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PF-07302048 (BNT162b2) Reporting Period
Summary Monthly Safety Report (SMSR) 4 01 March 2021 through 31 March 2021
CONFIDENTIAL
Page 1SUMMARY MONTHLY SAFETY REPORT 4
for
ACTIVE SUBSTANCE: PF-07302048 (BNT162b2)
ATC CODE: J07BX 031
AUTHORISATION PROCEDURE in the EU: Centralised
INTERNATIONAL BIRTH DATE (IBD):219 December 2020
EUROPEAN UNION REFERENCE DATE (EURD): 21 December 2020
INTERVAL COVERED BY THIS REPORT:
01 MARCH 2021through 31 MARCH 2021
DATE OF THIS REPORT: 14APRIL2021
Report Prepared by: Worldwide Medical & Safety
Pfizer-BioNTech
The information contained in this document is proprietary and confidential. Any disclosure, reproduction, distribution, or
other dissemination of this information outside of Pfizer and BioNTech , their Affiliates, their Licensees, or Regulatory
Agencies is stri ctly prohibited. Except as may be otherwise agreed to in writing, by accepting or reviewing these materials,
you agree to hold such information in confidence and not to disclose it to others (except where required by applicable law),
nor to use it for unau thorized purposes.
1Temporary ATC code.
2It corresponds to the earliest conditional approval date.
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Page 2EXECUTIVE SUMMARY
This is the 4thSummary Monthly Safet y Report (SMSR) for PF-07302048 [Coronavirus
disease 2019 (COVID -19) mRNA Vaccine, hereafter referred to as BNT162b2) ], covering
thereporting interval 01March 2021 through 31 March 2021 .
BNT162b2 is a white to off -white frozen dispersion (pH: 6.9 - 7.9), provided as concentrate
for dispersion for injection (sterile concentrate) as multidose vial to be diluted before use.
The multidose vial contains 6 doses of 0.3 mL after dilution ; low dead -volume sy ringes
and/or needles should be used in order to extract 6 doses from a single vial. The low
dead -volume s yringe and needle combination should have a dead volume of no more than 35
microlitres. If standard sy ringes and needles a re used, there may not be sufficient volume to
extract a sixth dose from a single vial. Each dose contains 30 micrograms of BNT162b2
embedded in lipid nanoparticle s(LNPs ). The vaccine also contains
(4-hydroxybutyl)azanediy l)bis(hexane -6,1-diyl)bis(2 -hexyldecanoate) (ALC -0315), 2-
[(poly ethylene gl ycol) -2000] -N,N-ditetradecy lacetamide (ALC -0159), 1,2 -Distearo yl-sn-
glycero-3-phosphocholine (DSPC), cholesterol, potassium chloride, potassium dihy drogen
phosphate, sodium chloride, disodium hydrogen phosphate dih ydrate, sucrose and water for
injections as excipients.
BNT162b2 is highly purified single -stranded, 5’ -capped mRNA produced using a cell- free in
vitro transcription from the corresponding DNA templates, encoding the viral spike (S)
protein of severe acute respiratory syndrome coronavirus 2 ( SARS -CoV -2). The nucleoside -
modified mRNA is formulated in L NPs, which enable delivery of the RNA into host cells to
allow expression of the SARS- CoV -2 S antigen. The vaccine elicits both neutralizing
antibody and cellular immune responses to the spike (S) antigen, which may contribute to
protection against COVID-19.
BNT162b2 is indicated for active immunisation to prevent COVID -19 caused by
SARS -CoV -2 virus, in individuals 16 years of age and older. No dosage adjustment is
required in elderl y individuals ≥65 y ears of age. It is administered intramuscularly in the
deltoid muscle after dilution as a series of 2 doses (0.3 mL each) at greater than or equal to
21 day s(prefer ably 3 weeks) apart.
It is estimated that approxi mately 243,145,305doses of BNT162b2 were shipped worldwide
from the receipt of the first temporary authorisation for emergency suppl y on
01December 2020 through 31 March 2021 and that approximately 120,917,940doses of
BNT162b2 were shipped worldwide dur ing the current reporting interval from
01March 2021through 31 March 2021. Estimated worldwide shipped doses may serve as a
reasonable indicator of subject exposure , considering that approximately 80% of the shipped
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Page 3doses were administered; this estimati on is based on the proportion of doses administered out
of those shipped upon review of data currently available for the EU3countries and the US .4
It is estimated that approximately doses of BNT162b2 were shipped in the EU
from the receipt of the first conditional marketing approval authorisation on 21
December 2020 through 31 March 2021 and that approximately doses of
BNT162b2 were shipped in the EU during the current reporting interval from 01March 2021
through 31 March 2021. Estimated shipped doses may serve as a reasonable indicator of
subject exposure , considering that in the EU approximately %3of the shipped doses were
administered .
BNT162b2 has received temporary authori sation for emergency suppl y in30 countries and
conditional marketing authorisation approval in 40 c ountries globally .
There were no authorisation withdrawals for safety reasons during the reporting interval.
Compared to the global supply of BNT162b2, an increased complaints rate for leakages was
observed b y the MAH from Hong Kong, with 19 vials with leakages reported from 3
different vaccination sites in the country ; overall 26 vials with leakages and/or loose caps
were reported. All vials were from 1 batch (the only batch in use for vaccination in Hong
Kong and Macau). During the investigation, it became apparent that the root cause of the
reported product quality complaints is a combination of the container closure process
(crimping) at one single contract manufacturing organization (CMO) and of the specific
transport conditions on dry ice that are required for BNT162b2. Vaccination in Hong Kong
and Macao was stopped as soon as the issue became apparent (24 March 2021). A total of 2
batches have been affected (the one being used and another one alread y shipped to Hong
Kong, but still in storage) and were quarantined. The root cause of the reported product
quality complaints wa s clearl y identified through analy sis of the data generated and collected
as of 31 March 2021. Due to the identified root cause, the MAH could exclude an y influence
on batches that are on the market an ywhere outside of Hong Kong and Macau. Vaccinations
in Hong Kong and Macau were resumed with a vaccine batch from a different CMO on 03
April 2021; discussions to address the issue and resume supplies with the previous CMO are
ongoing, no batches from this CMO are currently distributed.
The RSI for this SMSR i s the BNT162b2 CDS Version 2.0, dated 02 March 2021 , in effect at
the end of the reporting period. The previous CDS Version 1.0, dated 12 February 2021, was
also in effect during the reporting period, and was updated on 02 March 2021 with the
3% of shipped doses of Pfizer/BNT vaccine may be estimated as administered in the EU -EEA
countries; this proportion has been calculated considering t otal number of vaccine doses administered out of
total number of vaccine doses distributed in the EU-E FTA countries , as per report on
https://qap.ecdc.europa.eu/public/extensions/COVID -19/vaccine -tracker html#distribution -tab, as of 02 April
2021 .
4% of shipped doses of Pfizer/BNT vaccine may be estimated as administered in the US ; this
proportion has been calculated considering total number of vaccine doses administered out of total number of
vaccine doses distributed in the US, as per report on https://covid.cdc.gov/covid -data-tracker/#vaccinations , as
of 03 April 2021.
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(b) (4)
(b) (4)
(b) (4)
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Page 4following safet y-related changes made: Diarrhoea, Pain in extremity (arm) and Vomiting
were added as adverse reactions in Section 4.8 Undesirable effects.
During the reporting period, the following safet y topics and signals were addressed:
Vaccine stress-r elated responses (including Dizziness, Paraesthesia and Tachy cardia
among other events ) wasevaluated to be a risk (not important for the purpose of
inclusion in the Risk Management orPharmacovigilance Plans) and will be added to the
RSIand proposed for local labels in due course ;
Delay ed skin reactions w ereevaluated and determined not to be a risk;
Extensive swelling of the v accinated limb was evaluated and determined not to be a risk;
Reactions a ssociated with dermal fillers wereevaluated and determined not to be a risk;
Thromboembolic events, including those associated with thrombocy topenia, were
evaluated and determined not to be a risk;
Hepatic events evaluation is ongoing;
Herpes Zoster evaluation is ongoing;
Seizure evaluation is ongoing ;
Anosmia and Ageusia were safety topics determined not to be a validated signal;
Arrythmia was a safety topic determined not to be a validated signal;
Dysphagia was a safety topic determined not to be a validated signal;
Hoarseness (D ysphonia) was a safet y topic determined not to be a validated signal;
Hypertension was a safety topic determined not to be a validated signal;
Hypogly cemia was a safety topic determined not to be a validated signal;
Meningitis was a safet y topic determined not to be a validated signal;
Myasthenia gravis was a safet y topic determined not to be a validated signal;
Peripheral neuropath y was a safety topic determined not to be a validated signal;
Tran sverse Myelitis was a safet y topic determined not to be a val idated signal .
Based on the new safet y and efficacy /effectiveness data from the reporting interval for
BNT162b2, the benefit -risk profile of BNT162b2 remains favorable.
