Paper provided by MHRA for Joint Committee on Vaccination and Immunisation October 2013:

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1 Paper provided by MHRA for Joint Committee on Vaccination and Immunisation October 2013: VACCINE-ASSOCIATED SUSPECTED ADVERSE REACTIONS REPORTED VIA THE YELLOW CARD SCHEME DURING 2012/13 September 2013

2 CONTENTS Page I NTRODUCTION [1] 1. SECTION 1: YELLOW CARD DATA [2] 1.1. Routine Childhood Vaccines Menitorix (MenC/Hib combination) Prevenar 13 (Pneumococcal conjugate vaccine) Pediacel and Infanrix IPV HIB (DTaP/IPV/Hib) MMR Vaccine [2] [4] [6] [8] C Vaccine [10] Infanrix IPV (d/dtap/ipv) [12] Meningitis Repevax / Revaxis (dt/ipv) Human Papillomavirus Vaccine [14] [16] 1.2. Other Vaccines Hepatitis B Vaccine [18] Seasonal Influenza Vaccine [20] Pneumococcal polysaccharide vaccine [23] BCG Vaccine [25] Varivax and Varilrix (Varicella Zoster Virus) [27] 2. SECTION 2: KEY ISSUES REVIEWED BY MHRA 2.1. Update on Pandemrix vaccine and Narcolepsy [29] 2.2. Repevax use in pertussis vaccination programme in pregnant women [31] 2.3. HPV vaccine and Chronic Fatigue Syndrome [32]

3 Introduction This paper was prepared by the Medicines and Healthcare products Regulatory Agency (MHRA) for the October 2013 Meeting of the Joint Committee of Vaccination and Immunisation (JCVI). Section 1 of this paper provides an update on UK suspected adverse reactions (ADRs) associated with routine and/or commonly used vaccines reported to the MHRA via the Yellow Card Scheme during the time period of 1st January 2012 to 31st July Section 2 provides an update on key vaccine safety issues reviewed by MHRA during the period. It should be noted that a report of a suspected ADR to the MHRA does not necessarily mean that it has been caused by the vaccine. Many factors have to be taken into account in assessing the relationship between a vaccine and suspected reaction such as the possible role of underlying or undiagnosed illness or infection. The data contained in this report may therefore include some known side effects as well as purely coincidental events. For this reason, these data must not be considered as a list of known vaccine side effects. The recognised side effects of all vaccines are described in the product information (Summary of Product Characteristics [SPC] and Patient Information Leaflet [PIL]). These are provided with the vaccine and are available for viewing on the electronic Medicines Compendium (emc) website [ Furthermore, due to variable levels of reporting and as the precise number of individuals immunised is not included in this report, the number of ADR reports received should not be used as a basis for estimating the incidence of ADRs or for comparing relative safety of vaccines. For some routine childhood vaccines, exposure estimates in this report are based on COVER uptake data extrapolated to the relevant UK birth cohort. Exposure for non-routine vaccines has not been estimated in this report. As the reporting rates are broad estimates which do not take into account exposure outside of the routine schedule, and are not age-adjusted, no firm conclusions can be drawn on relative ADR reporting rates over time. Yellow Card reports may contain more than one ADR. Seriousness is determined by regulatory criteria based on the medical condition (MedDRA Dictionary serious) 1. Yellow Card data covers the whole of the UK. Prepared: August 2013 Vigilance and Risk Management of Medicines (VRMM) Medicines and Healthcare products Regulatory Agency 1 MedDRA - the Medical Dictionary for Regulatory Activities - is a standardised, medically validated adverse event terminology system used within the international medicines regulatory environment. 1

