0695380A South Africa HP 19 Months/M INJ .5ML 10Dec2010-10Dec2010 10Dec2010 U/Hours Oedema peripheral, Oedema peripheral, Contusion, Induration, Contusion, Vomiting, Pyrexia R D0072585A Germany MD 11 Months/M INJ U 29Aug2011-29Aug2011 01Jan2011 U/Unknown Oedema peripheral, Pain in extremity, Skin warm, Oedema peripheral, Pain in extremity, Skin discolouration U B0737868A Netherlands MD,RA 3 Months/F INJ U 14Jun2011-14Jun2011 14Jun2011 U/0 Days Oedema peripheral, Pyrexia U #B0709202A Italy MD,RA 3 Months/M INJ U 06Aug2009-06Aug2009, 27May2010-27May2010 07Aug2009 U/1 Days, U/U Oedema peripheral, Rash erythematous, Pain in extremity, Hyperaemia, Pallor, Cerumen impaction, Crying, Pyrexia R D0069390A Germany CO,MD 3 Months/M INJ U 28Oct2010-28Oct2010 31Oct2010 U/3 Days Oedema peripheral, Screaming, Erythema, Haematoma, Pain R CONFIDENTIAL 311 CONFIDENTIAL 359 #D0069502A Germany MD,RP 20 Months/F INJ .5ML 11Nov2010-11Nov2010 12Nov2010 U/1 Days Oedema peripheral*, Sepsis*, Swelling*, Erythema* R B0724153A Austria MD 17 Months/U INJ U 11Apr2011-11Apr2011 12Apr2011 U/1 Days Pain, Ill-defined disorder, Injection site swelling, Injection site erythema U B0724155A Austria MD 20 Months/U INJ U 14Apr2011-14Apr2011 15Apr2011 U/1 Days Pain, Ill-defined disorder, Injection site swelling, Injection site erythema U B0724160A Austria MD 17 Months/U INJ U 17Apr2011-17Apr2011 18Apr2011 U/1 Days Pain, Ill-defined disorder, Injection site swelling, Injection site erythema U #B0725047A France RA 2 Months/M INJ U 13May2011-13May2011 13May2011 U/Same day Pyrexia R #B0738737A Ireland MD,RA 4 Months/M INJ .5ML 28Jun2011-28Jun2011 28Jun2011 U/8 Hours Pyrexia R CONFIDENTIAL 312 CONFIDENTIAL 360 #B0705446A Italy HP,RA 13 Months/M INJ U 25Jan2011-25Jan2011 25Jan2011 U/0 Days Pyrexia R #B0692084A Latvia HP,RA 10 Months/F INJ U 02Nov2010-02Nov2010 03Nov2010 U/18 Hours Pyrexia R #B0733016A Latvia HP,RA 4 Months/F INJ .5ML 02Jun2011-02Jun2011 02Jun2011 U/6 Hours Pyrexia R #B0755542A Latvia HP,RA 19 Months/F INJ .5ML 09Sep2011-09Sep2011 09Sep2011 U/6 Hours Pyrexia R #B0688816A Poland MD,RA 17 Months/U INJ U 17Nov2010-17Nov2010 19Nov2010 U/48 Hours Pyrexia R #B0696766A Poland MD,RA 21 Months/U INJ U 05Jan2011-05Jan2011 05Jan2011 U/0 Days Pyrexia R CONFIDENTIAL 313 CONFIDENTIAL 361 #B0750972A Poland MD,RA 2 Months/U INJ U 04Aug2011-04Aug2011 04Aug2011 U/7 Hours Pyrexia R #B0686714A Spain HP,RA 4 Months/F INJ U 16Sep2010-16Sep2010 16Sep2010 U/0 Days Pyrexia R #D0072635A Germany RA 6 Months/M INJ .5ML 19May2011-19May2011 21May2011 U/2 Days Pyrexia* R #B0684627A Italy MD,RA 5 Months/M INJ U 26Apr2010-26Apr2010 26Apr2010 U/0 Days Pyrexia* R B0706993A France MD 2 Months/F INJ U 18Feb2011-18Feb2011 19Feb2011 U/1 Days Pyrexia, Crying R #B0728225A Namibia HP 3 Months/F INJ, INJ U, U 01Jan2011-01Jan2011, 10Jun2011-10Jun2011 U/0 Days, U/Unknown Pyrexia, Decreased appetite, Fluid intake reduced, Pyrexia, Diarrhoea U CONFIDENTIAL 314 CONFIDENTIAL 362 #B0728546A France MD 2 Months/F INJ U 19May2011-19May2011 19May2011 U/7 Hours Pyrexia, Decreased appetite, Somnolence, Fatigue R B0736206A Netherlands MD,RA 2 Months/M INJ U 12Jul2011-12Jul2011 12Jul2011 U/Hours Pyrexia, Decreased appetite, Wrong drug administered, Overdose U #B0705783A France RA 6 Months/M INJ, INJ U, U 14Dec2010-14Dec2010, 14Aug2010-14Aug2010 14Aug2010 U/6 Hours, U/6 Hours Pyrexia, Diarrhoea, Nausea, Vomiting, Inappropriate schedule of drug administration R D0070922A Germany HP 16 Months/F INJ U 06Apr2011-06Apr2011 06Apr2011 U/0 Days Pyrexia, Ear infection, Bronchitis, Wrong technique in drug usage process, Incorrect route of drug administration U B0745305A France MD 3 Months/U INJ, INJ U, U 01Sep2010-01Sep2010, 01Aug2010-01Aug2010, 01Jul2010-01Jul2010 01Aug2010 U/Unknown, U/0 Days, U/U Pyrexia, Erythema, Diarrhoea, Acne, Wrong drug administered R CONFIDENTIAL 315 CONFIDENTIAL 363 B0729547A France MD 26 Months/M INJ U 27Jun2011-27Jun2011 27Jun2011 U/See text Pyrexia, Expired drug administered R #D0072494A Germany MD,RP 13 Weeks/M INJ .5ML 07Jul2011-07Jul2011, 09Jun2011-09Jun2011 07Jul2011 U/4 Hours, U/U Pyrexia*, Fluid intake reduced*, Food aversion* R #B0704596A Spain P 4 Months/F INJ U 07Feb2011-07Feb2011 08Feb2011 U/1 Days Pyrexia*, Gastroenteritis rotavirus* R B0722680A France MD 2 Months/F INJ U 25May2011-25May2011 25May2011 U/12 Hours Pyrexia, Incorrect product storage R D0072069A Germany MD,RP 28 Months/M INJ U 28Jun2011-28Jun2011 U/0 Weeks Pyrexia, Injection site erythema, Injection site swelling, Skin induration, Injection site pruritus R CONFIDENTIAL 316 CONFIDENTIAL 364 #B0724988A Latvia HP,RA 2 Months/M INJ U 10May2011-10May2011 10May2011 U/7 Hours Pyrexia, Injection site extravasation, Injection site erythema R D0070161A Germany MD 5 Months/F INJ U 24Jan2011-24Jan2011 25Jan2011 U/1 Days Pyrexia, Injection site extravasation, Injection site erythema, Injection site swelling, Scab, Injection site haematoma N #B0740301A Austria MD,RA 1 Years/M INJ U 06Jul2011-06Jul2011 06Jul2011 U/10 Hours Pyrexia, Injection site haematoma, Injection site erythema R B0727206A Netherlands MD,RA 13 Months/M INJ U 13Oct2010-13Oct2010 14Oct2010 U/24 Hours Pyrexia, Injection site inflammation, Decreased appetite, Fibrosis N D0071584A Germany PH 25 Months/M INJ, INJ U, U 23May2011-23May2011, 01Jan2010-01Jan2010 01Jan2010 U/1 Days, U/Unknown Pyrexia, Injection site pain, Eczema I CONFIDENTIAL 317 CONFIDENTIAL 365 D0070985A Germany MD,RP 15 Months/M INJ U 08Apr2011-08Apr2011 09Apr2011 U/1 Days Pyrexia, Injection site swelling, Hyperaesthesia, Flatulence, Abdominal pain, Cow’s milk intolerance N #D0070119A Germany PH,MD 5 Months/M INJ U 21Jan2011-21Jan2011 21Jan2011 U/0 Days Pyrexia, Injection site swelling, Pain in extremity, Screaming U D0070134A Germany PH,MD 5 Months/M INJ U 21Jan2011-21Jan2011 21Jan2011 U/0 Days Pyrexia, Injection site swelling, Pain in extremity, Screaming R D0070136A Germany PH,MD 6 Months/F INJ U 25Jan2011-25Jan2011 25Jan2011 U/0 Days Pyrexia, Injection site swelling, Pain in extremity, Screaming U D0070135A Germany PH 6 Months/F INJ U 25Jan2011-25Jan2011 25Jan2011 U/0 Days Pyrexia, Injection site swelling, Pain in extremity, Screaming, Rash generalised R CONFIDENTIAL 318 CONFIDENTIAL 366 B0710855A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R B0710871A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R B0710875A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R B0710876A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R B0710877A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R B0710878A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R CONFIDENTIAL 319 CONFIDENTIAL 367 B0710879A Kenya CO,HP 6 Weeks/U INJ .5ML 1 Days U/Unknown Pyrexia, Overdose R B0708048A France MD 4 Months/M INJ U 23Mar2011-23Mar2011 23Mar2011 U/Same day Pyrexia, Overdose, Wrong drug administered R D0070270A Germany MD 3 Months/F INJ U 10Feb2011-10Feb2011 10Feb2011 U/0 Days Pyrexia, Restlessness, Accidental overdose R D0072493A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072684A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072685A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U CONFIDENTIAL 320 CONFIDENTIAL 368 D0072686A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072687A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072688A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072689A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072690A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072691A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U CONFIDENTIAL 321 CONFIDENTIAL 369 D0072692A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072693A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0072694A Germany MD,RP Child/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Months Pyrexia, Restlessness, Ill-defined disorder U D0070466A Germany MD 4 Months/F INJ U 25Jul2007-25Jul2007 25Jul2007 U/0 Days Pyrexia, Salmonellosis R #D0071783A Germany HP,RA 4 Months/M INJ U 07Jun2011-07Jun2011 07Jun2011 U/0 Days Pyrexia, Vaccination complication R #B0705290A France OT,MD,RA 10 Months/M INJ U 07Mar2011-07Mar2011 07Mar2011 U/4 Hours Sudden death, Pyrexia, Lymphadenopath y, Emphysema, Product quality issue, F CONFIDENTIAL 322 CONFIDENTIAL 370 Cardio-respiratory arrest, Asphyxia, Febrile convulsion #D0070324A Germany OM,MD,RP 3 Months/M INJ .5ML 18Jan2011-18Jan2011 23Jan2011 U/5 Days Sudden infant death syndrome*, Death*, Vomiting*, Cardiomyopathy* F #B0688734A France RA 10 Weeks/F INJ U 09Nov2010-09Nov2010 10Nov2010 U/1 Days Sudden infant death syndrome, Respiratory tract congestion, Cough, Nasal congestion F B0730530A Austria PH U/U INJ U 1 Days U/Unknown Swelling, Erythema U B0686436A France PH 20 Months/F INJ U 01Nov2010-01Nov2010 01Nov2010 U/See text Therapeutic response decreased, Incorrect product storage X D0070885A Germany MD 3 Months/F INJ, INJ U, U 14Feb2011-14Feb2011, 28Mar2011-28Mar2011 01Feb2011 U/2 Days, U/2 Days Vaccination site induration, Vaccination site induration I CONFIDENTIAL 323 CONFIDENTIAL 371 Hepatobiliary disorders #B0736978A Italy RA 7 Years/F INJ U 14Jul2011-14Jul2011 14Jul2011 U/0 Days Hypertransamina saemia, Vomiting R Immune system disorders #B0735456A Italy MD,RA 4 Months/M INJ U 12Jul2011-12Jul2011, 10May2011-10May2011 12Jul2011 U/0 Days, U/U Allergy to vaccine, Urticaria, Pyrexia, Rash maculo-papular R #B0698663A Italy MD,RA 4 Months/M INJ U 01Feb2011-01Feb2011 01Feb2011 U/0 Days Anaphylactic reaction, Circulatory collapse, Slow response to stimuli, Cyanosis, Hypotonia, Hypothermia, Pallor, Bradycardia, Oxygen saturation decreased, Pyrexia R #D0072050A Germany MD,RA,RP 3 Months/M INJ U 12Jul2011-12Jul2011 12Jul2011 U/0 Days Anaphylactic reaction, Swelling, Erythema, Crying, Petechiae R CONFIDENTIAL 324 CONFIDENTIAL 372 #D0071107A Germany MD 8 Months/M INJ U 10Jan2008-10Jan2008 U/Unknown Anaphylactic shock U #B0741646A Italy MD,RA 2 Months/F INJ .5ML 17Aug2011-17Aug2011 17Aug2011 U/0 Days Anaphylactic shock, Stridor, Respiratory disorder, Pulse pressure decreased, Heart rate increased, Crying I #B0680987A Belgium MD,RP 2 Months/F INJ U 20Oct2010-20Oct2010 20Oct2010 U/Minutes Anaphylactic shock, Syncope, Apnoea, Bronchospasm, Blood pressure decreased, Pallor, Respiratory rate decreased, Crying, Hypoventilation R #D0072500A Germany PH,MD,RP, VR 13 Weeks/M INJ .5ML 24Aug2011-24Aug2011, 15Jun2011-15Jun2011 24Aug2011 U/5 Minutes, U/U Anaphylactoid reaction*, Hypersensitivity*, Product quality issue, Urticaria*, Rash*, Apathy*, Anaphylactic reaction*, Erythema*, Petechiae*, Injection site erythema* U CONFIDENTIAL 325 CONFIDENTIAL 373 #B0747751A Czech Republic MD,RA 4 Months/F INJ U 04Feb2010-04Feb2010 01Apr2010 U/2 Months Hypersensitivity, Eye oedema, Rhinorrhoea, Pyrexia U #D0071600A Germany MD,RA 33 Months/M INJ U 17May2011-17May2011 19May2011 U/2 Days Hypersensitivity, Injection site swelling, Injection site erythema, Injection site warmth R #B0743870A France RA 33 Months/M INJ U 26Aug2011-26Aug2011 26Aug2011 U/0 Days Hypersensitivity, Pyrexia, Face oedema, Urticaria, Injection site inflammation R #B0683194A Sweden HP,RA 3 Months/M INJ, INJ U, .5ML 21Oct2010-21Oct2010, 01Jan2010-01Jan2010 26Aug2010 U/Unknown, U/20 Minutes Hypersensitivity, Rash, Skin discolouration, Rash, Rash, Pyrexia R #D0072638A Germany RA 3 Months/F INJ .5ML 31Aug2011-31Aug2011 31Aug2011 U/0 Days Hypersensitivity*, Swollen tongue*, Eyelid oedema* R Infections and infestations CONFIDENTIAL 326 CONFIDENTIAL 374 #D0070332A Germany RA 11 Months/M INJ U 06Aug2010-06Aug2010 28Sep2010 U/53 Days Abscess R D0072966A Germany MD,RA 17 Months/M INJ .5ML 19Jan2011-19Jan2011 11Apr2011 U/82 Days Abscess* N D0071349A Germany HP,RA 26 Months/F INJ U 15Oct2010-15Oct2010 11Apr2011 U/6 Months Abscess, Granuloma N #D0072765A Germany RA 9 Months/F INJ .5ML 22Mar2011-22Mar2011, 18Jan2011-18Jan2011, 15Feb2011-15Feb2011 12Jul2011 U/3 Months, U/U, U/U Abscess*, Haematoma* R D0072015A Germany PH,MD 4 Months/F INJ, INJ U, U 04May2011-04May2011, 22Jun2011-22Jun2011 04May2011 U/0 Days, U/0 Days Abscess, Induration, Erythema, Abscess, Induration, Erythema, Product quality issue S CONFIDENTIAL 327 CONFIDENTIAL 375 #B0740389A Italy MD,RA 10 Months/F INJ U 29Jun2011-29Jun2011 30Jun2011 U/1 Days Abscess limb, Pyrexia, Oedema peripheral, Erythema, Pain, Inflammation I #B0747749A Czech Republic MD,RA 6 Months/F INJ U 01Sep2010-01Sep2010, 01Aug2010-01Aug2010, 01Jul2010-01Jul2010 01Sep2010 U/0 Months, U/U, U/U Bronchitis, Pyrexia R #B0713564A Serbia MD,RP 2 Years/M INJ U 08Apr2011-08Apr2011 10Apr2011 U/2 Days Cellulitis, Erythema, Body temperature increased, Injection site swelling N #B0730177A Spain HP,RA 9 Months/F INJ U 22Feb2011-22Feb2011 01Mar2011 U/7 Days Cellulitis, Streptococcal bacteraemia, Local reaction, Pyrexia R #B0687557A Poland MD,RA 11 Months/U INJ U 10Nov2010-10Nov2010 10Nov2010 U/0 Days Ear infection, Injection site inflammation, Pyrexia, Vomiting U #B0692285A France RA 21 Months/F INJ U 08Dec2010-08Dec2010 08Dec2010 U/0 Days Encephalitic infection, Convulsion, Dyskinesia, Fatigue, Pyrexia, Hypertonia, U CONFIDENTIAL 328 CONFIDENTIAL 376 Depressed level of consciousness, Electroencephalo gram abnormal #B0712285A Austria MD,RA 3 Years/F INJ U 08Mar2011-08Mar2011 09Mar2011 U/1 Days Erysipelas, Erythema, Feeling hot, Swelling, Pyrexia R #B0735649A Italy MD,RA 5 Months/F INJ U 10May2011-10May2011, 08Mar2011-08Mar2011 26May2011 U/16 Days, U/U Gastroenteritis, Convulsion, Central nervous system inflammation, Conjunctivitis, Cheilitis, Pyrexia, Rash papular, Viral rash R #B0714131A Czech Republic MD,RA 7 Months/M INJ U 30Nov2010-30Nov2010, 05Jan2011-05Jan2011, 01Feb2011-01Feb2011 16Feb2011 U/15 Days, U/U, U/U Gastroenteritis rotavirus, Vaccination failure R #D0071047A Germany MD 12 Months/F INJ U 22Sep2010-22Sep2010 09Apr2011 U/6 Months Gastroenteritis rotavirus, Vaccination failure, Gastroenteritis astroviral, Gastroenteritis Escherichia coli R CONFIDENTIAL 329 CONFIDENTIAL 377 #D0070948A Germany MD,RP 19 Months/M INJ U 21Jan2011-21Jan2011 01Mar2011 U/0 Years Gastroenteritis rotavirus, Vaccination failure, Pyrexia, Vomiting, Diarrhoea, Ear infection R #B0684636A Austria MD 3 Months/M INJ U 18Oct2010-18Oct2010 22Oct2010 U/4 Days Gastroenteritis rotavirus*, Vomiting, Rash, Diarrhoea, Viral rash R #D0069326A Germany MD 4 Months/M INJ U 1 Days U/0 Months Gastroenteritis staphylococcal, Diarrhoea, Vomiting, Pyrexia, Fatigue U #B0748231A Czech Republic MD,RA 4 Months/M INJ U 05Apr2011-05Apr2011, 28Feb2011-28Feb2011 11Apr2011 U/6 Days, U/U Groin abscess, Abscess N #B0711894A Australia HP 28 Months/M INJ, INJ, INJ, INJ U, U, U, U 06Jan2009-06Jan2009, 02Mar2009-02Mar2009, 11May2009-11May2009, 10Nov2009-10Nov2009 17Mar2011 U/2 Years, U/2 Years, U/22 Months, U/16 Months Haemophilus infection, Bacteraemia, Pharyngitis, Lethargy, Pyrexia, Dyspnoea, Vaccination failure R CONFIDENTIAL 330 CONFIDENTIAL 378 #B0727263A Australia HP 10 Months/M INJ U 17Dec2010-17Dec2010, 17Sep2010-17Sep2010 30May2011 U/5 Months, U/U Haemophilus infection, Irritability, Pyrexia, Abasia R #B0685659A France MD 2 Months/M INJ U 01Oct2010-01Oct2010 01Nov2010 U/10 Days Herpes zoster U B0692979A France MD 18 Months/M INJ U 09Dec2010-09Dec2010 18Dec2010 U/9 Days Herpes zoster S B0697049A Sweden HP,MD 3 Months/M INJ, INJ U, U 01Jan2010-01Jan2010, 17Jan2011-17Jan2011 U/1 Weeks, U/1 Weeks Impetigo, Urticaria papular, Rash erythematous, Rash vesicular, Rash erythematous, Rash vesicular, Rash pruritic, Rash macular U B0705097A Austria MD 5 Years/F INJ, INJ, INJ, INJ, INJ, INJ U, U, U, U, U, U 01Feb2007-01Feb2007, 01May2007-01May2007, 01Jun2007-01Jun2007, 01Oct2007-01Oct2007, 01Jan2008-01Jan2008, 17Feb2011-17Feb2011 01Jan2009 U/0 Years, U/0 Years, U/0 Years, U/0 Years, U/1 Years, U/0 Months Infection, Injection site swelling, Injection site erythema, Pyrexia, No therapeutic response U CONFIDENTIAL 331 CONFIDENTIAL 379 B0756153A Ecuador MD,RP 4 Months/F INJ .5ML 01Jan2010-01Jan2010 U/1 Weeks Injection site abscess U D0072769A Germany MD 4 Months/M INJ U 1 Days U/2 Days Injection site abscess U D0072948A Germany MD 4 Months/M INJ U 1 Days U/2 Days Injection site abscess U D0071422A Germany MD,RA 6 Months/F INJ U 28Jun2010-28Jun2010 U/3 Months Injection site abscess, Injection site erythema, Injection site swelling, Foreign body reaction, Incision site abscess S D0071422B Germany MD,RA 14 Months/F INJ U 17Feb2011-17Feb2011 U/6 Weeks Injection site abscess, Injection site inflammation, Injection site swelling, Foreign body reaction, Incision site abscess S CONFIDENTIAL 332 CONFIDENTIAL 380 #B0718957A France MD 2 Months/M INJ U 1 Days U/Unknown Injection site abscess, Injection site nodule, Injection site erythema R #B0686567A Czech Republic MD,RA 9 Months/U INJ U 13Oct2010-13Oct2010 01Oct2010 U/16 Days Injection site abscess, Injection site oedema, Injection site swelling R B0747623A Belgium MD,RP 6 Months/M INJ U U 10Sep2011 U/Unknown Injection site cellulitis, Extensive swelling of vaccinated limb, Injection site oedema U #B0696664A France RA 17 Months/M INJ U 29Dec2010-29Dec2010 30Dec2010 U/1 Days Injection site infection, Erythema, Oedema, Feeling hot, C-reactive protein increased R B0683076A Poland MD,RA 21 Months/U INJ U 14Apr2010-14Apr2010 14Apr2010 U/0 Days Injection site pustule, Body temperature increased, Injection site erythema, Injection site pain, Injection site oedema R CONFIDENTIAL 333 CONFIDENTIAL 381 D0069888A Germany MD U/F INJ U 01Jan2005-01Jan2005 01Jan2005 U/1 Days Labyrinthitis, Gait disturbance, Balance disorder R #B0741331A South Africa HP 16 Weeks/U INJ U 1 Days U/10 Days Meningitis U #B0714940A France RA 4 Months/F INJ U 26Mar2011-26Mar2011 30Mar2011 U/4 Days Meningitis aseptic R #B0711853A Australia HP 11 Months/M INJ, INJ, INJ U, U, U 18May2010-18May2010, 04Aug2010-04Aug2010, 21Oct2010-21Oct2010 05Mar2011 U/10 Months, U/7 Months, U/4 Months Meningitis haemophilus, Bacteraemia, Vaccination failure R #B0727262A Australia HP 11 Months/F INJ, INJ, INJ U, U, U 16Nov2010-16Nov2010, 18Jan2011-18Jan2011, 31Aug2010-31Aug2010 28May2011 U/9 Months, U/6 Months, U/4 Months Meningitis haemophilus, Pyrexia, Headache, Lethargy, Decreased appetite, Vomiting, Vaccination failure R CONFIDENTIAL 334 CONFIDENTIAL 382 #B0685610A Andorra RA,RP 10 Months/M INJ, INJ U, U 04Feb2010-04Feb2010, 04Jun2010-04Jun2010 17Nov2010 U/9 Months, U/5 Months Meningitis haemophilus, Vaccination failure R #B0735156A South Africa MD 3 Years/F INJ, INJ, INJ, INJ U, U, U, U 12Sep2007-12Sep2007, 10Oct2007-10Oct2007, 07Nov2007-07Nov2007, 08Jan2009-08Jan2009 05Jun2011 U/4 Years, U/4 Years, U/4 Years, U/2 Years Meningitis haemophilus, Vaccination failure R #D0072024A Germany MD,RA 3 Months/M INJ U 24May2011-24May2011 25May2011 U/1 Days Meningitis pneumococcal, Gastroenteritis rotavirus, Respiratory syncytial virus infection, Pneumococcal sepsis, Pharyngitis, Somnolence, Pyrexia, Fluid intake reduced, Respiration abnormal, Crying, Diarrhoea, Cardiovascular insufficiency, Pallor, Tachypnoea, Anaemia, Thrombocytosis U CONFIDENTIAL 335 CONFIDENTIAL 383 #D0069889A Germany OM,MD 4 Months/M INJ U 01Oct2010-01Oct2010 04Oct2010 U/3 Days Meningitis pneumococcal, Grand mal convulsion, Epilepsy, Hydrocephalus, Subdural hygroma, Subdural empyema, Anaemia, Generalised oedema, Ileus paralytic, Conjunctivitis, Septic shock, Pneumonia primary atypical, Neurosurgery, Pyrexia, Abdominal distension, Ill-defined disorder, Restlessness, Hyperaesthesia, Oligodipsia, Eye movement disorder, Hypertonia, Tachycardia, Oxygen saturation decreased, Ascites, Respiratory arrest, Drug N CONFIDENTIAL 336 CONFIDENTIAL 384 ineffective, Cyanosis, Splenomegaly #B0700040A Sweden CO,HP 9 Months/F INJ U 20May2010-20May2010, 17Aug2010-17Aug2010 26Nov2010 U/101 Days, U/U Meningitis, Sepsis, Shock, Pneumococcal infection, Renal impairment, Hepatic function abnormal, Pyrexia, Diarrhoea, Vomiting F #B0683335A Netherlands HP,RA 2 Months/M INJ U 13Sep2010-13Sep2010 13Sep2010 U/3 Minutes Meningitis viral, Convulsion, Yellow skin, Cyanosis, Dehydration, Diarrhoea, Somnolence, Crying, Vomiting F B0719600A Netherlands HP,RA 11 Months/F INJ U 04Oct2010-04Oct2010 04Oct2010 U/4 Hours Nasopharyngitis, Insomnia, Injection site haematoma, Injection site inflammation, Injection site pain, Pyrexia, Crying R CONFIDENTIAL 337 CONFIDENTIAL 385 #D0069814A Germany MD,RA 9 Weeks/M INJ .5ML 29Oct2010-29Oct2010 03Nov2010 U/5 Days Osteomyelitis*, Bone abscess* R #D0070068A Germany RA 11 Months/M INJ, INJ U, U 13Dec2007-13Dec2007, 04Mar2008-04Mar2008 01Mar2008 U/2 Months, U/0 Months Otitis media N #B0748257A Czech Republic MD,RA 4 Months/M INJ U 01Dec2010-01Dec2010 U/Unknown Otitis media, Increased upper airway secretion, Snoring, Mucous membrane disorder, Lymphadenopath y U #D0069222A Germany MD 11 Months/M INJ, INJ, INJ U, U, U 14Jan2010-14Jan2010, 11Feb2010-11Feb2010, 26Apr2010-26Apr2010 04May2010 U/110 Days, U/82 Days, U/8 Days Pertussis R D0070831A Germany MD Child/U INJ U 1 Days U/Unknown Pertussis U CONFIDENTIAL 338 CONFIDENTIAL 386 D0071749A Germany HP,RA 5 Months/F INJ U 26Apr2011-26Apr2011 27Apr2011 U/1 Days Pertussis R D0072909A Germany PH 4 Years/U INJ U U U/U Pertussis U #D0072273A Germany MD,RP 5 Months/M INJ, INJ U, U 15Jun2011-15Jun2011, 08Apr2011-08Apr2011 27Jun2011 U/80 Days, U/12 Days Pertussis, Choking, Cyanosis, Apnoea, Bronchopneumon ia, Cough, Vomiting N #D0069277A Germany MD,RP 5 Years/F INJ, INJ, INJ, INJ U, U, U, U 19Oct2006-19Oct2006, 03Jan2006-03Jan2006, 29Nov2005-29Nov2005, 25Oct2005-25Oct2005 01Aug2010 U/3 Years, U/4 Years, U/4 Years, U/4 Years Pertussis*, Cough*, Cough*, Vomiting*, Rhinitis*, Decreased appetite*, Weight decreased*, Vaccination failure* R #D0071988A Germany MD,RP 2 Years/F INJ, INJ, INJ, INJ U, U, U, U 04Sep2009-04Sep2009, 06Oct2009-06Oct2009, 15Jul2010-15Jul2010, 07Aug2009-07Aug2009 01Jul2011 U/23 Months, U/22 Months, U/21 Months, U/12 Months Pertussis, Cough, Vaccination failure I CONFIDENTIAL 339 CONFIDENTIAL 387 #D0072008A Germany MD,RP 8 Years/F INJ, INJ, INJ, INJ U, U, U, U 15Jan2003-15Jan2003, 25Feb2003-25Feb2003, 25Mar2003-25Mar2003, 03Nov2003-03Nov2003 05Jul2011 U/8 Years, U/8 Years, U/8 Years, U/7 Years Pertussis, Cough, Vaccination failure I #D0072212A Germany MD,RA 6 Years/M INJ U 06Apr2006-06Apr2006 14Jul2011 U/5 Years Pertussis, Cough, Vaccination failure I #D0072947A Germany HP,RA 3 Years/M INJ, INJ, INJ, INJ U, U, U, U 18Dec2007-18Dec2007, 30Jan2008-30Jan2008, 04Apr2008-04Apr2008, 26Nov2008-26Nov2008 01Aug2011 U/3 Years, U/3 Years, U/3 Years, U/2 Years Pertussis, Cough, Vaccination failure U #D0072725A Germany MD 6 Months/M INJ, INJ, INJ U, U, U 05Apr2011-05Apr2011, 03May2011-03May2011, 31May2011-31May2011 05Jul2011 U/91 Days, U/63 Days, U/35 Days Pertussis, Cough, Vomiting, Vaccination failure I #B0745561A Switzerland MD 9 Months/F INJ, INJ, INJ U, U, U 05Jan2011-05Jan2011, 08Mar2011-08Mar2011, 24May2011-24May2011 09Aug2011 U/7 Months, U/5 Months, U/77 Days Pertussis, Cyanosis, Cough, Pyrexia, Vaccination failure I #D0072016A Germany MD 31 Months/F INJ, INJ, INJ, INJ U, U, U, U 30Mar2009-30Mar2009, 30Apr2009-30Apr2009, 25Jun2009-25Jun2009, 12Jan2010-12Jan2010 07Jul2011 U/2 Years, U/2 Years, U/24 Months, U/17 Months Pertussis, Pertussis, Vomiting, Rhinitis, Vaccination failure U CONFIDENTIAL 340 CONFIDENTIAL 388 D0072007A Germany MD,RP 6 Months/F INJ, INJ, INJ U, U, U 29Mar2011-29Mar2011, 03May2011-03May2011, 31May2011-31May2011 29Jun2011 U/92 Days, U/57 Days, U/29 Days Pertussis, Pyrexia, Cough, Rhinitis, Lymphadenopath y U #B0735430A South Africa HP 18 Months/F INJ U U U/Unknown Pertussis, Sneezing, Post-tussive vomiting, Rhinorrhoea, Respiratory syncytial virus infection, Pyrexia, Cough, Vaccination failure U #B0687509A Austria MD 5 Years/F INJ U 1 Days U/Unknown Pertussis, Vaccination failure U #D0069221A Germany MD 2 Years/M INJ U 17Dec2008-17Dec2008 06Sep2010 U/21 Months Pertussis, Vaccination failure R #D0069673A Germany MD,RP 1 Years/M INJ U 01Jul2010-01Jul2010 01Jan2010 U/0 Years Pertussis, Vaccination failure I CONFIDENTIAL 341 CONFIDENTIAL 389 #D0069696A Germany MD,RP 12 Years/M INJ U 1 Days U/Unknown Pertussis, Vaccination failure I #D0069697A Germany MD,RP 7 Years/M INJ U 1 Days U/Unknown Pertussis, Vaccination failure I #D0069698A Germany MD,RP Adult/F INJ U 1 Days U/Unknown Pertussis, Vaccination failure I #D0069825A Germany MD,RP 3 Years/F INJ, INJ, INJ, INJ U, U, U, U 10Dec2007-10Dec2007, 26Jan2008-26Jan2008, 25Sep2008-25Sep2008, 24Oct2007-24Oct2007 01Aug2010 U/3 Years, U/3 Years, U/2 Years, U/23 Months Pertussis, Vaccination failure R #D0070091A Germany MD 11 Months/F INJ, INJ, INJ U, U, U 20May2010-20May2010, 04Mar2010-04Mar2010, 22Apr2010-22Apr2010 20Oct2010 U/8 Months, U/6 Months, U/5 Months Pertussis, Vaccination failure R #D0070092A Germany MD 5 Years/U INJ, INJ, INJ, INJ U, U, U, U 25Oct2005-25Oct2005, 22Nov2005-22Nov2005, 20Dec2005-20Dec2005, 03Apr2007-03Apr2007 20Oct2010 U/5 Years, U/5 Years, U/5 Years, U/4 Years Pertussis, Vaccination failure R CONFIDENTIAL 342 CONFIDENTIAL 390 #D0070099A Germany RA 9 Years/F INJ, INJ, INJ, INJ U, U, U, U 29Oct2001-29Oct2001, 07Dec2001-07Dec2001, 17Jan2002-17Jan2002, 1 Days 08Nov2010 U/9 Years, U/9 Years, U/9 Years, U/Unknown Pertussis, Vaccination failure U #D0070108A Germany HP 4 Years/M INJ, INJ, INJ, INJ U, U, U, U 01Sep2006-01Sep2006, 13Oct2006-13Oct2006, 09Nov2006-09Nov2006, 27Jul2007-27Jul2007 01Jan2010 U/4 Years, U/4 Years, U/4 Years, U/3 Years Pertussis, Vaccination failure U #D0070132A Germany HP 4 Years/M INJ, INJ, INJ, INJ U, U, U, U 18Jul2006-18Jul2006, 16Aug2006-16Aug2006, 05Oct2006-05Oct2006, 08Jun2007-08Jun2007 01Jan2010 U/4 Years, U/4 Years, U/4 Years, U/3 Years Pertussis, Vaccination failure U #D0070264A Germany MD,RP Child/U INJ U 1 Days U/Unknown Pertussis, Vaccination failure U #D0070268A Germany MD,RP Child/U INJ U 1 Days U/Unknown Pertussis, Vaccination failure U #D0071806A Germany MD,RP 8 Years/F INJ U 1 Days 01Jun2011 U/Unknown Pertussis, Vaccination failure R CONFIDENTIAL 343 CONFIDENTIAL 391 #D0072784A Germany MD,RP 6 Years/F INJ U 1 Days 17Aug2011 U/Unknown Pertussis, Vaccination failure U #D0072839A Germany MD,RP Child/M INJ U 1 Days U/3 Years Pertussis, Vaccination failure U #D0072968A Germany MD,RA 5 Months/M INJ, INJ, INJ U, U, U 15Dec2010-15Dec2010, 19Jan2011-19Jan2011, 03Feb2011-03Feb2011 01Apr2011 U/107 Days, U/72 Days, U/57 Days Pertussis, Vaccination failure U #D0073001A Germany MD 6 Years/M INJ, INJ, INJ, INJ U, U, U, U 16Aug2005-16Aug2005, 20Sep2005-20Sep2005, 18Oct2005-18Oct2005, 25Jul2006-25Jul2006 21Jul2011 U/6 Years, U/5 Years, U/5 Years, U/5 Years Pertussis, Vaccination failure U #D0073013A Germany HP,RA 5 Years/F INJ, INJ, INJ, INJ U, U, U, U 01Jun2006-01Jun2006, 01Sep2006-01Sep2006, 01Dec2006-01Dec2006, 01Apr2007-01Apr2007 12Sep2011 U/5 Years, U/5 Years, U/4 Years, U/4 Years Pertussis, Vaccination failure N #D0073015A Germany HP,RA 27 Months/F INJ U 01Aug2009-01Aug2009 26Sep2011 U/2 Years Pertussis, Vaccination failure N CONFIDENTIAL 344 CONFIDENTIAL 392 #B0682709A Australia MD,RP 9 Years/F INJ, INJ, INJ, INJ U, U, U, U 1 Days, 1 Days, 1 Days, 1 Days U/Unknown, U/Unknown, U/Unknown, U/Unknown Pertussis, Vaccination failure, Bordetella test negative U #D0071888A Germany MD,RP 4 Years/M INJ, INJ, INJ, INJ U, U, U, U 20Sep2007-20Sep2007, 20Nov2007-20Nov2007, 23Oct2007-23Oct2007, 30Jun2008-30Jun2008 01May2011 U/4 Years, U/4 Years, U/4 Years, U/3 Years Pertussis, Vaccination failure, Cough, Infection R #D0070138A Germany HP 5 Years/F INJ, INJ, INJ, INJ U, U, U, U 31May2005-31May2005, 11Aug2005-11Aug2005, 08Sep2005-08Sep2005, 24Apr2006-24Apr2006 11Aug2005 U/5 Years, U/0 Days, U/5 Years, U/4 Years Pertussis, Vaccination failure, Inappropriate schedule of drug administration U #D0071587A Germany MD 9 Months/F INJ, INJ, INJ U, U, U 18Aug2010-18Aug2010, 13Oct2010-13Oct2010, 15Sep2010-15Sep2010 21Mar2011 U/7 Months, U/6 Months, U/5 Months Pertussis, Vaccination failure, Pertussis N D0071872A Germany MD 8 Months/F INJ, INJ U, U 03Mar2011-03Mar2011, 28Apr2011-28Apr2011 20Jun2011 U/3 Months, U/2 Months Purulent discharge, Injection site erythema I #B0685226A Netherlands HP,RA 11 Months/F INJ U 27Jul2010-27Jul2010 28Jul2010 U/1 Days Pyelonephritis, Urinary tract infection, Oligodipsia, Oliguria, C-reactive protein U CONFIDENTIAL 345 CONFIDENTIAL 393 increased, Escherichia infection, Pyrexia, Crying, Decreased appetite #B0712429A Czech Republic MD 7 Months/F INJ U 01Mar2011-01Mar2011, 27Jan2011-27Jan2011 01Mar2011 U/0 Days, U/U Salmonella sepsis, Rash generalised, Pyrexia, Diarrhoea, Drug hypersensitivity, Hypersensitivity R #B0707174A France RA 21 Months/M INJ U 25Nov2010-25Nov2010 01Dec2010 U/0 Weeks Staphylococcal abscess, Injection site abscess, Pyrexia, Injection site swelling, Leukocytosis, C-reactive protein increased, Injection site inflammation R #B0698641A Czech Republic MD 3 Months/M INJ U 03Jan2011-03Jan2011 01Jan2011 U/1 Weeks Staphylococcal abscess, Streptococcal abscess, Injection site abscess R #B0698651A Czech Republic MD 4 Months/M INJ U 03Jan2011-03Jan2011, 1 Days 01Jan2011 U/2 Weeks, U/U Staphylococcal abscess, Streptococcal abscess, Injection site abscess R CONFIDENTIAL 346 CONFIDENTIAL 394 B0698608A Poland MD,RA 20 Months/M INJ U 14Dec2010-14Dec2010 15Dec2010 U/1 Days Tonsillitis, Injection site extravasation, Injection site erythema, Pyrexia U D0069721A Germany MD 18 Months/F INJ U 06Dec2010-06Dec2010, 07Sep2010-07Sep2010 06Dec2010 U/0 Days, U/U Tonsillitis, Pyrexia, Incorrect dose administered U #B0716727A Austria MD Infant/M INJ U 19Apr2011-19Apr2011 20Apr2011 U/1 Days Transmission of an infectious agent via a medicinal product, Pain, Ill-defined disorder, Injection site erythema, Injection site swelling, Product quality issue U #B0696094A Poland P 2 Months/M INJ U 02Nov2010-02Nov2010 03Nov2010 U/1 Days Urinary tract infection* R #D0069935A Germany MD 35 Months/M INJ U 18Jul2009-18Jul2009 13Dec2010 U/16 Months Varicella*, Papule*, Rash vesicular*, Scab*, Vaccination failure* R CONFIDENTIAL 347 CONFIDENTIAL 395 #B0728665A Netherlands HP,RA 3 Months/M INJ U 14Oct2010-14Oct2010 14Oct2010 U/8 Hours Viral infection, Petechiae, Pyrexia, Vomiting R #D0070215A Germany MD,RP 8 Months/M INJ U 06Jan2011-06Jan2011 26Jan2011 U/20 Days Viral rash, Rash generalised, Hepatosplenome galy, Upper respiratory tract infection N Injury, poisoning and procedural complications B0730790A France MD Adult/F INJ U 30Jun2011-30Jun2011 30Jun2011 U/See text Accidental exposure X B0700347A France MD 2 Months/F INJ U 1 Days U/See text Accidental overdose X B0720905A France PH 3 Years/M INJ U 19May2011-19May2011 19May2011 U/See text Accidental overdose X CONFIDENTIAL 348 CONFIDENTIAL 396 D0070893A Germany MD 17 Years/F INJ U 05May2008-05May2008 05May2008 U/0 Days Accidental overdose X B0741664A France MD 14 Months/F INJ U 20Aug2011-20Aug2011, 20Aug2011-20Aug2011 20Aug2011 U/Same day, U/Same day Accidental overdose, Pyrexia R B0700269A South Africa HP 5 Months/F INJ, INJ U, U 11Feb2011-11Feb2011, 11Feb2011-11Feb2011 11Feb2011 U/See text, U/See text Accidental overdose, Wrong technique in drug usage process X B0705307A France MD 3 Months/M INJ U 23Dec2010-23Dec2010 23Dec2010 U/See text Drug administered to patient of inappropriate age X B0706474A France PH 1 Months/M INJ U 01Mar2011-01Mar2011 01Mar2011 U/See text Drug administered to patient of inappropriate age X B0708594A France MD 3 Years/U INJ, INJ U, U 01Sep2008-01Sep2008, 01Dec2008-01Dec2008 01Sep2008 U/See text, U/See text Drug administered to patient of inappropriate age X CONFIDENTIAL 349 CONFIDENTIAL 397 B0743865A France MD 5 Weeks/M INJ U 30Aug2011-30Aug2011 30Aug2011 U/See text Drug administered to patient of inappropriate age X B0756536A Belgium MD 20 Months/U INJ U 05Oct2011-05Oct2011, 28Aug2011-28Aug2011 05Oct2011 U/During, U/U Drug administration error X B0698939A France MD 1 Months/U INJ U 01Dec2010-01Dec2010 01Dec2010 U/See text Drug administration error X B0711341A France MD 7 Weeks/U INJ U 1 Days U/See text Drug administration error X B0718226A France MD 5 Weeks/U INJ U 01Apr2011-01Apr2011 01Apr2011 U/See text Drug administration error X B0725884A France MD 6 Weeks/U INJ U 09Jun2011-09Jun2011 09Jun2011 U/See text Drug administration error X CONFIDENTIAL 350 CONFIDENTIAL 398 B0735279A France MD 6 Weeks/M INJ U 21Jun2011-21Jun2011 21Jun2011 U/See text Drug administration error X B0735351A France MD 6 Weeks/U INJ U 22Jun2011-22Jun2011 22Jun2011 U/See text Drug administration error X B0741923A France MD 5 Weeks/U INJ U 08Aug2011-08Aug2011 08Aug2011 U/See text Drug administration error X B0742889A France MD 1 Months/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Drug administration error X B0745772A France MD 1 Months/U INJ U 01Aug2011-01Aug2011 01Aug2011 U/See text Drug administration error X B0755871A France HP 4 Weeks/U INJ U 05Sep2011-05Sep2011 05Sep2011 U/See text Drug administration error X CONFIDENTIAL 351 CONFIDENTIAL 399 D0070350A Germany MD 7 Years/F INJ U 01Apr2009-01Apr2009 01Apr2009 U/0 Days Drug administration error X D0071025A Germany MD 1 Months/F INJ U 1 Days U/During Drug administration error X D0071150A Germany MD,RP 1 Months/F INJ U 07Feb2011-07Feb2011 07Feb2011 U/0 Days Drug administration error X D0071390A Germany MD Neonate/M INJ U 10May2011-10May2011 10May2011 U/During Drug administration error X D0071673A Germany MD 4 Weeks/F INJ U 24Feb2011-24Feb2011 24Feb2011 U/0 Days Drug administration error X B0690209A France MD 8 Weeks/F INJ, INJ U, U 30Nov2010-30Nov2010, 20Dec2010-20Dec2010 30Nov2010 U/See text, U/See text Drug administration error, Inappropriate schedule of drug administration X CONFIDENTIAL 352 CONFIDENTIAL 400 B0735329A France MD 7 Weeks/M INJ, INJ U, U 13Jul2010-13Jul2010, 27Feb2010-27Feb2010, 15Jun2010-15Jun2010 27Feb2010 U/See text, U/See text, U/U Drug administration error, Inappropriate schedule of drug administration X D0072087A Germany MD,RP 4 Months/F INJ U 15Jul2011-15Jul2011 15Jul2011 U/0 Days Drug administration error, Wrong technique in drug usage process, Incorrect route of drug administration X B0732003A Australia MD 4 Months/U INJ U 27Jun2011-27Jun2011 03Jun2011 U/During Expired drug administered X B0752903A Australia HP Infant/U INJ U 18Sep2011-18Sep2011 18Sep2011 U/During Expired drug administered X A0947255A Canada HP 8 Weeks/F INJ U 27Sep2011-27Sep2011 27Sep2011 U/See text Expired drug administered X CONFIDENTIAL 353 CONFIDENTIAL 401 B0733807A France MD Infant/U INJ U 23May2011-23May2011 23May2011 U/See text Expired drug administered X B0731311A Ireland MD 6 Months/M INJ U 20May2011-20May2011 20May2011 U/During Expired drug administered X B0731312A Ireland MD 6 Months/F INJ U 20May2011-20May2011 20May2011 U/During Expired drug administered X B0680981A France PH 9 Months/M INJ U 01Oct2010-01Oct2010 01Oct2010 U/See text Inappropriate schedule of drug administration X B0683449A France MD 10 Months/U INJ U 03Jun2010-03Jun2010 03Jun2010 U/See text Inappropriate schedule of drug administration X B0691618A France MD 12 Months/U INJ U 01Dec2010-01Dec2010, 01Jan2010-01Jan2010, 01Jan2010-01Jan2010 01Dec2010 U/See text, U/U, U/U Inappropriate schedule of drug administration X CONFIDENTIAL 354 CONFIDENTIAL 402 B0696263A France MD 10 Months/M INJ U 26Jan2011-26Jan2011, 19Jul2010-19Jul2010, 06May2010-06May2010 26Jan2011 U/See text, U/U, U/U Inappropriate schedule of drug administration X B0698753A France MD 6 Months/M INJ U 15Feb2010-15Feb2010, 02Oct2009-02Oct2009, 16Dec2009-16Dec2009 15Feb2010 U/See text, U/U, U/U Inappropriate schedule of drug administration X B0704539A France PH 2 Months/U INJ U 04Mar2011-04Mar2011, 18Feb2011-18Feb2011 04Mar2011 U/See text, U/U Inappropriate schedule of drug administration X B0707438A France MD 9 Months/F INJ U 23Aug2010-23Aug2010 23Aug2010 U/See text Inappropriate schedule of drug administration X B0713996A France MD 4 Months/M INJ U 18Apr2011-18Apr2011, 18Feb2011-18Feb2011 18Apr2011 U/See text, U/U Inappropriate schedule of drug administration X B0719764A France MD 14 Months/F INJ U 16May2011-16May2011 16May2011 U/See text Inappropriate schedule of drug administration X CONFIDENTIAL 355 CONFIDENTIAL 403 B0727092A France MD 9 Months/M INJ U 05Nov2010-05Nov2010 05Nov2010 U/See text Inappropriate schedule of drug administration X B0735327A France MD Infant/U INJ U 30Jun2011-30Jun2011 30Jun2011 U/See text Inappropriate schedule of drug administration X B0735328A France MD 5 Months/M INJ U 01Oct2010-01Oct2010 01Oct2010 U/See text Inappropriate schedule of drug administration X B0748243A France MD 13 Months/M INJ U 03Aug2011-03Aug2011, 07Sep2010-07Sep2010, 10Nov2010-10Nov2010 03Aug2011 U/See text, U/U, U/U Inappropriate schedule of drug administration X B0750549A France MD 3 Years/U INJ U 04Jan2011-04Jan2011 04Jan2011 U/See text Inappropriate schedule of drug administration X D0069396A Germany MD,RP 6 Months/F INJ U 09Nov2010-09Nov2010, 18Oct2010-18Oct2010 09Nov2010 U/0 Days, U/U Inappropriate schedule of drug administration X CONFIDENTIAL 356 CONFIDENTIAL 404 D0069403A Germany MD 6 Months/M INJ U 1 Days U/0 Days Inappropriate schedule of drug administration X B0707392A France MD,RP 2 Months/F INJ U 19Mar2011-19Mar2011, 12Mar2011-12Mar2011 19Mar2011 U/See text, U/U Inappropriate schedule of drug administration, Decreased appetite, Weight decreased U B0702048A France MD 3 Months/F INJ U 27Jan2011-27Jan2011, 04Jan2011-04Jan2011 27Jan2011 U/See text, U/U Inappropriate schedule of drug administration, Inappropriate schedule of drug administration X B0713125A France MD,RP 7 Months/M INJ U 06Apr2011-06Apr2011 06Apr2011 U/See text Inappropriate schedule of drug administration, Incorrect route of drug administration X B0703975A France MD 3 Months/U INJ U 03Aug2009-03Aug2009, 15Jul2009-15Jul2009 03Aug2009 U/See text, U/U Inappropriate schedule of drug administration, Wrong drug administered X B0682314A France MD Infant/U INJ U 1 Days U/See text Incorrect dose administered X CONFIDENTIAL 357 CONFIDENTIAL 405 B0687936A France MD Infant/U INJ, INJ U, U 28May2010-28May2010, 20Jul2010-20Jul2010, 20Oct2009-20Oct2009, 08Jan2010-08Jan2010 28May2010 U/See text, U/See text, U/U, U/U Incorrect dose administered X B0698031A France MD 18 Months/M INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Incorrect dose administered X B0703977A France MD 6 Months/U INJ U 04Mar2011-04Mar2011, 07Jan2011-07Jan2011 04Mar2011 U/See text, U/U Incorrect dose administered X B0705846A France MD,RP 5 Months/F INJ U 01Jan2010-01Jan2010 01Jan2011 U/See text Incorrect dose administered X B0711997A France MD 7 Months/F INJ U 1 Days, 1 Days, 1 Days U/See text, U/U, U/U Incorrect dose administered X B0712293A France MD 1 Years/U INJ U 01Jan2010-01Jan2010 01Aug2009 U/See text Incorrect dose administered X CONFIDENTIAL 358 CONFIDENTIAL 406 B0719605A France CO,MD 5 Months/M INJ U 16May2011-16May2011 16May2011 U/See text Incorrect dose administered X B0728502A France MD 8 Months/M INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Incorrect dose administered X B0729496A France HP 5 Months/U INJ U 24Jun2011-24Jun2011 24Jun2011 U/See text Incorrect dose administered X B0745443A France MD 11 Months/F INJ U 03Sep2011-03Sep2011, 13May2011-13May2011, 16Feb2011-16Feb2011 03Sep2011 U/See text, U/U, U/U Incorrect dose administered X B0746444A France MD 5 Months/U INJ U 25Jul2011-25Jul2011, 01Jun2011-01Jun2011 25Jul2011 U/See text, U/U Incorrect dose administered X B0747140A France MD 7 Months/F INJ U 01Mar2011-01Mar2011, 01Jan2011-01Jan2011 01Mar2011 U/See text, U/U Incorrect dose administered X CONFIDENTIAL 359 CONFIDENTIAL 407 B0748238A France MD 16 Months/M INJ U 15Sep2011-15Sep2011, 01Apr2010-01Apr2010, 10Jun2010-10Jun2010, 27May2011-27May2011 15Sep2011 U/See text, U/U, U/U, U/U Incorrect dose administered X B0755884A France MD 8 Months/U INJ U 14Nov2010-14Nov2010 14Nov2010 U/See text Incorrect dose administered X B0730220A Singapore MD,RP 7 Months/F INJ U 11Jun2011-11Jun2011 11Jun2011 U/During