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Page 5TABLE OF CONTENTS
EXECUTIVE SUMMARY ................................ ................................ ................................ .......2
LIST OF TABLES ................................ ................................ ................................ ..................... 6
LIST OF FIGURES ................................ ................................ ................................ ................... 7
APPENDI CES ................................ ................................ ................................ ........................... 8
LIST OF ABBREVIATION S................................ ................................ ................................ ..10
1. INTRODUCTION ................................ ................................ ................................ ............... 12
2. WORLDWIDE APPROVA L OR AUTHORI SATION S TATUS ................................ ......13
3. ACTIONS TAKEN IN THE REPORTING INTERV AL FOR SAFETY REASON S ....... 13
4. CHANGES TO REFERENCE SAFETY INFORMATI ON................................ ............... 13
5. ESTI MATED EXPOSUR E AND USE PATTERNS ................................ .......................... 14
5.1. Cumulative and I nterval Exposure Data Worldwide ................................ .............. 14
5.2. Cumulative and I nterval Exposure Data in the EU ................................ ................. 16
6. DATA IN SUMMARY T ABU LATIONS ................................ ................................ ........... 19
6.1. Reference Information ................................ ................................ ............................. 19
6.2. Cumulative and I nterval Summary Tabulations from Post -Marketing Data
Sources ................................ ................................ ................................ ...................... 20
7. MEDI CATION ERRORS ................................ ................................ ................................ ....22
8. GENERAL OVERVIEW ................................ ................................ ................................ .....30
9. SI GNAL AND RISK E VALUATION ................................ ................................ ................ 48
9.1.Literature Review ................................ ................................ ................................ ....48
9.2. Overview of Safet y Topics and Signals During the Reporting Interval .................. 48
9.3. Summary of Safet y Concerns ................................ ................................ .................. 50
9.4. Summary of Adverse Events of Special Interest (AESIs) ................................ .......51
9.5. Evaluation of Safet y Concerns ................................ ................................ ................ 51
9.5.1. Evaluation of Important Identified and Important Potential Risks ............. 51
9.5.2. Evaluation of AESIs ................................ ................................ ................... 60
9.5.3. Evaluation of Special Situations ................................ ................................ .73
9.5.4. Evaluation of Missing Information ................................ ............................. 78
10. OVERALL BENEFIT- RISK EVALUATION ................................ ................................ ..85
10.1. Benefits ................................ ................................ ................................ .................. 85
10.2. Risks ................................ ................................ ................................ ...................... 86
10.3. Overall Benefit- Risk ................................ ................................ ............................. 87
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Page 611. CONCL USION AND A CTIONS ................................ ................................ ...................... 87
LIST OF TABLES
Table 1. List of SMSRs ................................ ................................ ................................ .......12
Table 2. Cumulative Estimated Shipped Doses of BNT162b2 by Region Worldwide ......14
Table 3. Interval Estimated Shipped Doses of BNT162b2 by Region Worldwide ............ 15
Table 4. Interval/Cumulative Estimated Shipped Doses of BNT162b2 b y EU -EFTA
Countries (30) ................................ ................................ ................................ .......17
Table 5. Cumulative Administered 1&2 doses of BNT162b2 by Age Group in
EU-EFTA Countries ................................ ................................ ............................. 18
Table 6. Interval Administered Doses 1&2 of BNT162b2 by Age Group in
EU-EFTA Countries ................................ ................................ ............................. 19
Table 7. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval ................................ ................................ ........................... 31
Table 8. Events Reported in ≥2%* Cases ................................ ................................ ........... 37
Table 9. Overview of Safet y Topics and Signals ................................ ................................ 48
Table 10. Safety Concerns ................................ ................................ ................................ ....50
Table 11. Risks Evaluation for BNT162b2 ................................ ................................ .......... 51
Table 12. AESI s Evaluation for BNT162b2................................ ................................ ......... 60
Table 13. Evaluation of Special Situations for BNT162b2 ................................ .................. 73
Table 14. Evaluation of Missing Information for BNT162b2 ................................ .............. 78
Table 15. Vaccine efficacy –First COVID -19 occurrence from 7 day s after Dose 2,
by age subgroup – participants without evidence of infection prior to 7
days after Dose 2 – evaluable efficacy (7days) population ................................ .85
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Page 7LIST OF FIGURES
Figure 1. Case Outcome b y Presence of Relevant Comorbidities ................................ .......32
Figure 2. Case Outcome b y Presence of Relevant Comorbidities, Gender and Age
Group ................................ ................................ ................................ .................... 33
Figure 3. Fatal Case Outcome b y Presence of Relevant Comorbidities and Age
Group ................................ ................................ ................................ .................... 35
Figure 4. General Overview: Total Number of Events by MedDRA SOC and Event
Seriousness ................................ ................................ ................................ ........... 36
Figure 5. Events Reported in ≥2% Cases in the Interval Period by Gender ........................ 39
Figure 6. PT Reported in ≥2% in the Interval Period - by SOC and Age Group ................. 40
Figure 7. Events Reported in ≥2% in the I nterval Period by Age Group within
Gender ................................ ................................ ................................ ................... 47
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APPENDICES
APPENDIX 1 REFERENCE INFORMATION ( CDS 02 MARCH 2021) ............................. 88
APPENDIX 1.1 SAFETY RELATED CHANGES TO CDS ................................ ............... 109
APPENDIX 2 INTERVAL NUMBER OF CASE REPORTS [(SERIOUS AND NON -
SERIOUS, MEDICALLY CONFIRMED AND NON -MEDICALLY CONFIRMED)
FROM POST -MARKETING DATA SOURCES, OVERALL, BY SEX, COUNTRY,
AGE GROUPS AND IN SPECIAL POPULATIONS ] AND SUMMARY TABULATION
BY PREFERRED TE RM AND MEDDRA SYSTEM ORGAN CLASS .................... 114
APPENDIX 2.1 CUMULATIVE NUMBER OF CASE REPORTS [(SERIOUS AND NON -
SERIOUS, MEDICALLY CONFIRMED AND NON -MEDICALLY CONFIRMED)
FROM POST -MARKETING DATA SOURCES, OVERALL, BY SEX, COUNTRY,
AGE GROUPS AND IN SPECIAL POPULATIONS ] AND SUMMARY TABULATION
BY PREFERRED TERM AND MEDDRA SYSTEM ORGAN CLASS .................... 181
APPENDIX 2.2 INTERVAL SUMMARY TABULATION OF CASE REPORTS WITH DME
EVENTS FROM POST -MARKETING DATA SOURCES ................................ .......268
APPENDIX 2.3 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS CASE REPORTS FROM POST -MARKETING DATA
SOURCES BY MEDICALLY CONFIRMED AND NON -MEDICALLY CONFIRMED,
REGION AND COUNTRY ................................ ................................ ......................... 271
APPENDIX 2.4 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF FATAL
CASE REPORTS FROM POST -MARKETING DATA SOURCES BY COUNTRY .....
................................ ................................ ................................ ................................ .....277
APPENDIX 2.5 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADVERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY
PREFERRED TERM ................................ ................................ ................................ ....279
APPENDIX 2.5.1 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADVERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY
PREFERRED TERM PER COUNTRY ................................ ................................ .......402
APPENDIX 2.5. 2 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADVERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER AGE GROUP BY PREFERRED TERM PER
COUNTRY ................................ ................................ ................................ ................. 1370
APPENDIX 2.5. 3 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADVERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER GENDER BY PREFERRED TERM PE R
COUNTRY ................................ ................................ ................................ ................. 2752
APPENDIX 2.5. 4 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADVERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER PATIENTS WITH RELEVANT CO -
MORBIDITIES BY PREFERRED TERM PER COUNTRY ................................ ....3704
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APPENDIX 2.6 CUMULATIVE AN D INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADVERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY HIGH
LEVEL TERM ................................ ................................ ................................ ............ 4034
APPENDIX 2.6.1 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERIOUS AND NON -SERIOUS ADV ERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY HIGH
LEVEL TERM PER COUNTRY ................................ ................................ ............... 4070
APPENDIX 3 TABULAR SUMMARY OF SAFETY TOPICS AND SIGNALS EVALUATED
DURING THE REPORTING PERIOD ................................ ................................ .....4071
APPENDIX 3.1 SUMMARY OF SAFETY TOPICS AND SIGNAL EVALUATIONS ...4076
APPENDIX 3. 2 SAFETY EVALUATION OF EMBOLIC AND THROMBOTIC EVENTS ..
................................ ................................ ................................ ................................ ...4079
APPENDIX 3. 3 SAFETY EVALUATION OF EXTENSIVE LIMB SWELLING ........... 4728
APPENDIX 3. 4 SAFETY EVALUATION OF ANOSMIA/AGEUSIA ............................ 4737
APPENDIX 3. 5 SAFETY EVALUATION OF REACTION TO DERMAL FILLERS ....4741
APPENDIX 3. 6 SAFETY EVALUATION OF HYPOGL YCAEMIA ............................... 4754
APPENDIX 3. 7 SAFETY EVALUATION OF DELAYED SKIN REACTIONS ............. 4758
APPENDIX 3. 8 SAFETY EVALUATION OF MYASTHENIA GRAVIS ....................... 4762
APPENDIX 4 CUMULATIVE APPROVAL/AUTHORISATION STATUS ................... 4767
APPENDIX 5 LIST OF ADVERSE EVENTS OF SPECIAL INTEREST ........................ 4772
APPENDIX 5.1 OBSERVED VERSUS EXPECTED ANALYSIS FOR ADVERSE EVENTS
OF SPECIAL INTEREST ................................ ................................ .......................... 4781
APPENDIX 6 LITERATURE REVIEW IN THE REPORTING PERIOD (METHODOLOGY)
................................ ................................ ................................ ................................ ...4798
APPENDIX 6.1 LITERATURE REVIEW IN THE REPORTING PERIOD (RETRIEVED
RESULTS) ................................ ................................ ................................ ........ NO D ATA
APPENDIX 7 NARRATIVES OF CASES REPORTING CVST, DIC, AND TTP .......... 4799
APPENDIX 8 Q&A SECTION – EMA PRAC REQUESTS FOR NEXT SMSR ............. 4821
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Page 10LIST OF ABBREVIATIONS
Acronym Term
AE adverse event
AESI adverse event of special interest
BC Brighton Collaboration
BMI body mass index
CDC Centers for Disease Control and Prevention
CDS core data sheet
CI confidence interval
CMO contract manufacturing organization
COPD chronic obstructive pulmonary disease
COVAX COVID -19 Vaccines Global Access
COVID -19 coronavirus disease 2019
DLP data lock point
DME designed medicall y event
DNA deox yribonucleic acid
DSPC Distearo yl-sn-glycero-3-phosphocholine
EEA European Economic Area
EMA European Medicines Agency
EU European Union
EUA emergency use authori sation
EURD European Union Reference Date
HA hyaluronic acid
HC Health Canada
HCP healthcare professional
HLGT (MedDRA ) High Group Level Term
HLT (MedDRA) High Level Term
HPRC Health Product Risk Communication
IBD international birth date
ICH International Conference on Harmonisation
LNP lipid nanoparticle
MAH marketing authorisation holder
MedDRA medical dictionary for regulatory activities
MHRA Medicines and Healthcare products Regulatory Agency
mRNA messenger ribonucleic acid
NAAT nucleic acid amplification tests
PCR Polymerase Chain Reaction
PI prescribing information
PRAC Pharmacovigilance Risk Assessment Committee
PT (MedDRA) Preferred Term
PVP pharmacovigilance plan
RMP risk management plan
RNA ribonucleic acid
ROW rest of world
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Page 11Acronym Term
RT-PCR Reverse Transcription -Polymerase Chain Reaction
RSI reference safet y information
TME targeted medically event
TTP thrombotic thrombocy topenic purpura
SAE serious adverse event
SARS -CoV -2 severe acute respiratory syndrome coronavirus 2
SmPC Summary of Product Characteristics
SMQ standardised MedDRA query
SMSR summary monthl y safety report
SOC (MedDRA) S ystem Organ Class
UK United Kingdom
US United States
VAED vaccine -associated enhanced disease
VAERD vaccine -associated enhanced respiratory disease
VAERS vaccine adverse event reporting s ystem
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Page 121.INTRODUCTION
This is the 4thSMSR for PF-07302048 ( COVID -19 mRNA Vaccine , hereafter referred to as
BNT162b2), covering the reporting interval 01 March 2021 through 31 March 2021 . The
format and content of this SMSR is in accordance with the EMA coreRMP19 Guidance
(EMA/544966/2020 ) and,as applicable , with ICH Guideline E2C (R2) Periodic Benefit -Risk
Evaluation Report [Step 5, January 2013] considering the informatio nfortheevidence from
post-EUA /conditional marketing authorisation approval data sources .
BNT162b2 i s a white to off -white frozen dispersion (pH: 6.9 - 7.9), provided as concentrate
for dispersion for injection (sterile concentrate) as multidose vial to be diluted before use.
The multidose vial contains 6doses of 0.3 mL after dilution ; low dead -volume s yringes
and/or needles should be used in order to extract 6 doses from a single vial. The low dead -
volume sy ringe and needle combination should have a dead volume of no more than 35
microlitres. If standard sy ringes and needles are used, there may not be sufficient volume to
extract a sixth dose from a single vial. E achdose contains 30 micrograms of BNT162b2
(embedded in LNPs ). The vaccine also contains ( (4-hydroxy butyl)azanedi yl)bis(hexane -6,1-
diyl)bis(2- hexy ldecanoate) (ALC -0315), 2- [(polyethy lene gl ycol) -2000]- N,N-
ditetradecy lacetamide (ALC -0159), 1,2 -Distearoy l-sn-glycero-3-phosphocholine (DSPC),
cholesterol, potassium chloride, potassium dihy drogen phosphate, sodium chloride, disodium
hydrogen phosphate dih ydrate, sucrose and water for injections as excipients.
BNT162b2 is highly purified single -stranded, 5’ -capped mRNA produced using a cell -free in
vitro transcription from the corresponding DNA templates , encoding the viral spike (S)
protein of SAR S-CoV -2.The nucleoside -modified mRNA is formulated in LNPs, which
enable delivery of the RNA into host cells to allow expression of the SARS- CoV -2 S antigen.
Thevaccine elicits both neutralizing antibod y and c ellular immune responses to the spike (S)
antigen, which may contribute to protection against COVI D-19.
BNT162b2 is indicated for active immunisation to prevent COVID -19 caused by
SARS -CoV -2 virus, in individuals 16 years of age and older. No dosage adjust ment is
required in elderl y individuals ≥65 y ears of age. It is administered intramuscularly in the
deltoid muscle after dilution as a series of 2 doses (0.3 mL each) at greater than or equal to
21 day s(preferabl y 3 weeks) apart.
Pfizer is responsible for the preparation of the SMSR on behalf of the MAH BioNTech
according to the Pharmacovigilance Agreement in place . Data from BioNTech are included
in the report when applicable.
A complete list of the finalized SMSRs is provided in Table 1below.
Table1.List of SMSRs
SMSR Number Reporting Period
1 01 December 2020 through 31 December 2020
2 01 January 2021through 31 January 2021
3 01 February 2021through 28 February 2021
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Page 132.WORLDWIDE APPROVAL OR AUTHORISATION STATUS
BNT162b2 received first temporary authori sation for emergency suppl yunder regulation 174
in the UK on 01 December 2020 and is currentl y authorised for emergency use in 30
countries.