4 1. YELLOW CARD DATA 1.1 Routine Childhood Vaccines Menitorix (MenC/Hib combination) Menitorix was introduced into the routine childhood schedule in September 2006 as a single dose MenC/Hib booster at around 12 months of age. The total number of suspected ADRs reported in association with Menitorix over the last 3 years is shown below (table 1). 2012/2013 exposure is based on the assumption of 93% uptake (one dose) for an annual birth cohort of 800,000 2, extrapolated to account for the time period analysed of 18 months. Table 1: Total number of Menitorix reports received (s erious reports in brackets) /13 Total number of reports 27 (13) 18 (13) 35 (20) Total number of reactions 74 (18) 40 (22) 122 (34) Total fatal Exposure 684, ,000 1,116,000 ERR per 100,000 doses 3.9 (1.9) 2.4 (1.8) 3.1 (1.8) ERR = Estimated Reporting Rate Figure 1 shows the serious ADRs reported in each MedDRA System Organ Class (SOC), as a percentage of the total ADRs, for the last three and a half years. Reporting rates have remained consistently very low. As number of reports is low, any relative percentage changes should be interpreted with caution. Three of the serious reports related to consequences of Meningococcal and Haemophilus infection (2 Meningococcal Infection and 1 Haemophilus Infection ), which were possible vaccine failures. As with all vaccines, meningitis C and Haemophilus type B vaccination may not be 100% successful and isolated cases of failure following primary vaccination are not unexpected. Other serious reports included 3 cases of Hypotonia, 2 cases of Convulsion and Febrile Convulsion and 1 case of Syncope. These are listed as possible side effects in the Menitorix SmPC. The remaining serious cases were likely to be isolated events coincidental with vaccination. Other reports were spread across 8 SOCs, and concerned either known rare side effects of primary immunisation or events coincidental with vaccination. Conclusion: No significant new safety issues were identified during 2012/

5 Vascular disorders Figure 1: Percentage of serious reactions per SOC associated with Menitorix vaccine Cardiac disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Infections and infestations Injury, poisoning and procedural complications Investigations Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders Skin and subcutaneous tissue disorders System Order Class (SOC) /13 Blood and lymphatic system disorders Percentage of serious reports (%)

6 Prevenar 13 (pneumococcal conjugate vaccine) In April 2010, Prevenar vaccine (PCV7) was replaced by Prevenar 13 (PCV13), which contains antigens against 13 strains, to broaden protection against pneumococcal disease. Prevenar is offered routinely at 2 and 4 months of age, and as a booster around/shortly after the first birthday. 2012/13 exposure is based on the assumption of combined 93% uptake for two primary doses and one booster dose for an annual birth cohort of 800,000. Table 2: Total number of Prevena r reports (serious reports in brackets) /13 Total number of reports 91(35) 181(135) 194 (126) Total number of reactions 253 (53) 504 (194) 610 (239) Total fatal Exposure 2,008,800 1,463,200 3,348,000 ERR per 100,000 doses 4.5 (1.7) 12.4 (9.2) 5.8(3.8) ERR = Estimated Reporting Rate The 126 serious reports were spread across 18 SOCs, with the majority falling into the Infections and infestations SOC and concerned mainly isolated events which were either known rare side effects of primary immunisation or events coincidental with vaccination. There were 3 cases of pneumococcal bacteraemia, 57 of pneumococcal infection, 10 of pneumococcal sepsis and 5 of pneumonia pneumococcal. Of the 75 cases of pneumococcal type reactions all but 4 were originated from Public Health England (PHE) (formerly Health Protection Agency (HPA)). Four fatal reports were received all of which included the ADR pneumococcal infection. With regard to vaccine effectiveness, data presented to the JCVI Pneumococcal sub-committee meeting in May indicated that Prevenar 7 and Prevenar 13 are similar in effectiveness against the common 7 serotypes in the vaccines and that there has been a decline by around one half in IPD in children aged under 5 years of age due to the additional 6 serotypes found in Prevenar 13. Figure 2 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last three years. Conclusion: No significant new safety issues were identified during 2012/ Pneumococcal-sub-committee-meeting-held-on-30-May-2012.pdf

7 Skin and subcutaneous tissue disorders Social Circumstances Vascular disorders Figure 2: Percentage of serious reactions per SOC associated with Prevenar 13 vaccine 5 Gastrointestinal disorders General Disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified (incl... Nervous system disorders Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders System Order Class (SOC) /13 Eye disorders Cardiac disorders nd lymphatic system disorders Percentage of serious reports (%) Blood a