Incorrect dose administered X B0691022A Spain HP 6 Months/F INJ U 1 Days, 1 Days U/During, U/U Incorrect dose administered X B0756912A Belgium MD 7 Months/M INJ U 05Jan2011-05Jan2011, 18Oct2010-18Oct2010, 20Sep2010-20Sep2010, 02Aug2010-02Aug2010 05Jan2011 U/During, U/U, U/U, U/U Incorrect dose administered, Irritability, Vomiting R B0754991A France MD 3 Years/F INJ U 01Dec2008-01Dec2008, 01Nov2008-01Nov2008, 02Jan2009-02Jan2009 01Dec2008 U/See text, U/See text, U/See text Incorrect dose administered, Wrong drug administered X CONFIDENTIAL 360 CONFIDENTIAL 408 B0681952A Australia MD 6 Months/F INJ U U, U U/See text, U/U Incorrect route of drug administration X B0686563A Belgium MD,RP 15 Months/F INJ U 23Nov2010-23Nov2010 23Nov2010 U/During Incorrect route of drug administration X B0733788A Sweden HP,MD 1 Years/M INJ U U U/During Incorrect route of drug administration, Dyskinesia, Underdose, Injection site erythema, Injection site swelling, Injection site swelling U B0742113A Australia CO,HP 6 Months/U INJ U 10Aug2011-10Aug2011 10Aug2011 U/During Incorrect route of drug administration, Injection site haematoma, Injection site swelling, Injection site pain, Injection site erythema R D0069542A Germany HP Adult/U INJ U 1 Days U/0 Days Incorrect route of drug administration, Overdose, Off label use, Wrong technique in drug X CONFIDENTIAL 361 CONFIDENTIAL 409 usage process B0731030A France CO,MD 2 Months/U INJ U 05Jul2011-05Jul2011 05Jul2011 U/See text Incorrect route of drug administration, Wrong technique in drug usage process X B0688919A Andorra HP 2 Months/M INJ U 07Dec2010-07Dec2010 07Dec2010 U/See text Incorrect storage of drug X B0686265A Australia HP 2 Months/U INJ U 12Oct2010-12Oct2010 U/See text Incorrect storage of drug X B0686993A Australia HP 6 Months/U INJ U 12Oct2010-12Oct2010 U/See text Incorrect storage of drug X B0686994A Australia HP 6 Months/U INJ U 12Oct2010-12Oct2010 U/See text Incorrect storage of drug X CONFIDENTIAL 362 CONFIDENTIAL 410 B0687001A Australia HP 2 Months/U INJ U 25Oct2010-25Oct2010 U/See text Incorrect storage of drug X B0687004A Australia HP 6 Months/U INJ U 27Oct2010-27Oct2010 U/See text Incorrect storage of drug X B0687005A Australia HP 4 Months/U INJ U 27Oct2010-27Oct2010 U/See text Incorrect storage of drug X B0687006A Australia HP 7 Months/U INJ U 27Oct2010-27Oct2010 U/See text Incorrect storage of drug X B0687007A Australia HP 2 Months/U INJ U 28Oct2010-28Oct2010 U/See text Incorrect storage of drug X B0687009A Australia HP 2 Months/U INJ U 04Nov2010-04Nov2010 U/See text Incorrect storage of drug X CONFIDENTIAL 363 CONFIDENTIAL 411 B0687011A Australia HP 2 Months/U INJ U 05Nov2010-05Nov2010 U/See text Incorrect storage of drug X B0687018A Australia HP 2 Months/U INJ U 08Nov2010-08Nov2010 U/See text Incorrect storage of drug X B0687024A Australia HP 4 Years/U INJ U 09Nov2010-09Nov2010 U/See text Incorrect storage of drug X B0730020A Australia PH U/U INJ U 1 Days U/See text Incorrect storage of drug X B0731392A Spain HP 6 Months/M INJ U 01Jun2011-01Jun2011 U/See text Incorrect storage of drug X B0731394A Spain HP 2 Months/M INJ U 01Jun2011-01Jun2011 U/See text Incorrect storage of drug X CONFIDENTIAL 364 CONFIDENTIAL 412 B0731396A Spain HP 4 Months/M INJ U 01Jun2011-01Jun2011 U/See text Incorrect storage of drug X B0747719A Belgium HP 5 Months/M INJ U 29Jun2011-29Jun2011, 27Jul2011-27Jul2011, 14Sep2011-14Sep2011 14Sep2011 U/See text, U/U, U/U Incorrect storage of drug, Pyrexia, Irritability, Diarrhoea, Abdominal pain R B0681410A France MD 20-29 Years/F INJ U 01Oct2010-01Oct2010 U/See text Maternal exposure during pregnancy, Off label use X B0726436A France MD 4 Months/M INJ U 15Jun2011-15Jun2011 15Jun2011 U/See text Overdose X D0069306A Germany MD Adult/U INJ U 1 Days U/0 Days Overdose X D0072554A Germany MD 8 Years/M INJ U 01Jan2006-01Jan2006, 05Aug2011-05Aug2011 05Aug2011 U/0 Days, U/U Overdose X CONFIDENTIAL 365 CONFIDENTIAL 413 B0692789A Italy MD,RP 5 Months/F INJ U 1 Days U/During Overdose X B0749458A New Zealand PH 6 Weeks/F INJ U 20Sep2011-20Sep2011 20Sep2011 U/During Overdose X D0072383A Germany MD 4 Months/F INJ U 12Aug2011-12Aug2011 12Aug2011 U/0 Days Overdose, Wrong drug administered X D0072476A Germany MD 23 Years/M INJ U 20Aug2011-20Aug2011 20Aug2011 U/0 Days Overdose, Wrong technique in drug usage process X B0707441A France MD 20 Months/F INJ U 18Mar2011-18Mar2011 18Mar2011 U/See text Underdose X B0713124A France MD 3 Months/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Underdose X CONFIDENTIAL 366 CONFIDENTIAL 414 B0715660A France MD 20 Months/U INJ U 22Apr2011-22Apr2011 22Apr2011 U/See text Underdose X B0730789A France MD Infant/U INJ U 30Jun2011-30Jun2011 30Jun2011 U/See text Underdose X B0733973A France MD Infant/F INJ U 14May2011-14May2011 14May2011 U/See text Underdose X B0746437A France MD 18 Months/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Underdose X B0748270A France PH 16 Months/M INJ U 15Sep2011-15Sep2011 15Sep2011 U/See text Underdose X B0750072A France MD,RP 1 Years/U INJ U 01Sep2011-01Sep2011 01Sep2011 U/See text Underdose X CONFIDENTIAL 367 CONFIDENTIAL 415 B0751895A France MD Infant/M INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Underdose X D0071408A Germany MD 6 Months/F INJ U 1 Days U/During Underdose X D0071608A Germany MD 15 Months/M INJ U 13May2011-13May2011 13May2011 U/During Underdose X B0741475A Hong Kong MD,RP 6 Months/M INJ U U U/During Underdose X B0703093A France MD 1 Years/U INJ U 01Feb2011-01Feb2011 01Feb2011 U/See text Underdose, Wrong technique in drug usage process X #B0686701A Poland MD,RA 3 Months/U INJ, INJ, INJ U, U, U 01Jan2009-01Jan2009, 01Jan2009-01Jan2009, 08Jul2009-08Jul2009 01Jan2009 U/Unknown, U/Unknown, U/4 Hours Vaccination complication*, Hypotonic-hypore sponsive episode*, Pallor*, Pyrexia*, R CONFIDENTIAL 368 CONFIDENTIAL 416 Immobile*, Pallor*, Hypotonia*, Pyrexia* #B0743708A Switzerland MD,RA 2 Years/M INJ .5ML 01Jul2011-01Jul2011 02Jul2011 U/20 Hours Vaccination complication, Injection site swelling, Injection site pruritus, Injection site warmth, Injection site erythema, Injection site pain R B0737216A Australia CO,HP 4 Weeks/U INJ U U U/During Wrong drug administered X B0683434A France MD 4 Years/M INJ U 04Nov2010-04Nov2010, 15May2007-15May2007, 01Feb2008-01Feb2008 04Nov2010 U/See text, U/U, U/U Wrong drug administered X B0683447A France MD 7 Years/F INJ U 19May2010-19May2010 19May2010 U/See text Wrong drug administered X CONFIDENTIAL 369 CONFIDENTIAL 417 B0693149A France PH 9 Years/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Wrong drug administered X B0742693A France MD 4 Years/F INJ, INJ U, U 01Apr2008-01Apr2009, 01Sep2009-01Sep2009 01Apr2008 U/See text, U/See text Wrong drug administered X B0742696A France MD 5 Years/M INJ U 01May2010-01May2010 01May2010 U/See text Wrong drug administered X D0069467A Germany MD 7 Years/F INJ U 17Nov2010-17Nov2010 17Nov2010 U/0 Days Wrong drug administered X D0069776A Germany PH 19 Years/F INJ U 01Jul2010-01Jul2010 01Jul2010 U/During Wrong drug administered X D0070452A Germany MD,RP U/U INJ U 1 Days U/During Wrong drug administered X CONFIDENTIAL 370 CONFIDENTIAL 418 D0070458A Germany MD 9 Years/M INJ U 1 Days U/0 Days Wrong drug administered X D0070469A Germany MD,RP 10 Years/F INJ U 28Feb2011-28Feb2011 28Feb2011 U/During Wrong drug administered X D0070961A Germany PH Adult/U INJ U 1 Days U/0 Days Wrong drug administered X D0071742A Germany PH Adult/U INJ U 1 Days U/During Wrong drug administered X D0072391A Germany MD 7 Years/M INJ U 05Aug2011-05Aug2011, 01Jan2006-01Jan2006 05Aug2011 U/0 Days, U/U Wrong drug administered X B0695871A Italy MD 3 Months/M INJ U 1 Days U/During Wrong drug administered X CONFIDENTIAL 371 CONFIDENTIAL 419 B0726160A Spain HP 6 Years/M INJ U 18May2011-18May2011 18May2011 U/During Wrong drug administered X B0703605A France MD 3 Months/F INJ U 25Feb2011-25Feb2011 31Jan2011 U/See text Wrong drug administered, Drug prescribing error, Inappropriate schedule of drug administration X B0685825A France MD 6 Months/U INJ U 26Apr2010-26Apr2010 26Apr2010 U/See text Wrong drug administered, Incorrect dose administered X B0683553A Australia HP U/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/During Wrong technique in drug usage process X Several subjects are concerned by this case. B0705458A Australia HP 2 Months/U INJ U 08Mar2011-08Mar2011 08Mar2011 U/During Wrong technique in drug usage process X CONFIDENTIAL 372 CONFIDENTIAL 420 B0729237A Australia MD U/M INJ U 1 Days U/During Wrong technique in drug usage process X B0732276A Australia HP Infant/U INJ U 1 Days U/See text Wrong technique in drug usage process X B0734749A Austria MD U/U INJ U 1 Days U/During Wrong technique in drug usage process X B0756904A Belgium PH Child/U INJ U U U/During Wrong technique in drug usage process X A0901113A Canada HP Infant/U INJ U U U/See text Wrong technique in drug usage process X 3 subjects were vaccinated with infanrix hexa without hib. A0901399A Canada PH Infant/U INJ U 01Dec2010-01Dec2010 U/See text Wrong technique in drug usage process X One subject was 67 day old male, MW. The second subject was a 77 day old female, JK. CONFIDENTIAL 373 CONFIDENTIAL 421 A0912540A Canada MD 21 Months/U INJ U U, U, U U/See text, U/U, U/U Wrong technique in drug usage process X A0936897A Canada MD Infant/U INJ U 1 Days U/See text Wrong technique in drug usage process X A0942606A Canada HP 8 Months/F INJ U 25Aug2011-25Aug2011, 17Mar2011-17Mar2011, 12Apr2011-12Apr2011 25Aug2011 U/See text, U/U, U/U Wrong technique in drug usage process X B0686842A France MD,RP 2 Months/M INJ U 01Jan2010-01Jan2010 01Jan2010 U/See text Wrong technique in drug usage process X B0689063A France MD 4 Months/M INJ U 11Dec2010-11Dec2010 11Dec2010 U/See text Wrong technique in drug usage process X B0689740A France MD 3 Months/F INJ U 16Dec2010-16Dec2010 16Dec2010 U/See text Wrong technique in drug usage process X CONFIDENTIAL 374 CONFIDENTIAL 422 B0693142A France MD 4 Months/F INJ U 10Jan2011-10Jan2011 10Jan2011 U/See text Wrong technique in drug usage process X B0693632A France PH Infant/M INJ U 01Jan2011-01Jan2011 01Jan2011 U/See text Wrong technique in drug usage process X B0693832A France MD Neonate/F INJ U 14Jan2011-14Jan2011 14Jan2011 U/See text Wrong technique in drug usage process X B0694085A France MD 12 Weeks/F INJ U 06Jan2011-06Jan2011 06Jan2011 U/See text Wrong technique in drug usage process X B0695154A France MD Infant/U INJ U 20Jan2011-20Jan2011 20Jan2011 U/See text Wrong technique in drug usage process X B0695607A France PH 4 Months/F INJ U 21Jan2011-21Jan2011 21Jan2011 U/See text Wrong technique in drug usage process X CONFIDENTIAL 375 CONFIDENTIAL 423 B0697401A France MD 18 Months/F INJ U 19Jul2010-19Jul2010 01Jul2010 U/See text Wrong technique in drug usage process X B0705091A France MD 4 Months/U INJ U 09Mar2011-09Mar2011 09Mar2011 U/See text Wrong technique in drug usage process X B0711335A France MD Infant/U INJ U 01Apr2011-01Apr2011 01Apr2011 U/See text Wrong technique in drug usage process X B0716261A France PH,MD 3 Months/F INJ U 01Apr2011-01Apr2011 01Apr2011 U/See text Wrong technique in drug usage process X B0716546A France MD 15 Months/F INJ U 27Apr2011-27Apr2011 27Apr2011 U/See text Wrong technique in drug usage process X B0724340A France MD 3 Months/F INJ U 01May2011-01May2011 01May2011 U/See text Wrong technique in drug usage process X CONFIDENTIAL 376 CONFIDENTIAL 424 B0724548A France MD Infant/U INJ U 03Jun2011-03Jun2011 03Jun2011 U/See text Wrong technique in drug usage process X B0725882A France MD 20 Months/U INJ U 10Jun2011-10Jun2011 10Jun2011 U/See text Wrong technique in drug usage process X B0731268A France MD 2 Months/U INJ U 05Jul2011-05Jul2011 05Jul2011 U/See text Wrong technique in drug usage process X B0733974A France PH,MD 4 Months/M INJ U 18Jul2011-18Jul2011 18Jul2011 U/See text Wrong technique in drug usage process X B0734159A France MD 20 Months/U INJ U 20Jul2011-20Jul2011 20Jul2011 U/See text Wrong technique in drug usage process X B0739075A France PH Infant/F INJ U 01Jul2011-01Jul2011 01Jul2011 U/See text Wrong technique in drug usage process X CONFIDENTIAL 377 CONFIDENTIAL 425 B0741941A France MD 2 Months/F INJ U 18Aug2011-18Aug2011 01Aug2011 U/See text Wrong technique in drug usage process X B0743864A France MD Infant/U INJ U 31Aug2011-31Aug2011 31Aug2011 U/See text Wrong technique in drug usage process X B0745767A France MD 2 Months/F INJ U 06Sep2011-06Sep2011 06Sep2011 U/See text Wrong technique in drug usage process X B0746700A France MD 2 Months/M INJ, INJ U, U 12Nov2009-12Nov2009, 11Jan2010-11Jan2010 12Nov2009 U/See text, U/See text Wrong technique in drug usage process X B0747182A France MD 2 Months/M INJ U 13Sep2011-13Sep2011 13Sep2011 U/See text Wrong technique in drug usage process X B0748276A France PH 18 Months/F INJ U 22Aug2011-22Aug2011 22Aug2011 U/See text Wrong technique in drug usage process X CONFIDENTIAL 378 CONFIDENTIAL 426 B0752261A France MD 4 Months/U INJ U 28Sep2011-28Sep2011 28Sep2011 U/See text Wrong technique in drug usage process X B0755901A France MD Infant/U INJ U 12Oct2011-12Oct2011 12Oct2011 U/See text Wrong technique in drug usage process X B0756751A France MD Infant/F INJ U 1 Days U/See text Wrong technique in drug usage process X D0069906A Germany MD 58 Days/M INJ U 10Jan2011-10Jan2011 10Jan2011 U/0 Days Wrong technique in drug usage process X D0069929A Germany MD 4 Months/M INJ U 10Jan2011-10Jan2011 10Jan2011 U/0 Days Wrong technique in drug usage process X D0070289A Germany PH U/U INJ U 1 Days U/0 Days Wrong technique in drug usage process X CONFIDENTIAL 379 CONFIDENTIAL 427 D0070361A Germany MD 6 Months/F INJ U 18Feb2011-18Feb2011 U/0 Days Wrong technique in drug usage process X D0070400A Germany PH,MD,RP 4 Months/F INJ U 1 Days U/During Wrong technique in drug usage process X D0070741A Germany MD U/U INJ U 1 Days U/0 Days Wrong technique in drug usage process X D0071160A Germany MD 13 Months/F INJ U 10Feb2011-10Feb2011 01Feb2011 U/During Wrong technique in drug usage process X D0071690A Germany MD 4 Months/M INJ U 09Jun2011-09Jun2011 09Jun2011 U/0 Days Wrong technique in drug usage process X D0072181A Germany MD 7 Months/U INJ U 1 Days U/0 Days Wrong technique in drug usage process X CONFIDENTIAL 380 CONFIDENTIAL 428 D0072443A Germany MD 3 Months/M INJ U 18Aug2011-18Aug2011 18Aug2011 U/0 Days Wrong technique in drug usage process X D0072513A Germany PH 15 Months/M INJ U 25Aug2011-25Aug2011 25Aug2011 U/0 Days Wrong technique in drug usage process X B0719869A Greece MD 4 Months/M INJ U 08May2011-08May2011 08May2011 U/During Wrong technique in drug usage process X B0735350A Ireland HP 4 Months/U INJ U U U/During Wrong technique in drug usage process X B0740627A Ireland PH 4 Months/F INJ U 10Aug2011-10Aug2011 10Aug2011 U/During Wrong technique in drug usage process X #B0755514A Ireland MD,RA 4 Months/M INJ U 22Sep2011-22Sep2011 22Sep2011 U/During Wrong technique in drug usage process X CONFIDENTIAL 381 CONFIDENTIAL 429 #B0682380A New Zealand PH 47 Days/F INJ .5ML 23Oct2010-23Oct2010 23Oct2010 U/During Wrong technique in drug usage process X B0693373A Spain PH 4 Months/U INJ U 10Jan2011-10Jan2011 10Jan2011 U/During Wrong technique in drug usage process X B0719758A Spain HP,RP 3 Months/F INJ U 26Apr2011-26Apr2011 26Apr2011 U/During Wrong technique in drug usage process X B0722815A Spain HP,MD 4 Months/M INJ U 02May2011-02May2011 02May2011 U/During Wrong technique in drug usage process X B0722819A Spain HP,MD 2 Months/M INJ U 02May2011-02May2011 02May2011 U/During Wrong technique in drug usage process X B0722820A Spain HP,MD 2 Months/F INJ U 02May2011-02May2011 02May2011 U/During Wrong technique in drug usage process X CONFIDENTIAL 382 CONFIDENTIAL 430 B0703738A Sweden HP U/U INJ U 1 Days U/During Wrong technique in drug usage process X B0703874A Sweden HP 3 Months/F INJ U 1 Days U/During Wrong technique in drug usage process X B0719890A Sweden HP 5 Months/F INJ U 10May2011-10May2011 U/During Wrong technique in drug usage process X B0740544A France MD 12 Weeks/M INJ, INJ U, U 11Aug2011-11Aug2011, 17Aug2011-17Aug2011 11Aug2011 U/See text, U/See text Wrong technique in drug usage process, Inappropriate schedule of drug administration X B0697148A France HP 18 Months/M INJ U 31Jan2011-31Jan2011 31Jan2011 U/See text Wrong technique in drug usage process, Incorrect route of drug administration X B0749413A France MD 21 Months/F INJ, INJ U, U 14Sep2011-14Sep2011, 14Sep2011-14Sep2011 14Sep2011 U/See text, U/See text Wrong technique in drug usage process, Overdose X CONFIDENTIAL 383 CONFIDENTIAL 431 B0753350A France MD 4 Months/F INJ, INJ U, U 04Oct2011-04Oct2011, 04Oct2011-04Oct2011, 01Aug2011-01Aug2011 04Oct2011 U/See text, U/See text, U/U Wrong technique in drug usage process, Overdose, Inappropriate schedule of drug administration X D0069699A Germany MD 16 Months/M INJ U 10Dec2010-10Dec2010, 1 Days 10Dec2010 U/During, U/U Wrong technique in drug usage process, Underdose X Investigations #D0070846A Germany MD,RP 10 Months/M INJ, INJ, INJ U, U, U 25Jan2011-25Jan2011, 27Oct2010-27Oct2010, 22Feb2011-22Feb2011 U/5 Months, U/55 Days, U/27 Days Aspartate aminotransferase increased, Alanine aminotransferase increased, Injection site nodule, Injection site induration, Injection site erythema, Febrile convulsion, Soft tissue infection, Abscess sterile, Respiratory tract infection N #D0071115A Germany MD 4 Years/F INJ, INJ, INJ, INJ U, U, U, U 11Jun2007-11Jun2007, 15Jul2007-15Jul2007, 09Oct2007-09Oct2007, 15Oct2008-15Oct2008 01Apr2011 U/4 Years, U/4 Years, U/4 Years, U/2 Years Aspartate aminotransferase increased, No therapeutic response, Infection U CONFIDENTIAL 384 CONFIDENTIAL 432 #B0756166A Poland MD,RA 1 Months/M INJ U 27Jul2011-27Jul2011 28Jul2011 U/1 Days Body temperature increased, Hypotonic-hypore sponsive episode, Somnolence R #D0070133A Germany HP 4 Years/F INJ, INJ, INJ, INJ U, U, U, U 03Apr2006-03Apr2006, 08May2006-08May2006, 12Jun2006-12Jun2006, 11May2007-11May2007 01Jan2010 U/4 Years, U/4 Years, U/4 Years, U/3 Years Bordetella test positive, Vaccination failure U #D0070137A Germany HP 5 Years/F INJ, INJ, INJ, INJ U, U, U, U 28Oct2005-28Oct2005, 25Nov2005-25Nov2005, 22Aug2006-22Aug2006, 14Dec2006-14Dec2006 01Jan2010 U/5 Years, U/5 Years, U/4 Years, U/4 Years Bordetella test positive, Vaccination failure U B0681488A Belgium MD,RP 30 Months/F INJ U 1 Days 01Jan2010 U/See text Clostridium test X D0072013A Germany MD 4 Years/M INJ U 1 Days U/Unknown Clostridium test negative X B0718002A France MD 4 Months/U INJ U 01Oct2010-01Oct2010 01Oct2010 U/See text Clostridium test negative, Underdose X CONFIDENTIAL 385 CONFIDENTIAL 433 B0699787A France PH 2 Years/U INJ, INJ, INJ U, U, U 01Feb2009-01Feb2009, 01Apr2009-01Apr2009, 01May2010-01May2010 01Jan2011 U/2 Years, U/2 Years, U/1 Years Corynebacterium test negative X B0717163A France MD 18 Months/F INJ, INJ U, U 01Jan2010-01Jan2010, 01Jan2010-01Jan2010 01Apr2011 U/1 Years, U/1 Years Corynebacterium test negative X B0731677A Austria MD 4 Years/M INJ, INJ, INJ, INJ U, U, U, U 19Mar2007-19Mar2007, 12May2007-12May2007, 31Mar2008-31Mar2008, 28Dec2006-28Dec2006 U/See text, U/See text, U/See text, U/See text Corynebacterium test negative, Clostridium test negative, Hepatitis B antibody negative X B0686689A Poland MD,RA 5 Months/U INJ U 21Jul2010-21Jul2010 21Jul2010 U/0 Days C-reactive protein increased, Restlessness, Decreased appetite, Pyrexia R B0728114A France MD Child/F INJ, INJ, INJ U, U, U 1 Days, 1 Days, 1 Days U/Unknown, U/Unknown, U/Unknown Hepatitis B antibody negative X D0072530A Germany MD U/U INJ U 1 Days U/1 Years Hepatitis B antibody negative X CONFIDENTIAL 386 CONFIDENTIAL 434 B0682838A Australia MD,RP 6 Years/M INJ U U U/During Immunology test abnormal X #B0736764A Viet Nam HP,RP 4 Months/M INJ U 02Aug2011-02Aug2011, 19May2011-19May2011, 28Jun2011-28Jun2011 02Aug2011 U/Hours, U/U, U/U Pulse absent, Dyspnoea, Injection site erythema, Injection site swelling, Crying U #B0720306A Spain MD,RP 21 Months/F INJ U 21Feb2010-21Feb2010, 21Dec2009-21Dec2009, 21Oct2009-21Oct2009 U/14 Months, U/U, U/U Transaminases increased, Hepatitis B antibody positive, Jaundice, Hepatomegaly, Diarrhoea, Pyrexia N #B0721308A Italy MD,RA 11 Months/F INJ U 19Apr2010-19Apr2010 19Apr2010 U/0 Days Transaminases increased, Pyrexia R Metabolism and nutrition disorders #B0752539A Italy MD,RA 7 Months/F INJ U 14Sep2011-14Sep2011 14Sep2011 U/0 Days Decreased appetite, Pyrexia, Weight decreased, Hyperaemia, Tympanic membrane disorder, Rhinitis, Rash pustular, U CONFIDENTIAL 387 CONFIDENTIAL 435 Upper respiratory tract inflammation B0727603A Netherlands MD,RA 3 Months/M INJ U 13Sep2010-13Sep2010 14Sep2010 U/Hours Oligodipsia, Injected limb mobility decreased, Injection site inflammation, Insomnia, Injection site pain, Crying, Pyrexia R B0733486A Netherlands HP,RA 2 Months/F INJ U 09Nov2010-09Nov2010 09Nov2010 U/5 Hours Oligodipsia, Insomnia, Malaise, Nasopharyngitis, Vomiting, Crying, Pyrexia, Erythema R #B0714244A Netherlands HP,RA 5 Months/M INJ, INJ .5ML, U 25Feb2011-25Feb2011, 1 Days U/6 Hours, U/1 Days Oligodipsia, Oligodipsia, Dehydration, Pyrexia, Diarrhoea, Diarrhoea, Crying R #B0752361A Italy MD,RA 17 Months/F INJ U 23Jul2010-23Jul2010 01Aug2010 U/9 Days Type 1 diabetes mellitus, Diabetic ketoacidosis, Polydipsia, Polyuria, Somnolence, Tachypnoea, Increased appetite, S CONFIDENTIAL 388 CONFIDENTIAL 436 Vomiting, Dermal cyst, Ketosis, Lip dry, Dehydration, Lymphadenopath y D0069358B Germany HP,RA 4 Months/M INJ U 07Jan2010-07Jan2010 07Jan2010 U/1 Hours Weight gain poor, Psychomotor hyperactivity, Pyrexia, Hyperhidrosis, Tremor, Injection site erythema, Injection site swelling, Sleep disorder N Musculoskeletal and connective tissue disorders #B0705706A France RA 18 Months/F INJ U 03Nov2010-03Nov2010 03Nov2010 U/Same day Arthralgia, Injection site oedema, Pain, Injected limb mobility decreased, Incorrect route of drug administration R #B0754191A Poland MD,RA 26 Months/U INJ U 04Jul2011-04Jul2011 06Jul2011 U/2 Days Joint swelling, Gait disturbance, Body temperature increased, Arthritis U CONFIDENTIAL 389 CONFIDENTIAL 437 #B0720309A Belgium RA 2 Months/F INJ U 22Apr2011-22Apr2011 22Apr2011 U/0 Days Muscle contracture, Muscle spasms, Erythema, Staring, Heart rate increased U #B0702855A Greece MD,RA 5 Months/F INJ U 03Nov2010-03Nov2010 03Nov2010 U/0 Days Muscle spasms, Pyrexia, Escherichia urinary tract infection U D0070972A Germany MD 2 Months/F INJ, INJ U, U 02Mar2011-02Mar2011, 08Apr2011-08Apr2011 02Mar2011 U/0 Days, U/0 Days Muscle spasms, Underdose, Muscle spasms, Underdose U B0756767A Netherlands HP,RA 2 Months/M INJ U 09Dec2010-09Dec2010 01Dec2010 U/4 Hours Muscle twitching, Pyrexia, Malaise R B0755146A South Africa HP 18 Months/U INJ U 21Sep2011-21Sep2011 22Sep2011 U/1 Days Musculoskeletal stiffness, Injection site erythema, Injection site swelling N #D0069239A Germany MD,RA 1 Years/M INJ U 01Jan2010-01Jan2010 01Jan2010 U/During Soft tissue necrosis, Debridement, Incorrect route of drug administration R CONFIDENTIAL 390 CONFIDENTIAL 438 Nervous system disorders #D0070015A Germany RA 16 Months/M INJ .5ML 09Dec2010-09Dec2010, 28Sep2009-28Sep2009, 04Jan2010-04Jan2010, 20Apr2010-20Apr2010 09Dec2010 U/0 Days, U/U, U/U, U/U Ataxia*, Balance disorder*, Balance disorder*, Encephalitis*, Encephalitis*, Gait disturbance*, Gait disturbance*, Pyrexia*, Upper respiratory tract infection*, Otitis media acute*, Cerebellar ataxia* R #B0705768A Italy MD,RA 1 Years/M INJ U 27Jan2011-27Jan2011 02Feb2011 U/6 Days Balance disorder, Irritability, Upper respiratory tract infection U #B0682833A France RA 17 Months/M INJ U 06Jul2010-06Jul2010 13Jul2010 U/7 Days Balance disorder, Lymphadenopath y, Fall, Otitis media, Pharyngeal erythema R D0069517A Germany HP,RA 13 Months/F INJ U 06Aug2010-06Aug2010 08Aug2010 U/2 Days Balance disorder, Vestibular neuronitis, Gait disturbance, Fall R CONFIDENTIAL 391 CONFIDENTIAL 439 #B0686955A Austria RA 1 Years/M INJ U 23Sep2010-23Sep2010 01Sep2010 U/Days Balance disorder*, Vomiting*, Body temperature increased* R #B0717146A Belgium RA 4 Months/F INJ U 01Mar2011-01Mar2011 17Mar2011 U/12 Hours Clonic convulsion R #B0708930A Italy MD,RA 3 Months/F INJ U 11Nov2010-11Nov2010 12Nov2010 U/1 Days Clonic convulsion U #B0720877A Australia HP 7 Months/M INJ U 18May2011-18May2011 19May2011 U/1 Days Convulsion U #D0072923A Germany MD U/U INJ U 1 Days U/Unknown Convulsion U #B0699990A Italy RA 4 Months/M INJ U 08Feb2011-08Feb2011 08Feb2011 U/3 Hours Convulsion R CONFIDENTIAL 392 CONFIDENTIAL 440 #B0746101A Italy RA 10 Months/F INJ U 22Mar2011-22Mar2011 22Mar2011 U/0 Days Convulsion R #B0727831A Spain MD,RA 6 Months/M INJ U 04May2010-04May2010 04May2010 U/0 Days Convulsion R #B0733815A Spain PH,MD,RA 4 Months/F INJ U 05Jul2011-05Jul2011 05Jul2011 U/0 Days Convulsion R #B0696081A Chile MD,RP 4 Months/M INJ U 01Jan2011-01Jan2011 01Jan2011 U/3 Hours Convulsion* R #D0070030A Germany HP,RA 3 Months/M INJ U 19Nov2010-19Nov2010 19Nov2010 U/0 Days Convulsion, Acute respiratory failure U #B0735347A Poland MD,RA 7 Weeks/U INJ U 07Jun2011-07Jun2011 08Jun2011 U/1 Days Convulsion, Apnoea, Hypotonic-hypore sponsive episode, Pallor, Dyspnoea, Musculoskeletal R CONFIDENTIAL 393 CONFIDENTIAL 441 stiffness #B0734875A Italy MD,RA 12 Months/F INJ U 07Jun2011-07Jun2011 07Jun2011 U/0 Days Convulsion, Clonus R #D0071407A Germany MD 4 Years/U INJ, INJ U, U 1 Days, 1 Days U/Unknown, U/Unknown Convulsion, Convulsion U #B0686062A Poland MD,RA 1 Months/U INJ U 09Sep2010-09Sep2010 09Sep2010 U/0 Days Convulsion, Crying R #B0750925A Singapore MD 4 Months/F INJ U 24Aug2011-24Aug2011 01Aug2011 U/0 Days Convulsion, Crying, Somnolence, Staring, Abnormal behaviour, Dyskinesia R #D0071366A Germany HP,RA 12 Months/F INJ U 06May2011-06May2011 07May2011 U/1 Days Convulsion, Depressed level of consciousness, Gaze palsy, Hypochromic anaemia, Pyrexia, U CONFIDENTIAL 394 CONFIDENTIAL 442 Injection site erythema, Musculoskeletal stiffness, Iron deficiency #D0071441A Germany MD,RA 15 Months/M INJ U 28Apr2011-28Apr2011 28Apr2011 U/0 Days Convulsion, Depressed level of consciousness, Staring, Pyrexia, Asthenia, Upper respiratory tract infection, Vaccination complication I #D0070499A Germany RA 18 Months/M INJ .5ML 15Feb2011-15Feb2011, 26Oct2009-26Oct2009, 01Dec2009-01Dec2009, 25Jan2010-25Jan2010 16Feb2011 U/1 Days, U/U, U/U, U/U Convulsion*, Endotracheal intubation*, Status epilepticus*, Pyrexia*, Febrile convulsion* R #D0070292A Germany RA 3 Months/F INJ U 22Oct2010-22Oct2010 25Oct2010 U/3 Days Convulsion, Eye movement disorder, Dyskinesia, Pallor, Somnolence R #D0070470A Germany MD,RA 2 Months/F INJ U 21Feb2011-21Feb2011 01Jan2011 U/0 Years Convulsion, Flushing, Autonomic nervous system imbalance U CONFIDENTIAL 395 CONFIDENTIAL 443 #B0739945A Italy RA 5 Months/M INJ .5MG 21Jul2011-21Jul2011 22Jul2011 U/1 Days Convulsion, Gaze palsy, Clonus, Pyrexia U #D0071548A Germany MD,RA 8 Months/F INJ U 10May2011-10May2011 11May2011 U/1 Days Convulsion*, Gaze palsy*, Cyanosis*, Vaccination complication*, Restlessness*, Feeling hot*, Staring*, Muscle twitching*, Dyspnoea*, Hypotonia*, Somnolence*, General physical health deterioration*, Body temperature increased* U #B0697392A Italy MD,RA 16 Months/M INJ U 17Aug2010-17Aug2010 17Aug2010 U/0 Days Convulsion, Grand mal convulsion, Hypotonia R #B0719212A Australia HP,MD,RA 3 Years/F INJ U 09May2011-09May2011 10May2011 U/16 Hours Convulsion, Hepatotoxicity, Macrocephaly, Renal impairment, Irritability, Restlessness N CONFIDENTIAL 396 CONFIDENTIAL 444 #B0682745A Netherlands HP,RA 6 Months/M INJ U 23Aug2010-23Aug2010 23Aug2010 U/Hours Convulsion, Loss of consciousness, Gaze palsy, Pallor, Pyrexia, Crying N #B0713916A Sweden HP,RA 1 Years/F INJ U 30Aug2010-30Aug2010 30Aug2010 U/0 Days Convulsion, Muscle twitching, Hypotonia, Staring, Body temperature increased R #B0704556A Italy RA 12 Months/M INJ U 09Aug2010-09Aug2010 09Aug2010 U/0 Days Convulsion, Muscular weakness, Pyrexia R #D0071067A Germany MD,RA 6 Months/F INJ, INJ U, U 31Mar2011-31Mar2011, 03Mar2011-03Mar2011 01Apr2011 U/0 Months, U/0 Days Convulsion, Myoclonus U #D0072213A Germany HP,RA 11 Weeks/F INJ U 05Jul2011-05Jul2011 06Jul2011 U/1 Days Convulsion, Myoclonus, Crying, Muscle twitching R #D0073004A Germany MD,RA 16 Months/F INJ .5ML 03May2011-03May2011 05May2011 U/48 Hours Convulsion*, Pallor*, Gaze palsy*, Depressed level of consciousness*, U CONFIDENTIAL 397 CONFIDENTIAL 445 Joint hyperextension* #B0681626A Italy MD,RA 13 Months/M INJ U 05Feb2010-05Feb2010 07Feb2010 U/2 Days Convulsion, Pyrexia R #D0072126A Germany RA 3 Months/M INJ, INJ .5ML, .5ML 25Jun2010-25Jun2010, 19May2010-19May2010 19May2010 U/Unknown, U/0 Days Convulsion*, Pyrexia*, Dyskinesia*, Convulsion*, Crying*, Pyrexia* I #D0070473A Germany HP,RA 4 Months/F INJ U 10Feb2011-10Feb2011 10Feb2011 U/0 Days Convulsion, Pyrexia, Eye movement disorder, Muscle twitching R #D0071376A Germany OM,MD,RA 3 Months/F INJ .5ML 10May2011-10May2011 10May2011 U/0 Days Convulsion, Pyrexia, Myoclonus, Salivary hypersecretion R #D0069319A Germany RA 6 Months/M INJ, INJ, INJ, INJ U, U, U, U 25Oct2010-25Oct2010, 03Aug2009-03Aug2009, 09Sep2009-09Sep2009, 13Oct2009-13Oct2009 01Jan2009 U/0 Days, U/0 Years, U/0 Years, U/0 Years Convulsion, Pyrexia, Pyrexia R CONFIDENTIAL 398 CONFIDENTIAL 446 #D0071014A Germany MD,RA 6 Months/M INJ, INJ U, U 04Apr2011-04Apr2011, 17Jan2011-17Jan2011 01Mar2011 U/0 Days, U/0 Years Convulsion, Pyrexia, Vomiting, Febrile convulsion, Partial seizures, Partial seizures R #B0716693A Italy RA 5 Months/M INJ U 31Mar2011-31Mar2011 31Mar2011 U/0 Days Convulsion, Slow response to stimuli, Cyanosis, Grand mal convulsion, Hypotonia, Pallor, Tremor, Staring, Salivary hypersecretion, Hypertonia, Tachycardia, Oxygen saturation decreased U #D0070906A Germany MD,RA 2 Months/F INJ U 31Mar2011-31Mar2011 01Apr2011 U/1 Days Convulsion, Staring, Pharyngeal erythema, Seborrhoeic dermatitis U #B0689913A Italy MD,RA 12 Months/M INJ U 13Sep2010-13Sep2010 13Sep2010 U/0 Days Convulsion, Stupor, Vomiting R CONFIDENTIAL 399 CONFIDENTIAL 447 #B0685462A France RA 2 Months/F INJ U 21Oct2010-21Oct2010 21Oct2010 U/5 Hours Convulsion, Tonic clonic movements, Tremor, Eye disorder, Pyrexia R #B0731868A Italy MD,RA 8 Months/F INJ U 27Jun2011-27Jun2011 02Jul2011 U/5 Days Convulsion, Viral infection, Pyrexia, Rash maculo-papular R B0701150A France MD 3 Months/U INJ U 01May2010-01May2010 01May2010 U/Same day Crying R B0708609A France MD 10 Weeks/M INJ U 05Jan2011-05Jan2011 05Jan2011 U/Same day Crying R B0718228A France MD 4 Months/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/24 Hours Crying R #B0730602A Italy MD,RA 3 Months/M INJ U 01Jun2011-01Jun2011 01Jun2011 U/0 Days Crying R CONFIDENTIAL 400 CONFIDENTIAL 448 #B0692151A Latvia HP,RA 2 Months/F INJ U 10Nov2010-10Nov2010 10Nov2010 U/Immediate Crying R #B0730049A France RA 2 Months/M INJ U 26May2011-26May2011 28May2011 U/48 Hours Crying, Decreased appetite I B0721457A France MD 2 Months/U INJ U 01Jan2011-01Jan2011 01Jan2011 U/10 Hours Crying, Diarrhoea R B0753926A France MD,RP 3 Months/M INJ U 24Aug2011-24Aug2011, 08Aug2011-08Aug2011 24Aug2011 U/See text, U/U Crying, Inappropriate schedule of drug administration R B0695532A Viet Nam MD 2 Months/M INJ U 12Jan2011-12Jan2011 12Jan2011 U/10 Minutes Crying, Injection site erythema, Erythema R B0727510A Netherlands HP,RA 4 Months/F INJ U 11Oct2010-11Oct2010 11Oct2010 U/0 Days Crying, Injection site pain, Rash, Insomnia, Pruritus R CONFIDENTIAL 401 CONFIDENTIAL 449 B0745247A Czech Republic MD 20 Months/M INJ U 02Sep2011-02Sep2011 02Sep2011 U/2 Days Crying, Muscle spasms, Injection site erythema R #B0725460A Italy MD,RA 3 Months/M INJ .5ML 01Jun2011-01Jun2011 01Jun2011 U/0 Days Crying, Oedema peripheral, Erythema R B0702044A Austria MD 5 Months/M INJ U 1 Days U/2 Hours Crying, Peripheral coldness, Chills, Tremor, Pyrexia, Agitation R B0719498A Netherlands HP,RA 10 Months/F INJ U 28Sep2010-28Sep2010 28Sep2010 U/Hours Crying, Pyrexia, Malaise U #B0736219A France RA 2 Months/M INJ U 05May2011-05May2011 05May2011 U/6 Hours Crying, Pyrexia, Pain in extremity R B0707083A Netherlands MD,RA 5 Months/F INJ U 11Nov2010-11Nov2010 11Nov2010 U/6 Hours Crying, Pyrexia, Pain, Nasopharyngitis, Eczema, Rash, Rash, Rash R CONFIDENTIAL 402 CONFIDENTIAL 450 #B0754599A Czech Republic RA 4 Months/F INJ U 23Sep2011-23Sep2011, 23Aug2011-23Aug2011 23Sep2011 U/0 Days, U/U Crying*, Pyrexia*, Restlessness*, Tachycardia* U #B0741601A Italy MD,RA 5 Months/F INJ U 27Jul2011-27Jul2011 27Jul2011 U/0 Days Crying, Respiratory tract inflammation R #B0681485A Poland MD,RA 3 Months/M INJ U 05Jul2010-05Jul2010 06Jul2010 U/1 Days Crying, Restlessness R #B0689246A Saudia Arabia MD,RP 4 Months/M INJ U 01Nov2010-01Nov2010 01Nov2010 U/0 Days Demyelination, Extrapyramidal disorder, Neurological symptom, Irritability, Crying, Pyrexia, Strabismus I #B0746088A Netherlands HP,RA 2 Months/M INJ U 12Oct2010-12Oct2010 12Oct2010 U/3 Seconds Depressed level of consciousness, Crying, Injection site inflammation, Pallor, Hypotonia, Oligodipsia, Somnolence, Respiratory disorder I CONFIDENTIAL 403 CONFIDENTIAL 451 #B0707035A Netherlands HP,MD,RA 3 Months/F INJ U 10Sep2010-10Sep2010 U/Unknown Depressed level of consciousness, Crying, Pyrexia, Injection site inflammation, Injection site pain, Insomnia, Nasopharyngitis R D0069325A Germany OM,MD 3 Months/M INJ U 04Oct2010-04Oct2010 04Oct2010 U/8 Hours Depressed level of consciousness, Hypotonic-hypore sponsive episode, Pallor, Fatigue, Eye movement disorder R #B0727317A Netherlands MD,RA 2 Months/M INJ U 29Apr2011-29Apr2011 01May2011 U/2 Days Depressed level of consciousness, Hypotonic-hypore sponsive episode, Pallor, Ill-defined disorder, Feeling abnormal, Pyrexia U #B0719423A Netherlands HP,RA 9 Months/M INJ U 17Sep2010-17Sep2010 17Sep2010 U/0 Days Depressed level of consciousness, Inflammation, Pain, Injected limb mobility decreased, Pyrexia, Crying R #B0712989A Netherlands HP,RA 3 Months/M INJ, INJ, INJ U, U, U 16Mar2011-16Mar2011, 01Apr2011-01Apr2011, 11May2011-11May2011 16Mar2011 U/2 Minutes, U/0 Months, U/0 Days Depressed level of consciousness, Pallor, Crying, Somnolence, Malaise, Malaise R CONFIDENTIAL 404 CONFIDENTIAL 452 #B0755401A Netherlands HP,RA 2 Months/M INJ U 08Apr2010-08Apr2010 09Apr2010 U/1 Days Depressed level of consciousness, Pyrexia, Inflammation, Pain, Vomiting, Somnolence, Diarrhoea, Staring R #B0732346A Netherlands HP,RA 2 Months/F INJ U 10May2011-10May2011 10May2011 U/4 Hours Depressed level of consciousness, Pyrexia, Somnolence U #B0712012A Netherlands HP,RA 2 Months/F INJ U 22Jul2010-22Jul2010 22Jul2010 U/Hours Depressed level of consciousness, Skin warm, Staring, Hypotonia, Respiration abnormal, Crying, Pyrexia, Injection site pain R #B0756437A Netherlands HP,RA 2 Months/M INJ .5ML 11Oct2011-11Oct2011 11Oct2011 U/5 Minutes Depressed level of consciousness, Staring, Pallor R #D0071549A Germany MD,RA 4 Months/M INJ U 07Apr2011-07Apr2011 07Apr2011 U/0 Days Encephalitis, Bronchitis, Lactic acidosis, Hyperglycaemia, Convulsion, Injection site induration, Pyrexia, N CONFIDENTIAL 405 CONFIDENTIAL 453 Somnolence, Hypotonia, Depressed level of consciousness, Respiration abnormal, Cough, Pallor, Lip haematoma, General physical health deterioration, Moaning, Respiratory tract infection, Restlessness, Rhinitis, Body temperature fluctuation #B0686208A Italy MD,RP 3 Months/U INJ U 08Nov2010-08Nov2010 U/0 Months Encephalitis, Epilepsy U #D0071841A Germany MD,RA,RP 4 Months/F INJ U 09Feb2011-U 10Feb2011 U/0 Days Encephalopathy, Infantile spasms, Lennox-Gastaut syndrome, Dyskinesia, Developmental delay, Eye movement disorder, Motor dysfunction, Posture abnormal, Fatigue, N CONFIDENTIAL 406 CONFIDENTIAL 454 Hyperhidrosis, Crying, Pallor, Diarrhoea, Musculoskeletal stiffness, Depressed level of consciousness, Headache, Hypotonia, Myoclonus, Constipation, Infantile spasms, Abdominal pain #R0014765A Spain C 4 Months/M INJ U 22Nov2010-22Nov2010 29Nov2010 U/7 Days Epilepsy* I #B0686639A Italy MD,RA 3 Months/F INJ U 08Nov2010-08Nov2010 18Nov2010 U/10 Days Epilepsy, Cerebral ischaemia, Partial seizures U #B0737600A Latvia HP,RA 3 Months/M INJ .5ML 14Dec2010-14Dec2010 26Dec2010 U/12 Days Epilepsy, Convulsion U #B0720048A Czech Republic MD,RA 6 Months/F INJ U 29Mar2011-29Mar2011 30Mar2011 U/1 Days Epilepsy, Infantile spasms, Tearfulness, Dyskinesia N CONFIDENTIAL 407 CONFIDENTIAL 455 #B0700168A Italy MD,RA 5 Months/M INJ U 04Nov2010-04Nov2010 04Nov2010 U/0 Days Epilepsy, Petit mal epilepsy, Staring, Clonus, Clonus, Dyskinesia, Pyrexia U #D0070004A Germany RA 4 Months/M INJ .5ML 28Jun2010-28Jun2010 01Jan2010 U/0 Years Facial paresis* R #D0070963A Germany MD,RP 22 Months/M INJ U 06Apr2011-06Apr2011 01Apr2011 U/0 Weeks Febrile convulsion R #D0072063A Germany MD,RP 15 Months/F INJ U 12Jul2011-12Jul2011 01Jul2011 U/8 Hours Febrile convulsion R #B0683431A Italy MD,RA 2 Months/F INJ U 21Oct2010-21Oct2010 22Oct2010 U/1 Days Febrile convulsion R #B0690567A Italy MD,RA 14 Months/M INJ U 06Dec2010-06Dec2010 06Dec2010 U/0 Days Febrile convulsion R CONFIDENTIAL 408 CONFIDENTIAL 456 #B0710862A Italy RA 2 Months/F INJ U 13Sep2010-13Sep2010 13Sep2010 U/0 Days Febrile convulsion R #B0722025A Italy RA 8 Months/M INJ U 21Sep2010-21Sep2010 22Sep2010 U/1 Days Febrile convulsion R #B0735096A Italy MD,RA 10 Months/M INJ U 19Jul2011-19Jul2011 19Jul2011 U/0 Days Febrile convulsion R #B0751261A Italy MD,RA 16 Months/M INJ U 19Sep2011-19Sep2011 20Sep2011 U/1 Days Febrile convulsion R #B0709252A Netherlands HP,RA 12 Months/F INJ U 20Jan2011-20Jan2011 20Jan2011 U/Hours Febrile convulsion R #B0744547A Philippines MD 0-9 Years/U INJ U 01Jan2011-01Jan2011 U/1 Days Febrile convulsion R CONFIDENTIAL 409 CONFIDENTIAL 457 #D0072283A Germany RA 20 Months/M INJ .5ML 08Jun2011-08Jun2011 01Jan2011 U/0 Years Febrile convulsion* R #B0747746A Poland MD,RA 4 Months/F INJ U 11Aug2011-11Aug2011 11Aug2011 U/5 Hours Febrile convulsion, Cyanosis, Lividity, Pyrexia R #B0716294A Italy MD,RA 13 Months/M INJ U 16Feb2011-16Feb2011 16Feb2011 U/0 Days Febrile convulsion, Cyanosis, Loss of consciousness, Clonus, Salivary hypersecretion, Hypertonia R #D0070029A Germany RA 14 Months/M INJ .5ML 06Oct2010-06Oct2010 06Oct2010 U/0 Days Febrile convulsion, Dyskinesia R #B0693711A Italy MD,RA 12 Months/F INJ U 02Feb2010-02Feb2010 03Feb2010 U/1 Days Febrile convulsion*, Febrile convulsion* CONFIDENTIAL 410 CONFIDENTIAL 458 #D0072871A Germany MD,RA 4 Months/M INJ U 21Sep2011-21Sep2011 21Sep2011 U/7 Hours Febrile convulsion, Hypotonia, Pallor, Staring, Muscle twitching R #B0741648A Italy MD,RA 5 Months/F INJ .5ML 12Aug2011-12Aug2011 12Aug2011 U/0 Days Febrile convulsion, Irritability I #B0692681A Netherlands HP,RA 18 Months/M INJ U 11Nov2010-11Nov2010 11Nov2010 U/4 Hours Febrile convulsion, Loss of consciousness, Pallor, Tremor, Hypotonia, Peripheral coldness, Respiratory disorder, Cyanosis, Chills, Postictal state, Pyrexia R #B0728516A Italy MD,RA 12 Months/M INJ U 26May2011-26May2011 27May2011 U/1 Days Febrile convulsion, Loss of consciousness, Tremor, Complex partial seizures, Grand mal convulsion, Pyrexia R CONFIDENTIAL 411 CONFIDENTIAL 459 #B0740272A France PH 17 Months/M INJ U 17Jun2011-17Jun2011 28Jun2011 U/11 Days Febrile convulsion, Lung infection, Hypertonia, Clonic convulsion, Pharyngeal erythema, Otitis media, Lymphadenopath y, Lung disorder, Pyrexia R #D0072315A Germany RA 4 Months/F INJ .5ML 24May2011-24May2011 25May2011 U/1 Days Febrile convulsion*, Muscle rigidity*, Opisthotonus*, Gaze palsy*, Pyrexia* R #B0696414A France MD 16 Months/U INJ U 26Jan2011-26Jan2011 26Jan2011 U/Same day Febrile convulsion, Pyrexia R #D0070007A Germany RA 8 Months/F INJ U 04Nov2010-04Nov2010 04Nov2010 U/0 Days Febrile convulsion, Pyrexia R #B0692011A Italy MD,RA 1 Years/F INJ U 07Jan2010-07Jan2010 07Jan2010 U/0 Days Febrile convulsion, Pyrexia R CONFIDENTIAL 412 CONFIDENTIAL 460 #B0741635A Italy