BNT162b2 received first regulatory conditional marketing authorisation approval in
Switzerland on 19 December 2020 and is currently conditionall y approved in 40countries
(including EEA) .
Details of the current authori sation/ approval status are presented in Appendix 4 .
3. ACTIONS TAKEN IN THE REPORTING INTERVAL FOR SAFETY REASONS
Compared to the global supply of BNT162b2, an increased complaints rate for leakages was
observed by the MAH in Hong Kong, with 19 vials with leakages reported from 3 different
vaccination sites in the country ; overall 26 vials with leakages and/or loose caps were
reported. All vials were from 1 batch, the onl y batch in use for vaccination in Hong Kong
and Macau. Du ring the investigation, it became apparent that the root cause of the reported
product quality complaints is a combination of the container closure process (crimping) at 1
single CMO and of the specific transport conditions on dry ice that are required for
BNT162b2. Vaccination in Hong Kong and Macau was stopped as soon as the issue became
apparent (24 March 2021). A total of 2 batches have been affected (including the one being
used and another one already shipped to Hong Kong, but still in storage) and we re
quarantined. The root cause of the reported product quality complaints was clearl y identified
through anal ysis of the data generated and collected as of 31 March 2021. According to the
data, the crimping process used for batches at the CMO fill and fini sh site requires
optimization to ensure the container integrity during storage and shipment with dry ice.
Under the ultra -cold conditions created by storing and shipping on dry ice, the stopper loses
flexibility and, if not optimally crimped, allows the ingress of ambient gas into the vial.
During thawing the flexibility of the stopper is regained and the stopper reseals the vial. This
can result in increased pressure in the vial and presence of elevated CO 2levels. Due to the
identified root cause the MAH could exclude an y influence on batches that are on the market
anywhere outside of Hong Kong and Macau. The CMO in question has not manufactured
any batch that was released for any market other than Hong Kong and Macau. Vaccinations
in Hong Kong and Macau w ere resumed with a vaccine batch from a different CMO on
03April 2021; discussions to address the issue and resume supplies with the previous CMO
are ongoing, no batches from this CMO are currently distributed.
There were no authorisation withdrawals for safety reasons during the reporting interval.
4. CHANGES TO REFERENCE SAFETY INFORMATION
The RSI for this SMSR is the BNT162b2 CDS Version 2.0, dated 02 March 2021, in effect at
the end of the reporting period which is located in Appendix 1 .
The previous CDS Version 1.0, dated 12 February 2021, was also in effect during the
reporting period, and it was updated on 02 March 2021 with the following safet y-related
changes made: Diarrhoea, Pain in extremity (arm) and Vomiting were added as adverse
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Page 14reactions from post -authorisation experience in Section 4.8 Undesirable effects. The
summary of the safety -related changes made is presented in Appendix 1.1.
5.ESTIMATED EXPOSURE AND USE PATTERNS
5.1. Cumulative and Interval Exposure Data Worldwide
It is not possible to determine with certaint y the number of individuals who received
BNT162b2 during the period of this review. Estimated worldwide shipped doses may serve
as a reasonable indicator of subject exposure , considering that approximately 80% o f the
shipped doses were administered ; this estimation is based on the proportion of doses
administered out of those shipped upon review of data currentl y available for the EU3
countries and the US .4
With these caveats in mind, it is estimated that:
approximately 243,145,305 doses of BNT162b2 were shipped worldwide from the
receipt of the first temporary authorisation for emergency suppl y on 01December 2020
through 31 March 2021 , corresponding to 194,516,244 estimated administered doses;
approximately 120,917,940doses of BNT162b2 were shipped worldwide during the
current reporting interval from 01 March 2021 through 31 March 2021 , corresponding to
96,734,352 estimated administered doses.
The estimated cumulative number of shipped doses of BNT162b2 by region5based on data
provided in the shipment tracker 6from the receipt of the first temporary
authorisation for emergency suppl y on 01 December 2020 through 31 March 2021, are
summarized in Table 2.
Table 2.Cumulative Estimated Shipped Doses of BNT162b2 by Region Worldwide
Region/Country/Other % of Doses Total Number of Shipped
Doses
Europe
European Uniona(27)
European Free Trade Associationa(3)
Switzerlanda
UKb
Other Countriesc
Commonwealth of Independent Statesd
North Am ericab
US
Canada
5Currently there are no avail able data that allow to estimate exposure by gender ; for age group data
available for some EU -EFTA countries were listed in below in Table 5.
6The is the mos t accurate tracker of shipment used as data source for all the Regions and
Countries; US shipment data not available in the w ere taken from the
.
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Page 15Table 2.Cumulative Estimated Shipped Doses of BNT162b2 by Region Worldwide
Region/Country/Other % of Doses Total Number of Shipped
Doses
Central and South Americae
Asia
Japana
Other Countriesf
Oceania
Australia/New Zealanda
Other Countries
Africag
Total 100.0% 243145305
a. I n this Region BNT162b2 w as conditionally approved;
b. I n this Region BNT162b2 received authorisation for emergency supply;
c.Includes Albania where BNT162b2 wa s conditionally app roved, Serbia where it received authorization
for emergency supply, Bosnia where it was shipped for COVAX and Turkey where it was shipped according
to a pharmacovigilance agreement in place by the MAH and the Turkish government;
d.Includes Georgia and Moldova ; in these countries BNT162b2 was shipped for COVAX;
e.Includes Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru and Uruguay where BNT162 b2
received authorisation for emergency supply (som e doses in Colombia and Peru w ere also shipped for
COVAX) , and El Salvador where BNT162b2 w as shipped for COVAX;
f. I ncludes Bahrain, Israel, Jordan, Kuwait, Lebanon, Malaysia, Oman, Qatar, Saudi Arabia, Singapore,
United Arab Emirates where BNT162b2 received authorization for emergency supply, South Korea where
BNT162b2 was conditionally approved (some doses in South Ko rea w ere also shipped for COVAX) , and
Palestine/West Bank & Gaza, Maldives and Mongolia where BNT162b2 w as shipped for COVAX;
g.Includes Cape Verde, Rw anda and Tunisia where BNT162b2 w as ship ped for COVAX.
The estimated interval number of shipped doses of BNT162b2 b y region7based on data
provided in the shipment tracker )8from 01 March 2021 through 31 March
2021 , are summarized in Table 3.
Table 3.Interval Estimated Shipped Doses of BNT162b2 by Region Worldwide
Region/Country/Other % of Doses Total Number of Shipped
Doses
Europe
European Uniona(27)
European Free Trade Associationa(3)
Switzerlanda
UKb
Other Countriesc
Commonwealth of Independent Statesd
North Am ericab
7Currently there were no available data that allow to estimate exposure by gender ; for age group data
available for some EU -EFTA countries were listed below in Table 6.
8The is the most accurate tracker of shipment used as data source for all the Regions and
Countries; US shipment data not available in the w ere taken from the
.
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Page 16Table 3.Interval Estimated Shipped Doses of BNT162b2 by Region Worldwide
Region/Country/Other % of Doses Total Number of Shipped
Doses
US
Canada
Central and South Americae
Asia
Japana
Other Countriesf
Oceania
Australia/New Zealanda
Other Countries
Africag
Total 100.0% 120917940
a. I n this Region BNT162b2 w as conditionally approved;
b. I n this Region BNT162b2 received authorisation for emergency supply;
c.Includes Albania where BNT162b2 w as conditionally app roved, Serbia where it received authorization
for emergency supply, Bosnia where it was shipped for COVAX and Turkey where it was shipped according
to a pharmacovigilance agreement in place by the MAH and the Turkish government;
d.Includes Georgia and Moldova; in these countries BNT162b2 w as shipped for COVAX;
e.Includes Chile, Colombia, Costa Rica, Ecuador, Mexico , Panama, Peru (som e doses in Peru w ere also
shipped for COVAX) and Uruguay where BNT162 b2received authorisation for emergency supply , and El
Salvador where BNT162b2 wasshipped for COVAX;
f.Includes Bahrain, Israel, Jordan, Kuwait, Lebanon, Malaysia, Oman, Qatar, Saudi Arabia, Singapore,
United Arab Emira teswhere BNT162b2 received authorization for emergency supply, South Korea where
BNT162b2 was conditionally approved, and Palestine/West Bank & Gaza , Maldives and Mongolia where
BNT162b2 w as shipped for COVAX ;
g.Includes Cape Verde, Rwanda and Tunisia where BNT162b2 was shipped fo r COVAX .
5.2.Cumulative and Interval Exposure Data in the EU
Estimated shipped doses in the EU- EFTA countries may serve as a reasonable indicator of
subject exposure in these countries , considering that approximately % of the shipped doses
were administere d; this estimation is based on the proportion of doses administered out of
those shipped upon review of data currentl y available for the EU3countries .
With these caveats in mind, it is estimated that:
approximately doses of BNT162b2 were shipped in the EU -EFTA countries
from the receipt of the first conditional marketing authoris ation approval on
21December 2020 through 31 March
2021, corresponding to 54,862,649 estimated
administered doses;
approximately doses of BNT162b2 were shipped in the EU -EFTA countries
during the current reporting interval from 01 March 2021 through 31 March 2021,
corresponding to 24,636,433 estimated administered doses.
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Page 17Table 4 provides the estimated interval/cumulative number of shipped doses of BNT162b2
from the receipt of the first conditi onal marketing authorisation approval through
31March 2021 for the 27 EU Countries and for the 3 EFTA Countries .
Table 4.Interval/Cumulative Estimated Shipped Doses of BNT162b2 by EU -EFTA
Countries (30)
EU Country Total Number of Interval Shipped
DosesTotal Number of Cumulative Shipped
Doses
EU(27)
Austria
Belgium
Bulgaria
Croatia
Cyprus
Czech Republic
Denmark
Estonia
Finland
France
Germ any
Greece
Hungary
Ireland
Italy
Latvia
Lithuania
Luxembourg
Malta
Netherlands
Poland
Portugal
Rom ania
Slovakia
Slovenia
Spain
Sweden
European Free
Trade Association
Iceland
Liechtenstein
Norw ay
Total
Table 5provides estimated number of persons who have received 1 dose and number of
persons who have received both doses of BNT162b2 by age group cumulatively in 23EU-
EFTAcountries.
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Page 18Table5.Cumulative Administered 1&2 doses of BNT16 2b2 by Age Group in
EU-EFTACountriesa
18-24years 25-49years 50-59years 60-69years 70-79years ≥80years
Countries Dose
1 Dose
2Dose
1Dose
2Dose
1Dose
2Dose
1Dose
2Dose
1Dose
2Dose
1Dose
2
Austria 1835
911307 13261
091776 91555 62362 73116 34154 14330
046746 30041
322318
7
Belgium 3803
429873 22600
518203
812248
498285 10168
764334 13199
242192 31001
512145
4
Bulgaria 2532 1300 47829 28246 37365 25513 33167 22810 14499 8589 4168 2395
Croatia 1929 1086 35215 22895 26895 15233 43223 14070 54577 11869 41967 16654
Cyprus 19778 7613
Czech
Republic1480
19232 18034
512508
710159
667545 73970 49040 28023
093389 21682
318999
7
Denmark 1024
67691 88611 72812 61161 48191 78038 58832 11644
066018 21021
213963
8
Estonia 2319 1805 18683 13770 12139 8398 15194 8405 29536 11522 30682 20695
Finland 6913 2775 65141 35493 37323 16870 37982 9110 32114
44742 24108
320270
Greece 4631 3637 12041
610260
964701 54303 31937 23475 14416
667552 39312
335459
9
Hungary 2249
914719 22806
410496
112280
459641 22389
249346 24391
360346 17980
611733
0
Iceland 464 241 3984 2487 1652 973 2340 1799 8076 4123 12308 12033
Ireland 1017
09749 84321 81325 35407 33875 20938 18635 11909
918192 15508
794515
Italy 8974
383182 75552
784107
147407
549789
838538
032716
535148
910735
624135
6014168
02
Latvia 862 768 2370 2047 1409 1164 1321 922 1778 984 805 462
Lithuania 3741 2966 37045 31593 32382 26906 44474 25500 55858 30405 41344 29068
Luxembou
rg651 525 5046 4564 2423 2105 1786 1123 11243 1019 17816 8969
Malta 2859 1750 19823 13933 8532 6756 8305 6560 26613 8902 20776 16486
Poland 6299
257303 44368
438587
725622
021240
341467
816861
410840
1945737
078264
260973
1
Portugal 1165
010414 13738
112806
364402 58119 50843 37323 79524 30896 51404
227343
5
Slovakia 54509 42702
Slovenia 1446 1299 18786 17440 11080 9950 11375 4885 64647 25057 58155 52044
Sweden 1151
79212 10038
584135 64403 54238 69331 53733 19274
568069 43406
222863
6
a.Source is https://covid19 -vaccine -report.ecdc.europa.eu/ (point 6, cumulative period as of week 1 3, 04
April 2021 , data presented only for EU -EFTA countries for which they were available ).