8 Pediacel (and Infanrix IPV Hib) (DTPa/IPV/Hib) Pediacel is the DTPa/IPV/Hib vaccine, offered routinely at 2, 3 and 4 months of age. The total number of suspected ADRs reported in association with DTPa/IPV/Hib for the last 3 years is shown below (table 3). 2012/13 exposure is based on the assumption of 95% uptake (3 doses) for an annual birth cohort of 800,000. Table 3: Total number of DTaP/IPV/Hib vaccine reports and doses distributed (serious reports in brackets) /13 Total number of reports 64 (29) 82 (44) 133 (48) Total number of reactions 187 (46) 261 (78) 411(82) Total fatal Exposure (doses) 2,030,400 2,280,000 3,420,000 ERR per 100,000 doses 3.2 (1.4) 3.6 (1.9) 3.8 (1.4) ERR = Estimated Reporting Rate Figure 3 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last three years. Reporting rates have remained consistently very low. The 48 serious reports were spread over 17 SOCs. As in previous years, most related to Nervous System Disorders and include the known rare side effects of fits, hypotonic- a wide hyporesponsive episodes and syncope. The remaining serious reports concerned range of isolated events which were either known rare side effects or likely coincidental with vaccination. Conclusion: No significant new safety issues were identified during 2012/13. 6

9 Social Circumstances Vascular disorders Figure 3: Percentage of serious reactions per SOC associated with DTPa/IPV/Hib vaccine Eye disorders Gastrointestinal disorders General Disorders and administration site c... Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Musculoskeletal and connective tissue disor... Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Congenital, familial and genetic disorders System Order Class (SOC) /13 Cardiac disorders Blood and lymphatic system disorders Percentage of serious reports (%)

10 MMR vaccine The first routine childhood dose of MMR vaccine is offered at months of age, with a second dose from 3 years 4 months. MMR may also be offered at anytime to unimmunised individuals. The total number of suspected ADRs reported in association with MMR vaccination for the last 3 years is shown below (table 4) exposure is based on the assumption of 90% uptake for 2 doses, for an annual birth cohort of 800,000. Note: the exposure estimates are based on only routine childhood. Data on non-routine use, and use in catch-up campaigns, are not available to MHRA at the time writing. Due to the extensive MMR vaccination catch-up programme initiated in April 2013, aimed at partially vaccinated 10 to 16 year olds in England, as well as the major catch-up undertaken in Wales, exposure in table 4 is an underestimate and the reporting rate is an overestimate. Table 4: Total number of MMR vaccine r eports and doses distributed (serious reports in brackets) /13 Total number of reports 125 (65) 145 (92) 248 (134) Total number of reactions 406 (123) 420 (168) 892 (220) Total fatal Exposure 1,307,200 1,408,800 2,160,000 ERR per 100,000 doses 9.6 (5.0) 10.2 (6.1) 11.5 (6.2) ERR = Estimated Reporting Rate Figure 4 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last three years. The apparent increased reporting rate should be interpreted with caution given that exposure is underestimated. The 134 serious reports were spread over 22 SOCs. The serious reports concerned a wide range of isolated events which were either known rare side effects or likely coincidental with vaccination. The majority of serious Nervous System Disorders related to the consequence of convulsion or fainting. Most reported Musculoskeletal and Connective Tissue Disorder related to arthralgia or myalgia, which are listed as possible side effects in the SmPC. Conclusion: No significant new safety issues were identified during 2012/13.

11 Vascular disorders Social Circumstances Skin and subcutaneous tissue disorders Figure 4: Percentage of serious reactions per SOC associated with MMR vaccine Endocrine disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disor... Neoplasms benign, malignant and unspecified... Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Ear and labyrinth disorders System Order Class (SOC) /13 Congenital, familial and genetic disorders Blood and lymphatic system disorders Cardiac disorders Percentage of serious reports (%)