RA 11 Months/F INJ U 25Jul2011-25Jul2011 25Jul2011 U/0 Days Febrile convulsion, Pyrexia R #B0743123A Italy RA 11 Months/F INJ U 22Jul2011-22Jul2011 22Jul2011 U/0 Days Febrile convulsion, Pyrexia R #D0072318A Germany RA 15 Months/F INJ .5ML 26Jul2011-26Jul2011, 24Jun2010-24Jun2010, 23Jul2010-23Jul2010, 20Aug2010-20Aug2010 26Jul2011 U/0 Days, U/U, U/U, U/U Febrile convulsion*, Pyrexia*, Chills*, Gaze palsy*, Eye movement disorder*, Cyanosis*, Unresponsive to stimuli*, Tremor*, Grand mal convulsion*, Upper respiratory tract infection* R #B0730181A France RA 2 Months/M INJ U 15Mar2011-15Mar2011 15Mar2011 U/8 Hours Febrile convulsion, Pyrexia, Eye disorder, Hypertonia R #D0069309A Germany MD,RA 4 Months/M INJ U 22Sep2010-22Sep2010 22Sep2010 U/0 Days Febrile convulsion, Pyrexia, Musculoskeletal stiffness, Gaze palsy, U CONFIDENTIAL 413 CONFIDENTIAL 461 Somnolence, Transaminases increased, Pharyngeal erythema, Tympanic membrane hyperaemia #B0733980A Italy PH,RA 27 Months/M INJ U 30Jun2011-30Jun2011 30Jun2011 U/0 Days Febrile convulsion, Pyrexia, Tonsillar hypertrophy, Hyperaemia R #D0072920A Germany HP,RA 15 Months/M INJ, INJ, INJ, INJ U, U, U, U 20Sep2011-20Sep2011, 30Jul2010-30Jul2010, 30Aug2010-30Aug2010, 30Sep2010-30Sep2010 01Jan2010 U/6 Hours, U/Unknown, U/Unknown, U/Unknown Febrile convulsion, Rash, Pyrexia, Pyrexia N #D0071016A Germany OM,MD 22 Months/M INJ U 06Apr2011-06Apr2011 06Apr2011 U/1 Hours Febrile convulsion, Vomiting, Unresponsive to stimuli, Staring, Muscle twitching R #B0683700A Italy MD,RA 5 Months/M INJ U 04Oct2010-04Oct2010 04Oct2010 U/0 Days Fontanelle bulging, Pyrexia, Hyperaemia R CONFIDENTIAL 414 CONFIDENTIAL 462 #B0691640A Spain RA 6 Years/F INJ U 18Aug2010-18Aug2010 18Aug2010 U/0 Days Grand mal convulsion* R #B0733550A Austria MD,RA 4 Months/F INJ .5ML 20Jun2011-20Jun2011 20Jun2011 U/0 Days Grand mal convulsion, Agitation, Crying, Decreased appetite R #B0689285A Slovakia MD,RA 3 Months/M INJ U 09Nov2010-09Nov2010 09Nov2010 U/Minutes Grand mal convulsion, Altered state of consciousness, Apnoea R #D0070812A Germany MD,RA 12 Months/F INJ U 14Mar2011-14Mar2011 11Feb2011 U/2 Days Grand mal convulsion, Convulsion, Hypersensitivity, Rash macular, Crying, Eye movement disorder, Dyskinesia, Salivary hypersecretion R #B0706275A Italy MD,RA 4 Months/M INJ U 24Feb2011-24Feb2011 24Feb2011 U/0 Days Grand mal convulsion, Loss of consciousness, Staring, Hypertonia, Erythema, Gastrooesophage al reflux disease, R CONFIDENTIAL 415 CONFIDENTIAL 463 Regurgitation #D0071096A Germany HP,OM 5 Months/M INJ U 02Dec2008-02Dec2008 02Dec2008 U/0 Days Grand mal convulsion, Muscle twitching, Somnolence, Pyrexia, Somnolence R #B0711246A Italy MD,RP 2 Months/F INJ U 10Mar2011-10Mar2011 10Mar2011 U/0 Days Grand mal convulsion, Myoclonus, Staring, Pyrexia N #B0733530A Italy MD,RA 5 Months/F INJ U 06Jul2011-06Jul2011 06Jul2011 U/0 Days Grand mal convulsion, Pyrexia I #B0749797A Italy MD,RA 5 Months/M INJ U 30Aug2011-30Aug2011 30Aug2011 U/0 Days Grand mal convulsion, Pyrexia R #B0702457A Italy MD,RA 12 Months/M INJ U 01Feb2011-01Feb2011 01Feb2011 U/0 Days Grand mal convulsion, Respiratory tract infection R CONFIDENTIAL 416 CONFIDENTIAL 464 #D0069554A Germany MD,RA 2 Months/F INJ, INJ, INJ U, U, U 22Aug2006-U, 26Sep2006-U, 24Oct2006-U 01Jan2006 U/Unknown, U/Unknown, U/Unknown Guillain-Barre syndrome, Congenital neuropathy, Demyelinating polyneuropathy, Hip deformity, Foot deformity, Motor developmental delay U #B0691863A Italy RA 15 Months/M INJ U 08Sep2010-08Sep2010 10Sep2010 U/2 Days Guillain-Barre syndrome*, Neuropathy peripheral*, Pyrexia*, General physical health deterioration*, Restlessness*, Asthma*, Decreased appetite*, Gait disturbance*, Dysstasia*, Nuchal rigidity*, General physical health deterioration*, Hyperaemia*, Dysphonia*, Hyporeflexia*, Hypotonia*, Asthenia* R CONFIDENTIAL 417 CONFIDENTIAL 465 #B0749283A Italy MD,RA 7 Months/M INJ U 25Jan2011-25Jan2011 25Jan2011 U/0 Days Hypertonia, Eye disorder, Pyrexia R #B0715581A France RA 2 Months/F INJ U 30Nov2010-30Nov2010 30Nov2010 U/Hours Hypertonia, Loss of consciousness, Cyanosis, Clonus, Eye disorder, Apathy, Convulsion R B0706811A Colombia MD Child/F INJ, INJ U, U 1 Days, 1 Days U/Unknown, U/Unknown Hypotonia I B0744733A Netherlands MD,RA 2 Months/F INJ U 22Jul2011-22Jul2011 22Jul2011 U/9 Hours Hypotonia R #B0686828A France RA 17 Months/M INJ U 29Oct2010-29Oct2010 29Oct2010 U/Immediate Hypotonia, Cerebellar ataxia, Gait disturbance, Pain, Hyperthermia, C-reactive protein increased R CONFIDENTIAL 418 CONFIDENTIAL 466 #B0712016A Italy MD,RA 11 Months/M INJ U 25Mar2011-25Mar2011 26Mar2011 U/1 Days Hypotonia, Hyperhidrosis, Pyrexia F #B0747819A France RA 7 Weeks/F INJ U 23May2011-23May2011 24May2011 U/0 Days Hypotonia, Hypersomnia, Feeding disorder neonatal, Drug administration error R #B0705448A Italy MD,RA 5 Months/F INJ U 25Jan2010-25Jan2010, 05Nov2010-05Nov2010 26Jan2010 U/1 Days, U/U Hypotonia, Hypokinesia, Musculoskeletal stiffness R B0693444A Netherlands HP,RA 3 Months/F INJ U 28Jun2010-28Jun2010 28Jun2010 U/1 Hours Hypotonia, Inflammation, Pyrexia, Crying R #B0703590A Italy MD,RA,RP 3 Months/M INJ U 08Feb2011-08Feb2011 08Feb2011 U/0 Days Hypotonia, Pyrexia R #B0716297A France RA 2 Months/M INJ U 1 Days U/1 Days Hypotonia, Slow response to stimuli, Pallor, Incorrect route of drug administration R CONFIDENTIAL 419 CONFIDENTIAL 467 #D0071308A Germany MD 5 Months/M INJ U 05May2011-05May2011 05May2011 U/0 Days Hypotonic-hypore sponsive episode R #D0071532A Germany RA 4 Months/F INJ U 1 Days 09Nov2010 U/U Hypotonic-hypore sponsive episode R B0707733A Netherlands MD,RA 2 Months/M INJ U 25Jan2011-25Jan2011 25Jan2011 U/10 Hours Hypotonic-hypore sponsive episode R #B0685055A Poland MD,RA 4 Months/U INJ U 29Oct2010-29Oct2010 29Oct2010 U/0 Days Hypotonic-hypore sponsive episode R #B0687935A Poland P 2 Months/M INJ U 04Nov2010-04Nov2010 06Nov2010 U/2 Days Hypotonic-hypore sponsive episode R #B0713426A Poland MD,RA 2 Months/U INJ U 1 Days 12Mar2011 U/Unknown Hypotonic-hypore sponsive episode U CONFIDENTIAL 420 CONFIDENTIAL 468 #B0725461A Spain MD,RA 4 Months/F INJ U 20Apr2011-20Apr2011 20Apr2011 U/0 Days Hypotonic-hypore sponsive episode R #R0014955A Czech Republic C 3 Months/M INJ U 08Dec2010-08Dec2010 08Dec2010 U/7 Hours Hypotonic-hypore sponsive episode* R #B0686455A Poland MD,RA 2 Months/U INJ U 04Nov2010-04Nov2010 07Nov2010 U/3 Days Hypotonic-hypore sponsive episode, Abdominal pain, Vaccination complication, Restlessness, Crying, Somnolence U #B0714363A Netherlands HP,RA 2 Months/M INJ U 01Mar2011-01Mar2011 01Mar2011 U/8 Hours Hypotonic-hypore sponsive episode, Anaemia, Hypotonia, Pallor, Dyspnoea, Bradycardia, Hypopnoea, Staring R #D0070026A Germany RA 9 Weeks/F INJ .5ML 22Dec2010-22Dec2010 22Dec2010 U/0 Days Hypotonic-hypore sponsive episode*, Apathy* R CONFIDENTIAL 421 CONFIDENTIAL 469 #D0071099A Germany MD,RA 11 Weeks/F INJ U 06Apr2011-06Apr2011 06Apr2011 U/0 Days Hypotonic-hypore sponsive episode, Body temperature increased, Crying, Asthenia, Pallor, Depressed level of consciousness, Pallor, Pharyngeal erythema R #D0071446A Germany OM,MD,RA 8 Weeks/M INJ U 15Apr2011-15Apr2011 15Apr2011 U/6 Hours Hypotonic-hypore sponsive episode, Circulatory collapse, Apathy, Pallor R #B0732350B Netherlands CO,RA 6 Months/M INJ U 17Aug2011-17Aug2011 17Aug2011 U/3 Hours Hypotonic-hypore sponsive episode, Crying, Pallor, Hypotonia, Somnolence, Unresponsive to stimuli R #B0693275A Poland MD,RA 4 Months/U INJ U 20Apr2010-20Apr2010 20Apr2010 U/0 Days Hypotonic-hypore sponsive episode, Cyanosis R #B0706016A Poland MD,RA 2 Months/F INJ U 27Jan2011-27Jan2011 27Jan2011 U/3 Hours Hypotonic-hypore sponsive episode, Cyanosis, Somnolence, Crying, Restlessness, Pyrexia, Hypotonia, R CONFIDENTIAL 422 CONFIDENTIAL 470 Anxiety, Lividity #B0709632A Poland MD,RA 4 Months/U INJ U 20Jan2011-20Jan2011 21Jan2011 U/1 Days Hypotonic-hypore sponsive episode, Decreased activity, Hypotonia, Decreased appetite R #D0072088A Germany MD,RA 8 Weeks/F INJ U 15Jun2011-15Jun2011 15Jun2011 U/7 Hours Hypotonic-hypore sponsive episode, Dyspnoea, Vomiting, Hypotonia, Apathy, Vaccination complication R #D0071728A Germany RA 3 Months/F INJ .5ML 30Mar2011-30Mar2011, 18May2011-18May2011 18May2011 U/0 Days, U/U Hypotonic-hypore sponsive episode*, Eye movement disorder*, Convulsion*, Gaze palsy*, Opisthotonus*, Crying* R #B0690071A Czech Republic MD,RA 3 Months/M INJ U 08Dec2010-08Dec2010 08Dec2010 U/8 Hours Hypotonic-hypore sponsive episode, Gaze palsy, Opisthotonus, Pallor, Apathy, Fear, Agitation, Hypotonia, Crying U CONFIDENTIAL 423 CONFIDENTIAL 471 #B0742512A Switzerland RA 2 Months/M INJ .5ML 28Jun2011-28Jun2011 28Jun2011 U/Immediate Hypotonic-hypore sponsive episode, Hypersensitivity, Pallor, Eye movement disorder, Dyspnoea, Crying, Hypotonia, Eye disorder R #B0724391A Spain HP,RA 2 Months/F INJ U 23May2011-23May2011 23May2011 U/Immediate Hypotonic-hypore sponsive episode, Hypotonia R #B0701374A Switzerland MD,RA,RP 2 Months/M INJ, INJ U, U 11Feb2011-11Feb2011, 29Apr2011-29Apr2011 11Feb2011 U/0 Days, U/3 Hours Hypotonic-hypore sponsive episode, Loss of consciousness, Depressed level of consciousness, Unresponsive to stimuli, Cyanosis, Cough, Ill-defined disorder, Fatigue, Adverse event, Vomiting, Eyelid disorder, Crying, Somnolence, Crying R #B0741462A Poland MD,RA 3 Months/U INJ U 29Jun2011-29Jun2011 29Jun2011 U/Immediate Hypotonic-hypore sponsive episode, Loss of consciousness, Somnolence, Pallor, Hypotonia, R CONFIDENTIAL 424 CONFIDENTIAL 472 Crying #B0722375A Poland MD,RA 22 Months/U INJ U 27Apr2011-27Apr2011 27Apr2011 U/Hours Hypotonic-hypore sponsive episode, Pain in extremity, Gait disturbance, Body temperature increased, Somnolence R #B0727152A Italy MD,RA 2 Months/M INJ U 03Jun2011-03Jun2011 03Jun2011 U/6 Hours Hypotonic-hypore sponsive episode, Pallor R #B0712205A Switzerland MD,RA 70 Days/M INJ .5ML 20Dec2010-20Dec2010 20Dec2010 U/5 Hours Hypotonic-hypore sponsive episode, Pallor R #B0686517A Greece MD,RA 4 Months/F INJ U 15Sep2010-15Sep2010 15Sep2010 U/5 Hours Hypotonic-hypore sponsive episode*, Pallor* R CONFIDENTIAL 425 CONFIDENTIAL 473 #B0727181A Sweden HP,RA 3 Months/F INJ U 02May2011-02May2011 02May2011 U/0 Days Hypotonic-hypore sponsive episode, Pallor, Ill-defined disorder, Nasopharyngitis R #B0727465A Poland MD,RA 1 Months/U INJ U 24May2011-24May2011 24May2011 U/0 Days Hypotonic-hypore sponsive episode, Pallor, Lividity, Cyanosis R #D0070873A Germany RA 2 Months/F INJ U 25Jan2011-25Jan2011 25Jan2011 U/0 Days Hypotonic-hypore sponsive episode, Pallor, Somnolence R D0070860A Germany MD 2 Months/M INJ, INJ U, U 01Mar2011-01Mar2011, 01Feb2011-01Feb2011 01Feb2011 U/0 Days, U/6 Hours Hypotonic-hypore sponsive episode, Pyrexia R #B0741329A Poland MD,RA 2 Months/U INJ U 20Jul2011-20Jul2011 20Jul2011 U/0 Days Hypotonic-hypore sponsive episode, Pyrexia R #B0720694A Poland MD,RA 19 Months/U INJ U 01Mar2011-01Mar2011 01Mar2011 U/0 Days Hypotonic-hypore sponsive episode, Pyrexia, Crying, Somnolence R CONFIDENTIAL 426 CONFIDENTIAL 474 #D0070819A Germany MD 4 Months/F INJ U 10Mar2011-10Mar2011 10Mar2011 U/0 Days Hypotonic-hypore sponsive episode, Pyrexia, Vomiting, Loss of consciousness, Restlessness, Hyperhidrosis, Abnormal faeces, Hypotonia, Eye movement disorder, Fatigue, Abdominal distension, Abnormal faeces, Pharyngeal erythema R #B0710929A Netherlands HP,RA 2 Months/F INJ U 11Mar2011-11Mar2011 11Mar2011 U/Minutes Hypotonic-hypore sponsive episode, Respiratory arrest, Crying R #B0686677A Poland MD,RA 4 Months/M INJ U 06Oct2010-06Oct2010 06Oct2010 U/0 Days Hypotonic-hypore sponsive episode*, Screaming*, Apathy*, Unresponsive to stimuli*, Sleep disorder*, Muscle tightness*, Abdominal pain*, Decreased activity*, Hypertonia*, Ill-defined disorder*, R CONFIDENTIAL 427 CONFIDENTIAL 475 Hypotonia*, Developmental delay*, Muscle spasms*, Restlessness*, Crying* #B0734272A Poland MD,RA 1 Months/F INJ U 25May2011-25May2011 28May2011 U/0 Days Hypotonic-hypore sponsive episode, Somnolence, Hypotonia, Body temperature decreased R #B0702562A France MD,RA 10 Weeks/M INJ U 23Feb2011-23Feb2011 24Feb2011 U/18 Hours Hypotonic-hypore sponsive episode, Somnolence, Pallor, Incorrect route of drug administration, Neurological examination abnormal R #D0069604A Germany MD 6 Months/F INJ .5ML 23Nov2010-23Nov2010 23Nov2010 U/Immediate Hypotonic-hypore sponsive episode*, Syncope*, Skin discolouration*, Pallor*, Crying*, Unresponsive to stimuli*, Cardiovascular disorder* R #B0700353A Spain CO,MD 2 Months/F INJ U 10Feb2011-10Feb2011 10Feb2011 U/Hours Hypotonic-hypore sponsive episode, Unresponsive to stimuli, Respiration abnormal, R CONFIDENTIAL 428 CONFIDENTIAL 476 Hypotonia, Pyrexia, Hypotonia #B0733152A Italy MD,RA 2 Months/F INJ U 27Jun2011-27Jun2011 28Jun2011 U/1 Days Hypotonic-hypore sponsive episode, Vomiting, Diarrhoea, Decreased appetite I #B0684471A Italy MD 7 Months/F INJ U 02Dec2003-02Dec2003, 29Sep2003-29Sep2003 01Feb2004 U/2 Months, U/U Infantile spasms N #D0069378A Germany HP,RA 5 Months/F INJ, INJ U, U 14Jun2010-14Jun2010, 19May2010-19May2010 29Jul2010 U/45 Days, U/71 Days Infantile spasms, Cerebral disorder N #D0070024A Germany HP 4 Months/F INJ, INJ U, U 08May2009-08May2009, 05Jun2009-05Jun2009, 17Jul2009-17Jul2009 05Jun2009 U/0 Days, U/7 Days, U/Unknown Infantile spasms, Developmental delay, Posture abnormal, Restlessness, Crying, Hypotonia, Microcephaly, Infantile spasms, Cerebral atrophy, Bone marrow failure, Vomiting, Dehydration, U CONFIDENTIAL 429 CONFIDENTIAL 477 Hypokalaemia, Pancytopenia #B0695552A Italy MD,RA 2 Months/M INJ .5ML 13Jan2011-13Jan2011 13Jan2011 U/Hours Infantile spasms, Slow response to stimuli, Hypertonia, Staring, Tremor, Clonus, Muscle spasms, Joint hyperextension, Adenovirus test positive, Pyrexia, Crying U #D0071516A Germany MD,RA 3 Months/F INJ .5ML 20Oct2010-20Oct2010 20Oct2010 U/30 Minutes Loss of consciousness R #B0717794A Netherlands HP,MD,RA 2 Months/F INJ U 21Sep2010-21Sep2010 01Sep2010 U/36 Hours Loss of consciousness, Apnoea, Depressed level of consciousness, Gaze palsy, Pallor, Cyanosis, Hypotonia, Peripheral coldness, Pyrexia R CONFIDENTIAL 430 CONFIDENTIAL 478 #B0732350A Netherlands MD,RA 3 Months/M INJ .5ML 09Jun2011-09Jun2011 09Jun2011 U/4 Hours Loss of consciousness, Apnoea, Hypotonic-hypore sponsive episode, Pallor, Hypotonia R #B0722809A Czech Republic MD,RA 3 Months/F INJ U 29Nov2010-29Nov2010 29Nov2010 U/0 Days Loss of consciousness, Convulsion, Cyanosis, Somnolence, Body temperature increased, Crying R #B0712712A Netherlands HP,RA 13 Months/M INJ U 10Aug2010-10Aug2010 10Aug2010 U/Hours Loss of consciousness, Depressed level of consciousness, Convulsion, Gaze palsy, Respiration abnormal, Pallor, Hypotonia, Drooling, Cyanosis, Pyrexia, Vomiting R #B0687865A Italy MD,RA 11 Months/M INJ U 11Jun2010-11Jun2010 13Jun2010 U/2 Days Loss of consciousness, Gaze palsy, Pallor, Hypotonia R #B0757269A France MD,RP 2 Months/U INJ U 01Oct2011-01Oct2011 01Oct2011 U/10 Minutes Loss of consciousness, Hypotonia, Somnolence R CONFIDENTIAL 431 CONFIDENTIAL 479 #B0716724A Poland MD,RA 2 Months/F INJ U 15Mar2011-15Mar2011 15Mar2011 U/0 Days Loss of consciousness, Hypotonic-hypore sponsive episode, Hypotonia, Diarrhoea R #B0744808A Italy MD,RA 5 Months/M INJ U 27Jan2011-27Jan2011 15Feb2011 U/19 Days Loss of consciousness, Nystagmus, Opisthotonus, Eye movement disorder, Pyrexia, Vomiting R #B0695521A Netherlands HP,RA 2 Months/M INJ U 23Jun2010-23Jun2010 01Jun2010 U/8 Hours Loss of consciousness, Pallor, Hypotonia, Feeling cold, Somnolence R #B0709247A Netherlands HP,RA 6 Months/M INJ U 13Mar2009-13Mar2009 13Mar2009 U/1 Hours Loss of consciousness, Pallor, Hypotonia, Hypotonic-hypore sponsive episode, Vomiting R #B0709210A Italy MD,RA 2 Months/M INJ U 31Jan2011-31Jan2011 31Jan2011 U/8 Hours Loss of consciousness, Pallor, Pyrexia R CONFIDENTIAL 432 CONFIDENTIAL 480 #B0702744A Italy MD,RA 2 Months/M INJ U 16Nov2009-16Nov2009 17Nov2009 U/1 Days Loss of consciousness, Pyrexia R #B0724363A Italy MD,RA 4 Months/M INJ U 12Nov2010-12Nov2010 12Nov2010 U/0 Days Loss of consciousness, Pyrexia, Pallor, Arrhythmia R #B0712309A Ireland MD,RA 9 Months/F INJ U 18Jan2011-18Jan2011 25Jan2011 U/7 Days Myelitis transverse, Muscular weakness, Mobility decreased, Hypotonia N B0732338A Mexico MD,RP Infant/U INJ U 08Apr2011-08Apr2011 09Apr2011 U/1 Days Myoclonus I D0069372A Germany MD,RA 5 Months/F INJ U 07Oct2010-07Oct2010 08Oct2010 U/1 Days Neuropathy peripheral, Infection N CONFIDENTIAL 433 CONFIDENTIAL 481 #D0073031A Germany HP U/U INJ U 13Nov2003-13Nov2003 U/Unknown Paresis U #B0713436A Italy MD,RA 5 Months/F INJ U 30Mar2011-30Mar2011 31Mar2011 U/1 Days Petit mal epilepsy, Blepharospasm, Dyskinesia R #D0070286A Germany CO,PH,MD, RP 1 Years/F INJ U 02Sep2010-02Sep2010 08Sep2010 U/6 Days Petit mal epilepsy, Staring, Dyskinesia U #B0705098A France MD 2 Months/F INJ U 22Dec2010-22Dec2010 22Dec2010 U/Immediate Presyncope, Bradycardia, Hypotonia, Injection site pain, Loss of consciousness, Cyanosis R #B0750040A Netherlands MD,RA 2 Months/F INJ U 11Jul2011-11Jul2011 11Jul2011 U/7 Hours Presyncope, Febrile convulsion, Depressed level of consciousness, Hypertonia, Myoclonus, Pallor, Pyrexia, Musculoskeletal stiffness R CONFIDENTIAL 434 CONFIDENTIAL 482 #B0683333A Netherlands HP,RA 3 Months/M INJ U 23Sep2010-23Sep2010, 26Aug2010-26Aug2010 01Sep2010 U/Hours, U/U Presyncope, Loss of consciousness, Depressed level of consciousness, Staring, Hypotonia, Pallor, Crying, Pyrexia, Pain, Mental impairment, Vomiting, Muscle contractions involuntary, Myoclonus, Abdominal abscess, Irritability, Hypotonic-hypore sponsive episode R #B0756838A Netherlands HP,MD,RA 2 Months/M INJ .5ML 03Oct2011-03Oct2011 03Oct2011 U/2 Minutes Presyncope, Pallor, Hyperhidrosis, Feeling cold, Heart rate increased R #B0733860A Italy RA 5 Months/F INJ U 25May2011-25May2011 25May2011 U/0 Days Presyncope, Syncope, Pallor, Hypotonia, Vomiting R #B0691520A United Arab Emirates MD 2 Months/F INJ U 10Oct2010-10Oct2010 10Oct2010 U/0 Days Seizure like phenomena R CONFIDENTIAL 435 CONFIDENTIAL 483 #B0690039A Greece CO,MD 8 Months/F INJ U 17Nov2010-17Nov2010 18Nov2010 U/1 Days Seizure like phenomena, Oedema peripheral, Immobile I #B0738735A Italy RA 3 Months/M INJ U 01Aug2011-01Aug2011 02Aug2011 U/1 Days Slow response to stimuli, Hypotonia R #B0693450A Italy RA 5 Months/M INJ U 16Mar2010-16Mar2010 16Mar2010 U/0 Days Slow response to stimuli, Hypotonia, Pyrexia R #B0709033A Italy MD,RA 2 Months/M INJ U 14Mar2011-14Mar2011 14Mar2011 U/10 Minutes Slow response to stimuli, Hypotonia, Rash macular, Petechiae, Ecchymosis, Conjunctival haemorrhage, Rash, Joint hyperextension R #B0696267A Italy RA 2 Months/M INJ U 24Jan2011-24Jan2011 24Jan2011 U/0 Days Slow response to stimuli, Pallor I CONFIDENTIAL 436 CONFIDENTIAL 484 #D0072337B Germany MD 7 Months/M INJ U 04Aug2011-04Aug2011 01Aug2011 U/8 Hours Slow response to stimuli, Pallor, Vomiting R #D0072337A Germany MD 5 Months/M INJ U 28Jun2011-28Jun2011 01Jan2011 U/8 Hours Slow response to stimuli, Pallor, Vomiting, Rash R #B0747384A Italy MD,RA 2 Months/M INJ U 01Jul2011-01Jul2011 01Jul2011 U/0 Days Slow response to stimuli, Pyrexia, Decreased appetite, Crying, Hypotonia, Opisthotonus R #B0720136A Italy RA 3 Months/F INJ U 14Jan2011-14Jan2011 14Jan2011 U/0 Days Slow response to stimuli, Tremor, Respiratory disorder, Pyrexia R #B0712001A Poland CO,MD 7 Weeks/F INJ U 30Mar2011-30Mar2011 31Mar2011 U/1 Days Somnolence, Injection site reaction R #B0710868A Netherlands HP,RA 11 Months/F INJ U 12Feb2010-12Feb2010 12Feb2010 U/0 Days Status epilepticus, Loss of consciousness, Apnoea, Convulsion, Vomiting, Skin R CONFIDENTIAL 437 CONFIDENTIAL 485 warm, Staring, Hypotonia, Nerve stimulation test abnormal, Crying, Erythema, Upper respiratory tract infection, Pyrexia, Hypertonia, Postictal state, Malaise, Listless #B0687818A Italy MD,RA 11 Months/F INJ U 02Dec2010-02Dec2010, 23Mar2010-23Mar2010, 25May2010-25May2010 02Dec2010 U/0 Days, U/U, U/U Syncope R #D0072433A Germany RA 6 Months/F INJ .5ML 09Aug2011-09Aug2011, 30Apr2011-30Apr2011, 28May2011-28May2011 09Aug2011 U/0 Days, U/U, U/U Syncope*, Cyanosis*, Restlessness*, Pallor*, Vomiting*, Hypotonia*, Unresponsive to stimuli* R #B0692220A Italy MD,RA 11 Months/M INJ, INJ, INJ U, U, U 20Dec2010-20Dec2010, 01Jan2010-01Jan2010, 01Jan2010-01Jan2010 U/Unknown, U/Unknown, U/1 Days Syncope, Loss of consciousness, Febrile convulsion, Eye movement disorder, Opisthotonus, Pallor, Pyrexia, Pyrexia, Pyrexia R CONFIDENTIAL 438 CONFIDENTIAL 486 #B0716232A Italy MD,RA 3 Months/M INJ U 14Feb2011-14Feb2011 14Feb2011 U/0 Days Syncope, Loss of consciousness, Pallor R #D0071075A Germany MD,RA 3 Months/M INJ U 24Mar2011-24Mar2011 25Mar2011 U/1 Days Thalamus haemorrhage, Convulsion, Facial paresis, Hemiparesis, Hypophagia, Restlessness, Pyrexia, Screaming, Somnolence, Pallor, Hyperaesthesia, Eyelid oedema, Abdominal distension, Hypotonia, Gaze palsy, Apnoea U #B0711562A Italy RA 14 Months/M INJ U 21Mar2011-21Mar2011 21Mar2011 U/0 Days Tongue paralysis, Clonus I #B0702721A France MD,RP 7 Weeks/M INJ U 26Feb2011-26Feb2011 27Feb2011 U/0 Days Tonic convulsion, Apnoeic attack, Pyrexia, Hypertonia, Pallor, Hypotonia, Staring, Opisthotonus, R CONFIDENTIAL 439 CONFIDENTIAL 487 Drug administration error #B0737089A Poland MD,RA 18 Months/F INJ U 21Jun2011-21Jun2011 22Jun2011 U/1 Days Tremor, Gait disturbance, Oropharyngeal pain, Injection site reaction, Tonsillar disorder, White blood cells urine positive, Bacterial test positive, Anxiety, Upper respiratory tract congestion, Crying, Restlessness R #B0684621A Italy MD,RA 4 Months/M INJ U 10Nov2010-10Nov2010 10Nov2010 U/0 Days Tremor, Pallor, Pyrexia I #B0735253A Italy RA 2 Months/M INJ U 27Jun2011-27Jun2011 27Jun2011 U/0 Days Unresponsive to stimuli, Hypotonia, Pallor, Pyrexia R CONFIDENTIAL 440 CONFIDENTIAL 488 #B0721081A Poland MD,RA 2 Months/U INJ U 30Mar2011-30Mar2011 01Apr2011 U/2 Days Unresponsive to stimuli, Loss of consciousness, Hypotonic-hypore sponsive episode, Apathy, Restlessness, Somnolence, Crying R #B0699467A Italy RA 3 Months/M INJ U 04Jan2011-04Jan2011 05Jan2011 U/1 Days Unresponsive to stimuli, Muscle contractions involuntary, Eye movement disorder, Pyrexia, Restlessness, Crying R #B0699755A Ireland MD,RA 2 Months/M INJ U 04Jan2011-04Jan2011 04Jan2011 U/0 Days Unresponsive to stimuli, Syncope, Pallor R #D0071922A Germany MD,RP 4 Months/M INJ .5ML 22Mar2011-22Mar2011, 18Jan2011-18Jan2011, 22Feb2011-22Feb2011 22Mar2011 U/0 Days, U/U, U/U VIIth nerve paralysis*, Facial paresis* N #B0728966A France MD,RP 23 Months/M INJ U 19May2011-19May2011 20May2011 U/1 Days VIIth nerve paralysis, Pain in extremity, Mobility decreased, Oedema peripheral, Erythema, Pyrexia, Facial U CONFIDENTIAL 441 CONFIDENTIAL 489 asymmetry #B0681066A Belgium HP 15 Months/M INJ U 13Sep2010-13Sep2010 05Oct2010 U/22 Days VIth nerve paralysis, Strabismus N Psychiatric disorders #B0713438A Ukraine MD 9 Months/F INJ .5ML 25Mar2011-25Mar2011 26Mar2011 U/1 Days Agitation, Hyperthermia, Crying R #B0756774A Ukraine MD 3 Months/F INJ .5ML 04Oct2011-04Oct2011 04Oct2011 U/0 Days Agitation, Hyperthermia, Crying, Asthenia R #B0740599A Poland RA 3 Months/F INJ, INJ U, U 01Jan2011-01Jan2011, 19Jul2011-19Jul2011 U/0 Days, U/0 Days Anxiety, Crying, Apathy, Body temperature increased, Anxiety U CONFIDENTIAL 442 CONFIDENTIAL 490 D0070801A Germany MD,RP 3 Months/M INJ U 01Jan2011-01Jan2011 01Jan2011 U/0 Days Apathy, Pallor U #B0719542A Poland RA 1 Months/M INJ U 24Feb2011-24Feb2011 24Feb2011 U/0 Days Decreased activity, Hypotonia, Somnolence U #B0720709A Poland MD,RA 23 Months/F INJ U 12Apr2011-12Apr2011 12Apr2011 U/6 Hours Insomnia, Gait disturbance, Hypotonic-hypore sponsive episode U B0712015A Netherlands HP,RA 11 Months/M INJ U 19May2010-19May2010 01May2010 U/Days Insomnia, Rash, Malaise, Crying R #B0708195A Austria MD,RA Infant/F INJ U 1 Days U/Unknown Insomnia, Restlessness, Circadian rhythm sleep disorder R B0695605A Netherlands MD,RA 3 Months/F INJ, INJ, INJ, INJ U, U, U, U 14Apr2010-14Apr2010, 19May2010-19May2010, 05Jan2011-05Jan2011, 16Jun2010-16Jun2010 01Jan2010 U/0 Months, U/0 Months, U/Unknown, U/10 Hours Listless, Rash, Listless, Rash, Listless, Rash, Rash morbilliform, Pyrexia, Pyrexia, Pyrexia, Pyrexia R CONFIDENTIAL 443 CONFIDENTIAL 491 D0069283A Germany MD,RP 4 Months/M INJ U 21Sep2010-21Sep2010 21Sep2010 U/0 Days Personality change, Restlessness, Sleep disorder R #D0072565A Germany MD,RA 3 Months/M INJ U 19Aug2011-19Aug2011 19Aug2011 U/0 Days Phonological disorder, Respiration abnormal, Screaming, Sleep disorder, Pyrexia, Fatigue, Crying, Middle insomnia N #B0750036A Poland MD,RA 7 Months/U INJ U 06Sep2011-06Sep2011 06Sep2011 U/2 Hours Restlessness, Body temperature increased, Crying, Asthenia R D0069714A Germany PH 2 Months/M INJ, INJ U, U 28Sep2010-28Sep2010, 09Nov2010-09Nov2010 29Sep2010 U/1 Days, U/0 Days Restlessness, Middle insomnia, Middle insomnia, Restlessness, Crying, Pyrexia, Sleep disorder U D0070495A Germany HP,RA 3 Months/M INJ U 27Oct2010-27Oct2010 29Oct2010 U/2 Days Restlessness, Muscle spasms, Insomnia, Crying N CONFIDENTIAL 444 CONFIDENTIAL 492 #D0070862A Germany MD,RP 2 Months/F INJ U 24Mar2011-24Mar2011 24Mar2011 U/0 Days Restlessness, Pallor, Hypophagia, Food aversion, Nasopharyngitis, Flatulence, Flatulence, Viral infection, Abnormal faeces, Screaming, Abnormal behaviour, Body temperature increased U D0072455A Germany MD 6 Months/M INJ U 15Jul2011-15Jul2011 15Jul2011 U/0 Days Restlessness, Pyrexia, Insomnia, Decreased appetite, Muscle spasms, Crying, Agitation, Fatigue, Rash, Vaccination complication, Herpes virus infection, Exanthema subitum N D0069449A Germany MD U/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/Unknown Screaming U CONFIDENTIAL 445 CONFIDENTIAL 493 #B0693315A Poland MD,RA 2 Months/M INJ U 27Dec2010-27Dec2010 27Dec2010 U/1 Hours Screaming, Crying R #B0684919A Latvia HP,RA 4 Months/M INJ U 17Aug2010-17Aug2010 17Aug2010 U/15 Minutes Screaming, Crying, Oedema peripheral, Rash, Crying, Screaming, Rash, Oedema peripheral R D0069663A Germany MD,RA 2 Months/F INJ U 05Nov2010-05Nov2010 05Nov2010 U/0 Minutes Screaming, Food aversion, Agitation, Crying R Respiratory, thoracic and mediastinal disorders #D0071220A Germany MD,RA 12 Weeks/M INJ U 18Apr2011-18Apr2011 18Apr2011 U/0 Days Apnoea, Bradycardia N #B0691130A France RA 2 Months/M INJ U 15Dec2010-15Dec2010 15Dec2010 U/5 Hours Apnoea, Bradycardia, Oxygen saturation decreased, Blood pressure decreased, Apparent life threatening event, Urine output R CONFIDENTIAL 446 CONFIDENTIAL 494 decreased, Cholinergic syndrome, Eye movement disorder, Gastrooesophage al reflux disease, Aspiration #A0901400A Canada PH 67 Days/F INJ .5ML 13Dec2010-13Dec2010 14Dec2010 U/Hours Apnoea, Bradycardia, Oxygen saturation decreased, Wrong technique in drug usage process I #B0754941A Belgium CO,MD 2 Months/F INJ U 03Oct2011-03Oct2011 03Oct2011 U/Minutes Apnoea, Bradycardia, Pallor, Foaming at mouth R #B0706228A Italy MD,RA 5 Months/M INJ U 27Jan2011-27Jan2011 27Jan2011 U/0 Days Apnoea, Cyanosis, Hypertonia, Pyrexia R #D0071156A Germany RA 8 Weeks/M INJ U 07Mar2011-07Mar2011 07Mar2011 U/6 Hours Apnoea, Cyanosis, Oxygen saturation decreased R CONFIDENTIAL 447 CONFIDENTIAL 495 #B0699372A Sweden HP,RA 5 Months/F INJ U 13Sep2010-13Sep2010 13Sep2010 U/0 Days Apnoea, Febrile convulsion, Mastication disorder, Skin discolouration R #B0690024A Netherlands HP,RA 2 Months/M INJ U 01Jun2010-01Jun2010 01Jun2010 U/1 Minutes Apnoea, Hypotonia, Pallor, Staring, Crying R #B0755056A France RA 2 Months/F INJ U 18May2011-18May2011 18May2011 U/Same day Apnoea, Hypoxia, Bradycardia, Malaise, Inflammation, Respiratory disorder R #B0691167A Italy RA 3 Months/M INJ U 09Jun2010-09Jun2010 09Jun2010 U/0 Days Apnoea*, Loss of consciousness*, Erythema*, Hypertonia* R #B0731112A Brazil CO,MD 2 Months/M INJ U 26Oct2010-26Oct2010 26Oct2010 U/0 Days Apnoea, Skin discolouration, Pallor, Rash macular, Erythema, Fatigue, Pyrexia, Vomiting, Cough, Crying*, Erythema, Petechiae, Hyperhidrosis, Hypersensitivity, Hypotonic-hypore U CONFIDENTIAL 448 CONFIDENTIAL 496 sponsive episode, General physical health deterioration, Pallor #D0071181A Germany RA 4 Months/M INJ U 25Feb2011-25Feb2011 25Feb2011 U/6 Hours Apnoeic attack, Cyanosis, Upper respiratory tract infection, Body temperature increased R #B0707044A Netherlands HP,RA 2 Months/M INJ U 28Feb2011-28Feb2011 01Mar2011 U/8 Hours Apparent life threatening event I #D0071421A Germany MD,RA 4 Months/M INJ U 29Mar2011-29Mar2011 02Apr2011 U/4 Days Apparent life threatening event, Altered state of consciousness, Hypothyroidism, Neutropenia, Staring, Hypotonia, Pallor, Respiratory arrest, Crying N #D0071146A Germany OM,MD 12 Weeks/F INJ .5ML 13Apr2011-13Apr2011 13Apr2011 U/2 Hours Apparent life threatening event, Pallor, Loss of consciousness, Erythema, Respiratory arrest, Somnolence R CONFIDENTIAL 449 CONFIDENTIAL 497 D0070592A Germany HP,RA 4 Months/M INJ U 20Jan2011-20Jan2011 25Jan2011 U/5 Days Bronchitis chronic, Bronchitis, Eye movement disorder, Pyrexia, Rash, Restlessness N B0707093A Netherlands MD,RA 11 Months/F INJ U 16Nov2010-16Nov2010 U/Unknown Cough, Inflammation, Pain, Crying, Pyrexia, Vomiting R #D0072854A Germany HP,RA 7 Years/F INJ, INJ, INJ, INJ U, U, U, U 12Nov2004-12Nov2004, 10Dec2004-10Dec2004, 25Jan2005-25Jan2005, 03Mar2006-03Mar2006 01Sep2011 U/7 Years, U/7 Years, U/6 Years, U/5 Years Cough, Vaccination failure U #B0682864A France RA 2 Years/F INJ U 12Oct2010-12Oct2010 12Oct2010 U/Same day Dyspnoea, Pallor, Erythema, Pruritus R #B0749418A Italy MD,RA 3 Months/F INJ U 01Sep2011-01Sep2011 01Sep2011 U/0 Days Dyspnoea, Pallor, Pyrexia, Hypotonia R CONFIDENTIAL 450 CONFIDENTIAL 498 #B0731155A Italy OT,MD,RA 2 Months/F INJ U 17May2011-17May2011 17May2011 U/0 Days Dyspnoea, Unresponsive to stimuli, Apnoeic attack, Irritability, Decreased appetite, Pallor U #D0071143A Germany MD,RA 6 Months/F INJ, INJ, INJ U, U, U 02Mar2011-02Mar2011, 08Jun2010-08Jun2010, 13Apr2010-13Apr2010, 19Jul2010-19Jul2010 08Jun2010 U/0 Days, U/0 Weeks, U/1 Days, U/U Febrile convulsion*, Gaze palsy*, Altered state of consciousness*, Convulsion*, Pyrexia*, Dyspnoea*, Infection*, Erythema*, Swelling*, Hypokinesia*, Pain*, Apnoea*, Cyanosis*, Body temperature increased, Breath holding*, Moaning* U #B0748225A Czech Republic MD,RA 6 Months/F INJ U 01Aug2010-01Aug2010, 01Jun2010-01Jun2010, 01Jul2010-01Jul2010 01Sep2010 U/1 Months, U/U, U/U Increased upper airway secretion, Sputum purulent, Cough R #D0072026A Germany MD,RA 4 Months/M INJ, INJ U, U 03Mar2011-03Mar2011, 05Apr2011-05Apr2011 05Mar2011 U/3 Days, U/2 Days Obstructive airways disorder, Obstructive airways disorder N CONFIDENTIAL 451 CONFIDENTIAL 499 B0719361A Netherlands HP,RA 2 Months/M INJ U 13Sep2010-13Sep2010 13Sep2010 U/90 Minutes Respiration abnormal, Eczema, Pain, Pyrexia, Crying R B0717816A Netherlands MD,RA 4 Months/U INJ U 23Aug2010-23Aug2010 23Aug2010 U/13 Hours Respiration abnormal, Oligodipsia, Skin discolouration, Chills, Somnolence, Pyrexia, Injection site pain R #B0741007A Netherlands MD,RA 10 Months/F INJ .5ML 09Aug2011-09Aug2011 09Aug2011 U/Immediate Respiratory arrest, Depressed level of consciousness, Breath holding, Crying, Eye movement disorder, Skin discolouration, Pallor N #D0070339A Germany RA 3 Months/M INJ .5ML 05Nov2010-05Nov2010 05Nov2010 U/1 Minutes Respiratory depression* R #B0707349A Italy MD,RA 14 Months/F INJ, INJ, INJ U, U, U 11Jan2011-11Jan2011, 09May2010-09May2010, 09Feb2010-09Feb2010 U/7 Days, U/7 Days, U/48 Hours Respiratory failure, Cyanosis, Bronchospasm, Bronchospasm, Respiratory disorder, Respiratory U CONFIDENTIAL 452 CONFIDENTIAL 500 disorder B0709886A South Africa HP 21 Months/M INJ U 23Mar2011-23Mar2011 23Mar2011 U/Hours Rhinorrhoea, Pyrexia, Irritability N #B0756155A Italy MD,RA 3 Months/M INJ U 05Oct2011-05Oct2011 05Oct2011 U/0 Days Sleep apnoea syndrome, Loss of consciousness, Cyanosis, Neutropenia, Salivary hypersecretion, Hyperpyrexia R #B0741792A Netherlands MD,RA 2 Months/F INJ U 04Jul2011-04Jul2011 04Jul2011 U/10 Hours Stridor, Febrile convulsion, Cyanosis, Myoclonus, Pyrexia, Dysphagia, Choking U Skin and subcutaneous tissue disorders #B0743733A Argentina OT,MD 7 Months/M INJ U 20Aug2011-20Aug2011 21Aug2011 U/1 Days Acute haemorrhagic oedema of infancy, Malaise, Tachycardia, Purpura, Pyrexia, Rash, Toxic skin eruption I CONFIDENTIAL 453 CONFIDENTIAL 501 #B0741876A Italy RA 11 Months/F INJ U 17Aug2011-17Aug2011 17Aug2011 U/0 Days Angioedema I #B0691862A Italy RA 5 Months/F INJ .5ML 17Dec2010-17Dec2010 17Dec2010 U/0 Days Angioedema* R #B0749275A Italy RA 5 Months/F INJ U 18Aug2011-18Aug2011, 20Jun2011-20Jun2011 18Aug2011 U/0 Days, U/U Angioedema, Hyperaemia, Pyrexia R #B0730009A Italy RA 13 Months/F INJ U 04May2011-04May2011 04May2011 U/0 Days Angioedema, Urticaria U #D0069340A Germany MD 11 Months/M INJ U 21Jul2010-21Jul2010 22Jul2010 U/24 Hours Blister, Injection site erythema, Skin lesion, Skin exfoliation R #D0070018A Germany RA 9 Weeks/M INJ U 02Nov2010-02Nov2010 02Nov2010 U/2 Hours Dermatitis allergic R CONFIDENTIAL 454 CONFIDENTIAL 502 B0727148A Czech Republic MD 4 Months/M INJ U 22Sep2010-22Sep2010 25Sep2010 U/3 Days Dermatitis atopic N B0730499A Switzerland MD 4 Months/F INJ .5ML 11Apr2011-11Apr2011, 11Feb2011-11Feb2011 12Apr2011 U/1 Days, U/U Dermatitis atopic, Erythema, Dry skin I D0069826A Germany MD,RP U/U INJ, INJ, INJ U, U, U 1 Days, 1 Days, 1 Days U/Unknown, U/Unknown, U/Unknown Eczema, Eczema, Eczema U B0711288A Netherlands HP,RA 2 Months/F INJ U 03Jun2010-03Jun2010 03Jun2010 U/0 Days Eczema, Eczema, Inflammation, Crying R B0690459A Netherlands HP,RA 3 Months/M INJ U 10May2010-10May2010 U/Hours Eczema, Milk allergy, Rash, Impetigo, Pyrexia R D0071785A Germany HP,RA 3 Months/M INJ U 08Apr2011-08Apr2011 16Apr2011 U/8 Days Eczema, Personality change, Immobile N CONFIDENTIAL 455 CONFIDENTIAL 503 B0728834A Netherlands CO,HP,RA 12 Months/M INJ U 11Jan2011-11Jan2011 11Jan2011 U/0 Days Eczema, Pruritus, Pyrexia, Restlessness N D0069510A Germany PH 2 Months/F INJ U 05Nov2010-05Nov2010 06Nov2010 U/1 Days Erythema I #B0703950A Italy MD,RA 3 Months/F INJ U 15Feb2011-15Feb2011 15Feb2011 U/15 Minutes Erythema I B0708066A France MD 2 Months/F INJ U 11Feb2011-11Feb2011 11Feb2011 U/1 Hours Erythema, Crying, Cyanosis, Hyperaesthesia R #B0705317A France PH,MD 16 Months/F INJ U 03Mar2011-03Mar2011 04Mar2011 U/12 Hours Erythema, Hyperthermia, Injection site erythema, Injection site oedema, Injection site induration, Injection site pain R CONFIDENTIAL 456 CONFIDENTIAL 504 D0070503A Germany MD 3 Months/M INJ U 13Dec2010-13Dec2010 13Dec2010 U/0 Days Erythema*, Injection site cyst* R #D0069303A Germany MD 9 Months/U INJ U 01Jan2010-01Jan2010 U/1 Days Erythema multiforme U #D0072847A Germany MD 2 Months/M INJ, INJ, INJ U, U, U 15Jul2011-15Jul2011, 12Aug2011-12Aug2011, 20Sep2011-20Sep2011 01Jan2011 U/28 Days, U/0 Days, U/0 Days Erythema multiforme, Urticaria, Arthropod bite, Swelling, Erythema, Pyrexia, Hypertonia, Herpes simplex, General physical health deterioration, Urticaria, Urticaria, Pyrexia, Rash R #D0071461A Germany HP,RA 19 Months/F INJ U 21Apr2011-21Apr2011 22Apr2011 U/1 Days Erythema, Myosclerosis R CONFIDENTIAL 457 CONFIDENTIAL 505 #B0715209A Netherlands HP,RA 13 Months/F INJ .5ML 08Feb2011-08Feb2011 13Feb2011 U/5 Days Erythema nodosum, Arthralgia, Petechiae R B0734938A France MD 2 Months/U INJ U 01Jun2011-01Jun2011 01Jun2011 U/Immediate Erythema, Oedema peripheral, Pain in extremity, Crying, Skin discolouration, Product quality issue N D0071643A Germany MD 3 Months/M INJ U 06Jun2011-06Jun2011 06Jun2011 U/0 Days Erythema, Oedema peripheral, Skin warm, Crying, Restlessness R B0687425A France MD,RP Infant/U INJ U 1 Days U/Unknown Erythema, Rash macular, Rash U B0727462A France MD 2 Months/U INJ U 01Jun2011-01Jun2011 01Jun2011 U/Seconds Erythema, Skin warm, Oedema peripheral, Malaise R CONFIDENTIAL 458 CONFIDENTIAL 506 D0070840A Germany HP,RA 6 Months/F INJ U 20Dec2010-20Dec2010 20Dec2010 U/0 Days Erythema, Swelling, Body temperature increased, Rash pustular, Swelling face R D0073090A Germany MD 3 Years/M U U U U/U Erythema, Swelling, Feeling hot U D0070150A Germany HP,RA 28 Months/M INJ .5ML 11Jan2011-11Jan2011 12Jan2011 U/1 Days Erythema*, Swelling*, Feeling hot*, Pain* N #B0734041A France RA 2 Months/F INJ U 26Apr2011-26Apr2011 26Apr2011 U/12 Hours Erythrosis, Pallor, Cyanosis, Hypotonia, Eye disorder, Crying R B0715665A France CO,MD 2 Months/F INJ U 07Feb2011-07Feb2011 01Jan2011 U/Same day Generalised erythema, Hypersensitivity, Skin erosion, Eczema, Skin depigmentation, Pruritus S CONFIDENTIAL 459 CONFIDENTIAL 507 #D0070216A Germany MD,RP 9 Months/M INJ U 01Apr2010-01Apr2010 01Apr2010 U/28 Days Henoch-Schonlei n purpura, Thrombocytopeni a, Petechiae, Pyrexia, Upper respiratory tract infection, Anaemia R B0726309A Poland MD,RA 2 Months/U INJ U 07Jan2011-07Jan2011 07Feb2011 U/31 Days Keloid scar, Lividity I #D0072895A Germany MD U/F INJ U 1 Days U/Unknown Lipoatrophy U #B0728714A Poland MD,RA 6 Months/M INJ U 11May2011-11May2011 11May2011 U/3 Hours Lividity, Ecchymosis, Anxiety, Petechiae, Erythema, Crying, Body temperature increased, Hypersensitivity, Restlessness R #D0070291A Germany HP,MD,RA 11 Weeks/F INJ U 23Nov2010-23Nov2010 10Dec2010 U/17 Days Neurodermatitis S CONFIDENTIAL 460 CONFIDENTIAL 508 D0071186A Germany HP,RA 2 Months/F INJ U 25Feb2011-25Feb2011 28Feb2011 U/3 Days Neurodermatitis, Staphylococcal infection N #B0729166A Spain LI 3 Months/F INJ U U U/3 Weeks Pemphigoid, Leukocytosis, Thrombocytosis, Blister, Scab, Skin lesion, Pruritus, Eosinophilia, Urticaria R M. Valdivioelso-Ramos et al, Infantile bullous pemphigoid developing after hexavalent, meningococcal and pneumococcal vaccinations, anales de pediatria, Elsevier, 2011. D0072699A Germany MD,RA 5 Months/F INJ U 1 Days 21Mar2011 U/Unknown Petechiae, Oedema peripheral R #B0705315A France PH,MD 18 Months/F INJ U 03Mar2011-03Mar2011 01Mar2011 U/12 Hours Purpura, Pyrexia, Injection site erythema, Injection site oedema, Injection site induration, Rash macular R B0682750A Argentina MD 2 Months/M INJ U 1 Days U/Unknown Rash U CONFIDENTIAL 461 CONFIDENTIAL 509 B0682883A Argentina MD Child/M INJ U 1 Days U/Unknown Rash U #B0748229A Czech Republic MD,RA 12 Months/F INJ U 01Dec2010-01Dec2010 01Dec2010 U/0 Months Rash N #B0714550A Ireland HP,RA 2 Months/M INJ U 06Apr2011-06Apr2011 06Apr2011 U/15 Minutes Rash R #D0071682A Germany MD,RA 15 Months/F INJ U 24May2011-24May2011 26May2011 U/2 Days Rash generalised, Pyrexia N B0731182A Sweden HP 5 Months/F INJ U 20Jun2011-20Jun2011 01Jun2011 U/Days Rash generalised, Pyrexia, Pain U B0711011A France MD 2 Months/M INJ U 01Mar2011-01Mar2011 01Mar2011 U/Same day Rash maculo-papular, Pyrexia, Hypersensitivity R CONFIDENTIAL 462 CONFIDENTIAL 510 #B0686640A Italy MD,RA 2 Months/M INJ U 03Nov2010-03Nov2010 03Nov2010 U/0 Days Rash papular, Pyrexia R #D0070018B Germany RA 4 Months/M INJ U 12Jan2011-12Jan2011 12Jan2011 U/8 Hours Rash, Pyrexia R #B0743128A France RA 14 Months/M INJ U 27Jun2011-27Jun2011 27Jun2011 U/0 Days Rash, Pyrexia, Eyelid oedema, Eosinophilia, Rash morbilliform, Cheilitis, Blister, Fatigue, Pain, Diarrhoea, Vomiting R B0690425A France MD 2 Months/U INJ U 01Jan2010-01Jan2010 01Jan2010 U/12 Hours Rash, Pyrexia, Hypersensitivity R D0071081A Germany MD 3 Months/F INJ U 15Apr2011-15Apr2011 15Apr2011 U/3 Minutes Rash, Skin warm, Restlessness R CONFIDENTIAL 463 CONFIDENTIAL 511 B0690447A Netherlands HP,RA 3 Months/F INJ U 27May2010-27May2010 U/0 Weeks Skin depigmentation, Macule R B0717275A Netherlands HP,RA 11 Months/M INJ U 14Feb2011-14Feb2011 15Feb2011 U/Hours Skin discolouration, Erythema, Oedema peripheral, Crying R B0733567A Netherlands MD,RA 4 Months/F INJ .5ML 17May2011-17May2011 17May2011 U/4 Hours Skin discolouration, Pallor, Pyrexia, Erythema R B0727162A Netherlands CO,MD,RA 2 Months/F INJ, INJ U, U 26May2011-26May2011, 30Jun2011-30Jun2011 