Table 6 provides estimated number of persons who have received 1 dose and number of
persons who have received both doses of BNT162b2 in the reporting period in 22 EU-EFTA
countries.
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Page 19Table 6.Interval A dministered Doses 1&2 of BNT162b2 by A ge Group in
EU-EFTACountriesa
18-24years25-49years 50-59years 60-69years 70-79years ≥80years
Countries Dose
1Dose
2Dose1Dose2Dose1Dose2Dose1Dose2Dose1Dose2Dose1Dose2
Austria 7819 2124 44908 15406 34048 12438 47099 13383 11570
127654 182407 161872
Belgium 1377
61520
372841 88819 44195 49768 56079 33308 98657 13862 194814 15101
Bulgaria 1746 934 26063 17095 16720 14206 15704 12961 9081 5839 2325 1456
Croatia 669 388 9359 5959 9322 4277 26229 5391 38230 6703 17622 7962
Czech
Republic7584 4150 83030 50531 54627 31746 41422 25140 25873
979391 58466 107977
Denmark 4179 3081 25427 20270 20772 17061 34314 32829 71764 43481 79704 92033
Estonia 1036 555 7248 2689 5271 1741 9086 2519 26017 8281 24934 15584
Finland 782 153 6760 1534 6113 781 17680 541 28390
7530 84006 3333
Greece 1792 1960 29823 34231 14998 13542 11229 7212 13067
062962 118969 171871
Hungary 7563 2244 12373
011147 63455 5824 17549
213392 18378
140320 61392 72697
Iceland 238 34 1553 154 707 81 1158 766 6200 2615 5726 6609
Ireland 364 1578 2461 11576 1247 5477 2141 4057 10755
511586 87052 78870
Italy 2442
93928
017730
025912
713825
713939
617372
810435
527654
755177 168882
2128277
1
Latvia 175 123 540 310 422 229 593 246 1621 873 768 449
Lithuania 789 704 4843 5357 4798 7700 21392 11837 44498 27071 16281 24612
Luxembou
rg131 273 514 1492 380 732 884 632 10324 642 12101 7550
Malta 886 709 4737 5134 1871 2994 3571 4986 22514 7743 3001 6444
Poland 5404 6278 59278 36689 44862 16806 25372
440769 71069
133835
5205441 263858
Portugal 706 1801 6257 16517 4714 8945 13689 8990 50150 13581 293509 214377
Slovakia 3833 27480
Slovenia 91 190 657 1532 695 816 6499 740 45442 21830 6562 33955
Sweden 2110 2451 14753 19434 9578 12721 18803 19210 13479
235021 256554 125582
a.Source is https://covid19 -vaccine -report.ecdc.europa.eu/ (point 6, w eeks 9,10, 11, 12, 13as of week 1 3,
04April 2021 , data presented for EU -EFTAcountries for which they were available).
6.DATA IN SUMMARY TABU LATIONS
6.1.Reference Information
The MedDRA version 23.1 wasused to code adverse events /reactions in summary
tabulations.
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Page 206.2.Cumulative and Interval Summary Tabulations from Post-Marketing Data
Sources9
Appendix 2 and Appendix 2.1 respectively provide interval and cumulative number sof
case reports (serious and non- serious, medicall y confirmed and non- medically confirmed)
received from post -marketing authoris ation data sources,9overall, b y sex, country, age
groups and in special populations, and summary tabulations of events by PT and SOC
respectivel y for the interval and cumulative periods.
The cumulative data include all data up to 31 March 2021 while the interval data are for
the period from 01 March 2021 to 31 March 2021.
Appendix 2.2 provides an interval summary tabulation of case reports with DMEs from
post-marketing data sources.9
Appendices 2.3 and2.4provide data stratified by country . In these appendices,
spontaneous cases (including regulatory authorit y and literature cases) are presented
separately from non-interventional cases :
oAppendix 2.3 provides a cumulative and interval summary tabulation of case sby
medically confirmed and non -medicall y confirmed status (fatal, serious and non -
serious).
oAppendix 2 .4provide sa cumulative and interval summary tabulation of fatal cases.
Appendix 2.5 and Appendix 2.6 provide a cumulative and interval summary tabulation of
adverse reactions from post -marketing authori sation data sources9respectively by PTand
by HLT organized according to SOC. Please refer to Appendix 2.5.110and
Appendix 2.6.110for data per country.
Adverse events totals presented in Appendix 2 , Appendix 2.1 and for safety topic evaluations
in Section 9.5may differ from those presented in Appendix 2.5 and Appendix 2.6, due to the
fact that Appendix 2.5 and Appendix 2.6 only display the number of serious and non- serious
reactions from spontaneous sources, serious reactions from non- interventional studies and
from solicited sources as described above, whereas Appendix 2 , Appendix 2.1 and the safety
topic evaluation sincludes all reported events.
Appendix 2.5.2,10Appendix 2.5.310and Appendix 2.5.410were added to include a cumulative
and interval summary tabulation of advers e events from post -authori sation data sources9by
PT per country , stratified respectively for age, gender and relevant co -morbidities.
9This refers to post-EUA/conditional marketing authorisation approval data sources.
10Due to a technical formatting issue, blank pages may be present in this Appendix; the total data are
however correctly displayed.
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Page 21Available relevant inform ation with regard to the differences in vaccination prioritization in
EU countries,11US12, UK and ROW13was taken into account in the evaluation of adverse
events trends, clusters or signals .
11Overview of the implementation of COVID -19 vaccination strategies and vaccine deployment plans in
the EU/EEA. ECDC, February 202 1.
12https:// www.cdc.gov/vaccines/hcp/acip -recs/vacc- specific/covid -19/evidence -table -phase -1b-1c.html .
13WHO Roadmap for Prioritizing Population Groups for Vaccines against COVID -19; ACIP COVID -19
Vaccines Working Group, Phased Allocation of COVID -19 Vacc ines (Dec 01, 2020); JCVI updated interim
advice on priority groups for COVID -19 vaccination (Sept 25, 2020)
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Page 227.MEDICATION ERRORS
Cases potentially indicative of medication errors14that occurred in the reporting period are
summarized below.
Number of cases: 771 (2.6% of 29,750 cases, the total PM9dataset ) of which 477
(61.9%) are medically confirmed, compared to 858 (3.6%) in the second monthly report
of which 75.1% were medically confirmed. Of the 771 cases, 33 cases were determined
to be non -contributory and are not included in the discussion for the following reas ons:
No indication that a consumer or patient experienced an event with the vaccine in 19
cases;
An unspecified number of individuals were described in 7 cases;
Medication error -related events were mistakenl y coded in 4 cases (e.g., underdose
reported for a reported vaccine dose of 30 micrograms, medication error was reported
for the second vaccine dose though reported details were for the first vaccine dose
only, a suspected AE from the vaccine was miscoded as an medication error, and
follow -up information received from a patient clarified that the vaccine injection site
and route of administration were aligned with the RSI )and have been flagged for
correction after the DLP ;
Product complaints and not medication errors were reported in 2 cases;
Unidentifiable patient in 1 case.
Number of relevant medication error cases: 738
Number of relevant events: 906.
Number of medication errors b y country :
There were 227 cases describing medication errors, which occurred in the EU/EEA
countries [France (77 ), German y (51), Italy (33), Ireland (12), Spain (10), Czech
Republic (7), Austria, Belgium, Portugal and Romania (5 each), Denmark (3),
14MedDRA (version 23.1) Higher Level Term s: Accidental exposures to product; Product administration
errors and issues; Product confusion errors and issues; Product dispensing errors and issues; Product label
issues; Product monitoring errors and issues; Product preparation errors and issues; Product selection errors and
issues; Product storage errors and issues in the product use system; Product tran scribing errors and
communication issues , OR Preferred Terms: Accidental poisoning; Circumstance or information capable of
leading to device use error; Circumstance or information capable of leading to medication error;
Contraindicated device used; Deprescribing error; Device use error; Dose calculation error; Drug titration error;
Expired device used; Exposure via direct contact; Exposure via eye contact; Exposure via mucosa; Exposure via
skin contact; Failure of child resistant product closure; Inadequate aseptic technique in use of product; Incorrect
disposal of product; Intercepted medication error; Intercepted product prescribing error; Medication error;
Multiple use of single -use product; Product advertising issue; Product distribution issue; Product p rescribing
error; Product prescribing issue; Product substitution error; Product temperature excursion issue; Product use in
unapproved therapeutic environment; Radiation underdose; Underdose; Unintentional medical device removal;
Unintentional use for una pproved indication; Vaccination error; Wrong device used; Wrong dosage form;
Wrong dosage formulation; Wrong dose; Wrong drug; Wrong patient; Wrong product procured; Wrong product
stored; Wrong rate; Wrong route; Wrong schedule; Wrong strength; Wrong techn ique in device usage process;
Wrong technique in product usage process.
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Page 23Finland, Greece and Netherlands (2 each), Bulgaria, Croatia, Hungary , Latvia,
Norway , Poland, Slovenia and Sweden (1 ea ch)].
There were 511 cases with medication errors from non-EU/EEA countries [US (236),
UK (215), Canada (33), Israel and Japan (6 each), Switzerland (4), Australia, Chile,
Lebanon and Mexico (2 each), Panama, Saudi Arabia and Serbia (1 each)].
In some instances, clusters of medication errors were reported, generally by HCP s,
suggesting that rather than a sy stematic issue worldwide, these errors were repeated
mistakes at certain vaccination locales:
In the EU/EEA region there were 9 clusters, the largest r eported clusters were
received from France [(100 cases, 75 cases, 66 cases and 15 cases (4 clusters )];
In non -EU/EEA countries there were 14 clusters, the largest reported clusters
were received from the UK (66 cases) and Canada (26 cases) (1 cluster each) .
Medication error PTs in the EU and ex -EU15
In the EU/EEA countries, a total of 287 PTs indicative of medication errors were
reported; those events reported at least thrice included: I ncorrect route of product
administration (69), Poor quality product administered (65), Product temperature
excursion issue (48), Inappropriate schedule of product administration (42),
Underdose (20), Product preparation issue (11), Incorrect dose administered (9),
Product administered at inappropriate site (5) and Product preparation error (4 ).16
In non -EU/EEA countries, a total of 619 medication errors were reported; those
events reported at least thrice included: Inappropriate schedule of product
administration (209), Poor quality product administered (82), Product tempera ture
excursion issue (70), Circumstance or information capable of leading to medication
error (35), Incorrect route of product administration (32), Underdose (27), Accidental
overdose (24), Product administered at inappropriate site (23), Product preparati on
error (21), Product preparation issue (16), Wrong technique in product usage process
(13), Incorrect dose administered (12), Wrong product administered (10), Product
administered to patient of inappropriate age (9), Product dose omission issue (8),
Acci dental exposure to product and Expired product administered (5 each), Exposure
via skin contact and Product administration error (4 each), and Medication error (3).
15As per EMA assessment received on the first SMSR, the MAH was requested to keep medication errors
under close scrutiny especially within the EU context and discuss whether the current product information is
sufficiently clear or w hether there is room for improvement. The Rapporteurs should be notified immedi ately
in case of unexpected findings or trends.
16The PTs reported less than 3 times included: Accidental exposure to product, Expired product
administered, Wrong product administered and Wrong technique in product usage process (2 each), Incorrect
dosage administered, Medication error, Product administration error, Product dose omission issue, Vaccination
error and Wrong patient received product (1 each).