12 Meningitis C vaccine During the period of this report, meningococcal group C conjugate vaccine was offered routinely at 3 and 4 months of age as a primary course (2 dose schedule) (with a MenC/Hib booster at months). The total number of suspected ADRs reported in association with Meningococcal group C conjugate vaccine for the last 3 and a half years is shown below (table 5). 2012/13 exposure is based on the assumption of 95% uptake (2 doses) for an annual birth cohort of 800,000. Table 5: Total number of Meningitis C vaccine reports and doses distributed (serious reports in bracket s) /13 Total number of reports 49 (24) 60 (35) 75 (35) Total number of reactions 133 (46) 207 (72) 210 (68) Total fatal Exposure 1,340,000 1,494,400 2,280,000 ERR per 100,000 doses 3.7 (1.8) 3.9 (2.3) 3.3 (1.5) ERR = Estimated Reporting Rate Figure 5 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last 3 years. Reporting rates have remained consistently very low. The 35 serious reports were spread over 12 SOCs. Most reactions were in the Infections and infestations SOC and the Injury, poisoning and procedural complications SOC. This included 11 reports of vaccination failures. As with most vaccines, isolated cases of vaccine failure may occur. The other serious reports concerned a wide range of isolated events which were either known rare side effects or likely coincidental with vaccination. Conclusion: No significant new safety issues were identified during 2012/13. 10

13 Social circumstances Vascular disorders Skin and subcutaneous tissue disorders Figure 5: Percentage of serious reactions per SOC associated with Meningitis C vaccine Gastrointestinal disorders General Disorders and administration site c... Immune system disorders Infections and infestations Injury, poisoning and procedural complications Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified... Nervous system disorders Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders System Order Class (SOC) /13 Eye disorders Cardiac disorders phatic system disorders Blood and lym Percentage of serious reports (%)

14 Repevax (dtap/ipv)/infanrix IPV (DTaP/IPV) Infanrix IPV or Repevax is recommended as a routine pre-school booster vaccine at 3 years 4 months of age. The recent 2011/2012 outbreak of pertussis also led to announce a UK-wide immunisation campaign to offer Repevax to all pregnant women between weeks pregnant to protect the newborn baby from October /13 exposure is based on the assumption of 89% uptake (1 dose) for a 2010 birth cohort of 800,000. Note: the exposure estimates are based on only routine childhood use and does not estimate usage in pregnant women. Therefore, the apparent increased reporting rate should be interpreted with caution given that exposure is underestimated. Table 6: Total number of reports and doses distributed (serious reports in brackets) /13 Total number of reports 68 (18) 43 (17) 137 (39) Total number of reactions 185 (32) 136 (30) 381 (55) Total fatal Exposure 612, ,200 1,068,000 ERR per 100,000 doses 11.1 (2.9) 6.3 (2.5) 12.8 (3.7) ERR = Estimated Reporting Rate Figure 6 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last 3 years. Thirty nine serious reports were spread over 17 SOCs and concerned a wide range of isolated events which were either known rare side effects or likely coincidental with vaccination. The number of serious reports in the Pregnancy, puerperium and perinatal conditions increased due to pregnant women being vaccinated for the first time. Seven suspected ADRs with a fatal outcome were reported in 2012/13. Six were associated with the Pregnancy, puerperium and perinatal conditions SOC (5 Still birth and 1 foetal death ). The seventh fatal case, metabolic acidosis, was likely related to underlying pregnancy complications. The MHRA has undertaken an epidemiological study using CPRD, which found no evidence to suggest that Repevax was causally-associated with adverse pregnancy outcomes. Further details of this study are discussed in section 2. Conclusion: No significant new safety issues have been identified during 2012/13.

15 Social Circumstances Vascular disorders Figure 6: Percentage of serious reactions per SOC associated with d/dtap/ipv vaccine Gastrointestinal disorders General Disorders and administration site c... Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Eye disorders System Order Class (SOC) /13 Blood and lymphatic system disorders Cardiac disorders Percentage of serious reports (%)

16 Revaxis (dt/ipv) Revaxis is a booster vaccine given to young people aged 14 years, as well as being used for adult boosters. The total number of suspected ADRs reported in association with dt/ipv vaccine for the last 3 years is shown below (table 7). An estimate of exposure is not given in this paper due to likely widespread use in a wide range of age groups outside of the routine childhood programme. Table 7: Total number of Revaxis reports and doses distributed (serious reports in brackets) /13 Total number of reports 92 (43) 98 (39) 153(89) Total number of reactions 279 (72) 277 (57) 592(132) Total fatal Exposure n/a n/a n/a ERR per 100,000 doses n/a n/a n/a ERR = Estimated Reporting Rate n/a: Data not available at the time of writing this report. The serious reports were spread over 17 SOCs, the majority of nervous system disorders related to the signs and symptoms of fainting and possibly other anxiety-related events. Conclusion: No significant new safety issues have been identified during 2012/