26May2011 U/6 Hours, U/Immediate Skin discolouration, Screaming, Oedema peripheral, Skin tightness, Oedema genital, Petechiae, Pyrexia, Crying, Injection site pain, Screaming, Skin discolouration, Crying, Oedema peripheral, Petechiae R CONFIDENTIAL 464 CONFIDENTIAL 512 D0072634A Germany MD,RA 2 Months/F INJ U 15Aug2011-15Aug2011 01Aug2011 U/0 Weeks Skin disorder, Fatigue, Screaming, Pain, Feeling hot, Swelling, Erythema, Injection site induration, Nasopharyngitis, Immune system disorder, Skin reaction U B0707675A France MD,RP 18 Months/M INJ U 14Mar2011-14Mar2011 14Mar2011 U/12 Hours Skin lesion, Injection site induration R #B0732862A Belgium MD,RP 2 Months/F INJ U 27Jun2011-27Jun2011 27Jun2011 U/3 Minutes Skin warm, Urticaria papular, Erythema, Urticaria R #B0700364A Australia HP 18 Months/F INJ U 08Feb2011-08Feb2011 10Feb2011 U/2 Days Stevens-Johnson syndrome, Eye swelling, Erythema, Conjunctivitis, Lethargy, Eating disorder, Rash, Tachypnoea, Skin exfoliation, Ill-defined disorder, Blister, Increased upper airway secretion, N CONFIDENTIAL 465 CONFIDENTIAL 513 Measles, Mucosal inflammation, Irritability B0745076A France MD 4 Months/M INJ, INJ U, U 04Jan2011-04Jan2011, 09Nov2010-09Nov2010 01Jan2011 U/3 Weeks, U/2 Months Subcutaneous nodule, Injection site pruritus, Injection site eczema, Injection site induration, Injection site nodule I B0682576A France MD 10 Weeks/F INJ U 27Oct2010-27Oct2010 28Oct2010 U/1 Days Swelling face, Local swelling, Hypersensitivity R #B0757243A France RA 2 Months/F INJ U 23Aug2011-23Aug2011 23Aug2011 U/0 Days Urticaria U #D0070154A Germany MD,RA U/M INJ U 1 Days 15Oct2010 U/Unknown Urticaria U CONFIDENTIAL 466 CONFIDENTIAL 514 #D0070854A Germany PH,MD 3 Months/M INJ U 12Jan2011-12Jan2011 01Jan2011 U/8 Hours Urticaria R #D0071462A Germany HP,RA 10 Months/F INJ U 09May2011-09May2011 11May2011 U/2 Days Urticaria R D0069610A Germany MD 1 Years/F INJ U 28Oct2010-28Oct2010 U/0 Years Urticaria, Granuloma, Injection site swelling, Injection site erythema, Injection site induration, Pyrexia N B0726556A Poland MD,RA 2 Months/M INJ U 04Apr2011-04Apr2011 05Apr2011 U/1 Days Urticaria, Rash R #B0737088A France MD 2 Months/M INJ U 04Jul2011-04Jul2011 05Jul2011 U/24 Hours Urticaria, Rash macular, Hypersensitivity R CONFIDENTIAL 467 CONFIDENTIAL 515 #D0071406A Germany MD,RA,RP 6 Months/M INJ .5ML 28Apr2011-28Apr2011, 15Feb2011-15Feb2011, 15Mar2011-15Mar2011 28Apr2011 U/1 Hours, U/U, U/U Urticaria, Rash, Rash erythematous, Blister, Restlessness, Cough, Skin reaction R #D0072586A Germany MD U/M INJ U 16Jul2010-16Jul2010 19Aug2010 U/34 Days Urticaria thermal N #B0731863A Ireland HP,RA 6 Months/M INJ U 08Dec2010-08Dec2010 09Dec2010 U/1 Days Urticaria, Tonsillitis R #B0712007A Netherlands RA 3 Months/M INJ U 02Sep2010-02Sep2010 02Sep2010 U/5 Hours Yellow skin, Crying, Malaise R Surgical and medical procedures B0680977A France MD 6 Weeks/M INJ U 27Sep2010-27Sep2010 27Sep2010 U/See text Off label use X CONFIDENTIAL 468 CONFIDENTIAL 516 B0680979A France MD 1 Months/F INJ U 17Sep2010-17Sep2010 U/See text Off label use X B0680980A France MD 5 Weeks/U INJ U 1 Days U/See text Off label use X B0682278A France MD 1 Months/U INJ U 1 Days U/See text Off label use X B0698936A France MD 3 Years/U INJ U 01Nov2010-01Nov2010 01Nov2010 U/See text Off label use X D0070180A Germany MD 17 Years/M INJ U 01Feb2011-01Feb2011 01Feb2011 U/0 Days Off label use X D0072603A Germany MD 5 Years/F INJ U 06Sep2011-06Sep2011 06Sep2011 U/During Off label use X CONFIDENTIAL 469 CONFIDENTIAL 517 D0070247A Germany MD 3 Years/F INJ, INJ U, U 01Nov2008-01Nov2008, 01Jul2010-01Jul2010 01Nov2008 U/During, U/During Off label use, Off label use X Vascular disorders #D0069460A Germany OM,MD,RP 3 Months/M INJ U 14Oct2010-14Oct2010 14Oct2010 U/Minutes Circulatory collapse, Apathy*, Pallor*, Asthenia*, Heart rate decreased*, Screaming*, Staring* R #D0069341A Germany MD 3 Months/M INJ U 05Nov2010-05Nov2010 05Nov2010 U/0 Hours Circulatory collapse, Apnoea, Loss of consciousness, Pallor, Bradycardia, Salivary hypersecretion, Cyanosis, Epilepsy, Partial seizures, Foaming at mouth, Hypotonia, Cardiac arrest, Vomiting, Dyskinesia, Eye movement disorder, Productive cough, Depressed level of consciousness, Hypokinesia, R CONFIDENTIAL 470 CONFIDENTIAL 518 Epilepsy, Bronchitis #B0713106A Netherlands MD,RA 12 Months/M INJ U 04Nov2010-04Nov2010 04Nov2010 U/22 Hours Circulatory collapse, Cyanosis, Pallor R #D0070901A Germany MD,RA 12 Weeks/M INJ U 22Mar2011-22Mar2011 22Mar2011 U/7 Hours Circulatory collapse, Respiratory arrest, Cyanosis, Hypotonic-hypore sponsive episode, Screaming, Agitation, Hypotonia, Peripheral coldness, Ill-defined disorder, Fatigue, Pyrexia R #D0072852A Germany HP,MD,RA, RP 5 Months/M INJ U 20Sep2011-20Sep2011 20Sep2011 U/1 Days Circulatory collapse, Sepsis, Shock, Crying, Pallor F CONFIDENTIAL 471 CONFIDENTIAL 519 D0071906A Germany MD 3 Months/M INJ .5ML 29Jun2011-29Jun2011 29Jun2011 U/5 Minutes Flushing* R #D0071144A Germany HP,RA 5 Months/F INJ U 06Apr2011-06Apr2011 07Apr2011 U/0 Days Haematoma, Injection site erythema, Vaccination complication R #D0071621A Germany MD,RA 12 Months/M INJ, INJ U, U 06May2011-06May2011, 02Nov2010-02Nov2010 09May2011 U/3 Days, U/Unknown Kawasaki’s disease*, Meningitis*, Leukocytosis*, Pericarditis*, Mitral valve incompetence*, Pyrexia*, Fluid intake reduced*, General physical health deterioration*, Rash maculo-papular*, Fungal skin infection*, Cheilitis*, Chapped lips*, Palmar erythema*, Lymphadenopath y*, Infection*, Pyrexia* N CONFIDENTIAL 472 CONFIDENTIAL 520 #D0070921A Germany MD,RA 2 Months/F INJ U 28Feb2011-28Feb2011 28Feb2011 U/0 Days Kawasaki’s disease*, Pyelonephritis*, Pyrexia*, Infection*, Somnolence*, Fluid intake reduced*, General physical health deterioration*, Pallor*, Ill-defined disorder*, Rash*, Conjunctivitis*, Erythema*, Enanthema*, Chapped lips*, Hypertrophy of tongue papillae* R #B0691861A Italy RA 2 Months/M INJ U 11Nov2010-11Nov2010 13Nov2010 U/2 Days Kawasaki’s disease*, Rash maculo-papular*, Diarrhoea*, Pyrexia*, Cheilitis*, Skin exfoliation*, Oedema peripheral*, Erythema* U #B0706959A Austria RA 4 Months/M INJ U 25Jan2011-25Jan2011 25Jan2011 U/3 Minutes Pallor, Hyperhidrosis, Screaming, Rash, Crying, Rash erythematous R CONFIDENTIAL 473 CONFIDENTIAL 521 B0689223A France MD 10 Weeks/U INJ U 01Dec2010-01Dec2010 01Dec2010 U/Immediate Pallor, Somnolence, Injection site erythema, Injection site oedema, Injection site inflammation U #D0072908A Germany RA 3 Months/M INJ U 22Sep2011-22Sep2011 22Sep2011 U/2 Hours Shock, Pallor, Vomiting, Hypophagia I #B0706503A Thailand MD 2 Months/F INJ .5ML 09Mar2011-09Mar2011 10Mar2011 U/1 Days Shock, Respiratory arrest, Cardiac arrest, Pyrexia, Somnolence, Hypotonia, Vomiting, Crying, Apnoea F B0703972A France PH 11 Weeks/M INJ U 17Feb2011-17Feb2011 26Feb2011 U/8 Days Vasodilatation, Petechiae, Erythema, Skin warm R CONFIDENTIAL 474 CONFIDENTIAL 522 475 CONFIDENTIAL APPENDIX 3B : All serious attributable clinical trial cases which were received prior to the period of this PSUR but unblinded during the reporting period (no such case was received during the period) CONFIDENTIAL 523 476 CONFIDENTIAL APPENDIX 3C : All non-serious listed cases (excluding consumer and regulatory authority reports) CONFIDENTIAL 524 Appendix 3C: Individual Case Histories of Non-Serious Listed Cases Received in Time Period of PSUR for: Infanrix hexa Case No. Country Report Source Age/Sex Form’n or Route TDD Treatment Dates† Event Onset TTO / TTOSLD Events Outcome Comments Blood and lymphatic system disorders D0072958A Germany MD U/U INJ U U U/U Lymphadenopathy U Gastrointestinal disorders B0712444A France MD 2 Months/F INJ, INJ U, U 01Dec2010-01Dec2010, 01Mar2011-01Mar2011 U/48 Hours, U/48 Hours Diarrhoea R D0071537A Germany MD,RP 2 Months/F INJ U 02May2011-02May2011 06May2011 U/4 Days Diarrhoea I CONFIDENTIAL 477 CONFIDENTIAL 525 B0682692A Hong Kong MD 5 Weeks/M INJ U 27Oct2010 -27Oct2010 U/0 Days Vomiting R B0683077A Poland MD,RA 2 Months/U INJ U 20May2010 -20May2010 20May2010 U/0 Days Vomiting R General disorders and administration site conditions B0734921A Austria MD U/U INJ U U U/Hours Pyrexia U B0706692A Belgium MD,RP 18 Months/U INJ U 1 Days U/Unknown Pyrexia R B0687293A France MD 18 Months/F INJ U 30Nov2010 -30Nov2010 01Dec2010 U/0 Weeks Injection site oedema, Injection site erythema N CONFIDENTIAL 478 CONFIDENTIAL 526 B0704749A France MD 2 Years/M INJ, INJ, INJ U, U, U 01Apr2009 -01Apr2009, 08Jun2009 -08Jun2009, 01Jun2010 -01Jun2010 U/Unknown, U/Unknown, U/Unknown No therapeutic response X B0705102A France MD Infant/U INJ U 1 Days U/Immediate Injection site pain U B0715647A France MD 2 Years/U INJ U 01Feb2011 -01Feb2011 01Feb2011 U/48 Hours Extensive swelling of vaccinated limb, Pyrexia R B0716266A France PH Infant/M INJ U 01Jan2011 -01Jan2011 01Jan2001 U/Unknown Injection site erythema, Pyrexia U B0755889A France MD 15 Months/U INJ U 10Oct2011 -10Oct2011 10Oct2011 U/Same day Pyrexia N D0069558A Germany HP,RA 19 Months/F INJ U 04Nov2010 -04Nov2010 06Nov2010 U/2 Days Injection site erythema, Injection site swelling R CONFIDENTIAL 479 CONFIDENTIAL 527 D0070056A Germany MD,RA 4 Months/M INJ U 13Dec2010-13Dec2010 13Dec2010 U/0 Days Pyrexia R D0070070A Germany HP,RA 15 Months/F INJ U 07Dec2010-07Dec2010 08Dec2010 U/1 Days Pyrexia R D0070269A Germany MD,RP Child/U INJ U 1 Days U/Unknown No therapeutic response X D0070393A Germany MD 2 Months/M INJ, INJ U, U 03Jan2011-03Jan2011, 03Feb2011-03Feb2011 01Jan2011 U/0 Months, U/0 Months Pyrexia, Restlessness, Pyrexia, Restlessness R D0070527A Germany OM,MD,RA U/F INJ, INJ U, U 1 Days, 1 Days U/Unknown, U/Unknown Pyrexia, Pyrexia U D0071619A Germany MD,RA 33 Months/M INJ U 21Apr2011-21Apr2011 22Apr2011 U/1 Days Pyrexia, Injection site swelling R CONFIDENTIAL 480 CONFIDENTIAL 528 D0072122A Germany MD U/F INJ U 1 Days U/0 Days Pyrexia, Pyrexia, Rash, Pyrexia I D0072481A Germany MD,RP 11 Years/M INJ U 1 Days U/Unknown Injection site swelling, Injection site erythema, Injection site pain U D0072494B Germany MD,RP 9 Weeks/M INJ .5ML 09Jun2011 -09Jun2011 09Jun2011 U/12 Hours Pyrexia* R D0072506A Germany MD Infant/M INJ, INJ U, U 01Jan2011 -01Jan2011, 01Jan2011 -01Jan2011 01Jan2011 U/0 Years, U/0 Years Pyrexia, Crying, Pyrexia, Crying U D0072890A Germany MD 2 Months/F INJ U 24Aug2011 -24Aug2011 01Aug2011 U/6 Hours Pyrexia, Rash R B0701433A Netherlands MD,RA 6 Months/M INJ U 30Dec2010 -30Dec2010 30Dec2010 U/1 Hours Pyrexia R CONFIDENTIAL 481 CONFIDENTIAL 529 B0709029A Netherlands HP,RA 3 Months/M INJ U 19Mar2009-19Mar2009 01Mar2009 U/1 Days Pyrexia, Urticaria R B0726092A Netherlands MD,RA 11 Months/F INJ U 17Nov2010-17Nov2010 17Nov2010 U/8 Hours Pyrexia R B0727154A Netherlands HP,RA 6 Months/M INJ U 08Apr2011-08Apr2011 08Apr2011 U/5 Hours Pyrexia R B0742965A Netherlands HP,RA 3 Months/F INJ U 28Jul2009-28Jul2009 28Jul2009 U/0 Days Pyrexia R B0755900A Netherlands MD,RA 2 Months/F INJ .5ML 25Jul2011-25Jul2011 25Jul2011 U/0 Days Pyrexia R B0708546A Peru MD 2 Years/M INJ U 11Feb2011-11Feb2011 11Feb2011 U/Hours Injection site erythema, Injection site oedema, Injection site pain, Injection site swelling R CONFIDENTIAL 482 CONFIDENTIAL 530 B0683070A Poland MD,RA 27 Months/U INJ U 10Jun2010 -10Jun2010 11Jun2010 U/1 Days Injection site oedema, Body temperature increased R B0683696A Poland MD,RA 19 Months/U INJ U 23Jun2010 -23Jun2010 24Jun2010 U/1 Days Injection site erythema, Injection site oedema R B0688156A Poland MD,RA 20 Months/U INJ U 22Jun2010 -22Jun2010 23Jun2010 U/24 Hours Injection site erythema, Injection site oedema U B0692009A Poland MD,RA 26 Months/U INJ U 15Sep2010 -15Sep2010 16Sep2010 U/1 Days Injection site oedema, Injection site erythema, Injection site pain, Body temperature increased, Extensive swelling of vaccinated limb R B0726137A Poland MD,RA 5 Months/U INJ U 12Apr2011 -12Apr2011 13Apr2011 U/1 Days Injection site oedema, Injection site erythema R CONFIDENTIAL 483 CONFIDENTIAL 531 B0727348A Poland MD,RA 20 Months/M INJ U 14Apr2011 -14Apr2011 15Apr2011 U/1 Days Injection site oedema, Injection site pain R B0730870A Poland MD,RA 18 Months/U INJ U 25May2011 -25May2011 25May2011 U/Hours Injection site oedema, Injection site erythema, Injection site pain, Pyrexia, Extensive swelling of vaccinated limb R B0731114A Poland MD,RA 8 Months/U INJ U 13Apr2011 -13Apr2011 14Apr2011 U/1 Days Injection site oedema, Injection site erythema, Extensive swelling of vaccinated limb R B0716355A Romania MD,RP 2 Months/U INJ U 05Jan2011 -05Jan2011 05Jan2011 U/0 Days Pyrexia, Diarrhoea R B0733647A Romania MD 2 Months/F INJ U 17Jun2011 -17Jun2011 U/0 Months Pyrexia R B0684776A South Africa HP 19 Months/M INJ U 15Nov2010 -15Nov2010 16Nov2010 U/1 Days Injection site swelling U CONFIDENTIAL 484 CONFIDENTIAL 532 B0695402A South Africa HP 18 Months/F INJ U 18Jan2011 -18Jan2011 18Jan2011 U/Hours Injection site erythema, Pyrexia U B0705537A Viet Nam MD,RP 16 Months/M INJ .5ML 05Mar2011 -05Mar2011 06Mar2011 U/1 Days Injection site swelling U B0730568A Viet Nam MD,RP 20 Months/F INJ U 12Jun2011 -12Jun2011 12Jun2011 U/0 Days Injection site erythema, Injection site swelling N Investigations B0698656A Poland MD,RA 23 Months/U INJ U 08Oct2010 -08Oct2010 09Oct2010 U/1 Days Body temperature increased, Injection site oedema, Injection site erythema R Nervous system disorders B0743970A France PH 2 Months/F INJ U 01Jan2011 -01Jan2011 01Jan2011 U/4 Hours Crying R CONFIDENTIAL 485 CONFIDENTIAL 533 B0727692A Netherlands MD,RA 3 Months/F INJ U 15Sep2010-15Sep2010 15Sep2010 U/3 Hours Crying R B0732813A Netherlands HP,RA 12 Weeks/F INJ, INJ U, U 21Apr2011-21Apr2011, 01Jan2011-U 21Apr2011 U/2 Hours, U/Hours Crying, Crying, Pyrexia U B0737130A Netherlands MD,RA 11 Months/F INJ, INJ U, .5ML 20Jul2011-20Jul2011, U U/Unknown, U/Hours Crying, Pyrexia, Crying, Pyrexia R B0705793A Peru MD 2 Months/F INJ U 09Mar2011-09Mar2011 09Mar2011 U/0 Days Crying R B0708789A Poland MD 2 Months/M INJ U 05Jan2011-05Jan2011 05Jan2011 U/30 Minutes Crying, Somnolence, Decreased appetite R B0741965A Romania CO,MD 6 Months/M INJ U 28Jun2011-28Jun2011 28Jun2011 U/45 Minutes Somnolence R CONFIDENTIAL 486 CONFIDENTIAL 534 Skin and subcutaneous tissue disorders B0741520A Belgium MD U/U INJ U 16Aug2011 -16Aug2011 17Aug2011 U/1 Days Rash U B0741521A Belgium MD U/U INJ U 16Aug2011 -16Aug2011 17Aug2011 U/1 Days Rash U B0687294A France MD 16 Months/F INJ U 01Aug2010 -01Aug2010 01Jan2010 U/1 Days Urticaria U B0692425A France MD 3 Months/F INJ, INJ U, U 23Oct2010 -23Oct2010, 21Dec2010 -21Dec2010 01Oct2010 U/0 Weeks, U/2 Days Urticaria R B0729681A France MD 16 Months/F INJ U 27Jun2011 -27Jun2011 27Jun2011 U/4 Hours Urticaria, Pyrexia, Diarrhoea U CONFIDENTIAL 487 CONFIDENTIAL 535 B0742850A France MD 2 Months/U INJ U 01Jan2011 -01Jan2011 01Jan2011 U/1 Days Urticaria R B0751893A France MD 14 Months/U INJ U 01Jan2011 -01Jan2011 01Jan2011 U/48 Hours Eczema, Hypersensitivity I D0069348A Germany HP,RA 4 Months/F INJ U 28Sep2010 -28Sep2010, 31Aug2010 -31Aug2010 29Sep2010 U/1 Days, U/U Urticaria R D0069457A Germany MD,RG,RA 27 Months/F INJ U 26Aug2010 -26Aug2010 26Aug2010 U/0 Days Urticaria R D0070920A Germany MD,RP 3 Months/M INJ U 04Mar2011 -04Mar2011 05Mar2011 U/1 Days Urticaria R D0071119A Germany MD,RP U/U INJ U 1 Days U/4 Hours Urticaria U CONFIDENTIAL 488 CONFIDENTIAL 536 D0072418A Germany MD 7 Months/F INJ U 09Aug2011 -09Aug2011 01Aug2011 U/1 Weeks Rash generalised U D0072419A Germany MD U/F INJ, INJ, INJ U, U, U 1 Days, 1 Days, 1 Days U/Unknown, U/Unknown, U/Unknown Pruritus, Pruritus, Pruritus U B0739776A Singapore MD,RP 2 Months/F INJ .5ML U, 25May2011 -25May2011 26May2011 U/1 Days, U/U Rash morbilliform R CONFIDENTIAL 489 CONFIDENTIAL 537 490 CONFIDENTIAL APPENDIX 3D : All non-medically verified cases CONFIDENTIAL 538 Appendix 3D: Individual Case Histories of Non-Medically Verified Cases Received in Time Period of PSUR for: Infanrix hexa Case No. Country Report Source Age/Sex Form’n or Route TDD Treatment Dates† Event Onset TTO / TTOSLD Events Outcome Comments Gastrointestinal disorders B0723208A Australia CO 4 Months/M SUS U U U/Unknown Infrequent bowel movements, Abnormal faeces U General disorders and administration site conditions D0071893A Germany CO 2 Months/F INJ, INJ U, U 1 Days, 1 Days U/Unknown, U/Unknown Adverse event, Off label use U #B0735723A Australia CO 6 Weeks/M INJ U 20Jul2011-20Jul2011 21Jul2011 U/14 Hours Death F CONFIDENTIAL 491 CONFIDENTIAL 539 B0735472A France CO,CN Infant/F INJ, INJ U, U 26Jul2011 -26Jul2011, 1 Days U/0 Days, U/Unknown Extensive swelling of vaccinated limb, Injection site reaction, Injection site nodule, Injection site erythema, Injection site warmth, Injection site induration, Injection site pruritus, Hypersensitivity N B0741549A Czech Republic CO 3 Months/F INJ U 09Aug2011 -09Aug2011 09Aug2011 U/0 Days Fatigue, Rash N B0695090A France CO 3 Months/M INJ U 01Jan2010 -01Jan2010 01Jan2010 U/See text Incorrect product storage X B0715826A France CO 2 Months/F INJ U 22Feb2011 -22Feb2011 22Feb2011 U/See text Incorrect product storage X B0734427A France CO,CN 2 Months/U INJ U 20Jul2011 -20Jul2011 20Jul2011 U/See text Incorrect product storage X CONFIDENTIAL 492 CONFIDENTIAL 540 B0690208A Italy CO 5 Years/M INJ U 1 Days U/Unknown Injection site anaesthesia, Injection site pain I B0734758A Italy CO 10 Months/M INJ U U 24Jun2011 U/Unknown Injection site erythema, Extensive swelling of vaccinated limb, Injection site induration N B0756909A Australia CO 4 Months/M INJ U U U/Unknown Injection site erythema, Injection site swelling, Irritability R B0711440A Brazil CO 6 Months/M INJ U 04Mar2011 -04Mar2011 04Mar2011 U/0 Days Injection site induration, Injection site reaction, Pyrexia, Irritability R D0070074A Germany CO 15 Months/M INJ U 24Jan2011 -24Jan2011 24Jan2011 U/0 Days Injection site irritation, Underdose U D0072541A Germany CO 40 Years/F INJ U U U/0 Days Injection site pain, Wrong drug administered U CONFIDENTIAL 493 CONFIDENTIAL 541 D0069937A Germany CO 13 Months/F INJ U 1 Days U/1 Days Injection site swelling, Injection site erythema, Injection site swelling R B0696960A Poland CO 19 Months/M INJ U 19Jan2011 -19Jan2011 27Jan2011 U/8 Days Oedema peripheral, Rash U B0684619A Austria CO Child/F INJ U 09Nov2010 -09Nov2010 09Nov2010 U/Hours Pyrexia R B0684560A France CO Infant/F INJ U 01Jan2010 -01Jan2010 01Jan2010 U/Unknown Pyrexia R D0070214A Germany CO 15 Months/M INJ U 04Feb2011 -04Feb2011 05Feb2011 U/1 Days Pyrexia U D0072188A Germany CO 2 Years/M INJ U 1 Days U/10 Days Pyrexia, Erythema, Pharyngitis, Malaise, Photophobia, White blood cell count increased, Bacterial U CONFIDENTIAL 494 CONFIDENTIAL 542 infection, Rash, Pyrexia, Rash, Pharyngeal erythema, Pyrexia B0684559A France CO 2 Months/U INJ U 01Nov2010 -01Nov2010 01Nov2010 U/Same day Pyrexia, Incorrect product storage R D0071039A Germany CO 10 Years/F INJ U 1 Days U/Unknown Pyrexia*, Pain* U D0069525A Germany CO 4 Years/M INJ U 18Nov2010 -18Nov2010 19Nov2010 U/1 Days Pyrexia, Pain, Vomiting R B0684422A Croatia CO 5 Months/F INJ, IN J U, .5ML 31Aug2010 -31Aug2010, 10Nov2010 -10Nov2010, 24Jun2010 -24Jun2010 01Jan2010 U/Unknown, U/8 Hours, U/U Pyrexia, Pyrexia R Infections and infestations CONFIDENTIAL 495 CONFIDENTIAL 543 #D0069806A Germany CO Infant/U INJ .5ML 1 Days U/Unknown Injection site abscess* U #B0737601A South Africa CO 18 Months/F INJ U 1 Days U/Unknown Pertussis U D0069959A Germany CO 24 Months/M INJ U 14Nov2010 -14Nov2010 15Nov2010 U/1 Days Rash pustular, Injection site erythema, Injection site warmth, Injection site induration, Pyrexia, Lymphadenopathy, Erythema U Injury, poisoning and procedural complications B0704430A South Africa CO 3 Months/U INJ U 04Mar2011 -04Mar2011 04Mar2011 U/During Accidental overdose X B0696711A Brazil CO 2 Months/F INJ .5ML 20Jan2011 -20Jan2011 20Jan2011 U/See text Expired drug administered X CONFIDENTIAL 496 CONFIDENTIAL 544 D0072542A Germany CO 28 Years/M INJ U U U/0 Days Wrong drug administered X B0684758A Sweden CO,NP 2 Years/M INJ U 1 Days U/During Wrong drug administered X B0691614A France CO 3 Months/F INJ, INJ U, U 01Jan2010 -01Jan2010, 01Jan2010 -01Jan2010, 01Jan2010 -01Jan2010, 01Jan2010 -01Jan2010 01Jan2010 U/See text, U/See text, U/U, U/U Wrong drug administered, Incorrect dose administered X B0683346A Australia CO 4 Months/M INJ U 01Nov2010 -01Nov2010 01Nov2010 U/24 Hours Wrong drug administered, Overdose, Somnolence, Irritability U B0716836A Argentina CO 6 Months/M INJ U 12Apr2011 -12Apr2011 12Apr2011 U/During Wrong technique in drug usage process X B0733404A Poland OT 18 Months/M INJ U 12Jul2011 -12Jul2011 12Jul2011 U/During Wrong technique in drug usage process, Oedema peripheral, Insomnia, Anxiety, Erythema R CONFIDENTIAL 497 CONFIDENTIAL 545 Musculoskeletal and connective tissue disorders D0072247A Germany CO 26 Months/M INJ U 29Jul2011 -29Jul2011 29Jul2011 U/0 Days Pain in extremity U D0072372A Germany CO U/F INJ U 1 Days U/0 Days Pain in extremity, Gait disturbance, Crying U Nervous system disorders D0069784A Germany CO,OT 12 Weeks/M INJ .5ML 03Dec2010 -03Dec2010 03Dec2010 U/0 Days Crying*, Respiratory disorder*, Presyncope*, Pyrexia*, Fatigue*, Apathy*, Crying*, Dyskinesia*, Inappropriate affect*, Fatigue*, Decreased interest*, Initial insomnia*, Diarrhoea* R D0072114A Germany CO 4 Months/F INJ U 15Jul2011 -15Jul2011 18Jul2011 U/3 Days Hypersomnia, Hypophagia U CONFIDENTIAL 498 CONFIDENTIAL 546 B0703207A Poland CO 2 Years/M INJ U 24Feb2011 -24Feb2011 24Feb2011 U/0 Days Lethargy, Face oedema, Sluggishness, Pain in extremity, Pyrexia N B0705201A Romania CO 2 Months/M INJ U 15Feb2011 -15Feb2011 15Feb2011 U/0 Days Somnolence, Urticaria, Acne R #B0722633A Kenya CO,RP 6 Weeks/F INJ U 01Apr2011 -01Apr2011 01Apr2011 U/0 Days Tremor, Pyrexia R Respiratory, thoracic and mediastinal disorders #B0703891A Kenya CO 2 Months/F INJ U 18Feb2011 -18Feb2011 20Feb2011 U/2 Days Cough, Dyspnoea, Wheezing N Skin and subcutaneous tissue disorders #B0720037A Poland CO 1 Years/M INJ U 1 Days U/Unknown Dermatitis allergic R CONFIDENTIAL 499 CONFIDENTIAL 547 B0692908A France CO 3 Months/M INJ U 06Dec2010-06Dec2010 01Dec2010 U/See text Eczema N B0744392A France CO,CN U/M INJ U 1 Days U/See text Eczema U #B0713508A France CO 3 Months/U INJ, INJ U, U 1 Seconds, 1 Days U/Hours, U/Hours Eczema, Hypersensitivity R B0755697A Ecuador CO 6 Months/F INJ .5ML 28Sep2011-28Sep2011, U, U 29Sep2011 U/1 Days, U/U, U/U Erythema, Pruritus N #B0710915A France CO,CN 5 Months/F INJ U 22Mar2011-22Mar2011 27Mar2011 U/5 Days Henoch-Schonlein purpura, Contusion I #D0072611A Germany CO 3 Months/M INJ .5ML 25Aug2011-25Aug2011 25Aug2011 U/5 Hours Petechiae*, Haematoma* R CONFIDENTIAL 500 CONFIDENTIAL 548 D0071437A Germany CO 4 Months/F INJ U 17May2011 -17May2011 17May2011 U/0 Days Petechiae, Skin discolouration U B0740880A South Africa CO 8 Weeks/F INJ U 12Aug2011 -12Aug2011 12Aug2011 U/0 Days Pigmentation disorder R B0726374A Italy CO 6 Months/F INJ U 18Apr2011 -18Apr2011 18Apr2011 U/0 Days Rash morbilliform, Pyrexia R B0687729A Poland CO 6 Weeks/F INJ U 03Dec2010 -03Dec2010 03Dec2010 U/0 Days Skin striae U CONFIDENTIAL 501 CONFIDENTIAL 549 502 CONFIDENTIAL APPENDIX 3E : Cases from a previous period not included in previous PSUR CONFIDENTIAL 550 Infanrix Hexa: line listing of cases from a previous period and not included in a previous PSUR Case No. Country Report Source Age/Sex Form’n or Route TDD Treatment Dates* Event Onset TTO Events Outcome Comments General disorders and administration site conditions D0061162A Germany RA 4M / F INJ U 10Dec2008 – 10Dec2008 10Dec2008 0D Pyrexia; Pyrexia; Resolved – INJ U 27Feb2009 – 27Feb2009 10Dec2008 0D B0637096A Italy RA 4M / F INJ U 23Oct2009 – 23Oct2009 23Oct2009 0D Injection site nodule, Injection site erythema; Resolved – Infections and infestations D0063259A Germany RA 3M / M INJ 0.5ml 15Sep2009 – 15Sep2009 29Sep2009 14D Bronchitis, Wheezing, Cough; Unresolved – D0060830A Germany RA 8M / M INJ U 29Jan2008 – 29Jan2008 2008 U Rhinitis, Vaccination complication; Resolved – INJ U 1Days 2008 U Nervous system disorders #B0591710A Netherlands RA 2M / F INJ U 18May2009 – 18May2009 May2009 6H Loss of consciousness, Hypotonia, Vomiting, Pallor, Cyanosis, Drooling; Resolved – B0647987A France MD 7W / F INJ U 15Feb2010 – 15Feb2010 15Feb2010 30D Crying, Pyrexia, Drug administered to patient of inappropriate age; Resolved – #B0674885A Italy RA MD 13M / F INJ U 01Sep2010 – 01Sep2010 02Sep2010 1D Febrile convulsion, Pyrexia; Resolved – #B0631888A Sweden RA 11M / M INJ U 16Sep2009 – 16Sep2009 17Sep2009 1D Febrile convulsion, Ill – defined disorder, Muscle twitching, Muscle twitching, Crying; Resolved – Skin and subcutaneous tissue disorders D0066216A Germany RA 11M / M INJ U 16Sep2009 – 16Sep2009 23Sep2009 7D Rash vesicular, Open wound, Rash pruritic, Bacterial infection; Unresolved – D0066224A Germany RA 4M / F INJ U 27Jul2009 – 27Jul2009 30Jul2009 3D Urticaria; Resolved – CONFIDENTIAL 503 CONFIDENTIAL 551 504 CONFIDENTIAL APPENDIX 4A : All reported AEs for cases included in APPENDIX 3A CONFIDENTIAL 552 Appendix 4A: Summary Tabulation of Adverse Events Included in the Line Listing for: Infanrix hexa N.B. Events are only considered serious if they fulfil GSK medically serious criteria. GSK medically serious criteria are applied automatically only to events from spontaneous, post-marketing or literature case reports. Events arising from Clinical trial cases are not run against the list of GSK medically serious terms. For this reason events may appear as both serious and non-serious. For full explanation see section 6.2.2. MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Anaemia No 6 0 6 Bone marrow failure No 1 0 1 Hypochromic anaemia No 1 0 1 Pancytopenia No 1 0 1 Coagulopathies and bleeding diatheses (excl thrombocytopenic) Haemorrhagic diathesis No 2 0 2 Haemolyses and related conditions Anaemia haemolytic autoimmune No 1 0 1 Platelet disorders Idiopathic thrombocytopenic purpura No 5 0 5 Thrombocytopenia Yes 9 0 9 Thrombocytopenic purpura No 4 0 4 Thrombocytosis No 2 0 2 Spleen, lymphatic and reticuloendothelial system disorders Lymphadenopathy Yes 0 12 12 Splenomegaly No 2 0 2 White blood cell disorders Agranulocytosis No 1 0 1 Eosinophilia No 0 2 2 CONFIDENTIAL 505 CONFIDENTIAL 553 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Leukocytosis No 4 0 4 Leukopenia No 1 0 1 Neutropenia No 2 0 2 Cardiac disorders Cardiac arrhythmias Arrhythmia No 0 1 1 Atrial tachycardia No 1 0 1 Bradycardia No 0 11 11 Cardiac arrest No 3 0 3 Cardio-respiratory arrest No 1 0 1 Supraventricular tachycardia No 1 0 1 Tachycardia No 0 4 4 Cardiac disorder signs and symptoms Cardiovascular disorder No 0 4 4 Cardiovascular insufficiency Yes 1 0 1 Cyanosis No 49 7 56 Cardiac valve disorders Mitral valve incompetence No 1 0 1 Heart failures Cardiac failure No 1 0 1 Cardiogenic shock No 1 0 1 Cardiopulmonary failure No 1 0 1 Myocardial disorders Cardiomyopathy No 1 0 1 Congestive cardiomyopathy No 1 0 1 CONFIDENTIAL 506 CONFIDENTIAL 554 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Pericardial disorders Pericarditis No 1 0 1 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Macrocephaly No 1 0 1 Microcephaly No 1 0 1 Talipes No 1 0 1 Neurological disorders congenital Congenital neuropathy No 1 0 1 Reproductive tract and breast disorders congenital Hydrocele No 1 0 1 Ear and labyrinth disorders External ear disorders (excl congenital) Cerumen impaction No 0 1 1 Middle ear disorders (excl congenital) Tympanic membrane disorder No 0 1 1 Tympanic membrane hyperaemia No 0 1 1 Tympanic membrane perforation No 0 2 2 Endocrine disorders Thyroid gland disorders Hypothyroidism No 2 0 2 Eye disorders Eye disorders NEC Eye disorder No 0 6 6 Eyelid disorder No 0 1 1 Eye oedema No 0 1 1 Eye swelling No 0 1 1 Ocular haemorrhages and vascular disorders NEC Conjunctival haemorrhage No 0 1 1 Ocular infections, irritations and inflammations Conjunctivitis No 0 4 4 Eyelid oedema Yes 0 4 4 Ocular neuromuscular disorders Blepharospasm No 0 1 1 CONFIDENTIAL 507 CONFIDENTIAL 555 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Eye movement disorder No 0 17 17 Gaze palsy No 18 0 18 Oculogyric crisis No 2 0 2 Pupils unequal No 0 1 1 Strabismus No 0 2 2 Vision disorders Visual acuity reduced No 0 1 1 Gastrointestinal disorders Dental and gingival conditions Gingival bleeding No 0 2 2 Gastrointestinal conditions NEC Gastrointestinal disorder No 0 2 2 Gastrointestinal haemorrhages NEC Haematochezia No 3 0 3 Rectal haemorrhage No 1 0 1 Gastrointestinal inflammatory conditions Colitis No 1 0 1 Gastrointestinal inflammation No 0 1 1 Gastrointestinal motility and defaecation conditions Constipation No 0 1 1 Diarrhoea Yes 0 27 27 Diarrhoea haemorrhagic No 2 0 2 Frequent bowel movements Yes 0 1 1 Gastrooesophageal reflux disease No 1 2 3 Ileus paralytic No 1 0 1 Gastrointestinal signs and symptoms Abdominal distension No 0 4 4 CONFIDENTIAL 508 CONFIDENTIAL 556 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Abdominal pain No 0 7 7 Abnormal faeces No 0 3 3 Dyspepsia No 0 1 1 Dysphagia No 0 1 1 Faeces discoloured No 0 2 2 Flatulence No 0 3 3 Gastrointestinal pain No 0 2 2 Nausea No 0 1 1 Post-tussive vomiting No 0 1 1 Regurgitation No 0 1 1 Vomiting Yes 0 53 53 Gastrointestinal stenosis and obstruction Intussusception No 1 0 1 Oral soft tissue conditions Chapped lips No 0 2 2 Cheilitis No 0 4 4 Lip haematoma No 0 1 1 Lip swelling Yes 0 2 2 Mouth haemorrhage No 1 1 1 Peritoneal and retroperitoneal conditions Ascites No 1 0 1 Salivary gland conditions Lip dry No 0 1 1 CONFIDENTIAL 509 CONFIDENTIAL 557 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Salivary hypersecretion No 0 6 6 Tongue conditions Glossoptosis No 0 1 1 Hypertrophy of tongue papillae No 0 1 1 Swollen tongue Yes 0 1 1 General disorders and administration site conditions Administration site reactions Injected limb mobility decreased No 0 3 3 Injection site abscess sterile No 0 1 1 Injection site cyst No 0 2 2 Injection site dermatitis Yes 0 1 1 Injection site discolouration No 0 19 19 Injection site eczema No 0 1 1 Injection site erythema Yes 0 89 89 Injection site extravasation No 0 6 6 Injection site haematoma No 0 8 8 Injection site haemorrhage No 0 2 2 Injection site induration Yes 0 40 40 Injection site inflammation No 0 31 31 Injection site nodule No 0 17 17 Injection site oedema Yes 0 21 21 Injection site pain Yes 0 37 37 CONFIDENTIAL 510 CONFIDENTIAL 558 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Injection site papule No 0 1 1 Injection site pruritus No 0 16 16 Injection site rash Yes 0 3 3 Injection site reaction No 0 20 20 Injection site scar No 0 1 1 Injection site swelling Yes 0 57 57 Injection site urticaria No 0 1 1 Injection site vesicles Yes 0 3 3 Injection site warmth No 0 39 39 Vaccination site induration Yes 0 1 1 Body temperature conditions Hyperpyrexia No 0 6 6 Hyperthermia No 0 4 4 Hypothermia No 0 2 2 Pyrexia Yes 1 284 285 Fatal outcomes Death No 4 0 4 Sudden death No 1 0 1 Sudden infant death syndrome No 3 0 3 General system disorders NEC Abasia No 0 1 1 Abscess sterile No 6 0 6 CONFIDENTIAL 511 CONFIDENTIAL 559 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Asthenia No 0 6 6 Chills No 0 5 5 Condition aggravated No 0 1 1 Developmental delay No 0 8 8 Discomfort No 0 1 1 Enanthema No 0 1 1 Extensive swelling of vaccinated limb Yes 0 18 18 Face oedema Yes 0 1 1 Fatigue No 0 16 16 Feeling abnormal No 0 1 1 Feeling cold No 0 2 2 Feeling hot No 0 7 7 Foaming at mouth No 0 3 3 Foreign body reaction No 0 3 3 Gait disturbance No 0 11 11 Generalised oedema No 0 1 1 General physical health deterioration No 0 7 7 Granuloma No 0 3 3 Ill-defined disorder No 0 32 32 CONFIDENTIAL 512 CONFIDENTIAL 560 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Induration No 0 6 6 Inflammation No 0 16 16 Irritability Yes 0 21 21 Localised oedema No 0 1 1 Local reaction No 0 1 1 Local swelling No 0 2 2 Malaise No 0 23 23 Mucosal inflammation No 0 1 1 Mucous membrane disorder No 0 1 1 Multi-organ failure No 1 0 1 Oedema No 0 5 5 Oedema peripheral No 0 26 26 Pain No 0 21 21 Swelling No 0 10 10 Tenderness No 0 1 1 Thirst decreased No 0 1 1 Product quality issues Incorrect product storage No 0 43 43 Product quality issue No 0 18 18 Therapeutic and nontherapeutic effects (excl toxicity) Adverse event No 0 2 2 CONFIDENTIAL 513 CONFIDENTIAL 561 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Drug ineffective Yes 0 1 1 No therapeutic response Yes 0 5 5 Therapeutic response decreased Yes 0 1 1 Tissue disorders NEC Cyst No 0 1 1 Fibrosis No 0 4 4 Nodule No 0 2 2 Hepatobiliary disorders Gallbladder disorders Cholecystitis No 1 0 1 Hepatic and hepatobiliary disorders Hepatic function abnormal No 0 1 1 Hepatomegaly No 0 1 1 Hepatosplenomegaly No 0 1 1 Hepatotoxicity No 1 0 1 Hypertransaminasaemia No 1 0 1 Jaundice No 1 0 1 Immune system disorders Allergic conditions Allergy to metals No 0 1 1 Allergy to vaccine Yes 0 1 1 Anaphylactic reaction Yes 3 0 3 Anaphylactic shock Yes 3 0 3 Anaphylactoid reaction Yes 1 0 1 Drug hypersensitivity Yes 0 1 1 CONFIDENTIAL 514 CONFIDENTIAL 562 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Hypersensitivity Yes 0 18 18 Milk allergy No 0 1 1 Immune disorders NEC Immune system disorder No 0 1 1 Infections and infestations Ancillary infectious topics Transmission of an infectious agent via a medicinal product No 1 0 1 Bacterial infectious disorders Bacterial infection No 0 1 1 Cellulitis No 2 0 2 Erysipelas No 0 1 1 Escherichia infection No 0 2 2 Escherichia urinary tract infection No 0 1 1 Gastroenteritis Escherichia coli No 1 0 1 Gastroenteritis staphylococcal No 1 0 1 Haemophilus infection No 0 3 3 Injection site cellulitis No 0 1 1 Meningitis haemophilus No 4 0 4 Meningitis pneumococcal No 2 0 2 Pertussis No 0 40 40 Pneumococcal infection No 0 1 1 Pneumococcal sepsis No 0 1 1 Salmonella sepsis No 1 0 1 CONFIDENTIAL 515 CONFIDENTIAL 563 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Salmonellosis No 0 1 1 Staphylococcal abscess No 0 3 3 Staphylococcal infection No 0 1 1 Streptococcal abscess No 0 2 2 Streptococcal bacteraemia No 0 1 1 Fungal infectious disorders Fungal skin infection Yes 0 1 1 Infections – pathogen unspecified Abdominal abscess No 0 1 1 Abscess No 0 8 8 Abscess limb No 0 1 1 Bacteraemia No 2 0 2 Bone abscess No 1 0 1 Bronchitis Yes 0 5 5 Bronchopneumonia No 1 0 1 Ear infection No 0 3 3 Encephalitic infection No 1 0 1 Gastroenteritis No 2 0 2 Groin abscess No 0 1 1 Impetigo No 0 3 3 Incision site abscess No 0 2 2 CONFIDENTIAL 516 CONFIDENTIAL 564 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Infection No 0 7 7 Injection site abscess No 0 11 11 Injection site infection No 0 2 2 Injection site pustule No 0 1 1 Labyrinthitis No 0 1 1 Lung infection No 0 1 1 Meningitis Yes 3 0 3 Meningitis aseptic Yes 1 0 1 Nasopharyngitis Yes 0 9 9 Osteomyelitis No 1 0 1 Otitis media No 0 5 5 Otitis media acute No 0 1 1 Pharyngitis Yes 0 2 2 Pneumonia primary atypical No 1 0 1 Purulence No 0 1 1 Purulent discharge No 0 1 1 Pyelonephritis No 2 0 2 Rash pustular Yes 0 2 2 Respiratory tract infection Yes 0 5 5 CONFIDENTIAL 517 CONFIDENTIAL 565 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Rhinitis Yes 0 7 7 Sepsis No 4 0 4 Septic shock No 1 0 1 Soft tissue infection No 0 1 1 Sputum purulent No 0 1 1 Subdural empyema No 0 1 1 Tonsillitis Yes 0 3 3 Upper respiratory tract infection Yes 0 10 10 Urinary tract infection No 1 1 2 Viral infectious disorders Exanthema subitum No 0 1 1 Gastroenteritis astroviral No 1 0 1 Gastroenteritis rotavirus No 7 0 7 H1N1 influenza No 0 1 1 Herpes simplex No 0 1 1 Herpes virus infection No 0 1 1 Herpes zoster Yes 0 2 2 Measles No 0 1 1 Meningitis viral Yes 1 0 1 Respiratory syncytial virus infection No 0 2 2 CONFIDENTIAL 518 CONFIDENTIAL 566 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Varicella No 0 1 1 Vestibular neuronitis No 0 1 1 Viral infection No 0 3 3 Viral rash Yes 0 3 3 Injury, poisoning and procedural complications Chemical injury and poisoning Maternal exposure during pregnancy No 0 1 1 Injuries NEC Arthropod bite No 0 1 1 Contusion No 0 2 2 Fall No 0 4 4 Medication errors Accidental exposure No 0 1 1 Accidental overdose No 0 6 6 Drug administered to patient of inappropriate age No 0 6 6 Drug administration error No 0 22 22 Drug prescribing error No 0 1 1 Expired drug administered No 0 9 9 Inappropriate schedule of drug administration No 0 28 28 Incorrect dose administered No 0 22 22 Incorrect route of drug administration No 0 18 18 Incorrect storage of drug No 0 18 18 Medication error No 0 1 1 CONFIDENTIAL 519 CONFIDENTIAL 567 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Overdose No 0 22 22 Underdose No 0 18 18 Wrong drug administered No 0 26 26 Wrong technique in drug usage process No 0 82 82 Procedural related injuries and complications NEC Vaccination complication No 0 10 10 Vaccination failure Yes 48 0 48 Investigations Cardiac and vascular investigations (excl enzyme tests) Blood pressure decreased Yes 0 2 2 Cardiac murmur No 0 1 1 Heart rate decreased No 0 1 1 Heart rate increased No 0 3 3 Pulse absent No 1 0 1 Pulse pressure decreased No 0 1 1 Enzyme investigations NEC Blood lactate dehydrogenase increased No 0 1 1 Haematology investigations (incl blood groups) Platelet count decreased Yes 0 2 2 Hepatobiliary investigations Alanine aminotransferase increased No 1 0 1 Aspartate aminotransferase increased No 2 0 2 Transaminases increased No 5 0 5 Immunology and allergy investigations Autoantibody positive No 0 1 1 Immunology test abnormal No 0 1 1 CONFIDENTIAL 520 CONFIDENTIAL 568 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Metabolic, nutritional and blood gas investigations Oxygen saturation decreased No 0 8 8 Microbiology and serology investigations Adenovirus test positive No 0 1 1 Bacterial test positive No 0 1 1 Bordetella test negative No 0 1 1 Bordetella test positive No 0 2 2 Clostridium test No 0 1 1 Clostridium test negative No 0 3 3 Corynebacterium test negative No 0 3 3 Cytomegalovirus test positive No 0 1 1 Hepatitis B antibody negative No 0 3 3 Hepatitis B antibody positive No 0 1 1 Neurological, special senses and psychiatric investigations Electroencephalogram abnormal No 0 1 1 Nerve stimulation test abnormal No 0 1 1 Reflex test normal No 0 1 1 Physical examination topics Body temperature No 0 1 1 Body temperature decreased No 0 1 1 Body temperature fluctuation No 0 1 1 Body temperature increased Yes 0 20 20 Lymph node palpable No 0 1 1 CONFIDENTIAL 521 CONFIDENTIAL 569 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Neurological examination abnormal No 0 1 1 Respiratory rate decreased No 0 1 1 Weight decreased No 0 4 4 Protein and chemistry analyses NEC C-reactive protein increased No 0 6 6 Inflammatory marker increased No 0 2 2 Renal and urinary tract investigations and urinalyses Urine output decreased No 0 1 1 White blood cells urine positive No 0 1 1 Metabolism and nutrition disorders Acid-base disorders Acidosis No 2 0 2 Ketosis No 0 1 1 Lactic acidosis No 1 0 1 Appetite and general nutritional disorders Decreased appetite Yes 0 19 19 Feeding disorder neonatal No 0 1 1 Hypophagia Yes 0 3 3 Increased appetite No 0 1 1 Weight gain poor No 0 2 2 Diabetic complications Diabetic ketoacidosis No 1 0 1 Electrolyte and fluid balance conditions Dehydration No 0 4 4 Fluid intake reduced No 0 6 6 Hypokalaemia No 2 0 2 CONFIDENTIAL 522 CONFIDENTIAL 570 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Oligodipsia No 0 7 7 Polydipsia No 0 1 1 Food intolerance syndromes Cow’s milk intolerance No 0 1 1 Glucose metabolism disorders (incl diabetes mellitus) Hyperglycaemia No 0 1 1 Type 1 diabetes mellitus No 1 0 1 Iron and trace metal metabolism disorders Iodine deficiency No 0 1 1 Iron deficiency No 0 1 1 Musculoskeletal and connective tissue disorders Joint disorders Arthralgia No 0 2 2 Arthritis Yes 0 1 1 Joint hyperextension