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Page 24Medication error sby seriousness:
Serious (19 events of medication error ):
oOf these serious events of medication error, 7 serious medication errors17
accompanied b y clinical AEs were reported in EU/EEA countries [Germany (3),
Belgium, France, Portugal and Romania (1 each)];
Seriousness criteria were medically significant events (4 events),
hospitalization required (2 events) and life -threatening event (1 event);
All but 1 event were medically confirmed.
Non-serious (887 events of medication error ).
Medication error event outcomes:
Resolved/resolving (15 event s, of which 2 events w ere serious),
Resolved with sequelae ( 1, serious),
Not resolved ( 3 events, all non -serious),
Unknown ( 887, of which 16 were serious).
Please see the Medication errors associated with harm and Medication errors without Harm
sections below for further deta ils on co-reported AEs in cases involving serious medication
error.
Medication Err ors Harm Analysis
Among the medication error cases, the following scenarios , categorized according to the
EMA guidance “Good practice guide on recording, coding, reporting and assessment of
medication errors” (EMA/762563/2014) were described :
Medication errors associated with harm [i.e., resulting in adverse reaction(s)] were
reported in 19 cases (17 in the third SMSR);
Medication errors without harm [i.e. not resulting in a dverse reaction(s)]18were
reported in 696 cases (in 345 of them there were co -reported AEs) compared to 774
cases of which 321 included co -reported AEs in the third SMSR;
Intercepted medication errors were not reported during the reporting interval,
compar ed to 2 cases in the third SMSR;
17PTs: Expired product administered, Inappropriate schedule of product administration, Incorrect route of
product administration, Poor quality product administered, Product administered at inappropriate site, Product
dose omission issue and Product temperature excursion issue (1 each).
18AEs may be co -reported in a case, but they are not considered to be a result of the medication error.
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Page 25Potential medication errors were reported in 23 cases, compared to 51 cases in the
third SMSR.
Medication errors associated with harm (21 medication errors in 19 cases)
There were 5 cases from the EU/EEA area [Belgium, Fran ce, Germany , Italy and Poland (1
each)] and 14 from non- EU/EEA countries [US (8), UK (4), Canada and Switzerland (1
each)].
Serious medication errors
In 5 cases (involving 6 medication error events), serious medication errors potentially
contributed to th e occurrence of serious adverse events.
Nerve injury (serious) accompanied by Nausea, Chills, Fatigue and Ly mphadenopathy
(all non-serious) were reported in 48- year-old woman after receiving the vaccine that was
administered beneath the deltoid muscle (PT Product administered at inappropriate site).
The patient was treated with corticosteroid therapy . At the time of the report, nerve
injury was not resolved and the outcome for the remaining events were resolved.
Pain, Asthenia, Neck pain, Pain in extremit y (arm), Condition aggravated (recurrence of
arm pain) (all serious) accompanied b y Contusion, Vaccination site pain, Neuralgia,
Condition aggravated (recurrence of nerve pain in the neck and shoulder), Feeling
abnormal and Fatigue (all non -serious) occurr ed in a 65- year-old woman after receiving
the vaccine injection that was reported to have “hit a nerve” in her left arm . Relevant
medical history included 2 major spinal surgeries that occurred approximately 15 and 18
months prior to receiving the vaccine to improve arm pain (unspecified arm) and nerve
damage on her left arm . The patient received unspecified treatment. Events of contusion
and vaccination site pain were resolved, pain and asthenia were not resolved, and the
outcome was unknown for the remaining events.
Vaccination site pain and Joint range of motion decreased (all serious) were reported in a
46-year-old man 4 hours after receiving the vaccine via an intra -articular injection to the
left shoulder (PT Incorrect route of product administration) . The patient was treated
symptomaticall y with a non- steroidal anti -inflammatory drug (unspecified) and
acetaminophen and both events were resolving.
Hypertensive crisis (serious) with manifestations of palpitation, sweating and tingling of
the extremitie s (blood pressure not reported) occurred in a 45 -year-old woman
immediately after receiving a vaccine that was improperl y thawed, in which the
temperature of the vials was “a bit lower” at the time of reconstitution. The patient’s
medical history included asthma and hay fever and concomitant medications were not
reported. Therapeutic measures were taken (unspecified), and the duration of the SAE
was reported as “one and a half hours”. The event was not resolved as the patient was
still hospitalized at the time of the report.
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Page 26Peripheral swelling (arm; serious) was reported in a 37 -year-old woman who received an
expired vaccine. The outcome of the event was not resolved at the time of the report.
Non-serious medication errors
In 14 cases (involving 15 medication error events), non -serious medication errors potentiall y
contributed to the occurrence of non -serious adverse events.
Administration of inadequately prepared vaccine (1 event, 1 case)
A 53 -year-old woman in the US experienced vaccination site pa in after she received a
dose of vaccine that may have possibly contained particulates described as “little black
specks” after reconstitution. The outcome of the event is unknown. The MAH is
investigating this product quality complaint and reached out to the reporter (HCP) for
further details; however, per the reporter, the vaccine vial was disposed of and pictures
were not taken as the particulates were “so minute that it would not be possible to capture
with a readil y available camera” and they were “very challenging to see with the naked
eye”. Investigation of this product quality complaint was still ongoing at the time of the
report.
Errors in administration technique (3 events, 3 cases)
All 3 cases were reported from the US and involved errors relate d to an improperl y
secured needle (1 event) and accidental injection to a blood vessel and nerve (1 event
each).
Errors in the route of administration (5 events, 5 cases)
This error occurred in 1 case from the EU/EEA area (Poland) and in 4 cases from non-
EU/EEA countries [UK (2 cases), US and Canada (1 case each)]. The vaccine was
administered intradermally , intravenousl y, intra -articularly , subcutaneousl y and “not
intramuscularl y” (1 event each). Local vaccination site reactions mainl y included
erythema, swelling and pain.
Error in vaccine dosage (1 event, 1 case)
This error occurred in the US, in which overdose was reported due to administration of
vaccine from vials reconstituted with 1. 3mL rather than 1.8 mL of diluent. Events of
pain, nausea, v omiting and diarrhea were reported.
Error in volume administered (2 events, 2 cases)
This error occurred in 1 case from the EU/EEA area (Ital y), in which the patient received
0.45 mL rather than 0.3 mL of vaccine, and in 1 case from the US, in which a partial dose
of vaccine was administered due to leakage from a needle malfunction (see
Administration technique errors above).
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Page 27Errors of vaccination at the wrong anatomical site (3 events, 3 cases)
This error occurred in 3 cases from the US (2 cases) and the UK (1 case). The
vaccination was not administered in the deltoid (PT Product administered at inappropriate
site). L ocal vaccination site reactions included ery thema, pain, mass, warmth, induration,
arthralgia and burning (1 event each).
Medication error s without harm (861 medication errors in 696 cases)
These m edication error PTs describe errors occurring during 1 or more steps of the
vaccination process: preparation, administration, or scheduling of second dose.
Overall, t here were
222 cases from the EU/EEA area: France (76), Germany (50), Italy (32), Ireland (12),
Spain (10), Czech Republic (7), Austria, Portugal and Romania (5 each), Belgium (4),
Denmark (3), Finland, Greece and Netherlands (2 each), Bulgaria, Croatia, Hungary ,
Latvia, Norway , Slovenia and Sweden (1 each);
474 cases from non -EU/EEA countries: (those with more than 1 medication error) UK
(210), US(206), Canada (32), Israel and Japan (6 each), Switzerland (3), Australia, Chile,
Lebanon and Mexico (2 each) and Saudi Arabia (1).
Vaccine preparation errors (172 events, 1 of which was serious) : events mainly described
errors in storage conditions or during dilution (before use).
Temperature excursion (120 events, all non- serious) : In the majority of the events, the
vaccine was either left i n the refrigerator or at room temperature for a longer time period
or the refrigerated temperature was higher than specified in the RSI ; no adverse events
were reported upon vaccine administration.
Incorrect dilution (49 events, 1 of which was serious19): Asingle vaccine dose or full
vial of vaccine was administered without performing the dilution (14 events and 2
events, respectivel y); dilution was performed either with a smaller volume of normal
saline (13 events) or with a larger volume of normal saline (9 events) than instructed;
dilution was performed with sterile water for injection rather than normal saline (7
events); doses described as “more concentrated” were prepared (details unknown) (2
events); improper dilution leading to excess vial pressure a nd accidental removal of
diluted vaccine upon reconstitution (1 event each).
19Clinical AEs were not reported in the case involving serious medication error (PTs Product preparation
issue and Underdose), in which the vaccine vial was diluted with 2 mL rather than 1.8 mL of diluent. This
medication error w as assessed as medically significant by the reporter (pharmacist).
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Page 28Other preparation errors (3 events ).
Vaccine administration errors (424 events, 6 of which were serious) : events mainly described
errors in administration of vaccine dose not adequately prepared (see Preparation subset),
errors in route of administration, errors in the volume or dosage of the vaccine administered,
and errors of vaccination at the wrong anatomical site.
Administration after inadequate preparation (128 events) : These events referred to
vaccine administered after inadequate preparation: vaccine was left in the refrigerator for
a longer time than specified in the RSI (67 events), temperature excursion of thawed vials
(41 events), dilution performed with sterile wate r for injection instead of normal saline (5
events), temperature excursion during frozen storage (4 events), unspecified temperature
excursion, presence of particulates in reconstituted vials [black particulates [2] and grey
particulates [1]) (3 events eac h), error in sterile technique during preparation (2 events)
and vaccine doses stored as pre -filled sy ringes in the refrigerator and an unspecified
preparation error (1 event).
Errors in the route of administration (95 events, 1 of which was serious20): The vaccine
was administered subcutaneously (59 events), intravenousl y (25 events), intradermall y (4
events), parenterally without any further detail ( 3 events); and through other routes (4
events).
Errors in the volume administered (60 events, all non-serious): A smaller volume of the
right dose of vaccine was administered (23 events), higher volume of right dose of
vaccine was administered (17 events), partial doses were administered due to leakage (13
events) and s yringe or needle malfunction (7 events).
Errors in vaccine dosage (47 events, 1 of which was serious19):These errors include
administration of improperly diluted vaccine from vials with reported excess pressure (15
events), 2 vaccine doses administered on the same day (10 events), vaccine dose s diluted
with a larger volume of normal saline (9 events) or smaller volume of normal saline (6
events) than recommended, administration of undiluted vaccine (4 events), vaccine doses
taken from vials containing only 4 doses were administered (2 events) a nd an unspecified
overdose (1 event).
Vaccination site other than deltoid muscle (23 events, 3 of which were serious21): The
vaccine was administered in the vaccinee’s arm but not in the deltoid muscle (15 events);
the administration site was in the hand (4 events), thigh (2 events), gluteus or leg (1 event
each).
20PTs Headache, Hypertension and Vaccination site pain.
21PTs Cellulitis gangrenous, Erythema, Joint sw elling, Pain, Pain in extremity, Paraesthesia , Vaccination
site erythema, Vaccination site joint erythema, Vaccination site pain, Vaccination site swelling and Vaccination
site warmth.
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Page 29Wrong vaccine administered (12 events, all non -serious) : The vaccinees received 1 dose
of Moderna vaccine and 1 dose of BioNTech -Pfizer vaccine (7 events); vaccinees were
scheduled to receive the Moderna vaccine, but were administered the BioNTech -Pfizer
vaccine (3 events); vaccinee received 1 dose of Sputnik V vaccine and 1 dose of
BioNTech- Pfizer vaccine; and vaccinee received 1 dose of AstraZeneca vaccine and 1
dose of BioNTech -Pfizer vaccine (1 event each).
Errors in administration technique (11 events, all non-serious) : These errors include the
withdrawal of a smaller volume or dose of vaccine from the vial, use of subcutaneous
needle for injection (2 events each), shaking the vial prior to use , additional vaccine dose
due to leakage of the initial injection, single dose withdrew from multiple vials, full dose
separated into multiple injections (unspecified number of injections), error in sterile
technique, premature retraction of the needle dur ing injection and poor injection leading
to pain (1 event each).
Use in unauthorized individuals (11 events, 1 of which was serious22): The vaccine was
inadvertentl y administered to paediatric individuals below 16 years of age (see
Section 9.5.4 Use in Paediatric Individuals <16 Years of Age ) (9 events) and pregnant
individuals (see Section 9.5.4 Use in Pregnancy and W hile Breast Feeding )(2 events).