17 Skin and subcutaneous tissue disorders Vascular disorders Figure 7: Percentage of serious reactions per SOC associated with Revaxis vaccine Ear and labyrinth disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Musculoskeletal and connective tissue disor... Neoplasms benign, malignant and unspecified... Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders System Order Class (SOC) /13 Blood and lymphatic system disorders Cardiac disorders Congenital, familial and genetic disorders Percentage of serious rep orts (%)

18 Human Papillomavirus (HPV) vaccines (Cervarix and Gardasil ) In September 2008 Cervarix, which protects against HPV types 16 and 18, was introduced in a new routine HPV immunisation programme for 12 to 13 year-old adolescent girls. This also included an initial catch-up campaign for older teenagers. At the time the MHRA put in place a proactive pharmacovigilance strategy to monitor the safety of Cervarix vaccine as it was used in the UK. Most recently in August/September 2012 a routine safety review of the UK experience with Cervarix was considered by the UK s Commission on Human Medicines (CHM). Overall no new safety issues were identified and the CHM endorsed the conclusions of the report that the benefit risk balance of Cervarix remains positive. From September 2012 Gardasil, with HPV types 6, 11, 16 and 18, replaced Cervarix within the national immunisation programme. The total number of suspected ADRs reported in association with human papillomavirus vaccine for the last 3 years is shown below (table 8). Table 8: Total number of Human Papillomavirus vaccine reports ( serious reports in brackets) /13 Total number of reports 1802 (397) 1081 (249) 1089 (298) Total number of reactions 3800 (571) 2439 (396) 2842 (504) Total fatal Further information regarding HPV vaccine, including MHRA s public safety assessment reports, can be found on the MHRA website at Conclusion: No significant new safety issues have been identified during 2012/13 since Gardasil was introduced. 16

19 Social Circumstances Vascular disorders Skin and subcutaneous tissue disorders Figure 9: Percentage of serious reactions per SOC associated with Human Papillomavirus vaccine Congenital, familial and genetic disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified... Nervous system disorders Pregnancy, puerperium and perinatal conditions Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders System Order Class (SOC) /13 Blood and lymphatic system disorders Cardiac disorders Percentage of serious repo rts (%)

20 1.2 Other vaccines Hepatitis B vaccine Hepatitis B vaccine is recommended in populations deemed to be at risk of contracting the disease. The total number of suspected ADRs reported in association with single hepatitis B vaccine for the last 3 years is shown below (table 9). Table 9: Total number of Hepatitis B (serious reports in brackets) vaccine reports and doses distributed /13 Total number of reports 78 (41) 122 (49) 131 (73) Total number of reactions 182 (61) 411 (101) 480 (127) Total fatal Exposure (doses) n/a n/a n/a ERR per 100,000 doses n/a n/a n/a ERR = Estimated Reporting Rate n/a: Data not available at the time of writing this report. Estimated exposure data for the vaccine were not available at the time of writing this report and as such, ERRs have not been calculated. The 73 serious reports were spread over 22 SOCs and concerned a wide range of isolated events which were either known rare side effects or likely coincidental with vaccination. Conclusion: No significant new safety issues have been identified during 2012/13. 18

21 Skin and subcutaneous tissue disorders Vascular disorders Figure 10: Percentage of serious reactions per SOC associated with Hepatitis B vaccine Congenital, familial and genetic disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disor... Neoplasms benign, malignant and unspecified... Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders System Order Class (SOC) /13 Blood and lymphatic system disorders Cardiac disorders Percentage of serious reports (%)