No 0 3 3 Joint swelling No 0 1 1 Muscle disorders Muscle rigidity No 0 1 1 Muscle spasms No 0 8 8 Muscle tightness No 0 1 1 Muscle twitching No 0 9 9 Muscular weakness Yes 0 2 2 Myosclerosis No 0 1 1 Nuchal rigidity No 0 2 2 CONFIDENTIAL 523 CONFIDENTIAL 571 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Facial asymmetry No 0 1 1 Foot deformity No 0 1 1 Hip deformity No 0 1 1 Musculoskeletal and connective tissue disorders NEC Mastication disorder No 0 1 1 Mobility decreased No 0 2 2 Muscle contracture No 0 1 1 Musculoskeletal stiffness No 0 8 8 Pain in extremity No 0 10 10 Posture abnormal No 0 3 3 Soft tissue necrosis No 1 0 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Skin neoplasms malignant and unspecified Neoplasm skin No 1 0 1 Nervous system disorders Central nervous system infections and inflammations Central nervous system inflammation No 0 1 1 Encephalitis Yes 3 0 3 Myelitis transverse No 1 0 1 Central nervous system vascular disorders Cerebral ischaemia No 2 0 2 Thalamus haemorrhage No 1 0 1 Cranial nerve disorders (excl neoplasms) Facial paresis Yes 3 0 3 CONFIDENTIAL 524 CONFIDENTIAL 572 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Tongue paralysis Yes 1 0 1 VIIth nerve paralysis Yes 2 0 2 VIth nerve paralysis Yes 1 0 1 Demyelinating disorders Demyelination No 1 0 1 Encephalopathies Encephalopathy Yes 1 0 1 Headaches Headache No 0 2 2 Increased intracranial pressure and hydrocephalus Hydrocephalus No 1 0 1 Mental impairment disorders Mental impairment No 0 1 1 Movement disorders (incl parkinsonism) Dyskinesia No 0 16 16 Extrapyramidal disorder No 1 0 1 Hemiparesis Yes 1 0 1 Hypokinesia No 0 3 3 Motor developmental delay No 0 1 1 Movement disorder No 0 1 1 Opisthotonus No 0 7 7 Paresis Yes 1 0 1 Psychomotor hyperactivity No 0 3 3 Tremor No 0 13 13 Neurological disorders NEC Altered state of consciousness No 3 0 3 CONFIDENTIAL 525 CONFIDENTIAL 573 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Areflexia No 0 1 1 Ataxia No 0 1 1 Balance disorder No 0 7 7 Cerebellar ataxia No 0 2 2 Cerebral disorder No 0 1 1 Clonus No 0 7 7 Crying Yes 0 126 126 Depressed level of consciousness No 24 0 24 Dizziness No 0 1 1 Drooling No 0 1 1 Dysstasia No 0 1 1 Fontanelle bulging No 0 1 1 Hyperaesthesia No 0 4 4 Hypoaesthesia Yes 0 1 1 Hyporeflexia No 0 1 1 Lethargy No 0 3 3 Loss of consciousness No 35 0 35 Motor dysfunction No 0 2 2 Myoclonus No 0 10 10 CONFIDENTIAL 526 CONFIDENTIAL 574 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Neurological symptom No 0 1 1 Nystagmus No 0 2 2 Postictal state No 0 2 2 Presyncope No 5 0 5 Slow response to stimuli No 12 0 12 Somnolence Yes 0 43 43 Speech disorder No 0 1 1 Stupor Yes 0 1 1 Syncope No 8 0 8 Unresponsive to stimuli No 15 0 15 Neuromuscular disorders Autonomic nervous system imbalance No 0 1 1 Cholinergic syndrome No 0 1 1 Hypertonia No 0 19 19 Hypotonia No 0 79 79 Hypotonic-hyporesponsive episode Yes 2 61 63 Muscle contractions involuntary No 0 2 2 Peripheral neuropathies Demyelinating polyneuropathy No 1 0 1 Guillain-Barre syndrome Yes 2 0 2 Neuropathy peripheral Yes 0 2 2 CONFIDENTIAL 527 CONFIDENTIAL 575 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Seizures (incl subtypes) Clonic convulsion Yes 4 0 4 Complex partial seizures Yes 1 0 1 Convulsion Yes 53 0 53 Epilepsy Yes 8 0 8 Febrile convulsion Yes 42 0 42 Grand mal convulsion Yes 15 0 15 Infantile spasms Yes 6 0 6 Lennox-Gastaut syndrome No 1 0 1 Partial seizures Yes 3 0 3 Petit mal epilepsy Yes 3 0 3 Seizure like phenomena No 2 0 2 Status epilepticus No 2 0 2 Tonic clonic movements Yes 0 1 1 Tonic convulsion Yes 1 0 1 Sleep disturbances (incl subtypes) Circadian rhythm sleep disorder No 0 1 1 Hypersomnia No 0 2 2 Structural brain disorders Cerebral atrophy No 1 0 1 Subdural hygroma No 0 1 1 Psychiatric disorders Anxiety disorders and symptoms Agitation No 0 9 9 CONFIDENTIAL 528 CONFIDENTIAL 576 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Anxiety No 0 5 5 Fear No 0 1 1 Changes in physical activity Decreased activity No 0 3 3 Restlessness Yes 0 50 50 Stereotypy No 0 1 1 Communication disorders and disturbances Phonological disorder No 0 1 1 Screaming No 0 21 21 Depressed mood disorders and disturbances Tearfulness Yes 0 1 1 Eating disorders and disturbances Eating disorder No 0 2 2 Food aversion Yes 0 3 3 Mood disorders and disturbances NEC Apathy No 0 13 13 Listless No 0 3 3 Moaning No 0 2 2 Personality disorders and disturbances in behaviour Personality change No 0 2 2 Psychiatric and behavioural symptoms NEC Abnormal behaviour No 0 4 4 Breath holding No 0 2 2 Staring No 0 26 26 Schizophrenia and other psychotic disorders Psychotic disorder No 1 0 1 Sleep disorders and disturbances Insomnia No 0 12 12 CONFIDENTIAL 529 CONFIDENTIAL 577 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Middle insomnia No 0 3 3 Sleep disorder No 0 8 8 Renal and urinary disorders Renal disorders (excl nephropathies) Oliguria No 0 1 1 Pyelocaliectasis No 0 1 1 Renal impairment No 0 2 2 Ureteric disorders Ureteric stenosis No 0 1 1 Urinary tract signs and symptoms Polyuria No 0 1 1 Reproductive system and breast disorders Reproductive tract disorders NEC Oedema genital No 0 1 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Asthma No 1 0 1 Bronchial hyperreactivity No 1 0 1 Bronchitis chronic Yes 0 1 1 Bronchospasm No 0 2 2 Obstructive airways disorder No 1 0 1 Lower respiratory tract disorders (excl obstruction and infection) Emphysema No 0 1 1 Pneumonia aspiration No 1 0 1 Neonatal respiratory disorders Apparent life threatening event No 4 0 4 Respiratory disorders NEC Acute respiratory failure No 1 0 1 Apnoea Yes 25 0 25 CONFIDENTIAL 530 CONFIDENTIAL 578 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Apnoeic attack Yes 0 3 3 Asphyxia No 1 0 1 Aspiration No 0 1 1 Choking No 2 0 2 Cough Yes 0 19 19 Dysphonia No 0 1 1 Dyspnoea No 0 15 15 Hypopnoea Yes 0 1 1 Hypoventilation Yes 2 0 2 Hypoxia No 1 0 1 Increased upper airway secretion No 0 3 3 Lung disorder No 0 1 1 Oropharyngeal pain No 0 1 1 Productive cough Yes 0 1 1 Respiration abnormal No 0 10 10 Respiratory arrest Yes 7 0 7 Respiratory depression Yes 1 0 1 Respiratory disorder No 0 6 6 Respiratory failure No 1 0 1 CONFIDENTIAL 531 CONFIDENTIAL 579 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Respiratory tract congestion No 0 1 1 Respiratory tract inflammation No 0 1 1 Rhinorrhoea No 0 3 3 Sleep apnoea syndrome No 0 1 1 Sneezing No 0 1 1 Snoring No 0 1 1 Tachypnoea No 0 3 3 Upper respiratory tract congestion No 0 1 1 Upper respiratory tract inflammation No 0 1 1 Upper respiratory tract disorders (excl infections) Epistaxis No 0 2 2 Nasal congestion No 0 1 1 Pharyngeal erythema No 0 7 7 Stridor No 2 0 2 Tonsillar disorder No 0 1 1 Tonsillar hypertrophy No 0 1 1 Skin and subcutaneous tissue disorders Angioedema and urticaria Angioedema Yes 4 0 4 Urticaria Yes 0 20 20 Urticaria papular No 0 2 2 Urticaria thermal No 0 1 1 CONFIDENTIAL 532 CONFIDENTIAL 580 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Cornification and dystrophic skin disorders Keloid scar No 0 1 1 Cutaneous neoplasms benign Dermal cyst No 0 1 1 Epidermal and dermal conditions Blister No 0 5 5 Decubitus ulcer No 0 1 1 Dermatitis Yes 0 1 1 Dermatitis allergic Yes 0 1 1 Dermatitis atopic Yes 0 2 2 Dermatitis diaper Yes 0 1 1 Dry skin No 0 1 1 Eczema Yes 0 10 10 Erythema Yes 0 57 57 Erythema multiforme Yes 2 0 2 Erythrosis No 0 1 1 Generalised erythema Yes 0 2 2 Granuloma skin No 0 1 1 Macule Yes 0 1 1 Neurodermatitis Yes 0 2 2 Palmar erythema Yes 0 1 1 Papule Yes 0 3 3 CONFIDENTIAL 533 CONFIDENTIAL 581 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Pemphigoid No 1 0 1 Pruritus Yes 0 5 5 Rash Yes 0 35 35 Rash erythematous Yes 0 4 4 Rash generalised Yes 0 7 7 Rash macular Yes 0 10 10 Rash maculo-papular Yes 0 5 5 Rash morbilliform Yes 0 5 5 Rash papular Yes 0 2 2 Rash pruritic Yes 0 1 1 Rash vesicular Yes 0 2 2 Scab No 0 3 3 Scar No 0 3 3 Seborrhoeic dermatitis Yes 0 1 1 Skin discolouration No 0 16 16 Skin disorder No 0 1 1 Skin exfoliation Yes 0 3 3 Skin induration No 0 1 1 Skin lesion No 0 3 3 CONFIDENTIAL 534 CONFIDENTIAL 582 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Skin reaction No 0 2 2 Skin tightness No 0 1 1 Skin warm No 0 9 9 Stevens-Johnson syndrome Yes 1 0 1 Swelling face Yes 0 2 2 Toxic skin eruption Yes 0 1 1 Yellow skin No 2 0 2 Pigmentation disorders Skin depigmentation No 0 2 2 Skin and subcutaneous tissue disorders NEC Erythema nodosum No 0 1 1 Lipoatrophy No 1 0 1 Skin erosion No 0 1 1 Skin ulcer No 0 1 1 Subcutaneous nodule No 0 2 2 Skin appendage conditions Acne Yes 0 1 1 Cold sweat No 0 1 1 Hyperhidrosis No 0 9 9 Hypertrichosis No 0 2 2 Skin vascular abnormalities Acute haemorrhagic oedema of infancy No 1 0 1 Ecchymosis No 0 3 3 CONFIDENTIAL 535 CONFIDENTIAL 583 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Henoch-Schonlein purpura No 1 0 1 Increased tendency to bruise No 0 1 1 Lividity No 0 5 5 Petechiae No 0 23 23 Purpura No 0 2 2 Social circumstances Lifestyle issues Disability No 1 0 1 Immobile No 0 3 3 Surgical and medical procedures Nervous system, skull and spine therapeutic procedures Neurosurgery No 0 1 1 Respiratory tract therapeutic procedures Endotracheal intubation No 0 1 1 Therapeutic procedures and supportive care NEC Abscess drainage No 0 1 1 Debridement No 0 1 1 Off label use No 0 11 11 Surgery No 0 1 1 Vascular disorders Arteriosclerosis, stenosis, vascular insufficiency and necrosis Peripheral coldness Yes 0 5 5 Decreased and nonspecific blood pressure disorders and shock Circulatory collapse Yes 7 0 7 Shock Yes 4 0 4 Vascular disorders NEC Flushing No 0 3 3 Hyperaemia No 0 7 7 CONFIDENTIAL 536 CONFIDENTIAL 584 MedDRA SOC HLGT Event (PT) Listed Serious Nonserious Total Cases for current period Pallor No 0 88 88 Vasodilatation No 0 1 1 Vascular haemorrhagic disorders Haematoma No 0 10 10 Haemorrhage No 1 0 1 Vascular hypertensive disorders Hypertension No 0 1 1 Vascular inflammations Kawasaki’s disease No 0 3 3 CONFIDENTIAL 537 CONFIDENTIAL 585 538 CONFIDENTIAL APPENDIX 4B : All reported AEs for cases included in APPENDIX 3C CONFIDENTIAL 586 Appendix 4B: Summary Tabulation of Adverse Events for Non-Serious Listed Cases for: Infanrix hexa N.B. Events are considered non serious against GSK list of medically serious terms (see section 6.3.) MedDRA SOC HLGT Event PT Non-serious Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymphadenopathy 1 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Diarrhoea 4 Gastrointestinal signs and symptoms Vomiting 2 General disorders and administration site conditions Administration site reactions Injection site erythema 14 Injection site oedema 11 Injection site pain 6 Injection site swelling 7 Body temperature conditions Pyrexia 27 General system disorders NEC Extensive swelling of vaccinated limb 4 Therapeutic and nontherapeutic effects (excl toxicity) No therapeutic response 2 Immune system disorders Allergic conditions Hypersensitivity 1 Investigations Physical examination topics Body temperature increased 3 Metabolism and nutrition disorders Appetite and general nutritional disorders Decreased appetite 1 Nervous system disorders Neurological disorders NEC Crying 7 Somnolence 2 Psychiatric disorders Changes in physical activity Restlessness 1 Skin and subcutaneous tissue disorders Angioedema and urticaria Urticaria 9 Epidermal and dermal conditions Eczema 1 Pruritus 1 Rash 4 Rash generalised 1 Rash morbilliform 1 CONFIDENTIAL 539 CONFIDENTIAL 587 540 CONFIDENTIAL APPENDIX 4C : All reported AEs from non-medically verified serious cases and non-serious unlisted cases (no such case was received during the period) CONFIDENTIAL 588 541 CONFIDENTIAL APPENDIX 4D : All reported AEs from non-medically verified non-serious listed cases CONFIDENTIAL 589 Appendix 4D: Summary Tabulation of Adverse Events from Non-Medically Verified, Non-Serious Listed Cases for: Infanrix hexa N.B. Events are considered non serious against GSK list of medically serious terms (see section 6.3.) MedDRA SOC HLGT Event (PT) Non-serious General disorders and administration site conditions Administration site reactions Injection site erythema 3 Injection site induration 1 Injection site swelling 2 Body temperature conditions Pyrexia 4 General system disorders NEC Extensive swelling of vaccinated limb 1 Irritability 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Eczema 1 Erythema 1 Pruritus 1 CONFIDENTIAL 542 CONFIDENTIAL 590 543 CONFIDENTIAL APPENDIX 4E : Cumulative tabulation of all unlisted events from serious unlisted spontaneous reports and all serious unlisted reactions from clinical trial cases reported since launch CONFIDENTIAL 591 MedDRA SOC MedDRA HLGT MedDRA PT Number of AEs Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Anaemia 1 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Anaemia 31 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Aplastic anaemia 1 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Bicytopenia 1 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Bone marrow failure 1 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Haemorrhagic anaemia 3 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Hypochromic anaemia 4 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Iron deficiency anaemia 4 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Microcytic anaemia 3 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Pancytopenia 4 Blood and lymphatic system disorders Anaemias nonhaemolytic and marrow depression Protein deficiency anaemia 1 Blood and lymphatic system disorders Coagulopathies and bleeding diatheses (excl thrombocytopenic) Coagulopathy 3 Blood and lymphatic system disorders Coagulopathies and bleeding diatheses (excl thrombocytopenic) Disseminated intravascular coagulation 5 Blood and lymphatic system disorders Coagulopathies and bleeding diatheses (excl thrombocytopenic) Haemorrhagic diathesis 4 Blood and lymphatic system disorders Haematological disorders NEC Hypergammaglobu linaemia 1 Blood and lymphatic system disorders Haemolyses and related conditions Anaemia haemolytic autoimmune 4 Blood and lymphatic system disorders Haemolyses and related conditions Haemolysis 4 Blood and lymphatic system disorders Haemolyses and related conditions Haemolytic anaemia 3 Blood and lymphatic system disorders Haemolyses and related conditions Haemolytic uraemic syndrome 1 Blood and lymphatic system disorders Haemolyses and related conditions Jaundice acholuric 1 Blood and lymphatic system disorders Haemolyses and related conditions Warm type haemolytic anaemia 1 Blood and lymphatic system disorders Platelet disorders Autoimmune thrombocytopenia 7 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Cumulative count 23oct2000 to 22oct2011 Drug PTT decode : IGA182 Date of Refresh : 07Nov2011 Event level Seriousness No CONFIDENTIAL 544 CONFIDENTIAL 592 Blood and lymphatic system disorders Platelet disorders Idiopathic thrombocytopenic purpura 26 Blood and lymphatic system disorders Platelet disorders Thrombocytopenia 1 Blood and lymphatic system disorders Platelet disorders Thrombocytopenia 41 Blood and lymphatic system disorders Platelet disorders Thrombocytopenic purpura 12 Blood and lymphatic system disorders Platelet disorders Thrombocytosis 10 Blood and lymphatic system disorders Red blood cell disorders Hypochromasia 1 Blood and lymphatic system disorders Red blood cell disorders Microcytosis 2 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymphadenitis 5 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymphadenitis 1 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymphadenopathy 25 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymphadenopathy 2 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymphatic disorder 1 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Lymph node pain 1 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Splenitis 1 Blood and lymphatic system disorders Spleen, lymphatic and reticuloendothelial system disorders Splenomegaly 6 Blood and lymphatic system disorders White blood cell disorders Agranulocytosis 3 Blood and lymphatic system disorders White blood cell disorders Autoimmune neutropenia 1 Blood and lymphatic system disorders White blood cell disorders Eosinophilia 7 Blood and lymphatic system disorders White blood cell disorders Febrile neutropenia 1 Blood and lymphatic system disorders White blood cell disorders Granulocytopenia 5 Blood and lymphatic system disorders White blood cell disorders Leukocytosis 1 Blood and lymphatic system disorders White blood cell disorders Leukocytosis 32 Blood and lymphatic system disorders White blood cell disorders Leukopenia 5 Blood and lymphatic system disorders White blood cell disorders Lymphocytic infiltration 1 Blood and lymphatic system disorders White blood cell disorders Lymphocytosis 7 Blood and lymphatic system disorders White blood cell disorders Lymphopenia 2 Yes Yes No Yes Yes Yes Yes No Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes No Yes Yes No Yes CONFIDENTIAL 545 CONFIDENTIAL 593 Blood and lymphatic system disorders White blood cell disorders Monocytosis 2 Blood and lymphatic system disorders White blood cell disorders Neutropenia 16 Blood and lymphatic system disorders White blood cell disorders Neutrophilia 1 Blood and lymphatic system disorders White blood cell disorders White blood cell disorder 1 Cardiac disorders Cardiac arrhythmias Arrhythmia 4 Cardiac disorders Cardiac arrhythmias Atrial tachycardia 1 Cardiac disorders Cardiac arrhythmias Atrioventricular block 1 Cardiac disorders Cardiac arrhythmias Bradycardia 43 Cardiac disorders Cardiac arrhythmias Cardiac arrest 12 Cardiac disorders Cardiac arrhythmias Cardio-respiratory arrest 6 Cardiac disorders Cardiac arrhythmias Extrasystoles 1 Cardiac disorders Cardiac arrhythmias Sinus arrhythmia 1 Cardiac disorders Cardiac arrhythmias Sinus bradycardia 1 Cardiac disorders Cardiac arrhythmias Sinus tachycardia 1 Cardiac disorders Cardiac arrhythmias Supraventricular tachycardia 1 Cardiac disorders Cardiac arrhythmias Tachycardia 30 Cardiac disorders Cardiac arrhythmias Tachycardia 1 Cardiac disorders Cardiac arrhythmias Ventricular asystole 1 Cardiac disorders Cardiac arrhythmias Ventricular flutter 1 Cardiac disorders Cardiac arrhythmias Ventricular tachycardia 1 Cardiac disorders Cardiac arrhythmias Wolff-ParkinsonWhite syndrome 2 Cardiac disorders Cardiac disorder signs and symptoms Cardiovascular disorder 12 Cardiac disorders Cardiac disorder signs and symptoms Cardiovascular disorder 1 Cardiac disorders Cardiac disorder signs and symptoms Cardiovascular insufficiency 1 Cardiac disorders Cardiac disorder signs and symptoms Cyanosis 38 Cardiac disorders Cardiac disorder signs and symptoms Cyanosis 234 Cardiac disorders Cardiac valve disorders Aortic valve incompetence 1 Cardiac disorders Cardiac valve disorders Mitral valve disease 2 Cardiac disorders Cardiac valve disorders Mitral valve incompetence 1 Cardiac disorders Cardiac valve disorders Pulmonary valve stenosis 1 Cardiac disorders Cardiac valve disorders Supravalvular aortic stenosis 1 Cardiac disorders Coronary artery disorders Arteritis coronary 2 Yes Yes Yes No Yes Yes No Yes Yes No Yes Yes No No Yes No Yes Yes Yes No Yes Yes No No Yes Yes Yes Yes No Yes Yes Yes CONFIDENTIAL 546 CONFIDENTIAL 594 Cardiac disorders Coronary artery disorders Coronary artery aneurysm 1 Cardiac disorders Coronary artery disorders Coronary artery dilatation 2 Cardiac disorders Coronary artery disorders Coronary artery disease 1 Cardiac disorders Coronary artery disorders Myocardial infarction 3 Cardiac disorders Endocardial disorders Endocardial fibrosis 1 Cardiac disorders Heart failures Cardiac failure 6 Cardiac disorders Heart failures Cardiac failure acute 1 Cardiac disorders Heart failures Cardiogenic shock 1 Cardiac disorders Heart failures Cardiopulmonary failure 4 Cardiac disorders Myocardial disorders Atrial septal defect acquired 1 Cardiac disorders Myocardial disorders Cardiomegaly 2 Cardiac disorders Myocardial disorders Cardiomyopathy 1 Cardiac disorders Myocardial disorders Congestive cardiomyopathy 3 Cardiac disorders Myocardial disorders Hypertrophic cardiomyopathy 1 Cardiac disorders Myocardial disorders Myocarditis 3 Cardiac disorders Pericardial disorders Pericardial effusion 4 Cardiac disorders Pericardial disorders Pericarditis 1 Congenital, familial and genetic disorders Blood and lymphatic system disorders congenital Haemophilia 1 Congenital, familial and genetic disorders Blood and lymphatic system disorders congenital Infantile genetic agranulocytosis 2 Congenital, familial and genetic disorders Cardiac and vascular disorders congenital Atrial septal defect 5 Congenital, familial and genetic disorders Chromosomal abnormalities and abnormal gene carriers Cytogenetic abnormality 1 Congenital, familial and genetic disorders Congenital and hereditary disorders NEC Familial mediterranean fever 1 Congenital, familial and genetic disorders Cytoplasmic disorders congenital Mitochondrial encephalomyopath y 1 Congenital, familial and genetic disorders Gastrointestinal tract disorders congenital Pyloric stenosis 1 Congenital, familial and genetic disorders Immune system disorders congenital Thymus hypoplasia 1 Congenital, familial and genetic disorders Metabolic and nutritional disorders congenital Glycogen storage disorder 1 Congenital, familial and genetic disorders Metabolic and nutritional disorders congenital Leukodystrophy 2 No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes No No Yes No CONFIDENTIAL 547 CONFIDENTIAL 595 Congenital, familial and genetic disorders Metabolic and nutritional disorders congenital Methylmalonic aciduria 1 Congenital, familial and genetic disorders Metabolic and nutritional disorders congenital Rett’s disorder 1 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Dysmorphism 1 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Macrocephaly 1 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Microcephaly 4 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Plagiocephaly 2 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Skull malformation 1 Congenital, familial and genetic disorders Musculoskeletal and connective tissue disorders congenital Talipes 1 Congenital, familial and genetic disorders Neurological disorders congenital Aicardi’s syndrome 1 Congenital, familial and genetic disorders Neurological disorders congenital Benign familial neonatal convulsions 1 Congenital, familial and genetic disorders Neurological disorders congenital Cerebral palsy 4 Congenital, familial and genetic disorders Neurological disorders congenital Congenital neuropathy 1 Congenital, familial and genetic disorders Neurological disorders congenital Lissencephaly 1 Congenital, familial and genetic disorders Neurological disorders congenital Microencephaly 1 Congenital, familial and genetic disorders Neurological disorders congenital Tuberous sclerosis 2 Congenital, familial and genetic disorders Renal and urinary tract disorders congenital Renal hypoplasia 1 Congenital, familial and genetic disorders Reproductive tract and breast disorders congenital Hydrocele 2 Congenital, familial and genetic disorders Reproductive tract and breast disorders congenital Hydrocele 2 Congenital, familial and genetic disorders Reproductive tract and breast disorders congenital Phimosis 1 Ear and labyrinth disorders Aural disorders NEC Ear pain 1 Ear and labyrinth disorders Aural disorders NEC Ear pain 1 Yes Yes Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes CONFIDENTIAL 548 CONFIDENTIAL 596 Ear and labyrinth disorders External ear disorders (excl congenital) Auricular perichondritis 1 Ear and labyrinth disorders External ear disorders (excl congenital) Auricular swelling 1 Ear and labyrinth disorders External ear disorders (excl congenital) Auricular swelling 1 Ear and labyrinth disorders External ear disorders (excl congenital) Cerumen impaction 1 Ear and labyrinth disorders Hearing disorders Deafness 2 Ear and labyrinth disorders Hearing disorders Deafness neurosensory 1 Ear and labyrinth disorders Hearing disorders Hyperacusis 1 Ear and labyrinth disorders Inner ear and VIIIth cranial nerve disorders Vertigo 1 Ear and labyrinth disorders Middle ear disorders (excl congenital) Otosalpingitis 1 Ear and labyrinth disorders Middle ear disorders (excl congenital) Tympanic membrane disorder 1 Ear and labyrinth disorders Middle ear disorders (excl congenital) Tympanic membrane hyperaemia 6 Ear and labyrinth disorders Middle ear disorders (excl congenital) Tympanic membrane perforation 2 Endocrine disorders Endocrine and glandular disorders NEC Endocrine pancreatic disorder 1 Endocrine disorders Thyroid gland disorders Hypothyroidism 5 Eye disorders Eye disorders NEC Eye disorder 22 Eye disorders Eye disorders NEC Eyelid disorder 7 Eye disorders Eye disorders NEC Eye oedema 1 Eye disorders Eye disorders NEC Eye swelling 2 Eye disorders Eye disorders NEC Lacrimation increased 4 Eye disorders Eye disorders NEC Periorbital oedema 1 Eye disorders Ocular haemorrhages and vascular disorders NEC Conjunctival haemorrhage 3 Eye disorders Ocular haemorrhages and vascular disorders NEC Corneal bleeding 1 Eye disorders Ocular infections, irritations and inflammations Conjunctival hyperaemia 3 Eye disorders Ocular infections, irritations and inflammations Conjunctivitis 16 Eye disorders Ocular infections, irritations and inflammations Eye discharge 1 Eye disorders Ocular infections, irritations and inflammations Eyelid oedema 9 Eye disorders Ocular infections, irritations and inflammations Ocular hyperaemia 1 Eye disorders Ocular neuromuscular disorders Binocular eye movement disorder 2 Eye disorders Ocular neuromuscular disorders Blepharospasm 3 Eye disorders Ocular neuromuscular disorders Excessive eye blinking 1 No No No No No No No No No No No Yes No No No Yes No No No Yes No No No No No No No Yes No Yes CONFIDENTIAL 549 CONFIDENTIAL 597 Eye disorders Ocular neuromuscular disorders Eyelid function disorder 1 Eye disorders Ocular neuromuscular disorders Eyelid ptosis 3 Eye disorders Ocular neuromuscular disorders Eye movement disorder 87 Eye disorders Ocular neuromuscular disorders Eye movement disorder 3 Eye disorders Ocular neuromuscular disorders Gaze palsy 68 Eye disorders Ocular neuromuscular disorders Mydriasis 1 Eye disorders Ocular neuromuscular disorders Oculogyric crisis 3 Eye disorders Ocular neuromuscular disorders Ophthalmoplegia 3 Eye disorders Ocular neuromuscular disorders Opsoclonus myoclonus 2 Eye disorders Ocular neuromuscular disorders Pupil fixed 1 Eye disorders Ocular neuromuscular disorders Pupillary reflex impaired 1 Eye disorders Ocular neuromuscular disorders Pupils unequal 1 Eye disorders Ocular neuromuscular disorders Saccadic eye movement 1 Eye disorders Ocular neuromuscular disorders Strabismus 18 Eye disorders Ocular sensory symptoms NEC Asthenopia 1 Eye disorders Ocular sensory symptoms NEC Photophobia 2 Eye disorders Retina, choroid and vitreous haemorrhages and vascular disorders Retinal haemorrhage 4 Eye disorders Vision disorders Anisometropia 1 Eye disorders Vision disorders Astigmatism 1 Eye disorders Vision disorders Diplopia 1 Eye disorders Vision disorders Hypermetropia 2 Eye disorders Vision disorders Vision blurred 2 Eye disorders Vision disorders Visual acuity reduced 1 Eye disorders Vision disorders Visual impairment 4 Gastrointestinal disorders Abdominal hernias and other abdominal wall conditions Inguinal hernia 2 Gastrointestinal disorders Abdominal hernias and other abdominal wall conditions Umbilical hernia 1 Gastrointestinal disorders Dental and gingival conditions Gingival bleeding 2 Gastrointestinal disorders Gastrointestinal conditions NEC Anal fistula 1 Gastrointestinal disorders Gastrointestinal conditions NEC Disbacteriosis 1 Gastrointestinal disorders Gastrointestinal conditions NEC Gastrointestinal disorder 2 Gastrointestinal disorders Gastrointestinal conditions NEC Hyperchlorhydria 1 Gastrointestinal disorders Gastrointestinal conditions NEC Intestinal mucosal hypertrophy 1 No No No No No No No No No No No No No No No No No No No No Yes No Yes Yes No No No No No No Yes Yes CONFIDENTIAL 550 CONFIDENTIAL 598 Gastrointestinal disorders Gastrointestinal haemorrhages NEC Gastrointestinal haemorrhage 2 Gastrointestinal disorders Gastrointestinal haemorrhages NEC Haematochezia 7 Gastrointestinal disorders Gastrointestinal haemorrhages NEC Haematochezia 9 Gastrointestinal disorders Gastrointestinal haemorrhages NEC Melaena 2 Gastrointestinal disorders Gastrointestinal haemorrhages NEC Rectal haemorrhage 4 Gastrointestinal disorders Gastrointestinal inflammatory conditions Colitis 4 Gastrointestinal disorders Gastrointestinal inflammatory conditions Duodenitis 2 Gastrointestinal disorders Gastrointestinal inflammatory conditions Enteritis 8 Gastrointestinal disorders Gastrointestinal inflammatory conditions Enterocolitis 1 Gastrointestinal disorders Gastrointestinal inflammatory conditions Eosinophilic colitis 1 Gastrointestinal disorders Gastrointestinal inflammatory conditions Gastritis 2 Gastrointestinal disorders Gastrointestinal inflammatory conditions Gastroenteritis eosinophilic 2 Gastrointestinal disorders Gastrointestinal inflammatory conditions Gastrointestinal inflammation 2 Gastrointestinal disorders Gastrointestinal inflammatory conditions Oesophagitis 2 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Constipation 11 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Diarrhoea 1 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Diarrhoea haemorrhagic 12 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Dyskinesia oesophageal 1 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Gastrointestinal hypomotility 1 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Gastrointestinal motility disorder 1 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Gastrooesophagea l reflux disease 17 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Gastrooesophagea l reflux disease 1 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Ileus paralytic 3 Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Intestinal dilatation 2 Gastrointestinal disorders Gastrointestinal signs and symptoms Abdominal discomfort 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Abdominal distension 8 Gastrointestinal disorders Gastrointestinal signs and symptoms Abdominal pain 14 Gastrointestinal disorders Gastrointestinal signs and symptoms Abdominal pain 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Abdominal pain upper 1 Yes No Yes Yes No No No No No Yes No No Yes No Yes No Yes No No No Yes Yes Yes No Yes Yes Yes No Yes CONFIDENTIAL 551 CONFIDENTIAL 599 Gastrointestinal disorders Gastrointestinal signs and symptoms Abdominal rigidity 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Abnormal faeces 13 Gastrointestinal disorders Gastrointestinal signs and symptoms Abnormal faeces 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Acute abdomen 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Aphagia 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Dyspepsia 3 Gastrointestinal disorders Gastrointestinal signs and symptoms Dysphagia 6 Gastrointestinal disorders Gastrointestinal signs and symptoms Faecal incontinence 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Faecal incontinence 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Faeces discoloured 11 Gastrointestinal disorders Gastrointestinal signs and symptoms Flatulence 7 Gastrointestinal disorders Gastrointestinal signs and symptoms Gastrointestinal pain 2 Gastrointestinal disorders Gastrointestinal signs and symptoms Gastrointestinal sounds abnormal 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Mucous stools 5 Gastrointestinal disorders Gastrointestinal signs and symptoms Nausea 7 Gastrointestinal disorders Gastrointestinal signs and symptoms Nausea 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Post-tussive vomiting 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Regurgitation 6 Gastrointestinal disorders Gastrointestinal signs and symptoms Vomiting 1 Gastrointestinal disorders Gastrointestinal signs and symptoms Vomiting 1 Gastrointestinal disorders Gastrointestinal stenosis and obstruction Intestinal obstruction 1 Gastrointestinal disorders Gastrointestinal stenosis and obstruction Intussusception 9 Gastrointestinal disorders Gastrointestinal stenosis and obstruction Subileus 1 Gastrointestinal disorders Malabsorption conditions Malabsorption 1 Gastrointestinal disorders Malabsorption conditions Steatorrhoea 1 Gastrointestinal disorders Oral soft tissue conditions Aphthous stomatitis 6 Gastrointestinal disorders Oral soft tissue conditions Chapped lips 4 Gastrointestinal disorders Oral soft tissue conditions Cheilitis 7 Gastrointestinal disorders Oral soft tissue conditions Lip disorder 2 No Yes No No No No No No No No Yes Yes Yes No No No No No Yes No No No No Yes No No No Yes Yes CONFIDENTIAL 552 CONFIDENTIAL 600 Gastrointestinal disorders Oral soft tissue conditions Lip haematoma 1 Gastrointestinal disorders Oral soft tissue conditions Lip oedema 3 Gastrointestinal disorders Oral soft tissue conditions Lip swelling 3 Gastrointestinal disorders Oral soft tissue conditions Mouth haemorrhage 6 Gastrointestinal disorders Oral soft tissue conditions Mouth haemorrhage 1 Gastrointestinal disorders Oral soft tissue conditions Oral discharge 1 Gastrointestinal disorders Oral soft tissue conditions Oral mucosal erythema 1 Gastrointestinal disorders Oral soft tissue conditions Stomatitis 3 Gastrointestinal disorders Oral soft tissue conditions Stomatitis haemorrhagic 1 Gastrointestinal disorders Peritoneal and retroperitoneal conditions Ascites 5 Gastrointestinal disorders Peritoneal and retroperitoneal conditions Peritoneal disorder 1 Gastrointestinal disorders Salivary gland conditions Lip dry 1 Gastrointestinal disorders Salivary gland conditions Salivary hypersecretion 36 Gastrointestinal disorders Tongue conditions Glossoptosis 1 Gastrointestinal disorders Tongue conditions Hypertrophy of tongue papillae 1 Gastrointestinal disorders Tongue conditions Protrusion tongue 2 Gastrointestinal disorders Tongue conditions Swollen tongue 1 Gastrointestinal disorders Tongue conditions Tongue discolouration 1 General disorders and administration site conditions Administration site reactions Application site discolouration 1 General disorders and administration site conditions Administration site reactions Application site rash 1 General disorders and administration site conditions Administration site reactions Embolia cutis medicamentosa 4 General disorders and administration site conditions Administration site reactions Injected limb mobility decreased 6 General disorders and administration site conditions Administration site reactions Injection site abscess sterile 7 General disorders and administration site conditions Administration site reactions Injection site abscess sterile 1 General disorders and administration site conditions Administration site reactions Injection site atrophy 1 General disorders and administration site conditions Administration site reactions Injection site dermatitis 1 Yes Yes No No No No Yes No No No No No No No No No Yes No Yes Yes No No No No No Yes CONFIDENTIAL 553 CONFIDENTIAL 601 General disorders and administration site conditions Administration site reactions Injection site discolouration 9 General disorders and administration site conditions Administration site reactions Injection site erythema 1 General disorders and administration site conditions Administration site reactions Injection site extravasation 14 General disorders and administration site conditions Administration site reactions Injection site haematoma 14 General disorders and administration site conditions Administration site reactions Injection site haemorrhage 4 General disorders and administration site conditions Administration site reactions Injection site induration 72 General disorders and administration site conditions Administration site reactions Injection site induration 3 General disorders and administration site conditions Administration site reactions Injection site inflammation 17 General disorders and administration site conditions Administration site reactions Injection site mass 1 General disorders and administration site conditions Administration site reactions Injection site necrosis 6 General disorders and administration site conditions Administration site reactions Injection site nodule 27 General disorders and administration site conditions Administration site reactions Injection site nodule 3 General disorders and administration site conditions Administration site reactions Injection site pain 1 General disorders and administration site conditions Administration site reactions Injection site pallor 1 General disorders and administration site conditions Administration site reactions Injection site pruritus 5 General disorders and administration site conditions Administration site reactions Injection site rash 6 General disorders and administration site conditions Administration site reactions Injection site reaction 55 General disorders and administration site conditions Administration site reactions Injection site scab 1 General disorders and administration site conditions Administration site reactions Injection site scar 1 General disorders and administration site conditions Administration site reactions Injection site swelling 1 General disorders and administration site conditions Administration site reactions Injection site swelling 1 No No No No No Yes Yes No Yes No No No No No No Yes No No No No No CONFIDENTIAL 554 CONFIDENTIAL 602 General disorders and administration site conditions Administration site reactions Injection site urticaria 4 General disorders and administration site conditions Administration site reactions Injection site vesicles 9 General disorders and administration site conditions Administration site reactions Injection site warmth 41 General disorders and administration site conditions Administration site reactions Injection site warmth 1 General disorders and administration site conditions Administration site reactions Vaccination site abscess sterile 1 General disorders and administration site conditions Body temperature conditions Hyperpyrexia 29 General disorders and administration site conditions Body temperature conditions Hyperpyrexia 2 General disorders and administration site conditions Body temperature conditions Hyperthermia 10 General disorders and administration site conditions Body temperature conditions Hyperthermia 1 General disorders and administration site conditions Body temperature conditions Hypothermia 9 General disorders and administration site conditions Body temperature conditions Pyrexia 4 General disorders and administration site conditions Device issues Device dislocation 1 General disorders and administration site conditions Fatal outcomes Brain death 2 General disorders and administration site conditions Fatal outcomes Death 20 General disorders and administration site conditions Fatal outcomes Sudden cardiac death 1 General disorders and administration site conditions Fatal outcomes Sudden death 9 General disorders and administration site conditions Fatal outcomes Sudden infant death syndrome 72 General disorders and administration site conditions General system disorders NEC Abasia 2 General disorders and administration site conditions General system disorders NEC Abscess sterile 22 General disorders and administration site conditions General system disorders NEC Asthenia 51 General disorders and administration site conditions General system disorders NEC Asthenia 2 Yes No Yes Yes Yes Yes Yes Yes No Yes No Yes No No No No No No Yes Yes No CONFIDENTIAL 555 CONFIDENTIAL 603 