Accidental exposure to vaccine (9 events, all non -serious) : These errors involved
exposure to the skin (8 events) and ey e (1 event).
Dose of vaccine not administered (3 events, all non-serious) : The s yringe was empt y (2
events) and the second dose was not administered at the scheduled date due to a missed
appointment (1 event).
Other vaccine administration errors (25 events, all non- serious) : Most events were
related to the use of concomitant drugs23(8 events) or concomitant vaccine (1 event);
unspecified underdose; expired vaccine24(6 events each); administration of a third dose
of vac cine (2 events); administration of a vaccine without patient consent; and confusion
on posology information for the BioNTech -Pfizer and Moderna vaccines (1 event each).
22PT Abortion spontaneous.
23Co-suspect in 1 instance.
24Two events involved vaccine administration from thawed vials left in the refrigerator for mor e than 5
days, 1 event involved administration of vaccine 1 day after the expiry date, and no details were provided for
the remaining 3 events.
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Page 30Vaccine scheduling errors (260 events, 4 of which were serious) : events mainly described
errors in administering or scheduling the second dose in less than 21 day s or more than 21
days after the first dose.
Incorrect interval between doses (205 events, 3 of which were serious25): The second
dose was administered or scheduled more than 21 day s after the first dose (113 events);
the second dose of the vaccine was administered or scheduled less than 21 days after the
first dose [92 events; interval between the first and the second dose ranged between 4
days (1 event) and 19 day s with the majorit y of the second doses administered between
the 14thand the 17thday after the first dose (52 events)];
Other scheduling errors (55 events, 1 of which was serious26): The second dose was
never administered (reason unknown) (32 events), the vaccinee cancelled or missed their
appointment (17 events), a scheduled appointment for the second dose was not made (4
events), the second dose was not available due to a supply issue, and the vaccination
appointment conflicted with another medical appointment (1 event each).
Other medication errors (5 events, 2 of which were serious27): A transcribing error of an
incorrect lot number on the vaccination card was reported in 1 event, and details on reported
medication errors were not provided in the remaining 4 event s.
Potential medication errors (24 medication errors in 23 cases)
All 23 cases were reported from non -EU/EEA countries [US (23) and UK (1)].
Potential dosing interval error (24 events, all non -serious) : Events mainly described
potential errors posed from consumer and HCP questions on vaccine administration in
individuals with a history of allergic reactions, potential drug- drug or drug -food
interactions, incorrect administration techniques and scheduling of the second dose
outside of the 21 -day interval.
Some medication errors are expected to occur despite written instructions and educational
activities for HCPs administering the vaccine. The number and seriousness of the reported
medication errors do not indicate aneed for additional mitigation activity .
8.GENERAL OVERVIEW
A total of 29,750 case reports (16,674 medicall y confirmed and 13,276 non-medicall y
confirmed) containing 116 ,113events fulfilled criteria for inclusion in this SMSR. Refer to
Appendix 2 for the summary tabulations of all cases received during the current reporting
period.
25PTs Dizziness, Headache , Lymphadenopathy (2 each), Confusional state, Ear pain, Hyperhidrosis,
Malaise, Mobil ity decreased, Nausea ,Pain, Pyrexia and Sensitive skin (1 each).
26PT SARS -CoV- 2 test positive.
27PTs Cold sw eat, Dizziness postural, Malaise, Nausea and Sensitive skin.
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Page 31PRESENTATION OF CASE CHARACTERISTICS
Table7. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval
Characteristics Relevant cases ( N=29750)
Gender: Female 21132
Male 7040
No Data 1578
Age range (years):
0.06 -105years
Mean =52.5years
Median =51 years
n= 2565917
18-30
31-50
51-64
65-74
≥75
Unknown113a
3378
9188
6222
2878
4014
3949b
Case outcome: Resolved/Resolving 14901
Resolve d with sequelae 434
Not re solved at the time of report 8398
Fatal 979
Unknown 5038
Presence of comorbidities Yes 6592c
No 23158
a.Including 6cases for which a paediatric age w as initially reported but that they re -evaluated as not
consistent with this age upon review (see Table 14, Use in Paediatric Individ uals <16 Years of Age ) and 29
breastfed babies for which paediatric age w as reported;
b.Including 49breastfed babies for which age was not reported;
c.Cases retrieved applying the criteria in place to identify the reports involving the special populations of
Immunocompromised patients, Patients with autoimmune or inflammatory disorders, Frail patients with co -
morbidities (e.g. COPD, diabetes, chronic neurological disease, cardiovascular disorders , active tuberculosis )
described as Missing Information in Table 14.
Case outcome b y age group, gender and presence of relevant comorbidities is presented in
Figure 1, Figure 2and Figure 3. Across all age groups, there were more females than males
reporting adverse events . Overall, the proportion of cases with fatal outcome is higher when
relevant comorbidities a re reported ( Figure 1). Among t he cases with a fatal outcome, the re
areno relevant differences between gende r and presence or absence of relevant comorbidities
(Figure 2-A). Keeping in consideration the age group (Figure 2-B), there are no differences
in the proportion of cases with a fatal outcome , with the highest number of cases in
individuals aged 75 years and older, either in presence or absence of relevant comorbidities.
(please also see Death inTable 13 and Frail patients with co -morbidities e.g. COPD,
diabetes, chronic ne urological disease, cardiovascular disorders , active tuberculosis,
described as Missing Information in Table 14).
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Page 32Figure1.Case Outcome by Presence of Relevant Comorbidities
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Page 33Figure2.Case Outcome by Presence of Relevant Comorbidities ,Gender and Age
Group
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Page 34
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Page 35Figure3.Fatal Case Outcome by Presence of Relevant Comorbidities and Age Group
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Page 36ADVERSE EVENT DATA
As shown in Figure 4, the MedDRA SOCs containing the greatest number of events ( ≥2%)
were General disorders and administration site conditions ( 36,493),Nervous sy stem
disorders ( 19,247), Musculoskeletal and connective tissue disorders (13,309 ),
Gastrointestinal disorders (10,025 ), Skin and subcutaneous tissue disorders ( 6127 ),
Respiratory , thoracic and mediastinal disorders ( 6082 ),Infections and inf estations ( 3790),
Investigations (2646 ), Injury , poisoning and procedural complications ( 2641), Cardiac
disorders (2520 )and Vascular disorders (2387) . Of note, multiple adverse events may be
reported in a single case.
Figure4.General Overview: Total Number of Events by MedDRA SOC and Event
Seriousness
The overall safet y evaluation includes a review of the most frequentl y reported events b y
SOC and by the PT for events reported in (≥2%) of all cases during the reporting interval as
compared to the cumulative period since the first temporary authorisation for emergency
supply on 01 December 2020 .050001000 01500 02000 02500 03000 03500 04000 0
General disorders
Nervous system
Musculoskeletal
Gastrointestinal
Skin
Respiratory
Infections
Investigations
Injury/procedural complications
Cardiac
Vascular
Psychiatric
Blood & lymphatic
Eye
Ear & labyrinth
Immune
Metabolism & nutrition
Renal & urinary
Reproductive & breast
Social circumstances
Product issues
Hepatobiliary
Pregnancy
Neoplasms
Endocrine
Congenital & genetic
Surgical & medical procedures NONSERIO US
SERIOUS
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Page 37Table8.Events Reported in ≥2% *Cases
01 March2021 Through 31
March2021Cumulatively Through 31
March2021
MedDRA SOC
MedDRA PTAEs (AERP%)
N = 29750AEs (AERP%)
N = 74575
Blood and lymphatic system disorders
Lymphadenopathya 1529 ( 5.14%) 3657 (4.90%)
Cardiac disorders
Tachycardia 654(2.20%) 1817 (2.44%)
Gastrointestinal disorders
Nauseaa 3603 (12.11%) 9099 (12.20%)
Diarrhoeaa 1298 (4.36%) 3323 (4.46%)
Vom itinga 1229 (4.13%) 3024(4.05%)
General disorders and administration site conditions
Pyrexiaa 5507 (18.51%) 13687 (18.35%)
Fatiguea 5320 (17.88%) 13036 (17.48%)
Chillsa 3632 (12.21%) 9504 (12.74%)
Vaccination site paina 3300 (11.09%) 8617 ( 11.55%)
Malaisea 2292 (7.70%) 5357 (7.18%)
Paina 2171 (7.30%) 6117 (8.20%)
Astheniaa 1945 (6.54%) 4440 (5.95%)
Influenza like illness 888(2.98%) 1772 (2.38%)
Drug ineffectiveb 752 (2.53%) 2725 (3.65%)
Vaccination site erythemaa 685(2.30%) 1647 (2.21%)
Vaccination site swellinga 619 (2.08%) 1545 (2.07%)
Chest pain 596 (2.00%) 1358 (1.82%)
Infections and infestations
COVID -19b 1251 (4.21%) 3253 (4.36%)
Musculoskeletal and connective tissue disorders
Myalgiaa 3737 (12.56%) 8921 (11.96%)
Pain in extremitya 2890 (9.71%) 7200 (9.65%)
Arthr algiaa 2843 (9.56%) 6606 (8.86%)
Nervous system disorders
Headachea 7137 (23.99%) 17839 (23.92%)
Dizziness 2398 (8.06%) 6274 (8.41%)
Paraesthesia 1054 (3.54%) 2679 (3.59%)
Hypoaesthesia 667(2.24%) 1709 (2.29%)
Respiratory, thoracic and mediastinal disorders
Dyspnoeac 1499 (5.04%) 3658 (4.91%)
Coughc 789(2.65%) 1994 (2.67%)
Skin and subcutaneous tissue disorders
Pruritusa 1031 (3.47%) 2632 (3.53%)
Rasha 955(3.21%) 2522 (3.38%)
Erythemaa 757(2.54%) 1902 (2.55%)
Hyperhidrosis 599(2.01%) 1535 (2.06%)
Vascular disorders
Hypertension 615 (2.07%) 1290 (1.73%)
Total number of events 64242 160739
a.Listed or consistent with listed AEs in current RSI;
b.Listed per case processing conventions , except for fatal cases ; for discussion of relevant cases of Drug
ineffective/COVID -19 see Table 13, Lack of Efficacy subsection;
c.Consistent with anaphylactic reactions listed in the current RSI;
* Reporting propo rtion (% of total cases) in the current reporting period.
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Page 38Most of the frequently reported events are listed or consistent with listed event s as per the
current RSI. Of note, the frequentl y reported events Dizziness ,Paraes thesia and Tach ycardia ,
not listed as per the current RSI ,are signals addressed during the reporting period (see
Section 9.2)evaluated as risks (not important for the purpose of inclusion in the R MPs and
PVP) that will be added as ADRs to the RSI .
During the reporting interval, t he distribution of the AEs reported in more than 2% of the
cases by gender is presented in Figure 5. The observed imbalance in the female gender
distribution reflect sthe imbalance in the gender distribution of the cases received in the
reporting period.
The distribution of the AEs reported in more than 2% of the cases by age group and by SOC
is show nin Figure 6and Figure 7.Across the SOCs, the largest number of events is reported
overall in the 31- 50 years age group, followed by the 51- 64 years age group with few
except ions. When the age was reported, Drug ineffective and COVID -19, mostly occurred in
the 75 y ears and older group , while Influenza like illness was more fre quently reported in the
51-64 years age group . For Hy pertension, the number of occurrences between the 31- 50 and
the 51-64 age groups w eresimilar and higher th an those reported in the 75 years and older
group.
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Page 39Figure5.Events Reported in ≥2%Cases in the Interval Period by Gender
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Page 40Figure6.PTReported in ≥2% in the Interval Period - by SOCand Age Group
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Page 47Figure7.Events Reported in ≥2% in the Interval Period by Age Group within
Gender
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Page 489.SIGNAL AND RISK EVAL UATION
9.1.Literature Review
Please refer to Appendix 6 for a summary description of the interval literature review that is
performed for the purpose of signal detection .