22 Seasonal Influenza Vaccine Until recently influenza vaccine has only been offered to at-risk populations in the community on a yearly basis, including the elderly and those at increased risk of complications of influenza infection 4. Seasonal influenza vaccines used in recent years are the trivalent inactivated influenza vaccines (TIV) that contain two subtypes of influenza A and one type B virus as recommended by the World Health Organization (WHO). The cases reported in the current period therefore relate only to TIV vaccines. The total number of suspected ADRs reported in association with seasonal influenza vaccine for the last 3 and a half years is shown below (table 10). In line with the other data in this report, this relates to calendar years (rather than influenza seasons). As in previous years, exposure has been estimated simply at an upper level of 14m doses. Reporting rates have remained consistently very low. As the additional 6 month period of ADR collection covered a time when relatively few doses of flu vaccine will have been administered (Jan to July), estimated exposure for the 18 month 2012/13 period was adjusted to only 16 million. Table 10: Total nu mber of Influenza reports and doses distributed (serious reports in brackets) /13 Total number of reports 331 (189) 458 (254) 393(253) Total number of reactions 1108 (311) 1506 (402) 1441(449) Total fatal Exposure 14,000,000 14,000,000 16,000,000 ERR per 100,000 doses 2.4 (1.4) 3.3 (1.8) 2.5(1.6) ERR = Estimated Reporting Rate Figure 11 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last three and a half years. The distribution of adverse reactions has stayed relatively constant over the last few years, with the majority of serious reactions occurring within the Musculoskeletal and Connective Tissue Disorders SOC and the Nervous System Disorders SOC. There were nine suspected ADRs with a fatal outcome in 2012/13. There were two cases of Death and single cases of Multi-Organ failure, Cardiopulmonary failure, Circulatory collapse, Respiratory failure, Sudden death, Stillbirth and Metabolic acidosis. A causal association with the influenza vaccines has not been established for any of these cases the vaccine is largely given to those at high background risk of morbidity regardless of vaccination, and coincidental medical events are to be expected. Conclusion: No significant new safety issues have been identified during 2012/

23 Social Circumstances Vascular disorders Skin and subcutaneous tissue disorders Figure 11: Percentage of serious reactions per SOC associated with Influenza vaccine Ear and labyrinth disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disor... Neoplasms benign, malignant and unspecified... Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders System Order Class (SOC) /13 lood and lymphatic system disorders Cardiac disorders Congenital, familial and genetic disorders Percentage of serious reports (%) B

24 Pneumococcal polysaccharide vaccine (PPV) The total number of suspected ADRs reported in association with pneumococcal polysaccharide vaccine for the last 3 years is shown below (table 11). Table 11: Total number of Pneumococcal polysaccharide vaccine reports and doses distributed (serious re ports in brackets) /13 Total number of reports 67 (34) 61 (26) 81 (44) Total number of reactions 199 (51) 234 (38) 299 (71) Total fatal Exposure n/a n/a n/a ERR per 100,000 doses n/a n/a n/a ERR = Estimated Reporting Rate n/a: Data not available at the time of writing this report. The distribution data for the vaccine during 2012/13 were not available at writing this report and as such, ERRs have not been calculated. the time of Figure 12 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last three years. The majority of serious reactions occurred within the Infections and Infestations SOC. There was one fatal report associated with pneumococcal polysaccharide vaccine in 2012/13, of Multi-organ failure. This is the same case as seen above for the influenza vaccine. A causal association with vaccination has not been established for any of these cases. Conclusion: No significant new safety issues have been identified during 2012/13. 23

25 Vascular disorders Figure 12: Percentage of serious reactions per SOC associated with Pneumococcal Polysaccharide vaccine Cardiac disorders Eye disorders Gastrointestinal disorders General Disorders and administration site c... Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disor... Neoplasms benign, malignant and unspecified... Nervous system disorders Pregnancy, puerperium and perinatal condit... Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders System Order Class (SOC) /13 od and lymphatic system disorders Percentage of serious reports (%) Blo

26 BCG vaccine The aim of the UK BCG immunisation programme is to immunise those at increased risk of developing severe disease and/or of exposure to TB infection The total number of suspected ADRs reported in association with BCG vaccine for the last 3 and a half years is shown below (table 12). Table 12: Total number of BCG reports and doses distributed (serious reports in brackets) /13 Total number of reports 40 (24) 34 (17) 26 (13) Total number of reactions 76 (25) 69 (26) 75 (19) Total fatal Exposure n/a n/a n/a ERR per 100,000 doses n/a n/a n/a ERR = Estimated Reporting Rate n/a: Data not available at the time of writing this report. Figure 13 shows the serious ADRs reported in each SOC, as a percentage of the total ADRs, for the last three years. The majority of serious reactions related to known possible side effects of lymphadenitis and disseminated BCG infection. There were no fatal reactions reported in 2012/13. Conclusion: No significant new safety issues have been identified during 2012/13. 25