General disorders and administration site conditions General system disorders NEC Chest discomfort 1 General disorders and administration site conditions General system disorders NEC Chest pain 1 General disorders and administration site conditions General system disorders NEC Chills 21 General disorders and administration site conditions General system disorders NEC Condition aggravated 4 General disorders and administration site conditions General system disorders NEC Developmental delay 39 General disorders and administration site conditions General system disorders NEC Developmental delay 3 General disorders and administration site conditions General system disorders NEC Discomfort 4 General disorders and administration site conditions General system disorders NEC Disease recurrence 1 General disorders and administration site conditions General system disorders NEC Enanthema 1 General disorders and administration site conditions General system disorders NEC Face oedema 3 General disorders and administration site conditions General system disorders NEC Fatigue 67 General disorders and administration site conditions General system disorders NEC Fatigue 1 General disorders and administration site conditions General system disorders NEC Feeling abnormal 5 General disorders and administration site conditions General system disorders NEC Feeling cold 4 General disorders and administration site conditions General system disorders NEC Feeling hot 11 General disorders and administration site conditions General system disorders NEC Feeling of body temperature change 1 General disorders and administration site conditions General system disorders NEC Feeling of relaxation 3 General disorders and administration site conditions General system disorders NEC Feeling of relaxation 1 General disorders and administration site conditions General system disorders NEC Foaming at mouth 17 General disorders and administration site conditions General system disorders NEC Foreign body reaction 2 General disorders and administration site conditions General system disorders NEC Gait disturbance 23 No No Yes No No No No No Yes No No No No No Yes No No No No No No CONFIDENTIAL 556 CONFIDENTIAL 604 General disorders and administration site conditions General system disorders NEC Gait disturbance 1 General disorders and administration site conditions General system disorders NEC Generalised oedema 1 General disorders and administration site conditions General system disorders NEC Generalised oedema 1 General disorders and administration site conditions General system disorders NEC General physical health deterioration 53 General disorders and administration site conditions General system disorders NEC General physical health deterioration 3 General disorders and administration site conditions General system disorders NEC General symptom 1 General disorders and administration site conditions General system disorders NEC Granuloma 2 General disorders and administration site conditions General system disorders NEC Ill-defined disorder 58 General disorders and administration site conditions General system disorders NEC Ill-defined disorder 1 General disorders and administration site conditions General system disorders NEC Induration 11 General disorders and administration site conditions General system disorders NEC Induration 1 General disorders and administration site conditions General system disorders NEC Inflammation 31 General disorders and administration site conditions General system disorders NEC Influenza like illness 3 General disorders and administration site conditions General system disorders NEC Irritability 1 General disorders and administration site conditions General system disorders NEC Irritability 1 General disorders and administration site conditions General system disorders NEC Localised oedema 3 General disorders and administration site conditions General system disorders NEC Local reaction 11 General disorders and administration site conditions General system disorders NEC Local swelling 7 General disorders and administration site conditions General system disorders NEC Malaise 36 General disorders and administration site conditions General system disorders NEC Mucosal dryness 1 General disorders and administration site conditions General system disorders NEC Mucosal haemorrhage 1 No No Yes No No Yes No No No No No Yes No Yes No Yes No Yes No Yes No CONFIDENTIAL 557 CONFIDENTIAL 605 General disorders and administration site conditions General system disorders NEC Mucosal inflammation 1 General disorders and administration site conditions General system disorders NEC Mucous membrane disorder 1 General disorders and administration site conditions General system disorders NEC Multi-organ failure 7 General disorders and administration site conditions General system disorders NEC No adverse event 2 General disorders and administration site conditions General system disorders NEC Nonspecific reaction 2 General disorders and administration site conditions General system disorders NEC Oedema 9 General disorders and administration site conditions General system disorders NEC Oedema peripheral 82 General disorders and administration site conditions General system disorders NEC Oedema peripheral 9 General disorders and administration site conditions General system disorders NEC Pain 43 General disorders and administration site conditions General system disorders NEC Pneumatosis 1 General disorders and administration site conditions General system disorders NEC Sense of oppression 1 General disorders and administration site conditions General system disorders NEC Swelling 22 General disorders and administration site conditions General system disorders NEC Systemic inflammatory response syndrome 2 General disorders and administration site conditions General system disorders NEC Thirst decreased 2 General disorders and administration site conditions Product quality issues Product quality issue 28 General disorders and administration site conditions Therapeutic and nontherapeutic effects (excl toxicity) Adverse drug reaction 1 General disorders and administration site conditions Therapeutic and nontherapeutic effects (excl toxicity) Adverse event 2 General disorders and administration site conditions Tissue disorders NEC Atrophy 1 General disorders and administration site conditions Tissue disorders NEC Cyst 2 General disorders and administration site conditions Tissue disorders NEC Cyst 1 No No Yes No Yes No No No Yes No No No No No No Yes No No No Yes CONFIDENTIAL 558 CONFIDENTIAL 606 General disorders and administration site conditions Tissue disorders NEC Dysplasia 2 General disorders and administration site conditions Tissue disorders NEC Hyperplasia 3 General disorders and administration site conditions Tissue disorders NEC Hypertrophy 1 General disorders and administration site conditions Tissue disorders NEC Mass 1 General disorders and administration site conditions Tissue disorders NEC Necrosis 4 General disorders and administration site conditions Tissue disorders NEC Nodule 4 General disorders and administration site conditions Tissue disorders NEC Ulcer 1 Hepatobiliary disorders Gallbladder disorders Cholecystitis 1 Hepatobiliary disorders Gallbladder disorders Cholelithiasis 1 Hepatobiliary disorders Gallbladder disorders Gallbladder disorder 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Acute hepatic failure 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Cholestasis 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatic failure 2 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatic function abnormal 3 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatic steatosis 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatitis acute 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatitis neonatal 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatomegaly 2 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatosplenomeg aly 2 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hepatotoxicity 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Hypertransaminas aemia 1 Hepatobiliary disorders Hepatic and hepatobiliary disorders Jaundice 8 Hepatobiliary disorders Hepatic and hepatobiliary disorders Liver disorder 4 Immune system disorders Allergic conditions Allergy to metals 2 Immune system disorders Allergic conditions Anaphylactic reaction 1 Immune system disorders Allergic conditions Atopy 1 No Yes Yes Yes No No Yes No Yes Yes Yes No No Yes No No Yes Yes Yes No No No Yes No No No CONFIDENTIAL 559 CONFIDENTIAL 607 Immune system disorders Allergic conditions Food allergy 3 Immune system disorders Allergic conditions Hypersensitivity 1 Immune system disorders Allergic conditions Milk allergy 2 Immune system disorders Allergic conditions Multiple allergies 1 Immune system disorders Allergic conditions Serum sickness 1 Immune system disorders Allergic conditions Type III immune complex mediated reaction 2 Immune system disorders Immune disorders NEC Decreased immune responsiveness 1 Immune system disorders Immune disorders NEC Immunisation reaction 1 Immune system disorders Immune disorders NEC Immunisation reaction 1 Immune system disorders Immunodeficiency syndromes Hypogammaglobul inaemia 1 Infections and infestations Ancillary infectious topics Transmission of an infectious agent via a medicinal product 1 Infections and infestations Bacterial infectious disorders Bacterial infection 5 Infections and infestations Bacterial infectious disorders Bacterial pyelonephritis 1 Infections and infestations Bacterial infectious disorders Bacterial tracheitis 1 Infections and infestations Bacterial infectious disorders Bronchitis bacterial 2 Infections and infestations Bacterial infectious disorders Cellulitis 28 Infections and infestations Bacterial infectious disorders Clostridial infection 1 Infections and infestations Bacterial infectious disorders Conjunctivitis bacterial 1 Infections and infestations Bacterial infectious disorders Erysipelas 7 Infections and infestations Bacterial infectious disorders Erysipelas 1 Infections and infestations Bacterial infectious disorders Erythema migrans 1 Infections and infestations Bacterial infectious disorders Escherichia infection 5 Infections and infestations Bacterial infectious disorders Escherichia urinary tract infection 3 Infections and infestations Bacterial infectious disorders Gastroenteritis bacterial 1 Infections and infestations Bacterial infectious disorders Gastroenteritis Escherichia coli 1 Infections and infestations Bacterial infectious disorders Gastroenteritis staphylococcal 1 Yes Yes Yes No No Yes No No No No Yes Yes No Yes No No No No Yes No Yes No Yes No No No CONFIDENTIAL 560 CONFIDENTIAL 608 Infections and infestations Bacterial infectious disorders Haemophilus infection 11 Infections and infestations Bacterial infectious disorders Haemophilus sepsis 3 Infections and infestations Bacterial infectious disorders Injection site cellulitis 5 Infections and infestations Bacterial infectious disorders Injection site cellulitis 2 Infections and infestations Bacterial infectious disorders Meningitis bacterial 3 Infections and infestations Bacterial infectious disorders Meningitis haemophilus 11 Infections and infestations Bacterial infectious disorders Meningitis pneumococcal 6 Infections and infestations Bacterial infectious disorders Meningococcal sepsis 1 Infections and infestations Bacterial infectious disorders Meningoencephalit is bacterial 1 Infections and infestations Bacterial infectious disorders Necrotising ulcerative gingivostomatitis 1 Infections and infestations Bacterial infectious disorders Neuroborreliosis 1 Infections and infestations Bacterial infectious disorders Pertussis 98 Infections and infestations Bacterial infectious disorders Pertussis 1 Infections and infestations Bacterial infectious disorders Pharyngitis streptococcal 1 Infections and infestations Bacterial infectious disorders Pneumococcal infection 2 Infections and infestations Bacterial infectious disorders Pneumococcal sepsis 2 Infections and infestations Bacterial infectious disorders Pneumonia pneumococcal 1 Infections and infestations Bacterial infectious disorders Proteus infection 1 Infections and infestations Bacterial infectious disorders Salmonella sepsis 1 Infections and infestations Bacterial infectious disorders Scarlet fever 1 Infections and infestations Bacterial infectious disorders Staphylococcal abscess 4 Infections and infestations Bacterial infectious disorders Staphylococcal abscess 1 Infections and infestations Bacterial infectious disorders Staphylococcal infection 5 Infections and infestations Bacterial infectious disorders Staphylococcal infection 1 Infections and infestations Bacterial infectious disorders Staphylococcal scalded skin syndrome 1 Infections and infestations Bacterial infectious disorders Staphylococcal sepsis 2 Infections and infestations Bacterial infectious disorders Streptococcal abscess 2 Infections and infestations Bacterial infectious disorders Streptococcal bacteraemia 1 No Yes No Yes No Yes No No Yes Yes Yes No No Yes Yes No Yes No No Yes Yes Yes Yes No Yes No No No CONFIDENTIAL 561 CONFIDENTIAL 609 Infections and infestations Bacterial infectious disorders Streptococcal infection 1 Infections and infestations Bacterial infectious disorders Superinfection bacterial 1 Infections and infestations Bacterial infectious disorders WaterhouseFriderichsen syndrome 1 Infections and infestations Fungal infectious disorders Candida nappy rash 3 Infections and infestations Fungal infectious disorders Candidiasis 3 Infections and infestations Fungal infectious disorders Fungal skin infection 1 Infections and infestations Fungal infectious disorders Genital candidiasis 3 Infections and infestations Fungal infectious disorders Oral candidiasis 4 Infections and infestations Infections – pathogen unspecified Abdominal abscess 1 Infections and infestations Infections – pathogen unspecified Abscess 15 Infections and infestations Infections – pathogen unspecified Abscess 5 Infections and infestations Infections – pathogen unspecified Abscess limb 9 Infections and infestations Infections – pathogen unspecified Abscess soft tissue 1 Infections and infestations Infections – pathogen unspecified Acute tonsillitis 3 Infections and infestations Infections – pathogen unspecified Bacteraemia 3 Infections and infestations Infections – pathogen unspecified Bone abscess 1 Infections and infestations Infections – pathogen unspecified Bronchitis 22 Infections and infestations Infections – pathogen unspecified Bronchitis 2 Infections and infestations Infections – pathogen unspecified Bronchopneumoni a 8 Infections and infestations Infections – pathogen unspecified Conjunctivitis infective 1 Infections and infestations Infections – pathogen unspecified Device related sepsis 1 Infections and infestations Infections – pathogen unspecified Ear infection 10 Infections and infestations Infections – pathogen unspecified Eczema infected 1 Infections and infestations Infections – pathogen unspecified Empyema 1 Infections and infestations Infections – pathogen unspecified Encephalitic infection 1 Infections and infestations Infections – pathogen unspecified Enteritis infectious 2 Infections and infestations Infections – pathogen unspecified Enteritis infectious 2 Infections and infestations Infections – pathogen unspecified Epiglottitis 1 Infections and infestations Infections – pathogen unspecified Febrile infection 13 No Yes No Yes Yes No Yes Yes No Yes No No No No No Yes Yes No No No No No No Yes No No Yes No No CONFIDENTIAL 562 CONFIDENTIAL 610 Infections and infestations Infections – pathogen unspecified Febrile infection 1 Infections and infestations Infections – pathogen unspecified Gastroenteritis 3 Infections and infestations Infections – pathogen unspecified Gastroenteritis 36 Infections and infestations Infections – pathogen unspecified Gastrointestinal infection 3 Infections and infestations Infections – pathogen unspecified Groin abscess 2 Infections and infestations Infections – pathogen unspecified Impetigo 1 Infections and infestations Infections – pathogen unspecified Incision site abscess 6 Infections and infestations Infections – pathogen unspecified Infection 21 Infections and infestations Infections – pathogen unspecified Infection 3 Infections and infestations Infections – pathogen unspecified Infectious peritonitis 1 Infections and infestations Infections – pathogen unspecified Injection site abscess 45 Infections and infestations Infections – pathogen unspecified Injection site abscess 10 Infections and infestations Infections – pathogen unspecified Injection site infection 4 Infections and infestations Infections – pathogen unspecified Laryngitis 2 Infections and infestations Infections – pathogen unspecified Localised infection 1 Infections and infestations Infections – pathogen unspecified Lung infection 1 Infections and infestations Infections – pathogen unspecified Lymph node abscess 1 Infections and infestations Infections – pathogen unspecified Mastoiditis 3 Infections and infestations Infections – pathogen unspecified Meningitis 14 Infections and infestations Infections – pathogen unspecified Meningitis aseptic 2 Infections and infestations Infections – pathogen unspecified Nasopharyngitis 21 Infections and infestations Infections – pathogen unspecified Nasopharyngitis 2 Infections and infestations Infections – pathogen unspecified Necrotising fasciitis 1 Infections and infestations Infections – pathogen unspecified Orchitis 1 Infections and infestations Infections – pathogen unspecified Osteomyelitis 4 Infections and infestations Infections – pathogen unspecified Otitis media 15 Infections and infestations Infections – pathogen unspecified Otitis media 1 Infections and infestations Infections – pathogen unspecified Otitis media acute 2 Infections and infestations Infections – pathogen unspecified Peritonsillar abscess 1 Infections and infestations Infections – pathogen unspecified Pharyngitis 13 Yes No Yes No No No Yes Yes No Yes Yes No No No No No No No No No Yes Yes No Yes Yes No Yes No No No CONFIDENTIAL 563 CONFIDENTIAL 611 Infections and infestations Infections – pathogen unspecified Pharyngitis 1 Infections and infestations Infections – pathogen unspecified Pharyngotonsillitis 2 Infections and infestations Infections – pathogen unspecified Pneumonia 1 Infections and infestations Infections – pathogen unspecified Pneumonia 27 Infections and infestations Infections – pathogen unspecified Pneumonia primary atypical 1 Infections and infestations Infections – pathogen unspecified Pseudocroup 2 Infections and infestations Infections – pathogen unspecified Purulence 3 Infections and infestations Infections – pathogen unspecified Pyelonephritis 6 Infections and infestations Infections – pathogen unspecified Pyelonephritis acute 1 Infections and infestations Infections – pathogen unspecified Rash pustular 5 Infections and infestations Infections – pathogen unspecified Respiratory tract infection 13 Infections and infestations Infections – pathogen unspecified Rhinitis 37 Infections and infestations Infections – pathogen unspecified Sepsis 33 Infections and infestations Infections – pathogen unspecified Sepsis syndrome 2 Infections and infestations Infections – pathogen unspecified Septic shock 1 Infections and infestations Infections – pathogen unspecified Sinusitis 1 Infections and infestations Infections – pathogen unspecified Skin infection 1 Infections and infestations Infections – pathogen unspecified Soft tissue infection 6 Infections and infestations Infections – pathogen unspecified Soft tissue infection 1 Infections and infestations Infections – pathogen unspecified Sputum purulent 1 Infections and infestations Infections – pathogen unspecified Subcutaneous abscess 1 Infections and infestations Infections – pathogen unspecified Subdural empyema 1 Infections and infestations Infections – pathogen unspecified Superinfection 4 Infections and infestations Infections – pathogen unspecified Tonsillitis 7 Infections and infestations Infections – pathogen unspecified Tonsillitis 1 Infections and infestations Infections – pathogen unspecified Tracheitis 2 Infections and infestations Infections – pathogen unspecified Upper respiratory tract infection 35 Infections and infestations Infections – pathogen unspecified Upper respiratory tract infection 2 Infections and infestations Infections – pathogen unspecified Urinary tract infection 6 Yes No No Yes No Yes No No No No No Yes No Yes No No No No Yes Yes No No No Yes No No Yes Yes No CONFIDENTIAL 564 CONFIDENTIAL 612 Infections and infestations Infections – pathogen unspecified Urinary tract infection 1 Infections and infestations Infections – pathogen unspecified Vaccination site abscess 2 Infections and infestations Infections – pathogen unspecified Vaccination site infection 1 Infections and infestations Infections – pathogen unspecified Viraemia 1 Infections and infestations Infections – pathogen unspecified Wound infection 1 Infections and infestations Viral infectious disorders Adenovirus infection 1 Infections and infestations Viral infectious disorders Bronchiolitis 7 Infections and infestations Viral infectious disorders Coxsackie viral infection 1 Infections and infestations Viral infectious disorders Croup infectious 2 Infections and infestations Viral infectious disorders Cytomegalovirus infection 3 Infections and infestations Viral infectious disorders Cytomegalovirus infection 1 Infections and infestations Viral infectious disorders Eczema herpeticum 1 Infections and infestations Viral infectious disorders Encephalitis herpes 2 Infections and infestations Viral infectious disorders Encephalitis viral 1 Infections and infestations Viral infectious disorders Enterovirus infection 1 Infections and infestations Viral infectious disorders Epstein-Barr virus infection 1 Infections and infestations Viral infectious disorders Exanthema subitum 4 Infections and infestations Viral infectious disorders Exanthema subitum 3 Infections and infestations Viral infectious disorders Gastroenteritis adenovirus 3 Infections and infestations Viral infectious disorders Gastroenteritis astroviral 1 Infections and infestations Viral infectious disorders Gastroenteritis norovirus 6 Infections and infestations Viral infectious disorders Gastroenteritis rotavirus 20 Infections and infestations Viral infectious disorders Gastroenteritis viral 3 Infections and infestations Viral infectious disorders Gianotti-Crosti syndrome 3 Infections and infestations Viral infectious disorders Gianotti-Crosti syndrome 1 Infections and infestations Viral infectious disorders H1N1 influenza 1 Infections and infestations Viral infectious disorders Hepatitis B 1 Infections and infestations Viral infectious disorders Herpes ophthalmic 1 Infections and infestations Viral infectious disorders Herpes simplex 2 Infections and infestations Viral infectious disorders Herpes zoster 1 No No No No No Yes Yes Yes Yes No Yes Yes No No No Yes Yes No No No Yes No Yes Yes No Yes No No No Yes CONFIDENTIAL 565 CONFIDENTIAL 613 Infections and infestations Viral infectious disorders Human herpesvirus 6 infection 2 Infections and infestations Viral infectious disorders Influenza 2 Infections and infestations Viral infectious disorders Measles 1 Infections and infestations Viral infectious disorders Meningitis viral 4 Infections and infestations Viral infectious disorders Pneumonia respiratory syncytial viral 1 Infections and infestations Viral infectious disorders Pneumonia viral 1 Infections and infestations Viral infectious disorders Respiratory syncytial virus bronchiolitis 2 Infections and infestations Viral infectious disorders Respiratory syncytial virus infection 8 Infections and infestations Viral infectious disorders Respiratory tract infection viral 1 Infections and infestations Viral infectious disorders Rotavirus infection 5 Infections and infestations Viral infectious disorders Varicella 2 Infections and infestations Viral infectious disorders Viral infection 28 Infections and infestations Viral infectious disorders Viral infection 2 Infections and infestations Viral infectious disorders Viral pharyngitis 1 Infections and infestations Viral infectious disorders Viral rash 3 Infections and infestations Viral infectious disorders Viral upper respiratory tract infection 1 Injury, poisoning and procedural complications Bone and joint injuries Forearm fracture 1 Injury, poisoning and procedural complications Bone and joint injuries Joint dislocation 2 Injury, poisoning and procedural complications Bone and joint injuries Limb injury 1 Injury, poisoning and procedural complications Bone and joint injuries Skull fracture 1 Injury, poisoning and procedural complications Chemical injury and poisoning Carbon monoxide poisoning 1 Injury, poisoning and procedural complications Chemical injury and poisoning Poisoning 1 Injury, poisoning and procedural complications Chemical injury and poisoning Toxicity to various agents 1 Injury, poisoning and procedural complications Injuries NEC Arthropod bite 1 Yes No No No No No No No Yes Yes No No Yes No No No Yes No No Yes Yes Yes No No CONFIDENTIAL 566 CONFIDENTIAL 614 Injury, poisoning and procedural complications Injuries NEC Child maltreatment syndrome 2 Injury, poisoning and procedural complications Injuries NEC Concussion 1 Injury, poisoning and procedural complications Injuries NEC Contusion 7 Injury, poisoning and procedural complications Injuries NEC Craniocerebral injury 1 Injury, poisoning and procedural complications Injuries NEC Eschar 1 Injury, poisoning and procedural complications Injuries NEC Excoriation 1 Injury, poisoning and procedural complications Injuries NEC Fall 14 Injury, poisoning and procedural complications Injuries NEC Injury 1 Injury, poisoning and procedural complications Injuries NEC Subdural haematoma 2 Injury, poisoning and procedural complications Medication errors Drug administered to patient of inappropriate age 4 Injury, poisoning and procedural complications Medication errors Drug administration error 3 Injury, poisoning and procedural complications Medication errors Expired drug administered 1 Injury, poisoning and procedural complications Medication errors Inappropriate schedule of drug administration 9 Injury, poisoning and procedural complications Medication errors Incorrect route of drug administration 16 Injury, poisoning and procedural complications Medication errors Medication error 2 Injury, poisoning and procedural complications Medication errors Overdose 5 Injury, poisoning and procedural complications Medication errors Wrong drug administered 3 Injury, poisoning and procedural complications Medication errors Wrong technique in drug usage process 9 Injury, poisoning and procedural complications Procedural related injuries and complications NEC Seroma 1 No No No No No No No Yes No No No No Yes No Yes No No No No CONFIDENTIAL 567 CONFIDENTIAL 615 Injury, poisoning and procedural complications Procedural related injuries and complications NEC Vaccination complication 50 Injury, poisoning and procedural complications Procedural related injuries and complications NEC Vaccination complication 2 Investigations Cardiac and vascular investigations (excl enzyme tests) Blood pressure decreased 2 Investigations Cardiac and vascular investigations (excl enzyme tests) Blood pressure immeasurable 1 Investigations Cardiac and vascular investigations (excl enzyme tests) Cardiac murmur 9 Investigations Cardiac and vascular investigations (excl enzyme tests) Heart rate decreased 4 Investigations Cardiac and vascular investigations (excl enzyme tests) Heart rate increased 9 Investigations Cardiac and vascular investigations (excl enzyme tests) Heart sounds abnormal 1 Investigations Cardiac and vascular investigations (excl enzyme tests) Peripheral pulse decreased 1 Investigations Cardiac and vascular investigations (excl enzyme tests) Pulse absent 1 Investigations Cardiac and vascular investigations (excl enzyme tests) Pulse absent 1 Investigations Cardiac and vascular investigations (excl enzyme tests) Pulse pressure decreased 1 Investigations Cardiac and vascular investigations (excl enzyme tests) Pulse pressure increased 1 Investigations Enzyme investigations NEC Blood alkaline phosphatase increased 1 Investigations Enzyme investigations NEC Blood creatine phosphokinase increased 1 Investigations Enzyme investigations NEC Blood lactate dehydrogenase increased 3 Investigations Haematology investigations (incl blood groups) Activated partial thromboplastin time prolonged 1 Investigations Haematology investigations (incl blood groups) Bleeding time prolonged 1 Investigations Haematology investigations (incl blood groups) Blood thromboplastin decreased 1 Investigations Haematology investigations (incl blood groups) Coombs test positive 1 Investigations Haematology investigations (incl blood groups) Haematocrit decreased 1 No No Yes No No No No No Yes No No No No Yes No No Yes No Yes No No CONFIDENTIAL 568 CONFIDENTIAL 616 Investigations Haematology investigations (incl blood groups) Haemoglobin decreased 4 Investigations Haematology investigations (incl blood groups) Haemoglobin decreased 1 Investigations Haematology investigations (incl blood groups) Lymphocyte count increased 1 Investigations Haematology investigations (incl blood groups) Neutrophil toxic granulation present 1 Investigations Haematology investigations (incl blood groups) Platelet count abnormal 2 Investigations Haematology investigations (incl blood groups) Platelet count decreased 5 Investigations Haematology investigations (incl blood groups) Platelet count increased 2 Investigations Haematology investigations (incl blood groups) Prothrombin time prolonged 1 Investigations Haematology investigations (incl blood groups) Red blood cell count increased 1 Investigations Haematology investigations (incl blood groups) Red blood cell sedimentation rate increased 2 Investigations Haematology investigations (incl blood groups) Shift to the left 1 Investigations Haematology investigations (incl blood groups) White blood cell count decreased 1 Investigations Haematology investigations (incl blood groups) White blood cell count increased 5 Investigations Haematology investigations (incl blood groups) White blood cell count increased 1 Investigations Hepatobiliary investigations Alanine aminotransferase increased 10 Investigations Hepatobiliary investigations Ammonia increased 2 Investigations Hepatobiliary investigations Aspartate aminotransferase increased 9 Investigations Hepatobiliary investigations Blood bilirubin increased 1 Investigations Hepatobiliary investigations Hepatic enzyme increased 5 Investigations Hepatobiliary investigations Liver function test abnormal 1 Investigations Hepatobiliary investigations Transaminases increased 17 Investigations Immunology and allergy investigations Autoantibody positive 1 Investigations Immunology and allergy investigations Blood immunoglobulin A increased 1 Investigations Immunology and allergy investigations Blood immunoglobulin E increased 1 Investigations Immunology and allergy investigations Blood immunoglobulin M increased 1 No Yes No No No Yes Yes Yes Yes Yes No No No No Yes Yes No No No No No No No Yes No CONFIDENTIAL 569 CONFIDENTIAL 617 Investigations Immunology and allergy investigations Blood immunoglobulin M increased 1 Investigations Lipid analyses Carnitine decreased 1 Investigations Metabolic, nutritional and blood gas investigations Blood glucose increased 1 Investigations Metabolic, nutritional and blood gas investigations Blood lactic acid increased 2 Investigations Metabolic, nutritional and blood gas investigations Blood pH decreased 1 Investigations Metabolic, nutritional and blood gas investigations Oxygen saturation decreased 34 Investigations Microbiology and serology investigations Adenovirus test positive 1 Investigations Microbiology and serology investigations Bacterial test positive 1 Investigations Microbiology and serology investigations Bordetella test negative 2 Investigations Microbiology and serology investigations Bordetella test positive 2 Investigations Microbiology and serology investigations Cytomegalovirus test positive 1 Investigations Microbiology and serology investigations Hepatitis B antibody negative 2 Investigations Microbiology and serology investigations Hepatitis B antibody positive 1 Investigations Microbiology and serology investigations Hepatitis B surface antigen positive 1 Investigations Microbiology and serology investigations Mycoplasma test positive 1 Investigations Microbiology and serology investigations Rotavirus test positive 3 Investigations Microbiology and serology investigations Staphylococcus test positive 1 Investigations Microbiology and serology investigations Viral test positive 5 Investigations Neurological, special senses and psychiatric investigations Electroencephalog ram abnormal 8 Investigations Neurological, special senses and psychiatric investigations Nerve stimulation test abnormal 4 Investigations Neurological, special senses and psychiatric investigations Otoacoustic emissions test abnormal 1 Investigations Neurological, special senses and psychiatric investigations Reflex test normal 1 Investigations Physical examination topics Body height below normal 2 Investigations Physical examination topics Body mass index decreased 1 Investigations Physical examination topics Body temperature 1 No No No No No No No No No No No No No No No No No No No No No No No Yes No CONFIDENTIAL 570 CONFIDENTIAL 618 Investigations Physical examination topics Body temperature decreased 5 Investigations Physical examination topics Body temperature fluctuation 1 Investigations Physical examination topics Breath sounds abnormal 3 Investigations Physical examination topics Head circumference abnormal 1 Investigations Physical examination topics Liver palpable subcostal 1 Investigations Physical examination topics Lymph node palpable 2 Investigations Physical examination topics Neurological examination abnormal 1 Investigations Physical examination topics Respiratory rate decreased 3 Investigations Physical examination topics Respiratory rate increased 4 Investigations Physical examination topics Skin turgor decreased 1 Investigations Physical examination topics Weight decreased 15 Investigations Protein and chemistry analyses NEC C-reactive protein increased 28 Investigations Protein and chemistry analyses NEC C-reactive protein increased 2 Investigations Protein and chemistry analyses NEC Inflammatory marker increased 2 Investigations Protein and chemistry analyses NEC Protein total abnormal 1 Investigations Protein and chemistry analyses NEC Protein total increased 1 Investigations Renal and urinary tract investigations and urinalyses Glucose urine present 1 Investigations Renal and urinary tract investigations and urinalyses Urine output decreased 2 Investigations Renal and urinary tract investigations and urinalyses White blood cells urine positive 1 Investigations Toxicology and therapeutic drug monitoring Anticonvulsant drug level above therapeutic 1 Investigations Water, electrolyte and mineral investigations Blood iron decreased 1 Investigations Water, electrolyte and mineral investigations Blood osmolarity increased 1 Investigations Water, electrolyte and mineral investigations Blood sodium decreased 1 Investigations Water, electrolyte and mineral investigations Serum ferritin increased 1 Metabolism and nutrition disorders Acid-base disorders Acidosis 4 No No No No No No No No No No No No No No No No No Yes No No No No No No No CONFIDENTIAL 571 CONFIDENTIAL 619 Metabolism and nutrition disorders Acid-base disorders Acidosis 3 Metabolism and nutrition disorders Acid-base disorders Alkalosis 1 Metabolism and nutrition disorders Acid-base disorders Ketoacidosis 1 Metabolism and nutrition disorders Acid-base disorders Ketosis 1 Metabolism and nutrition disorders Acid-base disorders Lactic acidosis 2 Metabolism and nutrition disorders Acid-base disorders Metabolic acidosis 4 Metabolism and nutrition disorders Appetite and general nutritional disorders Appetite disorder 2 Metabolism and nutrition disorders Appetite and general nutritional disorders Decreased appetite 5 Metabolism and nutrition disorders Appetite and general nutritional disorders Decreased appetite 3 Metabolism and nutrition disorders Appetite and general nutritional disorders Failure to thrive 2 Metabolism and nutrition disorders Appetite and general nutritional disorders Feeding disorder neonatal 4 Metabolism and nutrition disorders Appetite and general nutritional disorders Feeding disorder of infancy or early childhood 5 Metabolism and nutrition disorders Appetite and general nutritional disorders Increased appetite 2 Metabolism and nutrition disorders Appetite and general nutritional disorders Malnutrition 2 Metabolism and nutrition disorders Appetite and general nutritional disorders Underweight 4 Metabolism and nutrition disorders Appetite and general nutritional disorders Weight gain poor 3 Metabolism and nutrition disorders Bone, calcium, magnesium and phosphorus metabolism disorders Tetany 2 Metabolism and nutrition disorders Diabetic complications Diabetic ketoacidosis 3 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Dehydration 25 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Dehydration 2 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Electrolyte imbalance 1 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Fluid intake reduced 22 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Hypernatraemia 1 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Hypokalaemia 6 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Hyponatraemia 6 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Hypovolaemia 1 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Oligodipsia 30 Metabolism and nutrition disorders Electrolyte and fluid balance conditions Polydipsia 5 No No No No No Yes No No No Yes No No No No Yes Yes No No Yes Yes No No Yes No Yes No Yes Yes CONFIDENTIAL 572 CONFIDENTIAL 620 Metabolism and nutrition disorders Food intolerance syndromes Cow’s milk intolerance 1 Metabolism and nutrition disorders Food intolerance syndromes Disaccharide metabolism disorder 1 Metabolism and nutrition disorders Food intolerance syndromes Lactose intolerance 2 Metabolism and nutrition disorders Glucose metabolism disorders (incl diabetes mellitus) Hyperglycaemia 4 Metabolism and nutrition disorders Glucose metabolism disorders (incl diabetes mellitus) Hyperinsulinaemia 1 Metabolism and nutrition disorders Glucose metabolism disorders (incl diabetes mellitus) Hypoglycaemia 4 Metabolism and nutrition disorders Glucose metabolism disorders (incl diabetes mellitus) Type 1 diabetes mellitus 7 Metabolism and nutrition disorders Iron and trace metal metabolism disorders Haemosiderosis 1 Metabolism and nutrition disorders Iron and trace metal metabolism disorders Iodine deficiency 1 Metabolism and nutrition disorders Iron and trace metal metabolism disorders Iron deficiency 2 Metabolism and nutrition disorders Lipid metabolism disorders Hypercholesterola emia 1 Metabolism and nutrition disorders Lipid metabolism disorders Hyperlipidaemia 1 Metabolism and nutrition disorders Lipid metabolism disorders Hypertriglyceridae mia 1 Metabolism and nutrition disorders Metabolism disorders NEC Enzyme abnormality 1 Metabolism and nutrition disorders Metabolism disorders NEC Metabolic disorder 3 Metabolism and nutrition disorders Metabolism disorders NEC Mitochondrial cytopathy 1 Metabolism and nutrition disorders Protein and amino acid metabolism disorders NEC Hyperammonaemi a 2 Metabolism and nutrition disorders Protein and amino acid metabolism