There was 1 literature article identify ing a new safety topic related to delayed inflammatory
reactions to h yaluronic acid dermal fillers after exposure to the COVID -19.The article
described 3 cases of what the authors deemed a COVID- 19 spike protein triggered
inflammatory reaction to dermal HA filler. The authors state that although the exact
mechanism of delay ed inflammatory reactions is unknown, it is possible that the COVID -19
spike protein evokes a pro- inflammatory response in the location of dermal H A fillers
through blockade of a cutaneous ACE2 inhibitory pathway . It is to be determined w hether
the delay ed inflammatory reactions is related specificall y to the mRNA -1237 vaccine or is a
potential adverse reaction to widespread immunosurveillance follow ing infection. A detailed
evaluation of the safet y topic “ Reaction associated with dermal fillers” can be found in
Appendix 3.5.
In addition, as pe rthe EMA PRAC assessment report (Product No.
EMEA/H/C/005735/MEA/002 .2) received on the third SMSR , the MAH reviewed an article
by Krammer et al., entitled “Robust spike antibody responses and increased reactogenicity in
seropositive individuals after a single dose of SARS -CoV -2 mRNA vaccine.” The authors
raised a question on whether individuals who al ready had a SARS -CoV -2 infection should
receive 1 or 2shots of the currently authorized mRNA vaccines. In the article, the authors
show that the antibody response to the first vaccine dose in individuals with pre -existing
immunity is equal to or even exce eds the titers found in naïve individuals after the second
dose. The authors also showed that the reactogenicity is significantl y higher in individuals
who have been infected with SARS -CoV -2 in the past and suggested that a possible changing
the policy to give these individuals only one dose of vaccine would not negatively impact on
their antibody titers, spare patients from unnecessary pain and free up many urgently needed
vaccine doses. This concept can onl y be evaluated at the setting of a clinical trial ; no
supporting data is available at this time.
9.2.Overview of Safety Topics and Signals During the Reporting Interval
Safety topics and S ignals addressed during the reporting interval are presented below in
Table 9.
Table 9.Overview of S afety Topics and Signals
Signal/Safety Topic Status Category
Vaccine stress -related responses
(including Dizziness, Paraesthesia
and Tachycardia among other )Signal Closed Identified Risk (Not Important)
Delayed Skin Reactions Signal Closed No Risk
Extensive Swelling of Vaccinated
LimbSignal Closed NoRisk
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Page 49Table 9.Overview of S afety Topics and Signals
Signal/Safety Topic Status Category
Reactions Associated with Dermal
FillersSignal Closed No Risk
Thromboembolic Events , Including
Those Associated With
ThrombocytopeniaSignal Closed No Risk
Anosmia and Ageusia Safety Topic
ClosedNo Validated Signal
Hypoglycaemia Safety Topic
ClosedNo Validated Signal
Hoarseness (Dysphonia), Dysphagia,
Arrhythmia, HypertensionSafety Topic
ClosedNo Validated Signal
Meningitis Safety Topic
ClosedNo Validated Signal
Myasthenia gravis Safety Topic
ClosedNo Validated Signal
Peripheral Neuropathy Safety Topic
ClosedNo Validated Signal
Transverse Myelitis Safety Topic
ClosedNo Validated Signal
Herpes Zoster Signal Ongoing Under Evaluation
Hepatic Events Safety Topic
OngoingUnder Evaluation
Seizure Safety Topic
OngoingUnder Evaluation
Appendix 3 provides a summary of the safet ytopics and signals addressed during the
reporting interval and Appendix 3.1 an evaluation of these safet y topics and signals .
As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002 .2)
received on the thirdSMSR, the following cumulative overviews wereperformed for:
Thromboembolic Events (Appendix 3.2);
Extensive L imb Swelling (Appendix 3.3);
Anosmia/Ageusia (Appendix 3. 4).
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Page 50As per EMA Separate Request on Reaction to Dermal Fillers , the following cumulative
overview was performed:
Safety evaluation of Reaction to Dermal Fillers (Appendix 3.5).
As per request received from MedSafe, the following cumulative overview was performed
for:
Safety evaluation of Hypoglycaemia (Appendix 3. 6);
As per request received from MHRA, the following cumulative overview was performed for:
Safety evaluation of Delay ed Skin Reactions (Appendix 3. 7).
Additionally , Safet y evaluation of My asthenia gravis was performed ( Appendix 3.8 ).
9.3.Summary of Safety Concern s
Table 10 summari sesthe comprehensive list of important risks and missing information
reflected in risk management and pharmacovigilance plans globall yfor BNT162b2 at the
beginning of the reporting period .The pharmacovigilance and risk management activities
implemented for the safety concerns by Pfizer on behalf of BioNTech are global.
Table 10.Safety Concerns
Important Identified Risk Anaphylaxisa
Important Potential Risk Vaccine- Associated Enhanced Disease (VAED), Including
Vaccine -Associated Enhanced Respiratory Disease (VAERD)a
Missing Information Use in Pregnancy and While Breast Feedinga
Use in Immunocompromised Patientsb
Use in Frail Patients With Co-M orbidities (e.g. COPD, Diabetes,
Chronic Neurological Disease, Cardiovascular disorders , Active
tuberculosis )b,d
Use in Patients With Autoimmune or Inflammatory Disordersb
Interaction With Other Vaccinesb
Long -Term Safety D atab
Use in Paediatric Individuals <16 Years of Agec
Vaccine Effectivenessc,e
a.As per both the EU RMP Version 1.0, dated 21 December 2020 and the US PVP Version 0.3, dated 20
January 2021;
b.As per the EU RMP Version 1.0, dated 21 December 2020 ;
c.As per the US PVP Version 0. 3, dated 20 January 2021 ;
d.As per the South Africa RMP, Version 1.0, dated 24 March 2021, active tuberculosis is included as an
additional co -morbidity;
e.As per the South Africa RMP, Version 1.0, dated 24 March 2021, this safety concern is s tated as
“Vaccine effectiveness against novel variant(s) in South Africa”. For vaccine effectiveness against novel
variant(s) in South Africa, in the Lack of Efficacy Section (Section 9.5.3) it will be reviewed whether any
reports and/or virological analys is of variant type on any breakthrough infection is reported among the
relevant cases.
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Page 519.4. Summary of Adverse Events of Special Interest (AESIs)
Please refer to Appendix 5for the list of the company ’s AESIs for BNT162b2 .Please refer to
Appendix 5 .1 for the observed versus expected analy sis for AESIs.28,29
The compan y’s AESI list takes into consideration the lists of AESI s from the following
expert groups and regulatory authorities: Brighton Collaboration (SPEAC), ACCESS
protocol, US CDC (preliminary list of AE SI for VAERS surveillance), MHRA (unpublished
guideline).
The AESI terms are incorporated into a TME list andinclude events of interest due to their
association with severe COVID -19 and events of interest for vaccines in general.
The AESI list includes MedDRA PTs, HLTs , HLGTs or MedDRA SMQs and can be
changed as appropriate based on the evolving safety profile of the vaccine.
9.5.Evaluation of Safety Concerns
Evaluation of new information collected from post -marketing data sources9for BNT162b2
during the interval reporting period for important identified andimportant potential risks,
AESI s,special situations and missing information is provided below in Section 9.5.1 ,
Section 9.5.2 ,Section 9.5.3 and Section 9.5.4 .
9.5.1.Evaluation of Important Identified and Important Potential Risks
Table 11 below presents the evaluation of new information received during the interval
reporting period from post -marketing data sources9for the important identified and
important potential risks of BNT162b2 .
Table 11.Risks Evaluation for BNT162b2
SafetyRisk Post-MarketingaCasesEvaluation
Total Number of Cases in the Reporting Period (N= 29750)
Important Identified Risk
Anaphylaxisb
Search criteria: Anaphylactic
reaction SMQ (Narrow and Broad,
with the algorithm applied),
selecting relevant cases according
to BC criteriaNumber of cases from the Anaphylactic reaction SMQ (Narrow and
Broad) search strategy, applying the MedDRA algorithm based on all
terms in the SMQ: 131830(4.4% compared to 4.9% of the total PM
dataset of the previous SMSR), of which 985 w ere medically
confirmed and 333 w ere non -medically confirmed;
Number of events: 2927;
28It should be noted that for the O/E analyses, the numbers of doses of vaccine admin istrated had been
estimated based on publicly available data from health authorities in various regions.
29As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002.1) sSpecific O/E
analysis for arrythmias, deafness, hypertension, tinnitus, sudden hearing loss were also included in
Appendix 5.1.
30Two (2) additional cases w ere m ade invalid after the DLP due to lack of minimum valid criteria to
process these cases.
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SafetyRisk Post-MarketingaCasesEvaluation
Total Number of Cases in the Reporting Period (N= 29750)
Country of incidence ( 2%): Japan (302), UK (265), US (152),
Mexico (94), Italy (71), Germany (69), France (43), Belgium (32),
Spain (30) and Canada (28);
Subjects’ gender: female (1075), male (158) and unknown (85);
Subjects’ age (n = 1183): ranged from 4 years (1 subject) to 100
years (mean = 48.6 years, median = 46 years);
Most frequently reported individual PTs ( ≥2%): Anaphylactic
reaction (565), Dyspnoea (320), Pruritus (197), Cough (177),
Erythema (153), Ra sh (144), Urticaria (84), Respiratory distress
(81), Chest discomfort (79), Hypotension (78), Sw ollen tongue
(69), Throat tightness (63), Anaphylactic shock (61), Lip swelling
(56), Flushing (55), Circulatory collapse (53), Oedema (52),
Swelling face (51), Pharyngeal swelling and Swelling (41 each),
Wheezing (34), Angioedema (31) and Blood pressure decreased
(28);
Relevant event seriousness:dserious (2177), non -serious (752);
Relevant event outcome: fatal (71), resolved/resolving (1696),
resolved with sequelae (48), not resolved (333), unknown (788).
Cases (1318) w ere individually reviewed and assessed according to
Brighton Col laboration (BC) case definition and level of diagnostic
certainty as shown in the Table below .
Brighton Collaboration Level Number of cases
BC 1 134
BC 2 210
BC 3 9
BC 4 376
BC 5 589
Total 1318
Level 1 indicates a case with the highest level of diagnostic certainty
of anaphylaxis, whereas the diagnostic certainty is low est for Level 3.
Level 4 is defined as “reported event of anaphylaxis, with insufficient
evidence to meet the case definition” and Level 5 as not a case of
anaphylaxis.
BC Level 1 and 2 cases:
Number of cases : 344 (1211 events of interest).
Medical history (n=230): the most frequently ( ≥2%) reported medical
conditions included Asthma (72), Drug hypersensitivity (42),
Hypersensitivity (39), Food allergy (33), Hypertension (24), Seasonal
allergy (17), Suppressed lactation (14), Anaphylactic reaction (13),
Type 2 diabetes mellitus (10), Allergy to animal and Hypothyroidism
(9 each), Allergy to metals, Migraine and Urticaria (8 each), Contrast
media allergy, COVID -19 and Rubber sensitivity (7 each), Allergy to
arthropod sting and Rheumatoid arthritis (6 each) .
Number of vaccine doses administered at the time of the event onset:
1 dose in 215 cases, 2 doses in 82 cases and number of doses w as not
specified in 47 cases.
Time to event onset :
Within 15 minutes: 123 cases
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SafetyRisk Post-MarketingaCasesEvaluation
Total Number of Cases in the Reporting Period (N= 29750)
20 to 30 minutes: 58 cases
30 minutes to 2 hours: 30 cases
3 to 12 hours: 35 cases
Same day (timing unspecified): 94 cases
After 1 day (1 case)
After 2 days (2 cases)
Not specified (1 case)
Relevant PTs (2%): Dyspnoea (162), Pruritus (100), Erythema (98),
Anaphylactic reaction (94), Cough (83), Rash (82), Urticaria (58),
Respiratory distress (45), Throat tightness (41), Sw ollen tongue (40),
Hypotension (31), Lip sw elling (30), Pharyngeal swelling (27),
Swelling face (24), Oedema (24), Chest discomfort and Wheezing (23
each), Flushing (19), Angio edem a (18), Blood pressure decreased
(16), Rash erythematous (14), Face oedema (13), Anaphylactic shock
and Bronchospasm (12 each), Asthma, Laryngeal oedema and
Tongue oedema (9 each), Eyelid oedema and Rash pruritic (8 each)
and Swelling (7).