27 Skin and subcutaneous tissue disorders Vascular disorders Figure 13: Percentage of serious reactions per SOC associated with BCG vaccine General Disorders and administration site c... Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Nervous system disorders Psychiatric disorders System Order Class (SOC) /13 Cardiac disorders lood and lymphatic system disorders Percentage of serious reports (%) B

28 , Varivax, Varilrix and Zostavax (Varicella Zoster virus) vaccines Since 2003, the UK recommendation includes vaccinating non-immune healthcare workers who themselves will derive benefit as they will be protected from contact with infectious patients. Varicella vaccine is also recommended for healthy susceptible close household contacts of immunocompromised patients. Zostavax is indicated for prevention of shingles and post-herpetic neuralgia in those aged over 50 years. From September 2013, it is to be routinely offered to patients aged 70 years, with a catch up campaign for those aged 79 years. Table 13: Total number of Varicella Zoster vaccine reports (serious reports in brackets) /13 Total number of reports 12 (8) 5 (3) 33 (22) Total number of reactions 33 (13) 17 (6) 92 (30) Total fatal Exposure n/a n/a n/a ERR per 100,000 doses n/a n/a n/a ERR = Estimated Reporting Rate n/a: Data not available at the time of writing this report. The usage data for the vaccines was not available at the time of writing this as such, ERRs have not been calculated. report and As can be seen, very few ADR reports have been submitted for varicella vaccines, although the number of reports received has increased in 2012/2013 compared with previous years. The increase mainly relates to reports associated with Zostavax, and may be driven by increased use during the 2012/13 period. The majority of serious reactions related to known side effects of the vaccines. Conclusion: No significant new safety issues have been identified during 2012/13. 27

29 Social Circumstances Figure 14: Percentage of serious reactions per SOC associated with Varicella Zoster vaccine Ear and labyrinth disorders Eye disorders Gastrointestinal disorders Infections and infestations Injury, poisoning and procedural complications Investigations Musculoskeletal and connective tissue disorders Nervous system disorders Renal and urinary disorders Skin and subcutaneous tissue disorders System Order Class (SOC) /13 Blood and lymphatic system disorders Percentage of serious reports (%)

30 2. SECTION 2: IKEY ISSUES REVIEWED BY MHRA 2.1 Pandemrix and Narcolepsy In last year s update to the JCVI, it was discussed that since the initial restriction of Pandemrix in those aged less than 20 years, results from additional epidemiological studies performed in several countries (Ireland, France and the UK) had become available and that the findings were broadly in line with the initial studies in children and adolescents from Sweden and Finland which first suggested an association between Pandemrix and narcolepsy. In 2013 the product information has been updated to reflect these findings from additional countries: Epidemiological studies relating to Pandemrix in several European countries have indicated a five to 14-fold increased risk of narcolepsy with or without cataplexy in vaccinated as compared with unvaccinated children/adolescents, corresponding to an absolute risk ranging from three to seven additional cases in vaccinated subjects. This risk increase has not been found in adults (older than 20 years). The relationship between Pandemrix and narcolepsy is still under investigation. Since the last update to the JCVI, data from studies undertaken in France, Sweden and Finland have suggested that adults may also be at an increased risk of narcolepsy following Pandemrix vaccination. The French study 5 suggested a four-fold increased risk in >20 year olds, although this was based on small numbers of cases and there were uncertainties over how vaccination status was validated. The Swedish registry study indicated a two-fold increased risk in adults aged between 21 and 30 years with a trend towards a decline in excess risk at age of vaccination 6. However, there were uncertainties over how incident (as opposed to pre-existing) cases of narcolepsy were determined. The results of the Finnish study 7 in adults corresponded to one additional case per 100,000 vaccinated adults aged >20 years (although the majority of the cases were less than 40 years old). The available epidemiological data appear to suggest that the younger adult population may also be susceptible, to some degree, to an increased risk of narcolepsy following Pandemrix vaccination. However the currently available data on the risk of narcolepsy with Pandemrix in >20 year olds do not allow firm conclusions to be drawn on either the extent to which the increased risk affects the adult population, or on the exact upper age limit of vaccine-induced risk. As a result of the findings in adults, the product information will be further revised to reflect the totality of the epidemiological data. 5 grippe-a-h1n1-et-narcolepsie-resultats-de-l-etude-europeenne-et-de-l-etude-cas-temoins-francaise- Point-d-information/(language)/fre-FR