disorders NEC Hypoalbuminaemi a 4 Metabolism and nutrition disorders Purine and pyrimidine metabolism disorders Hyperuricaemia 1 Metabolism and nutrition disorders Vitamin related disorders Vitamin B12 deficiency 2 Metabolism and nutrition disorders Vitamin related disorders Vitamin K deficiency 2 Musculoskeletal and connective tissue disorders Bone disorders (excl congenital and fractures) Bone disorder 1 Musculoskeletal and connective tissue disorders Bone disorders (excl congenital and fractures) Bone pain 1 Musculoskeletal and connective tissue disorders Bone disorders (excl congenital and fractures) Osteitis 1 Musculoskeletal and connective tissue disorders Connective tissue disorders (excl congenital) Myofascitis 1 Musculoskeletal and connective tissue disorders Connective tissue disorders (excl congenital) Myofascitis 1 No No No Yes No Yes No Yes No No No No No No No No No No No No No Yes Yes No No No CONFIDENTIAL 573 CONFIDENTIAL 621 Musculoskeletal and connective tissue disorders Joint disorders Arthralgia 3 Musculoskeletal and connective tissue disorders Joint disorders Arthritis 3 Musculoskeletal and connective tissue disorders Joint disorders Arthritis 1 Musculoskeletal and connective tissue disorders Joint disorders Arthropathy 1 Musculoskeletal and connective tissue disorders Joint disorders Joint contracture 1 Musculoskeletal and connective tissue disorders Joint disorders Joint hyperextension 5 Musculoskeletal and connective tissue disorders Joint disorders Joint range of motion decreased 1 Musculoskeletal and connective tissue disorders Joint disorders Joint swelling 5 Musculoskeletal and connective tissue disorders Joint disorders Juvenile arthritis 1 Musculoskeletal and connective tissue disorders Joint disorders Polyarthritis 1 Musculoskeletal and connective tissue disorders Muscle disorders Floppy infant 1 Musculoskeletal and connective tissue disorders Muscle disorders Hypotonia neonatal 4 Musculoskeletal and connective tissue disorders Muscle disorders Muscle disorder 3 Musculoskeletal and connective tissue disorders Muscle disorders Muscle hypertrophy 2 Musculoskeletal and connective tissue disorders Muscle disorders Muscle rigidity 6 Musculoskeletal and connective tissue disorders Muscle disorders Muscle rigidity 2 Musculoskeletal and connective tissue disorders Muscle disorders Muscle spasms 39 Musculoskeletal and connective tissue disorders Muscle disorders Muscle spasms 1 Musculoskeletal and connective tissue disorders Muscle disorders Muscle tightness 1 Musculoskeletal and connective tissue disorders Muscle disorders Muscle twitching 36 Musculoskeletal and connective tissue disorders Muscle disorders Muscle twitching 1 No No Yes No No No Yes No Yes No No Yes No No No No No Yes No No No CONFIDENTIAL 574 CONFIDENTIAL 622 Musculoskeletal and connective tissue disorders Muscle disorders Muscular weakness 13 Musculoskeletal and connective tissue disorders Muscle disorders Myalgia 4 Musculoskeletal and connective tissue disorders Muscle disorders Myopathy 1 Musculoskeletal and connective tissue disorders Muscle disorders Myosclerosis 2 Musculoskeletal and connective tissue disorders Muscle disorders Myositis 4 Musculoskeletal and connective tissue disorders Muscle disorders Myositis 1 Musculoskeletal and connective tissue disorders Muscle disorders Nuchal rigidity 4 Musculoskeletal and connective tissue disorders Muscle disorders Rhabdomyolysis 1 Musculoskeletal and connective tissue disorders Muscle disorders Torticollis 3 Musculoskeletal and connective tissue disorders Muscle disorders Trismus 2 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Delayed fontanelle closure 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Facial asymmetry 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Foot deformity 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Hip deformity 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Limb asymmetry 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) Lordosis 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Groin pain 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Growth retardation 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Mastication disorder 1 No No No No No No No No No No No No Yes No Yes No No No No CONFIDENTIAL 575 CONFIDENTIAL 623 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Mobility decreased 9 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Muscle contracture 2 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Musculoskeletal pain 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Musculoskeletal stiffness 39 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Pain in extremity 25 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Pain in extremity 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Posture abnormal 8 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Soft tissue disorder 2 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Soft tissue disorder 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Soft tissue haemorrhage 1 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders NEC Soft tissue necrosis 2 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cutaneous neoplasms benign Melanocytic naevus 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Haematopoietic neoplasms (excl leukaemias and lymphomas) Histiocytosis haematophagic 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Leukaemias B precursor type acute leukaemia 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Leukaemias Myelodysplastic syndrome 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphomas NEC Lymphoma 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Miscellaneous and site unspecified neoplasms benign Haemangioma 3 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous system neoplasms benign Cerebral hygroma 2 Yes Yes No No Yes Yes Yes Yes Yes Yes No No No Yes No No No No CONFIDENTIAL 576 CONFIDENTIAL 624 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous system neoplasms malignant and unspecified NEC Neuroblastoma 2 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous system neoplasms malignant and unspecified NEC Optic nerve glioma 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Skeletal neoplasms malignant and unspecified Ewing’s sarcoma 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Skin neoplasms malignant and unspecified Neoplasm skin 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Soft tissue neoplasms benign Lymphangioma 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Soft tissue neoplasms malignant and unspecified (excl sarcomas) Soft tissue neoplasm 2 Nervous system disorders Central nervous system infections and inflammations Central nervous system inflammation 1 Nervous system disorders Central nervous system infections and inflammations Encephalitis 1 Nervous system disorders Central nervous system infections and inflammations Encephalitis 19 Nervous system disorders Central nervous system infections and inflammations Encephalitis haemorrhagic 1 Nervous system disorders Central nervous system infections and inflammations Encephalomyelitis 1 Nervous system disorders Central nervous system infections and inflammations Myelitis transverse 1 Nervous system disorders Central nervous system vascular disorders Blood brain barrier defect 1 Nervous system disorders Central nervous system vascular disorders Brain stem thrombosis 1 Nervous system disorders Central nervous system vascular disorders Cerebral haemorrhage 5 Nervous system disorders Central nervous system vascular disorders Cerebral infarction 1 Nervous system disorders Central nervous system vascular disorders Cerebral ischaemia 4 Nervous system disorders Central nervous system vascular disorders Cerebrovascular accident 1 Nervous system disorders Central nervous system vascular disorders Cerebrovascular disorder 1 Nervous system disorders Central nervous system vascular disorders Subarachnoid haemorrhage 3 Nervous system disorders Central nervous system vascular disorders Thalamus haemorrhage 1 Nervous system disorders Central nervous system vascular disorders Vasculitis cerebral 1 Nervous system disorders Cranial nerve disorders (excl neoplasms) Facial paresis 10 Nervous system disorders Cranial nerve disorders (excl neoplasms) Facial spasm 1 Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes CONFIDENTIAL 577 CONFIDENTIAL 625 Nervous system disorders Cranial nerve disorders (excl neoplasms) Paresis cranial nerve 1 Nervous system disorders Cranial nerve disorders (excl neoplasms) Tongue paralysis 2 Nervous system disorders Cranial nerve disorders (excl neoplasms) VIIth nerve paralysis 2 Nervous system disorders Cranial nerve disorders (excl neoplasms) VIth nerve paralysis 4 Nervous system disorders Demyelinating disorders Acute disseminated encephalomyelitis 3 Nervous system disorders Demyelinating disorders Demyelination 5 Nervous system disorders Encephalopathies Encephalopathy 14 Nervous system disorders Encephalopathies Hypoxic-ischaemic encephalopathy 7 Nervous system disorders Encephalopathies Leukoencephalopa thy 2 Nervous system disorders Encephalopathies Periventricular leukomalacia 2 Nervous system disorders Headaches Headache 3 Nervous system disorders Increased intracranial pressure and hydrocephalus Brain oedema 11 Nervous system disorders Increased intracranial pressure and hydrocephalus Hydrocephalus 5 Nervous system disorders Increased intracranial pressure and hydrocephalus Intracranial pressure increased 4 Nervous system disorders Mental impairment disorders Autism 1 Nervous system disorders Mental impairment disorders Autism 5 Nervous system disorders Mental impairment disorders Cognitive disorder 2 Nervous system disorders Mental impairment disorders Disturbance in attention 2 Nervous system disorders Mental impairment disorders Memory impairment 1 Nervous system disorders Mental impairment disorders Mental impairment 7 Nervous system disorders Mental impairment disorders Mental retardation 5 Nervous system disorders Movement disorders (incl parkinsonism) Athetosis 1 Nervous system disorders Movement disorders (incl parkinsonism) Bradykinesia 1 Nervous system disorders Movement disorders (incl parkinsonism) Choreoathetosis 2 Nervous system disorders Movement disorders (incl parkinsonism) Dyskinesia 46 Nervous system disorders Movement disorders (incl parkinsonism) Dyskinesia 1 Nervous system disorders Movement disorders (incl parkinsonism) Dystonia 3 Nervous system disorders Movement disorders (incl parkinsonism) Dystonia 1 No Yes No No No No No Yes No Yes No No No No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes CONFIDENTIAL 578 CONFIDENTIAL 626 Nervous system disorders Movement disorders (incl parkinsonism) Extrapyramidal disorder 3 Nervous system disorders Movement disorders (incl parkinsonism) Head titubation 6 Nervous system disorders Movement disorders (incl parkinsonism) Hemiparesis 8 Nervous system disorders Movement disorders (incl parkinsonism) Hemiplegia 4 Nervous system disorders Movement disorders (incl parkinsonism) Hypokinesia 13 Nervous system disorders Movement disorders (incl parkinsonism) Hypokinesia 2 Nervous system disorders Movement disorders (incl parkinsonism) Monoparesis 5 Nervous system disorders Movement disorders (incl parkinsonism) Monoplegia 5 Nervous system disorders Movement disorders (incl parkinsonism) Motor developmental delay 6 Nervous system disorders Movement disorders (incl parkinsonism) Movement disorder 15 Nervous system disorders Movement disorders (incl parkinsonism) Opisthotonus 20 Nervous system disorders Movement disorders (incl parkinsonism) Opisthotonus 1 Nervous system disorders Movement disorders (incl parkinsonism) Paralysis 3 Nervous system disorders Movement disorders (incl parkinsonism) Paralysis flaccid 1 Nervous system disorders Movement disorders (incl parkinsonism) Paraplegia 1 Nervous system disorders Movement disorders (incl parkinsonism) Paresis 4 Nervous system disorders Movement disorders (incl parkinsonism) Postictal paralysis 1 Nervous system disorders Movement disorders (incl parkinsonism) Psychomotor hyperactivity 9 Nervous system disorders Movement disorders (incl parkinsonism) Quadriparesis 4 Nervous system disorders Movement disorders (incl parkinsonism) Tardive dyskinesia 1 Nervous system disorders Movement disorders (incl parkinsonism) Tremor 55 Nervous system disorders Movement disorders (incl parkinsonism) Tremor 3 Nervous system disorders Neurological disorders NEC Altered state of consciousness 15 Nervous system disorders Neurological disorders NEC Aphasia 3 Nervous system disorders Neurological disorders NEC Areflexia 8 Nervous system disorders Neurological disorders NEC Ataxia 5 Nervous system disorders Neurological disorders NEC Ataxia 1 Nervous system disorders Neurological disorders NEC Balance disorder 10 Nervous system disorders Neurological disorders NEC Cerebellar ataxia 2 No Yes Yes No No Yes No Yes No Yes No No Yes No Yes Yes Yes Yes Yes No Yes Yes Yes No No Yes No Yes Yes CONFIDENTIAL 579 CONFIDENTIAL 627 Nervous system disorders Neurological disorders NEC Cerebral disorder 5 Nervous system disorders Neurological disorders NEC Cerebral disorder 1 Nervous system disorders Neurological disorders NEC Clonus 21 Nervous system disorders Neurological disorders NEC Coma 7 Nervous system disorders Neurological disorders NEC Coordination abnormal 7 Nervous system disorders Neurological disorders NEC Coordination abnormal 1 Nervous system disorders Neurological disorders NEC Crying 24 Nervous system disorders Neurological disorders NEC Depressed level of consciousness 122 Nervous system disorders Neurological disorders NEC Dizziness 4 Nervous system disorders Neurological disorders NEC Drooling 11 Nervous system disorders Neurological disorders NEC Dysaesthesia 1 Nervous system disorders Neurological disorders NEC Dysstasia 2 Nervous system disorders Neurological disorders NEC Fontanelle bulging 10 Nervous system disorders Neurological disorders NEC Fontanelle bulging 1 Nervous system disorders Neurological disorders NEC Fontanelle depressed 2 Nervous system disorders Neurological disorders NEC Grimacing 1 Nervous system disorders Neurological disorders NEC Hyperaesthesia 18 Nervous system disorders Neurological disorders NEC Hyperreflexia 2 Nervous system disorders Neurological disorders NEC Hypoaesthesia 1 Nervous system disorders Neurological disorders NEC Hyporeflexia 3 Nervous system disorders Neurological disorders NEC Lethargy 16 Nervous system disorders Neurological disorders NEC Lethargy 1 Nervous system disorders Neurological disorders NEC Loss of consciousness 169 Nervous system disorders Neurological disorders NEC Meningism 5 Nervous system disorders Neurological disorders NEC Motor dysfunction 10 Nervous system disorders Neurological disorders NEC Motor dysfunction 1 Nervous system disorders Neurological disorders NEC Myoclonus 32 Nervous system disorders Neurological disorders NEC Myoclonus 2 Nervous system disorders Neurological disorders NEC Nerve degeneration 1 No No Yes No Yes No No No No No Yes Yes No No Yes No No No Yes No Yes No No No No Yes No Yes No CONFIDENTIAL 580 CONFIDENTIAL 628 Nervous system disorders Neurological disorders NEC Nervous system disorder 10 Nervous system disorders Neurological disorders NEC Neurodegenerative disorder 1 Nervous system disorders Neurological disorders NEC Neurological symptom 2 Nervous system disorders Neurological disorders NEC Neurotoxicity 1 Nervous system disorders Neurological disorders NEC Nystagmus 12 Nervous system disorders Neurological disorders NEC Pleocytosis 1 Nervous system disorders Neurological disorders NEC Poor sucking reflex 1 Nervous system disorders Neurological disorders NEC Postictal state 3 Nervous system disorders Neurological disorders NEC Presyncope 2 Nervous system disorders Neurological disorders NEC Presyncope 21 Nervous system disorders Neurological disorders NEC Psychomotor skills impaired 11 Nervous system disorders Neurological disorders NEC Reflexes abnormal 1 Nervous system disorders Neurological disorders NEC Sensory loss 1 Nervous system disorders Neurological disorders NEC Slow response to stimuli 109 Nervous system disorders Neurological disorders NEC Somnolence 4 Nervous system disorders Neurological disorders NEC Somnolence 2 Nervous system disorders Neurological disorders NEC Speech disorder 2 Nervous system disorders Neurological disorders NEC Speech disorder developmental 5 Nervous system disorders Neurological disorders NEC Stupor 1 Nervous system disorders Neurological disorders NEC Subdural effusion 3 Nervous system disorders Neurological disorders NEC Syncope 38 Nervous system disorders Neurological disorders NEC Unresponsive to stimuli 11 Nervous system disorders Neurological disorders NEC Unresponsive to stimuli 32 Nervous system disorders Neuromuscular disorders Autonomic nervous system imbalance 2 Nervous system disorders Neuromuscular disorders Cholinergic syndrome 2 Nervous system disorders Neuromuscular disorders Hypertonia 54 Nervous system disorders Neuromuscular disorders Hypertonia 2 Nervous system disorders Neuromuscular disorders Hypotonia 427 Nervous system disorders Neuromuscular disorders Hypotonia 5 No No Yes No Yes Yes No Yes No Yes No No Yes No Yes No No No No No Yes No No No No No Yes No No CONFIDENTIAL 581 CONFIDENTIAL 629 Nervous system disorders Neuromuscular disorders Hypotonichyporesponsive episode 184 Nervous system disorders Neuromuscular disorders Hypotonichyporesponsive episode 5 Nervous system disorders Neuromuscular disorders Muscle contractions involuntary 6 Nervous system disorders Neuromuscular disorders Muscle spasticity 1 Nervous system disorders Neuromuscular disorders Neuromyopathy 1 Nervous system disorders Neuromuscular disorders Sensorimotor disorder 1 Nervous system disorders Peripheral neuropathies Demyelinating polyneuropathy 1 Nervous system disorders Peripheral neuropathies Guillain-Barre syndrome 5 Nervous system disorders Peripheral neuropathies Neuropathy peripheral 1 Nervous system disorders Seizures (incl subtypes) Atonic seizures 6 Nervous system disorders Seizures (incl subtypes) Clonic convulsion 8 Nervous system disorders Seizures (incl subtypes) Complex partial seizures 2 Nervous system disorders Seizures (incl subtypes) Convulsion 307 Nervous system disorders Seizures (incl subtypes) Convulsions local 1 Nervous system disorders Seizures (incl subtypes) Epilepsy 68 Nervous system disorders Seizures (incl subtypes) Febrile convulsion 244 Nervous system disorders Seizures (incl subtypes) Grand mal convulsion 74 Nervous system disorders Seizures (incl subtypes) Infantile spasms 46 Nervous system disorders Seizures (incl subtypes) Infantile spasms 15 Nervous system disorders Seizures (incl subtypes) Juvenile myoclonic epilepsy 3 Nervous system disorders Seizures (incl subtypes) Lennox-Gastaut syndrome 1 Nervous system disorders Seizures (incl subtypes) Myoclonic epilepsy 4 Nervous system disorders Seizures (incl subtypes) Partial seizures 1 Nervous system disorders Seizures (incl subtypes) Partial seizures 26 Nervous system disorders Seizures (incl subtypes) Petit mal epilepsy 14 Nervous system disorders Seizures (incl subtypes) Post-traumatic epilepsy 1 Nervous system disorders Seizures (incl subtypes) Seizure anoxic 1 Nervous system disorders Seizures (incl subtypes) Seizure like phenomena 5 Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes No Yes Yes No Yes Yes Yes Yes Yes No No No No Yes No CONFIDENTIAL 582 CONFIDENTIAL 630 Nervous system disorders Seizures (incl subtypes) Status epilepticus 15 Nervous system disorders Seizures (incl subtypes) Tonic clonic movements 4 Nervous system disorders Seizures (incl subtypes) Tonic convulsion 11 Nervous system disorders Sleep disturbances (incl subtypes) Cataplexy 1 Nervous system disorders Sleep disturbances (incl subtypes) Circadian rhythm sleep disorder 3 Nervous system disorders Sleep disturbances (incl subtypes) Hypersomnia 13 Nervous system disorders Sleep disturbances (incl subtypes) Poor quality sleep 5 Nervous system disorders Sleep disturbances (incl subtypes) Sleep phase rhythm disturbance 1 Nervous system disorders Spinal cord and nerve root disorders Nerve root lesion 1 Nervous system disorders Spinal cord and nerve root disorders Radiculitis brachial 2 Nervous system disorders Spinal cord and nerve root disorders Spinal cord compression 1 Nervous system disorders Spinal cord and nerve root disorders Tethered cord syndrome 1 Nervous system disorders Structural brain disorders Brain injury 2 Nervous system disorders Structural brain disorders Cerebral atrophy 1 Nervous system disorders Structural brain disorders Cerebral atrophy 6 Nervous system disorders Structural brain disorders Cerebral ventricle dilatation 1 Nervous system disorders Structural brain disorders Subdural hygroma 2 Psychiatric disorders Anxiety disorders and symptoms Agitation 34 Psychiatric disorders Anxiety disorders and symptoms Agitation neonatal 1 Psychiatric disorders Anxiety disorders and symptoms Anxiety 13 Psychiatric disorders Anxiety disorders and symptoms Fear 3 Psychiatric disorders Anxiety disorders and symptoms Tension 2 Psychiatric disorders Changes in physical activity Decreased activity 8 Psychiatric disorders Changes in physical activity Restlessness 5 Psychiatric disorders Changes in physical activity Stereotypy 1 Psychiatric disorders Changes in physical activity Stereotypy 1 Psychiatric disorders Changes in physical activity Tic 1 Psychiatric disorders Cognitive and attention disorders and disturbances Attention deficit/hyperactivity disorder 1 No No No No No Yes No Yes No No No No No No No Yes Yes No Yes Yes No No No No No Yes No Yes CONFIDENTIAL 583 CONFIDENTIAL 631 Psychiatric disorders Cognitive and attention disorders and disturbances Daydreaming 3 Psychiatric disorders Communication disorders and disturbances Communication disorder 1 Psychiatric disorders Communication disorders and disturbances Dysphemia 1 Psychiatric disorders Communication disorders and disturbances Mutism 1 Psychiatric disorders Communication disorders and disturbances Phonological disorder 1 Psychiatric disorders Communication disorders and disturbances Screaming 37 Psychiatric disorders Deliria (incl confusion) Confusional state 1 Psychiatric disorders Deliria (incl confusion) Delirium 1 Psychiatric disorders Deliria (incl confusion) Disorientation 6 Psychiatric disorders Depressed mood disorders and disturbances Morose 2 Psychiatric disorders Depressed mood disorders and disturbances Psychomotor retardation 7 Psychiatric disorders Developmental disorders NEC Autism spectrum disorder 1 Psychiatric disorders Dissociative disorders Dissociation 1 Psychiatric disorders Disturbances in thinking and perception Illusion 1 Psychiatric disorders Disturbances in thinking and perception Illusion 1 Psychiatric disorders Eating disorders and disturbances Eating disorder 5 Psychiatric disorders Eating disorders and disturbances Eating disorder 1 Psychiatric disorders Eating disorders and disturbances Food aversion 4 Psychiatric disorders Eating disorders and disturbances Food aversion 1 Psychiatric disorders Eating disorders and disturbances Merycism 1 Psychiatric disorders Mood disorders and disturbances NEC Apathy 67 Psychiatric disorders Mood disorders and disturbances NEC Apathy 3 Psychiatric disorders Mood disorders and disturbances NEC Emotional distress 1 Psychiatric disorders Mood disorders and disturbances NEC Inappropriate affect 1 Psychiatric disorders Mood disorders and disturbances NEC Listless 11 Psychiatric disorders Mood disorders and disturbances NEC Moaning 13 Psychiatric disorders Mood disorders and disturbances NEC Moaning 1 Psychiatric disorders Mood disorders and disturbances NEC Mood altered 3 Psychiatric disorders Personality disorders and disturbances in behaviour Aggression 1 No No No Yes No No No Yes No No Yes No No No No Yes No Yes No No Yes No No No No No Yes No No CONFIDENTIAL 584 CONFIDENTIAL 632 Psychiatric disorders Personality disorders and disturbances in behaviour Aggression 4 Psychiatric disorders Personality disorders and disturbances in behaviour Antisocial behaviour 2 Psychiatric disorders Personality disorders and disturbances in behaviour Impatience 1 Psychiatric disorders Personality disorders and disturbances in behaviour Indifference 3 Psychiatric disorders Personality disorders and disturbances in behaviour Personality change 5 Psychiatric disorders Personality disorders and disturbances in behaviour Personality disorder 1 Psychiatric disorders Personality disorders and disturbances in behaviour Social avoidant behaviour 7 Psychiatric disorders Psychiatric and behavioural symptoms NEC Abnormal behaviour 15 Psychiatric disorders Psychiatric and behavioural symptoms NEC Abnormal behaviour 1 Psychiatric disorders Psychiatric and behavioural symptoms NEC Breath holding 10 Psychiatric disorders Psychiatric and behavioural symptoms NEC Breath holding 3 Psychiatric disorders Psychiatric and behavioural symptoms NEC Decreased eye contact 5 Psychiatric disorders Psychiatric and behavioural symptoms NEC Regressive behaviour 1 Psychiatric disorders Psychiatric and behavioural symptoms NEC Staring 98 Psychiatric disorders Psychiatric and behavioural symptoms NEC Staring 1 Psychiatric disorders Psychiatric disorders NEC Mental disorder 1 Psychiatric disorders Schizophrenia and other psychotic disorders Psychotic disorder 1 Psychiatric disorders Sexual dysfunctions, disturbances and gender identity disorders Excessive masturbation 1 Psychiatric disorders Sleep disorders and disturbances Initial insomnia 1 Psychiatric disorders Sleep disorders and disturbances Insomnia 26 Psychiatric disorders Sleep disorders and disturbances Middle insomnia 1 Psychiatric disorders Sleep disorders and disturbances Sleep disorder 19 Psychiatric disorders Suicidal and self-injurious behaviours NEC Intentional selfinjury 1 Renal and urinary disorders Genitourinary tract disorders NEC Urinary tract disorder 1 Renal and urinary disorders Nephropathies Nephritic syndrome 1 Renal and urinary disorders Nephropathies Nephrotic syndrome 2 Renal and urinary disorders Nephropathies Nephrotic syndrome 1 Renal and urinary disorders Renal disorders (excl nephropathies) Anuria 1 Renal and urinary disorders Renal disorders (excl nephropathies) Hydronephrosis 1 No No Yes Yes No No No No No Yes No No No Yes No Yes No No No Yes No Yes No Yes No No No No No CONFIDENTIAL 585 CONFIDENTIAL 633 Renal and urinary disorders Renal disorders (excl nephropathies) Oliguria 5 Renal and urinary disorders Renal disorders (excl nephropathies) Pyelocaliectasis 2 Renal and urinary disorders Renal disorders (excl nephropathies) Renal failure 1 Renal and urinary disorders Renal disorders (excl nephropathies) Renal failure 2 Renal and urinary disorders Renal disorders (excl nephropathies) Renal failure acute 3 Renal and urinary disorders Renal disorders (excl nephropathies) Renal hypertension 1 Renal and urinary disorders Renal disorders (excl nephropathies) Renal impairment 2 Renal and urinary disorders Ureteric disorders Ureteric stenosis 1 Renal and urinary disorders Urinary tract signs and symptoms Chromaturia 1 Renal and urinary disorders Urinary tract signs and symptoms Enuresis 2 Renal and urinary disorders Urinary tract signs and symptoms Haematuria 3 Renal and urinary disorders Urinary tract signs and symptoms Incontinence 1 Renal and urinary disorders Urinary tract signs and symptoms Leukocyturia 1 Renal and urinary disorders Urinary tract signs and symptoms Polyuria 3 Renal and urinary disorders Urinary tract signs and symptoms Proteinuria 1 Renal and urinary disorders Urinary tract signs and symptoms Urinary incontinence 1 Reproductive system and breast disorders Breast disorders Lactation disorder 1 Reproductive system and breast disorders Male reproductive tract infections and inflammations Balanitis 1 Reproductive system and breast disorders Penile and scrotal disorders (excl infections and inflammations) Acquired phimosis 1 Reproductive system and breast disorders Reproductive tract disorders NEC Oedema genital 2 Reproductive system and breast disorders Testicular and epididymal disorders Testicular retraction 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Asthma 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Asthma 8 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Bronchial hyperreactivity 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Bronchial hyperreactivity 1 No No No Yes No Yes No No No No No Yes No No No No Yes No No No Yes Yes No No No CONFIDENTIAL 586 CONFIDENTIAL 634 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Bronchial obstruction 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Bronchitis chronic 1 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Bronchospasm 11 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Obstructive airways disorder 2 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Obstructive airways disorder 2 Respiratory, thoracic and mediastinal disorders Bronchial disorders (excl neoplasms) Wheezing 4 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Acute respiratory distress syndrome 1 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Atelectasis 1 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Atelectasis 1 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Emphysema 3 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Interstitial lung disease 3 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Lung infiltration 1 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Pneumonia aspiration 7 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Pneumonitis 1 Respiratory, thoracic and mediastinal disorders Lower respiratory tract disorders (excl obstruction and infection) Pulmonary oedema 5 Respiratory, thoracic and mediastinal disorders Neonatal respiratory disorders Apparent life threatening event 2 Respiratory, thoracic and mediastinal disorders Neonatal respiratory disorders Apparent life threatening event 33 Respiratory, thoracic and mediastinal disorders Neonatal respiratory disorders Infantile apnoeic attack 1 Respiratory, thoracic and mediastinal disorders Pleural disorders Haemothorax 1 Respiratory, thoracic and mediastinal disorders Pleural disorders Pleural effusion 1 No Yes Yes Yes Yes No Yes Yes Yes No Yes No Yes No No No No No Yes No CONFIDENTIAL 587 CONFIDENTIAL 635 Respiratory, thoracic and mediastinal disorders Pulmonary vascular disorders Pulmonary embolism 1 Respiratory, thoracic and mediastinal disorders Pulmonary vascular disorders Pulmonary hypertension 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Acute respiratory failure 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Apnoea 127 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Apnoeic attack 10 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Apnoeic attack 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Asphyxia 4 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Asphyxia 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Aspiration 10 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Aspiration 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Bradypnoea 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Choking 7 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Choking sensation 3 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Cough 72 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Cough 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Cyanosis central 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Cyanosis central 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Dry throat 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Dysphonia 5 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Dyspnoea 73 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Dyspnoea 2 Yes No No No Yes No Yes No No Yes No No Yes No Yes No Yes Yes Yes Yes Yes CONFIDENTIAL 588 CONFIDENTIAL 636 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Hiccups 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Hyperventilation 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Hypopnoea 4 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Hypoventilation 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Hypoventilation 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Hypoxia 4 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Increased upper airway secretion 3 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Kussmaul respiration 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Lung disorder 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Nasal obstruction 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Oropharyngeal pain 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Productive cough 6 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Rales 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiration abnormal 30 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory acidosis 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory alkalosis 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory arrest 34 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory depression 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory disorder 28 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory disorder 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory distress 4 Yes Yes No No No Yes Yes No Yes No No No No No Yes No No Yes Yes No No CONFIDENTIAL 589 CONFIDENTIAL 637 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory failure 8 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory tract congestion 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Respiratory tract inflammation 5 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Rhinorrhoea 5 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Sleep apnoea syndrome 3 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Sleep apnoea syndrome 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Sneezing 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Snoring 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Sputum increased 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Suffocation feeling 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Tachypnoea 11 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Tachypnoea 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Upper respiratory tract congestion 1 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Upper respiratory tract inflammation 3 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Use of accessory respiratory muscles 2 Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Yawning 1 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Epistaxis 4 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Laryngeal oedema 1 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Laryngospasm 3 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Nasal congestion 1 No Yes No No No Yes No No No No No Yes No No No No Yes No No No CONFIDENTIAL 590 CONFIDENTIAL 638 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Pharyngeal disorder 2 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Pharyngeal erythema 32 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Rhinitis allergic 1 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Stridor 7 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Tonsillar disorder 1 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders (excl infections) Tonsillar hypertrophy 3 Skin and subcutaneous tissue disorders Angioedema and urticaria Circumoral oedema 1 Skin and subcutaneous tissue disorders Angioedema and urticaria Urticaria papular 2 Skin and subcutaneous tissue disorders Angioedema and urticaria Urticaria pressure 1 Skin and subcutaneous tissue disorders Angioedema and urticaria Urticaria thermal 1 Skin and subcutaneous tissue disorders Cornification and dystrophic skin disorders Hyperkeratosis 1 Skin and subcutaneous tissue disorders Cornification and dystrophic skin disorders Skin hypertrophy 1 Skin and subcutaneous tissue disorders Cutaneous neoplasms benign Dermal cyst 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Blister 16 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Blister 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Decubitus ulcer 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis 3 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis atopic 8 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis atopic 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis bullous 6 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis contact 1 Yes Yes No No No Yes Yes No No No No No No No Yes No No No No No No CONFIDENTIAL 591 CONFIDENTIAL 639 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis diaper 7 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dermatitis exfoliative 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Drug eruption 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Dry skin 3 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Eczema 9 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Erythema 100 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Erythema 4 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Erythema multiforme 14 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Erythrosis 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Exfoliative rash 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Generalised erythema 4 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Granuloma skin 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Lichenification 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Lichen striatus 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Neurodermatitis 9 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Neurodermatitis 3 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Palmar erythema 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Papule 6 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Peau d’orange 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Pemphigoid 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Photosensitivity reaction 1 No No Yes No No No No No Yes No No Yes Yes No No No No No No No No CONFIDENTIAL 592 CONFIDENTIAL 640 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Pruritus 14 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash 99 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash erythematous 8 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash generalised 17 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash macular 19 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash maculopapular 18 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash morbilliform 3 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash papular 7 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash pruritic 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Rash vesicular 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Scab 3 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Scab 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Scar 9 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Seborrhoeic dermatitis 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin chapped 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin discolouration 38 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin discolouration 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin disorder 6 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin exfoliation 7 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin induration 1 No No No No Yes No No No No No No Yes No Yes No No No No No No No CONFIDENTIAL 593 CONFIDENTIAL 641 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin irritation 