31 It should be noted that this safety review is specific to Pandemrix vaccine; the safety signal of narcolepsy is so far not apparent for other types of influenza vaccine, such as TIVs. Additionally, pandemic H1N1 vaccines used outside of Europe, including a similar GSK vaccine used in Canada and unadjuvanted vaccines used elsewhere have so far not been associated with this signal. Pandemrix vaccine is no longer being used; however the MHRA will continue to review emerging data on the association with narcolepsy as it becomes available. More information on the EU review of narcolepsy can be found at ews_detail_ jsp&murl=menus/news_and_events/news_and_events.jsp&mid=w C0b01ac058004d5c1 2.2 Cervarix HPV vaccine MHRA study of Chronic Fatigue Syndrome The MHRA recently completed an ecological analysis and a self-controlled case series (SCCS), both using the Clinical Practice Research Datalink (CPRD), to compare the incidence rate of fatigue syndromes including chronic fatigue syndrome (CFS) in girls before and after the start of the vaccination campaign. CFS is a naturally-occurring medical condition, and the MHRA found no evidence to suggest that the vaccine may be a cause of the condition. The results of this study have been recently published in a peer-reviewed scientific journal (Vaccine 2013 Aug 31 [Epub ahead of print]) [ The published abstract is as follows: INTRODUCTION: Over 70% of cervical cancers are related to human papillomavirus types 16 and 18. In 2008, the vaccine Cervarix, protecting against these two strains, was introduced into the routine UK immunisation programme for girls aged years, with a catch-up in girls aged up to 18 years. As part of the risk management planning for this new campaign, the Medicines and Healthcare products Regulatory Agency (MHRA) anticipated a range of conditions, including chronic fatigue syndrome, which might be reported as adverse events in temporal association with the vaccine. METHODS: Near-real time 'observed vs. expected' analyses were conducted comparing the number of reports of fatigue syndromes submitted via the MHRA's Yellow Card passive surveillance scheme to the expected number, using background rates calculated from the Clinical Practice Research Datalink (CPRD) and estimates of vaccination coverage. Subsequently, an ecological analysis and a self-controlled case series (SCCS), both using CPRD, compared the incidence rate of fatigue syndromes in girls before and after

32 the start of the vaccination campaign and the risk in the year post-vaccination compared to other periods. RESULTS: The number of spontaneous reports of chronic fatigue following Cervarix vaccination was consistent with estimated background rates even assuming low reporting. Ecological analyses suggested that there had been no change in the incidence of fatigue syndromes in girls aged years after the introduction of the vaccination despite high uptake (IRR: 0.94, 95% CI: ). The SCCS, including 187 girls, also showed no evidence of an increased risk of fatigue syndromes in the year post first vaccination (IRR: 1.07, 95% CI: , p=0.84). DISCUSSION: The successful implementation of an enhanced pharmacovigilance plan provided immediate reassuring evidence that there was no association between vaccination with Cervarix and an increased risk of chronic fatigue syndromes. This has now also been further demonstrated in more comprehensive epidemiological studies. As with all vaccines, the safety of Cervarix and Gardasil will remain under constant monitoring by the MHRA. 2.3 Repevax use in pertussis vaccination programme in pregnant women To reduce the burden of pertussis disease, including fatalities, in neonates too young for vaccination the JCVI recommended the use of Repevax in the late stages of 8 pregnancy (between 28 and 38 weeks). The MHRA took a proactive approach to risk management of the new temporary pertussis programme in pregnant women and conducted a controlled epidemiological study on the safety of pertussis vaccination in pregnancy using the CPRD. The study showed no signal of a short term increased risk of stillbirth (intrauterine death after 24 weeks gestation) following vaccination. There were also no significant differences in the rates of any of the pre-specified events. The study has been submitted for review in a peer-reviewed scientific publication alongside PHE s study on the impact and effectiveness of the pertussis vaccination programme in pregnant women using CPRD. 8 ug_2012_pertussis_-_final.pdf