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin lesion 4 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin necrosis 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin odour abnormal 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin reaction 2 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin warm 17 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Skin warm 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Stevens-Johnson syndrome 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Swelling face 5 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Toxic skin eruption 1 Skin and subcutaneous tissue disorders Epidermal and dermal conditions Yellow skin 5 Skin and subcutaneous tissue disorders Pigmentation disorders Melanodermia 1 Skin and subcutaneous tissue disorders Pigmentation disorders Schamberg’s disease 1 Skin and subcutaneous tissue disorders Pigmentation disorders Skin depigmentation 1 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders NEC Erythema nodosum 3 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders NEC Lipoatrophy 1 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders NEC Palmar-plantar erythrodysaesthesi a syndrome 1 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders NEC Skin ulcer 2 Skin and subcutaneous tissue disorders Skin appendage conditions Cold sweat 8 Skin and subcutaneous tissue disorders Skin appendage conditions Heat rash 1 Skin and subcutaneous tissue disorders Skin appendage conditions Hirsutism 1 No No No No No No No No Yes No No Yes Yes No No Yes No No Yes No No CONFIDENTIAL 594 CONFIDENTIAL 642 Skin and subcutaneous tissue disorders Skin appendage conditions Hyperhidrosis 37 Skin and subcutaneous tissue disorders Skin appendage conditions Hyperhidrosis 1 Skin and subcutaneous tissue disorders Skin appendage conditions Hypertrichosis 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Acute haemorrhagic oedema of infancy 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Cutaneous vasculitis 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Ecchymosis 15 Skin and subcutaneous tissue disorders Skin vascular abnormalities Ecchymosis 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Henoch-Schonlein purpura 7 Skin and subcutaneous tissue disorders Skin vascular abnormalities Increased tendency to bruise 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Leukocytoclastic vasculitis 2 Skin and subcutaneous tissue disorders Skin vascular abnormalities Livedo reticularis 9 Skin and subcutaneous tissue disorders Skin vascular abnormalities Lividity 16 Skin and subcutaneous tissue disorders Skin vascular abnormalities Petechiae 96 Skin and subcutaneous tissue disorders Skin vascular abnormalities Petechiae 4 Skin and subcutaneous tissue disorders Skin vascular abnormalities Purpura 21 Skin and subcutaneous tissue disorders Skin vascular abnormalities Purpura 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Skin haemorrhage 2 Skin and subcutaneous tissue disorders Skin vascular abnormalities Skin haemorrhage 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Skin oedema 1 Skin and subcutaneous tissue disorders Skin vascular abnormalities Vasculitic rash 1 Social circumstances Lifestyle issues Disability 1 Yes No Yes No Yes No Yes No Yes No No No Yes No Yes Yes No Yes Yes No Yes CONFIDENTIAL 595 CONFIDENTIAL 643 Social circumstances Lifestyle issues Immobile 3 Social circumstances Lifestyle issues Mentally late developer 1 Social circumstances Lifestyle issues Walking disability 1 Surgical and medical procedures Gastrointestinal therapeutic procedures Colectomy 1 Surgical and medical procedures Gastrointestinal therapeutic procedures Ileostomy 1 Surgical and medical procedures Gastrointestinal therapeutic procedures Small intestinal resection 1 Surgical and medical procedures Haematological and lymphoid tissue therapeutic procedures Haemostasis 2 Surgical and medical procedures Male genital tract therapeutic procedures Orchidectomy 1 Surgical and medical procedures Nervous system, skull and spine therapeutic procedures Neurosurgery 1 Surgical and medical procedures Respiratory tract therapeutic procedures Endotracheal intubation 1 Surgical and medical procedures Respiratory tract therapeutic procedures Mechanical ventilation 3 Surgical and medical procedures Respiratory tract therapeutic procedures Oxygen supplementation 2 Surgical and medical procedures Skin and subcutaneous tissue therapeutic procedures Skin lesion excision 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Abscess drainage 3 Surgical and medical procedures Therapeutic procedures and supportive care NEC Debridement 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Emergency care 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Enteral nutrition 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Hyperthermia therapy 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Light anaesthesia 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Macrophage activation 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Off label use 1 Surgical and medical procedures Therapeutic procedures and supportive care NEC Resuscitation 11 Surgical and medical procedures Therapeutic procedures and supportive care NEC Surgery 3 Vascular disorders Aneurysms and artery dissections Aneurysm 1 Vascular disorders Arteriosclerosis, stenosis, vascular insufficiency and necrosis Ischaemia 1 Vascular disorders Arteriosclerosis, stenosis, vascular insufficiency and necrosis Peripheral coldness 13 Vascular disorders Arteriosclerosis, stenosis, vascular insufficiency and necrosis Poor peripheral circulation 1 Yes No No Yes No No No No No No No No No No No No No No Yes No No No No No No No No CONFIDENTIAL 596 CONFIDENTIAL 644 Vascular disorders Arteriosclerosis, stenosis, vascular insufficiency and necrosis Vasospasm 1 Vascular disorders Decreased and nonspecific blood pressure disorders and shock Circulatory collapse 35 Vascular disorders Decreased and nonspecific blood pressure disorders and shock Hypotension 10 Vascular disorders Decreased and nonspecific blood pressure disorders and shock Hypotension 1 Vascular disorders Decreased and nonspecific blood pressure disorders and shock Hypovolaemic shock 1 Vascular disorders Decreased and nonspecific blood pressure disorders and shock Peripheral circulatory failure 1 Vascular disorders Decreased and nonspecific blood pressure disorders and shock Shock 9 Vascular disorders Embolism and thrombosis Embolism 1 Vascular disorders Embolism and thrombosis Jugular vein thrombosis 1 Vascular disorders Embolism and thrombosis Thrombosis 2 Vascular disorders Lymphatic vessel disorders Lymphoedema 2 Vascular disorders Vascular disorders NEC Angiopathy 2 Vascular disorders Vascular disorders NEC Capillary disorder 1 Vascular disorders Vascular disorders NEC Flushing 6 Vascular disorders Vascular disorders NEC Hyperaemia 18 Vascular disorders Vascular disorders NEC Hyperaemia 1 Vascular disorders Vascular disorders NEC Pallor 402 Vascular disorders Vascular disorders NEC Pallor 5 Vascular disorders Vascular disorders NEC Peripheral vascular disorder 1 Vascular disorders Vascular disorders NEC Vasodilatation 3 Vascular disorders Vascular haemorrhagic disorders Extravasation blood 1 Vascular disorders Vascular haemorrhagic disorders Haematoma 33 Vascular disorders Vascular haemorrhagic disorders Haematoma 1 Vascular disorders Vascular haemorrhagic disorders Haemorrhage 5 Vascular disorders Vascular hypertensive disorders Hypertension 6 Vascular disorders Vascular inflammations Kawasaki’s disease 18 Vascular disorders Vascular inflammations Kawasaki’s disease 2 Vascular disorders Vascular inflammations Vasculitis 23 Yes Yes No No Yes Yes No No No Yes No Yes No No Yes Yes No Yes No No No Yes Yes Yes Yes Yes No Yes CONFIDENTIAL 597 CONFIDENTIAL 645 598 CONFIDENTIAL APPENDIX 5A : Fatal cases occurred in period CONFIDENTIAL 646 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 2) Unknown Netherlands 19Jul2010 M 13Sep2010 B0683335A NL2010/01987 09FEB2011 17FEB2011 Meningitis viral, Convulsion, Yellow skin, Cyanosis, Dehydration, (See attached page) Diarrhoea, Somnolence, Crying, Vomiting, This case was reported by a regulatory authority (NL-College ter Beoordeling van Geneesmiddelen # NL-LRB-111158) and described the occurrence of meningitis in a 2-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar) for prophylaxis. The subject had no medical history and no concomitant medication. On 13 September 2010 the subject received 1st dose of Infanrix hexa (unknown route, unknown injection site), 1st dose of Prevenar (unknown route, unknown injection site). In September 2010, unspecified time after vaccination with Infanrix hexa and Prevenar, the subject experienced meningitis. PROPHYLAXIS 13Sep2010-13Sep2010 X X Unknown 1 Days Unknown Infanrix hexa Injection A21CA740A (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline PROPHYLAXIS 13Sep2010-13Sep2010 X X Unknown 1 Days Unknown Prevenar Injection E34002 (Pneumococcal vac NonGSK) Wyeth Labs   CONFIDENTIAL 599 CONFIDENTIAL 647 B0683335A DESK COPY (Page 2 of 2) 7. & 13. DESCRIBE EVENT(S) The subject was hospitalised. On 25 September 2010, 12 days after vaccination with Infanrix hexa and Prevenar, the subject died from meningitis. It was unknown whether an autopsy was performed. Hospital report was pending. No further information could be obtained from regulatory authority. Additional data will be sent to us in a proactive way. In the meanwhile, the case has been closed. Follow up information received on 1 February 2011: The case has received a second regulatory number : NL-LRB-116469 On 13 September 2010, 3 minutes after vaccination, the subject experienced crying and sleepiness on the same day. On 18 September 2010, 5 days after vaccination, the subject was found in bed with eyes half-opened and a blue mouth. His skin was yellow/pale. He vomited pink, foaming milk. No fever was observed (37 degrees C). The boy was hospitalized, diarrhea aggravated and dehydration was diagnosed. Blood test and spinal tap were performed. The boy had several afebrile convulsions and a MRI showed severe damage of the brain. No further treatment was given. On 25 September 2010, 12 days after vaccination, the subject died from viral meningitis. The regulatory authority considered the events were unlikely to be related with vaccination with Infanrix hexa and Prevenar. Additional information has been requested but could not be obtained from regulatory authority. The case has therefore been closed. LABORATORY TEST NAME TEST DATE TEST RESULT LOW NORMAL HIGH NORMAL Blood test Sep2010 unknown NMR Sep2010 brain damage Spinal tap Sep2010 unknown   CONFIDENTIAL 600 CONFIDENTIAL 648 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 2) Unknown France 10 W F 10Nov2010 B0688734A 13DEC2010 20DEC2010 Sudden infant death syndrome, Respiratory tract congestion, Cough, (See attached page) Nasal congestion, This case was reported by the French regulatory authority (AFSSaPS reference PS20101095) and described a sudden infant death in a 10-week-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccine (Prevenar, non-gsk) for prophylaxis. The subject had mixted diet. At birth she weighed 2.99 kg and her heigh was 49.5 cm. She had no neonatal disorder. Medical condition included jaundice with abnormal skin reflection on 01 October 2010. On 09 November 2010, the subject received primary course of Infanrix hexa (batch A21CA777A as data entry and 121CA777A as reported, intramuscular, injection site unknown) and a primary course of PROPHYLAXIS 09Nov2010-09Nov2010 X X Intramuscular 1 Days Unknown Infanrix hexa Injection A21CA777A (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline PROPHYLAXIS 09Nov2010-09Nov2010 X X Intramuscular 1 Days Unknown Prevenar Injection E74711 (Pneumococcal vac NonGSK) Other 2.99 kg and 49.5 cm at birth, no neonatal disorder (See attached page) The subject had mixted diet.   CONFIDENTIAL 601 CONFIDENTIAL 649 B0688734A DESK COPY (Page 2 of 2) 7. & 13. DESCRIBE EVENT(S) Prevenar (batch E74711, intramuscular, injection site unknown). On 10 November 2010, the subject presented with bronchial and nasal congestions, cough, and serous fluid in tympanum (with crying at night) which was diagnosed before the administration of vaccines (medical condition). At 19:00, the subject received her last bottle (250 ml). She went to bed at 19:15 and she was layed in her parent’s bed, on a pillow. At 21:45, the father went to bed and found the subject unconscious. Mobile emergency medical unit was contacted which arrived at 22:00. At 22:23 pm, a pediatric mobile emergency medical unit arrived. Resuscitation procedure was started. The subject was intubated and received adrenaline. She was hospitalized and died at 00:00. Tracheal aspiration was positive for klebsiella pneumoniae. It was unknown whether an autopsy was performed. Causal relationship of vaccination with Infanrix hexa and Prevenar and sudden infant death was assessed as dubious, according to the French method of imputability. LABORATORY TEST NAME TEST DATE TEST RESULT LOW NORMAL HIGH NORMAL Tracheal aspiration 10Nov2010 positive for kle MEDICAL CONDITION START DATE END DATE CONTINUING JAUNDICE 01Oct2010 Unknown Unknown SEROUS FLUID IN TYMPANUM Unknown Unknown Yes CRYING AT NIGHT Unknown Unknown Yes KLEBSIELLA PNEUMONIAE INFECTION Unknown Unknown Yes   CONFIDENTIAL 602 CONFIDENTIAL 650 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 2) PRIVACY Sweden 14Feb2010 F 26Nov2010 B0700040A SE2011/00097 21FEB2011 21FEB2011 Meningitis, Sepsis, Shock, Pneumococcal infection, Renal impairment, (See attached page) Hepatic function abnormal, Pyrexia, Diarrhoea, Vomiting, This case was reported by a consumer and described the occurrence of meningitis in a 9-month-old female subject who was vaccinated with synflorix (GlaxoSmithKline) and combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) for prophylaxis. A physician or other health care professional has not verified this report. Previous and/or concurrent vaccination included bacillus calmette-guerin vaccine (non-gsk) ;non-GSK manufacturer;unknown;unknown given on 28 October 2010; diphtheria and tetanus toxoids and acellular pertussis vaccine ;GlaxoSmithKline;unknown;unknown given on 20 May 2010; hepatitis B vaccine recombinant ;manufacturer unspecified;unknown;unknown given on 20 May 2010; synflorix ;GlaxoSmithKline;unknown;unknown given on 20 May 2010. PROPHYLAXIS 17Aug2010-17Aug2010 X X Intramuscular 1 Days Unknown Synflorix Injection ASPNA017CK (Pneumoc.polysac S.Type 1 + Pneumoc.polysac S.Type 4 + Pneumoc.polysac S.Type 5 + Pneumoc.polysac S.Type 6B + Pneumoc.polysac S.Type 7F + Pneumoc.polysac S.Type 9V + Pneumoc.polysac S.Type 14 + PROPHYLAXIS 17Aug2010-17Aug2010 X X Intramuscular 1 Days Unknown Infanrix hexa Injection A21CA674A (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline Synflorix (GlaxoSmithKline) 20May2010 – 20May2010 (Pneumoc.polysac S.Type 1 + Pneumoc.polysac S.Type 4 + Pneumoc.polysac S.Type 5 + Pneumoc.polysac S.Type 6B + Pneumoc.polysac S.Type 7F + Pneumoc.polysac S Infanrix hexa (GlaxoSmithKline) 20May2010 – 20May2010 (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) Hepatitis B vaccine (Unk Manufacturer) 20May2010 – 20May2010 (Hepatitis B vaccine)   CONFIDENTIAL 603 CONFIDENTIAL 651 B0700040A DESK COPY (Page 2 of 2) 7. & 13. DESCRIBE EVENT(S) Concurrent medications included Paracetamol for her growing teeth. On 17 August 2010, the subject received 2nd dose of Synflorix (administration site and route unknown, batch number not provided). On 26 November 2010, 101 days after vaccination with Synflorix, the subject experienced fever, vomiting and diarrhea. This continued the whole day between 11 am to 6 pm. She suddenly got better and she was not vomiting and her fever went down. She got fluid replacement and was able to urinate. On 27 November 2010, at 7 am, the subject was not breathing any longer. At the hospital, they tried to save her during 40 minutes. The subject died on 27 November 2010 from meningitis and sepsis. An autopsy was performed and showed abnormal renal function, hepatic function abnormal and possible pneumococcal infection. The body was in shock. Follow-up information received on 18 February 2011: This case was also reported by a nurse. The subject was healthy and didn’t have any other medicines. Previous and/or concurrent vaccination included bacillus calmette-guerin vaccine (non-gsk) ;non-GSK manufacturer;unknown;unknown given on 28 May 2010; combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. ;GlaxoSmithKline;unknown;unknown given on 20 May 2010; hepatitis B vaccine recombinant ;manufacturer unspecified;unknown;unknown given on 20 May 2010; synflorix ;GlaxoSmithKline;unknown;unknown given on 20 May 2010. On 17 August 2010, the subject received also a 2nd dose of Infanrix hexa. On 26 November 2010, at 6 am, the subject got fever (40 deg.C). The subject was treated with paracetamol (Alvedon). Until 3.30 am, she received fluid replacement and then her parents let her rest. On 27 November 2010, at 6.49 am, she sighed in a strange way and stopped breathing. Follow-up information received on 21 February 2011: The batch numbers and route were provided. Bacillus calmette-guerin vaccine (non-gsk) was as initially reported, administered on 28 October 2010. LABORATORY TEST NAME TEST DATE TEST RESULT LOW NORMAL HIGH NORMAL Body temperature 26Nov2010 40deg.C CONCOMITANT DRUGS AND DATES OF ADMINISTRATION BCG vaccine (Other) 28Oct2010 – 28Oct2010 (Bacillus Calmette-Guerin) Paracetamol Unknown   CONFIDENTIAL 604 CONFIDENTIAL 652 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 3) PRIVACY France 10Apr2010 M 07Mar2011 B0705290A 21APR2011 29APR2011 Sudden death, Pyrexia, Lymphadenopathy, Emphysema, Product quality (See attached page) issue, Cardio-respiratory arrest, Asphyxia, Febrile convulsion, This case was reported by a physician and described the occurrence of death (cause unknown) in a 10-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix Hexa, GlaxoSmithKline) for prophylaxis. The subject had no known pathology and took no concurrent medication. Vaccinal history included one dose of DTPa-IPV-Hib vaccine (Infanrixquinta, GlaxoSmithKline) administered on 31 August 2010 and one dose of tuberculosis vaccine (BCG) on 01 June 2010. The vaccination schedule of the subject did not comply with French medical authority recommendations. The subject’’s medical history included bronchiolitis during last winter. On 07 March 2011, the subject received a second dose of Infanrix Hexa (batch A21CA598F, route and injection site unknown). During the PROPHYLAXIS 07Mar2011-07Mar2011 X X Intramuscular 1 Days Unknown Infanrix hexa Injection A21CA598F (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline Vaccinal history included one dose of DTPa-IPV-Hib vaccine (Infanrixquinta, (See attached page) glaxoSmithKline) administered on 31 August 2010 and one dose of tuberculosis vaccine (BCG) on 01 June 2010. The vaccination schedule of the subject did not comply with French medical authority redcommendations. The subject had no known pathology. The subject was born at 41 weeks of amenorrhea by normal vaginal way. He weighed 4.09 kg   CONFIDENTIAL 605 CONFIDENTIAL 653 B0705290A DESK COPY (Page 2 of 3) 7. & 13. DESCRIBE EVENT(S) following night, the subject experienced fever. Mobile emergency medical unit was contacted by the parents. On their arrival, the subject was dead. No diagnostic was made, sudden infant death was suspected. An autopsy was agreed by the parents (not a complete forensic). Results were not available at the time of reporting. According to the reporter, a causal relationship between the death and Infanrix Hexa was not established. Upon follow-up received from the AFFSaPS (reference TO20110471A) on 22 March 2011: On 31 August 2010, tuberculosis vaccine (BCG) was made instead of 01 June 2010 (inconsistent information given). Clinical examination was normal before vaccination. Infanrix Hexa was administered intramuscularly at 11:00 on 07 March 2011. At 15:00, he presented with fever which resolved after paracetamol administration. The evening meal was taken without reportable incident. During the following night, fever recurred and the parents called the mobile emergency unit. On 08 March 2011, the subject was dead on mobile emergency medical unit arrival. He was found, by his father, lay on his stomach with face on his pillow. There were no signs of inhalation or vomiting. There was no sign of righting reflex, normaly present at this age. Post mortem analyses were negative for C-reactive protein, blood culture and cerebrospinal fluid. Post-mortem virus tests were negative excepted positive for Respiratory Syncytial Virus in nose sample. Anatomical pathology evidenced major mesenteric adenopathy. Further informations conerning autopsy report were pending. According to the French method of assessment, the AFSSaPS considered the causal relationship between vaccination with Infanrix Hexa and sudden death as dubious. Upon follow-up received from quality department on 31 March 2011: A product complaint has been recorded (Ref 2011-13789). QA analysis revealed the complaint to be unsubstantiated. A complete review of the batch records had been performed and no deviation that could have an impact on the product was highlighted. A search was also performed in the GSK safety database for the final bulk A21CA598 and it did not reveal a safety signal. Upon follow-up received from a physician on 05 April 2011: The subject was born at 41 weeks of amenorrhea by normal vaginal way. He weighed 4.09 kg and measured 50 cm with a head circumference of 37 cm. APGAR scores at 1 and 5 min were at 10. No congenital abnormality or fetal distress were observed. The pregnancy occurred without problem. It was not known if the mother took any treatment during this pregnancy or during breast feeding or if she had smoked. He was breast fed until October 2010. He had a normal growth (in or upper the 97th percentile) with a normal head circumference. At the time of event, he weighed 11.34 kg. The subject had no known allergy, no know congenital metabolic or enzymatic abnormality. Medical history did not included cyanosis, respiratory arrest or apnea episodes, gastroesophagal reflux, convulsion, sleep disorder, surgery, maltreatment. Within the 2 weeks before death, the subject had no pathology including no infection, no fever, no excessive sweat during sleep, no snore during sleep, no vomiting, no modification of appetite, no diarrhea or modification of stools, no dyspnea, no abnormal crying, no lethargy. He was not admitted to emergency unit. It was unknown if he was exposed to contagious disease. The father was 25-year-old. The mother was 24-year-old and had two other children (from another father). Both had no relevant medical history. It was not known if they were smokers. The family had a city life. During the last winter, the family moved house. Infanrix hexa was administered intramuscularly in unknown thigh. The assessment of this reporter was not provided. Upon follow-up received from AFSSaPS on 14 April 2011: Autopsy results were provided and evidenced major lymphoid hyperplasia of mesenteric lymph nodes, of intestinal lymphoid tissu and of appendix with cellular dystrophy suggestive of viral etiology possibly subclinical. No Cytomegalovirus, Epstein-Barr virus or Herpes virus infection was found. At lung level, bilateral pseudo-emphysemateous pulmonary lesions were noticed, suggestive of suffocation phenomenon as no resuscitation was attempted. No sign suggestive of massive inhalation, no sign suggestive of infectious pneumopathy   CONFIDENTIAL 606 CONFIDENTIAL 654 B0705290A DESK COPY (Page 3 of 3) and no visceral congenital anomaly were reported. According to the AFSSAPS, based on the French method of assessment, the events were unlikely related to vaccination with Infanrix hexa. Follow-up was received on 21 April 2011 from the AFSSAPS : Psychomotor development was normal. The subject had one half-brother and one half-sister aged 6 and 5 years with medical history of convulsions. The half-brother was treated with Micropakine. On 07 March 2011, at 03:00PM, body temperature was at 39.6 Celsius degrees. On 08 March 2011, around midnight, the father still had not heard from him while he usually woke up at this time for his feed. When the father went to the bedroom, the subject was in ventral decubitus with the face on his pillow, he had cyanosis and was cold. The mobile emergency unit arrived and cardiorespiratory arrest was confirmed (the subject could not be resuscitated). His body temperature was at 35 Celsius degrees. Skull and skeleton ultrasounds were normal. The AFSSAPS reported that the respiratory syncytial virus responsibility in digestive inflammatory lesions was unlikely. Concerning the responsibility of Infanrix hexa vaccination, the administration was too recent to provide a probable explanation for the inflammation. In conclusion, no clear explanation was found to the subject death. Hypothesis of respiratory asphyxia as cause of death was made, due to circumstances in which the subject was found as well as the aspect of his lungs at autopsy. Another hypothesis was febrile convulsion. Post mortem tests: C reactive protein negative, CSF negative, blood culture negative and virus tests negative excepted positive for Respiratory Syncytial Virus in nose sample. Autopsy: -major lymphoid hyperplasia of mesenteric lymph nodes, of intestinal lymphoid tissu and of appendix with cellular dystrophy suggestive of viral etiology possibly subclinical. -no Cytomegalovirus, Epstein-Barr virus or Herpes virus infection. -bilateral pseudo-emphysemateous pulmonary lesions suggestive of suffocation phenomenon as no resuscitation was attempted. -no sign suggestive of massive inhalation. -no sign suggestive of infectious pneumopathy. -no visceral congenital anomaly. LABORATORY TEST NAME TEST DATE TEST RESULT LOW NORMAL HIGH NORMAL Autopsy Mar2011 see text Blood culture 08Mar2011 negative Body temperature 07Mar2011 39.6Celsius degr Body temperature 08Mar2011 35Celsius degr C-reactive protein 08Mar2011 negative CSF test 08Mar2011 negative Full blood count 08Mar2011 normal Physical examination 07Mar2011 normal Scan NOS whole body 08Mar2011 normal Ultrasound skull 08Mar2011 normal OTHER RELEVANT HISTORY and measured 50 cm with a head circumference of 37 cm. APGAR scores at 1 and 5 min were at 10. No congenital abnormality of fetal distress were observed. The pregnancy occurred without problem. It was not known if the mother took any treatment during this pregnancy or during breast feeding or if she smoke. He was breast fed until October 2010. He had a normal growth (in or upper the 97th percentile) with a normal head circumference. The subject had no known allergy, no know congenital metabolic or enzymatic abnormality. Medical history did not included cyanosis, respiratory arrest or apnea episodes, gastroesophagal reflux, convulsion, sleep disorder, surgery, maltreatment. Within the 2 weeks before death, the subject had no pathology including no infection, no fever, no excessive sweat during sleep, no snore during sleep, no vomiting, no modification of appetite, no diarrhea or modification of stools, no dyspnea, no abnormal crying, no lethargy. He was not admitted to emergency unit. It was unknown if he was exposed to contagious disease. The father was 25-year-old. The mother was 24-year-old and had two other children (other father). Both had no relevant medical history. It was not known if they were smokers. The family had a city life. During the last winter, the family moved house. The subject had one half-brother and one half-sister aged 6 and 5 years with medical history of convulsions. The half-brother was treated with Micropakine. MEDICAL CONDITION START DATE END DATE CONTINUING BRONCHIOLITIS Unknown Unknown No POSSIBLE VIRAL INFECTION Unknown Unknown Yes   CONFIDENTIAL 607 CONFIDENTIAL 655 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 2) Unknown Thailand 2 M F 10Mar2011 B0706503A TH2011/00009 21MAR2011 29MAR2011 Shock, Respiratory arrest, Cardiac arrest, Pyrexia, Somnolence, Hypotonia, Vomiting, Crying, Apnoea, This case was reported by a physician and described the occurrence of fatal shock in a 2-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline) for prophylaxis. The subject was born by C-section. Apgar score was 10 at 0 and 5 min. Birth weight was 3.2 kg and experienced a normal growth and development. Medical condition included a possible genetic abnormality due to a family history of death after vaccination (subject’s brother died 2 years ago after vaccination with DTwP). On 9 March 2011, the subject received unspecified dose of Infanrix hexa (.5 ml, unknown route of adminstration). PROPHYLAXIS 09Mar2011-09Mar2011 X X Unknown 1 Days .5 ml xxxxxxx Infanrix hexa Injection A21CA959B (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline (See attached page)   CONFIDENTIAL 608 CONFIDENTIAL 656 B0706503A DESK COPY (Page 2 of 2) 7. & 13. DESCRIBE EVENT(S) The subject was normal before vaccination. On 10 March 2011, 24 hours after vaccination with Infanrix hexa, the subject experienced shock. She experienced low-grade fever, drowsiness and stopped breathing. The subject was floppy and had no heart rate. Cardiopulmonary resuscitation was performed during 3 hours but the subject did not respond to it. The physician considered the events were probably related to vaccination with Infanrix hexa. The subject died on 10 March 2011 from cardiorespiratory arrest. An autopsy was not performed. Follow-up received on 21 March 2011: The subject’s brother was 2 month-old when he died (11 years ago), after received DTwP which was EPI vaccine (no record available). After vaccination (no specific time available), the subject experienced vomiting (single episode) and had colicky crying at home. On 10 March 2011, the subject was taken to the clinic due to fever and crying. After massive crying, the subject experienced apnea and no heart beat was detected after stimulation. Cardiopulmonary resuscitation was performed for 10 minutes and subject responded by crying. One hour later, the subject experienced apnea again and resuscitation was continued for 3 hours without any response. No lab results nor autopsy results were available. Shock was the final diagnosis. MEDICAL CONDITION START DATE END DATE CONTINUING GENETIC ABNORMALITY Unknown Unknown Yes   CONFIDENTIAL 609 CONFIDENTIAL 657 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 2) PRIVACY Italy 07Apr2010 M 26Mar2011 B0712016A IT2011/00988 04APR2011 12APR2011 Hypotonia, Hyperhidrosis, Pyrexia, (See attached page) This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 137473) and described the occurrence of hypotonia nos in a 11-month-old male subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine. (Infanrix hexa, GlaxoSmithKline) and pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. The subject was born after 41 weeks + 3 days, normal pregnancy and spontaneous delivery. Concurrent medical conditions included severe respiratory distress at birth. He was reanimated and resigned from the prenatal intensive care on 20 May 2010. He was not able to feed spontaneously (dysphagia) so a nasogastric tube was inserted with pump infusion. According to the doctor, the subject had contraindication to the PROPHYLAXIS 25Mar2011-25Mar2011 X X Intramuscular 1 Days Unknown Infanrix hexa Injection A21CB001A (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline PROPHYLAXIS 25Mar2011-25Mar2011 X X Intramuscular 1 Days Unknown Prevenar 13 Injection E87109 (Pneumococcal vac NonGSK) Wyeth Labs Paracetamol Unknown Vitamin Unknown Vigabatrin Unknown Topiramate Unknown Antibiotics Unknown Bronchodilator Unknown (See attached page)   CONFIDENTIAL 610 CONFIDENTIAL 658 B0712016A DESK COPY (Page 2 of 2) 7. & 13. DESCRIBE EVENT(S) vaccine. He was hospitalised from 22 May 2010 to 25 May 2010 due to respiratory distress. From 14 to 21 July 2010 due to seizures. On 18 August 2010, diagnostic results showed cerebral palsy, gastroesophageal reflux, hypoxic-ischemic encephalopathy of grade 3, microcephaly, psychomotor retardation and spastic quadriplegia (mainly the upper limbs). Concurrent medications included Paracetamol (Tachipirina), Vitamin, Vigabatrin, Topiramate, Antibiotics (Antibiotic), Bronchodilator and Steroid. On 25 March 2011, the subject received 3rd dose of Infanrix hexa (intramuscular, right thigh) and 3rd dose of Prevenar 13 (intramuscular, left thigh). On 26 March 2011, 1 day after vaccination with Infanrix hexa and Prevenar 13, the subject experienced fever (38 to 38.5 deg.C). On 27 March 2011, 2 days after vaccination with Infanrix hexa and Prevenar 13, the subject experienced hypotonia nos and crisis of sweating. The regulatory authority reported that the events were possibly related to vaccination with Infanrix hexa and Prevenar 13. The subject died on 28 March 2011, cause of death was not reported. It was unknown whether an autopsy was performed. Follow-up information received on 15 July 2011: As no additional information could be obtained, the case has been closed. LABORATORY TEST NAME TEST DATE TEST RESULT LOW NORMAL HIGH NORMAL Body temperature 26Mar2011 38-38.5deg.C CONCOMITANT DRUGS AND DATES OF ADMINISTRATION Steroid Unknown MEDICAL CONDITION START DATE END DATE CONTINUING HYPOXIC-ISCHEMIC ENCEPHALOPATHY Unknown Unknown Yes CEREBRAL PALSY Unknown Unknown Unknown SEIZURE Unknown Unknown No DYSPHAGIA Unknown Unknown Unknown RESPIRATORY DISTRESS Unknown Unknown No NASOGASTRIC TUBE INSERTION Unknown Unknown Yes MICROCEPHALY Unknown Unknown Yes GASTROESOPHAGEAL REFLUX Unknown Unknown Unknown SPASTIC QUADRIPLEGIA Unknown Unknown Yes PSYCHOMOTOR RETARDATION Unknown Unknown Yes   CONFIDENTIAL 611 CONFIDENTIAL 659 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION X X X GlaxoSmithKline Rue De L’Institut 89, Rixensart, B-1330, Belgium DESK COPY (Page 1 of 3) PRIVACY Italy 21Nov2010 F 23Apr2011 B0716780A IT2011/01280 14SEP2011 15SEP2011 Cardiac arrest, Multi-organ failure, Pneumonia aspiration, Cerebral (See attached page) ischaemia, Sudden infant death syndrome, Unresponsive to stimuli, Peripheral coldness, Staring, Musculoskeletal stiffness, Pyrexia, Somnolence, This case was reported by a regulatory authority (IT-Agenzia Italiana del Farmaco # 139520) and described the occurrence of cardiac arrest in a 5-month-old female subject who was vaccinated with combined diphtheria, tetanus-acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b vaccine (Infanrix hexa, GlaxoSmithKline), pneumococcal vaccines (non-gsk) (Prevenar 13) for prophylaxis. On an unspecified date, the subject received 1st dose of Infanrix hexa (unknown route of administration, unknown site of injection, batch number not provided). At an unspecified time after vaccination with 1st dose of Infanrix Hexa, the subject experienced fever. This is the reason why the PROPHYLAXIS 10Feb2011-10Feb2011 X X Unknown 1 Days Unknown 1) Infanrix hexa Injection (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline PROPHYLAXIS 14Apr2011-14Apr2011 X X Intramuscular 1 Days .5 ml xxxxxxx 2) Infanrix hexa Injection A21FA980A (Hepatitis B vaccine + Polio.vaccine inactivated + Tetanus vaccine + Diphtheria toxoid + Haemophilus influenzae ty + Acellular pertussis vax) GlaxoSmithKline   CONFIDENTIAL 612 CONFIDENTIAL 660 EVENT INFORMATION DRUG INFORMATION CONCOMITANT DRUGS AND HISTORY IV. ONLY FOR REPORTS SUBMITTED BY MANUFACTURER I. II. III. 1. PATIENT INITIALS 7. & 13. DESCRIBE EVENT(S) 2a. AGE 3. SEX 4. – 6. EVENT ONSET 8. – 12. CHECK ALL LIFE THREATENING CLINICALLY SIGNIFICANT / REQUIRED INTERVENTION CONGENITAL ANOMALY OTHER APPROPRIATE 22. CONCOMITANT DRUGS AND DATES OF ADMINISTRATION (Exclude those used to treat event) 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 14. IDENTIFIED DRUG(S) 15. DAILY/CUMULATIVE DOSE 17. INDICATION(S) FOR USE 18. THERAPY DATES (From / To) 16. ROUTE OF ADMINISTRATION 19. THERAPY DURATION 20. DID EVENT ABATE AFTER STOPPING DRUG? YES NO N/A 21. DID EVENT REAPPEAR AFTER REINTRODUCTION? YES NO N/A 23. OTHER RELEVANT HISTORY 24. NAME AND ADDRESS OF MANUFACTURER (Include Zip Code) 25a. REPORT TYPE DATE OF REPORT INITIAL FOLLOW-UP 24c. DATE RECEIVED 24d. REPORT SOURCE HEALTH PROFESSIONAL STUDY LITERATURE INTERNATIONAL EVENT REPORT PATIENT DIED AS OUTCOME OF EVENT INVOLVED PERSISTENCE OF SIGNIFICANT DISABILITY OR INCAPACITY TO EVENT 1a. COUNTRY 2. DATE OF BIRTH RESULTED IN OR PROLONGED INPATIENT HOSPITALISATION DESK COPY (Page 2 of 3) PRIVACY Italy 21Nov2010 F 23Apr2011 B0716780A IT2011/01280 14SEP2011 15SEP2011 second dose was not administered in the last 4 weeks. On 14 April 2011, the subject received 2nd dose of Infanrix hexa (.5 ml, intramuscular, unknown route of administration), and 2nd dose of Prevenar 13 (.5 ml, intramuscular, unknown route of administration, batch number not provided). On 14 April 2011, less than one day after vaccination with 2nd doses of Infanrix hexa and Prevenar 13, the subject experienced fever (more than 39 Deg.C). On 15 April 2011, the fever was resolved. In the afternoon of 15 April 2011, the subject did not respond to stimuli. She was admitted at the first aid with cold extremities, fixed gaze, overtone, stiff neck and normotensive fontanel. Afterwards, the subject recovered completely. At the neurological visit, the subject was alert, reactive and the PROPHYLAXIS 10Feb2011-10Feb2011 X X Unknown 1 Days Unknown 3) Prevenar 13 Injection (Pneumococcal vac NonGSK) Other PROPHYLAXIS 14Apr2011-14Apr2011 X X Intramuscular 1 Days .5 ml xxxxxxx 4) Prevenar 13 Injection E57714 (Pneumococcal vac NonGSK) Other   CONFIDENTIAL 613 CONFIDENTIAL 661 B0716780A DESK COPY (Page 3 of 3) 7. & 13. DESCRIBE EVENT(S) state of drowsiness has been related to vaccination. Electroencephalogram was without clear anomalies irritative. On 23 April 2011 (night), the subject had a cardiac arrest. After 20 minutes of reanimation the cardiac activity resumed but with irreversible neurological sequelae. The regulatory authority reported that fever, stiff neck, fixed gaze, cold extremities, unresponsive to stimuli and cardiac arrest were possibly related to vaccination with Infanrix hexa and Prevenar 13, but almost certainly for drowsiness. On 25 April 2011, the subject died, cause of death is not specified. It was unknown whether an autopsy was performed. Follow-up information received on 19 May 2011: The parents of the subject were young, both were born in 1992. No information regarding important diseases or neonatal problems were reported. Artificial sucking from the early days due to maternal hypogalactia, was reported. The subject’s growth had always been regular, between 50 Deg and 75 Deg percentile. The first dose of the vaccines Infanrix Hexa and Prevenar 13 were administered on 10 February 2011. Within weeks of vaccination with 1st dose of Infanrix Hexa and Prevenar 13, the subject experienced fever. An autopsy was performed and there had been no element attributed to encephalitis. The histological evaluation was in course. Follow-up information received on 6 September 2011: An autopsy was performed and the results were reported on the basis of available information and histological investigations. The death occurred at 15:10 on 25 April 2011. The death was caused by multiple organ failure, ab-ingestis pneumonia, cerebral anoxia, following sudden cardiac arrest. Other significant causes were not found, therefore cardiac arrest might correspond to Sudden Infant Death Syndrome (SIDS). There was no available scientific evidence to show a causal relationship between vaccine administrations and cardiac arrest. Follow-up information received on 14 September