Relevant e vent outcome :efatal (4), resolved/resolving (768), resolved
with sequelae (31), not resolved (118), unknown (497).
Fatal cas es: 2
1.Country : Australia;
Subject’s gender and age : male subject aged 92 years;
Medical history : Cardiac failure chronic, Gastrointestinal
carcinoma, Dementia Alzheimer's type, Diverticulitis,
Hypertension and Osteoarthritis.
Concomitant medications: not reported
Vaccine dose: 1
Lot Number : Not available at the time of the report.
Events onset date: Day 0; (the vaccine was administered in the
morning and clinical conditions worsened in the afternoon).
PTs: General physical health deterioration, Dyspno ea,
Pneumonia, Acute pulmonary oedema, Hypotension, Heart rate
increased, Oedema peripheral and Oxygen saturation decreased;
all w ere reported w ith fatal outcome. The patient died the day
after receiving the vaccine.
Treatments : Trial of non -invasive venti lation, IV antibiotics
and steroids.
Autopsy : it was not specified if the autopsy was performed.
2.Country : Hungary
Subject’s age and gender : male subject aged 86 years;
Medical history : ongoing Pulmonary fibrosis, Carotid artery
stenosis, Cerebrovascular disorder, Dyspnoea, Emphysema,
Hypertension, Peripheral arterial occlusive disease, T ype 2
diabetes mellitus and a past history of Helicobacter infection.
Concomitant medications : allopurinol, alprazolam,
beclometasone/formoterol, captopril, carvedilol, clo pidogrel,
famotidine, gliclazide, ipratropium, midazolam, nifedipine,
pentoxifylline and rosuvastatin.
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Total Number of Cases in the Reporting Period (N= 29750)
Vaccine dose : 2 (after receiving the first vaccine dose, no adverse
event occurred).
Lot number : EJ 6790
Event onset date: Day 0 (3 hours after receiving the vaccine);
PTs: Cardiac failure, Dyspnoea and Hypotension. All events
reported a fatal outcome. The cardiac failure was reported as the
cause of death linked to the underlying patient’s pulmonary
fibrosis rather than to the vaccine administration.
Treatments : it was not reported if the subject received any
treatments.
Autopsy : results of the performed autopsy were not available at
the time of the report.
Discussion
Anaphylaxis is an adverse reaction in Section 4.8 of the EU SmPC, in
the CDS and local labels/fact sheets. It is also included as an Important
identified risk in the EU RMP and in the US PVP. Based upon review
ofthe available information, no additional change to the RSI is
warranted at this time.
Based on the assessment report for the pos t-authorisation measure
LEG -022.1 for the ‘cumulative review anaphylaxis’
(EMA/PRAC/181346/2021), at the moment no amendment of the
current labeling is warranted.
Conclusion: Evaluation of BC cases Level 1 and 2 as well as 3 and 4
did not reveal any significant new safety information. Anaphylaxis is
appropriately described in the product labeling as are non -
anaphylactic hypersensitivity events. Surveillance will continue.
Important Potential R isk
Vaccine- Associated Enhanced
Disease (VAED) Including
Vaccine- Associated Enhanced
Respiratory Disease (VAERD)b,cVAED is a modified and/or severe presentation of an infectious
disease affecting individuals exposed to the wild -type pathogen after
having received vaccine designed to prevent infection.31
As noted by the Brighton Collaboration, there is currently no
uniformly accepted definition of VAED (or VAERD) and the BC
working group considers that a definitive case of VAED (Level 1
diagnostic certainty) cannot be ascertained with current knowledge of
the mechanisms of pathogenesis of the condition ; they have provided
guidance onlevels of diagnostic certainty of VAED cases based on
various laboratory and clinical findings .
No post -authorized AE reports have been identified as cases of
VAED/VAERD, therefore, there is no observed data at this time. An
expected rate of VAED is difficult to establish so a meaningful
observed/expected analysis cannot be conducted at this point based on
31Flor M Munoz, et al. Vaccine -associated Enhanced Disease: Case Definition an d Guidelines for Data
Collection, Analysis, and Presentation of Immunization Safety Data. Brighton Collaboration. September 2020,
Vaccine Journal Draft Manuscript.
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available data. The feasibility of conducting such an an alysis w ill be
re-evaluated on an ongoing basis as data on the virus grows and the
vaccine safety data continues to accrue.
The search criteria utilised to identify potential cases of VAED for this
SMSR include sPTs indicating a lack of effect of the vaccine and
medical disorders chosen because they are PTs potentially indicative
of severe or atypical COVID- 19.
Overview
Number of cases based on search strategy: 82f(0.3% of the total
PM dataset , which is same as the previous reporting period ), all
serious (of which 57are medically confirmed ).
Country of incidence: UK (2 1), US (1 3), France (12), Italy (6),
Germ any (5), Spain (4), Hungary (3), Austria, Belgium, Czech
Republic, Mexico, Poland (2 each); the remaining 8 cases
originated from 8 different countries.
Gender: female (4 1), male ( 39), unknown ( 2).
Age: 18 to 100 years (n = 7 6), mean = 72.6years,
median = 81.0 years.
Respiratory system PTs: Dyspnoea ( 23), Respiratory failure (7),
Pulmonary embolism (4), Acute respiratory distress syndrome
(2), Hypoxia, and Tachypnoea (1 each) .
Infections related PTs: COVID -19 pneumonia ( 26) and
Mening itis (1) .
Gastrointestinal system PTs: Diarrhoea (13), Vomiting (7), and
Abdominal pain (4) .
Cardiac PTs: Cardiac failure (4), Arrhythmia (3), and Cardiogenic
shock (1) .
Renal PTs: Renal failure (4) and Acute kidney injury (2)
Nervous system PTs: Cerebrova scular accident and Seizure
(2each).
Blood disorders PTs: Thrombocytopenia (2) .
Vascular disorders PT: Vasculitis (1) .
Case outcome: resolved/resolving (20), resolved w ith sequelae
(1), not resolved (22), unknown (14), and fatal (25).
COVID-19 positivity and severity of events
Suspected COVID- 19 infection: 7 (no information on
confirmatory tests performed or test result inconclusive).
Confirmed COVID -19 infection: 7 5(test positive or confirmed
diagnosis reported).
Seriousness criteria for the total 8 2cases:
oMedically significant: 28
oHospitalisation required (non -fatal/non -life threatening):
22(of which 1 serious also for disability)
oLife threatening: 7 (of which 1 serious also for disability)
oDeath: 25
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Seriousness criteria: medically significant ( 28)
In 24out of 28cases where the seriousness criterion was
“medically significant”, the subjects had a confirmed COVID- 19
infection after vaccination, while 4 subjects had unconfirmed
suspected COVID- 19 infection. These 28subjects did not require
hospi talisation.
In the 24confirmed COVID -19 cases , subjects’ age ranged from
18 to 92 years (n = 24), Mean = 57. 5years,
Median = 5 3.5years.
Among the 24confirmed COVID- 19 cases, latency of COVID
occurrence w as reported for 16 cases:
o13 to 20 days after dose 1 (5).
o4 to 28 days after dose 2 (8).
o15 to 44 days after vaccination [dose number not
reported] (3).
The PTs reported more than twice in these 24cases were: Drug
ineffective (1 9), COVID- 19 (1 8), Dyspnoea (1 1), Diarrhoea (8),
Cough ( 7), Headache (6), Nausea, Pyrexia, Vaccination failure
(5each), Abdominal pain, Fatigue, Vomiting (4 each), Arthralgia,
Chills, COVID -19 pneumonia, Oxygen saturation decreased,
Rhinorrhoea, and SARS -CoV -2 test positive (3 each).
The outcome of COVID -19 infection related events (25) reported in
these 24 cases were : resolved/resolving ( 10), not resolved (3), and
unknown (1 2).
Seriousness criteria: hospitalization (non -fatal, non -life
threatening) (22)
Hospitalisation occurred in 22 subjects , for 1 of them COVID- 19
was not confirmed.
In the 21 confirmed COVID -19 cases, subjects’ age ranged from
33 to 99 years (n = 19), Mean = 76.4 years,
Median =83.0 years
Among the 21 confirmed COVID- 19 cases, latency of COVID
occurrence w as reported for 15 cases:
o14 to 20 days after do se 1 (6).
o2 to 34 days after dose 2 (9).
The PTs reported more than twice in these 21 cases were: COVID -19
(16), Drug ineffective (14), Vaccination failure (7), COVID -19
pneumonia (6), Asthenia, Dyspnoea, Pulmonary embolism, Pyrexia,
and Respiratory failu re (3 each).
The outcome of COVID -19 infection related events (24) reported in
these 21 cases were : resolved/resolving (3), resolved w ith sequelae (1),
not resolved ( 7), and unknown (1 3).
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Seriousness criteria: life threatening (7)
Hospitalisation occurr ed in 6 of the 7 cases characterised as
life-threatening; COVID- 19 was confirmed in all the 7 subjects .
Age: 61 to 97 years (n = 6), Mean = 81.0 years,
Median = 80.5 years
Latency of COVID -19 occurrence was reported in 6 of the
7cases:
o14 to 41 days after dose 1 (4)
o29 and 33 days after dose 2 (2)
The PTs reported more than once in these 7 cases were: COVID -19
pneumonia (6), Drug ineffective (5), COVID -19, and Vaccination
failure (2 each).
The outcome of COVID -19 infection related events (8) reported in
these 7 cases were : resolved/resolving (3), not resolved ( 4), and
unknown (1).
Seriousness criteria: death (25)
Twenty-five (25) subjects died, of w hich COVID -19 w as not
confirmed in 2 cases; the remaining 23 confirmed cases are
described below .
oAge: 68 to 100 years (n = 21), Mean = 84.2 years,
Median = 85.0 years.
oCount ryof incidence: France (8), UK (6), Germany,
Poland (2 each), Belgium, Hungary, Israel, Lithuania,
and Spain (1 each).
oGender: female (7), male (16).
oMedical history (n = 17) of clinical significance included
PTs in the following SOCs:
Vascular disorders: 10 (43.5%) [Hypertension (7),
Peripheral venous disease (2), and Orthostatic
hypotension (1)]
Respiratory, thoracic and mediastinal disorders: 9
(39.1%) [Chronic obstructive pulm onary disease (3),
Asthma (2), Bronchitis chronic, Lung disorder, Nasal
polyps, Pleurisy, Pulmonary embolism, Emphysema,
and Interstitial lung disease (1 each)]
Cardiac disorders: 7 (30.4%) [Atrial fibrillation (4),
Angina pectoris, Cardiac failure (2 each ), Cardiac
failure congestive, Coronary artery disease, and
Myocardial ischaemia (1 each)]
Metabolism and nutrition disorders: 5 (21.7%)
[Diabetes mellitus (3), Hypercholesterolaemia,
Obesity, and Type 2 diabetes mellitus (1 each)]
Neoplasms benign, malignant and unspecified (incl
cysts and polyps): 4 (17.4%) [Chronic lymphocytic
leukaemia, Colon cancer, Colorectal
adenocarcinoma, Prostate cancer, and Prostatic
adenoma (1 each)]
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SafetyRisk Post-MarketingaCasesEvaluation
Total Number of Cases in the Reporting Period (N= 29750)
Nervous system disorders: 4 (17.4%) [Dementia (2),
Intellectual disabilit y, and Ischaemic stroke (1 each)]
Renal and urinary disorders: 2 (8.7%) [Chronic
kidney disease and Urinary incontinence (1 each)]
Blood and lymphatic system disorders: 1 (4.3%)
[Neutropenia and Thrombocytopenia (1 each)]
Hepatobiliary disorders: 1 (4.3%) [Liver injury (1)]
Social circumstances: 1 (4.3%) [Tobacco user (1)]
Latency of COVID -19 occurrence was reported in 19 of the 23
confirmed COVID -19cases:
o16 to 42 days after dose 1 ( 8).
ofrom the day of dose 2 to 23 days after dose 2 (9).
o16 days after va ccination [dose number not reported] (2).
Cause of death (n = 23) reported more than once were: Drug
ineffective (14), COVID -19 (11), COVID -19 pneumonia (8),
Death (4), Renal failure, Respiratory failure, and Vaccination
failure (2 each)
In 5 fatal cases , vaccination failure was reported (cross ref. with
Section 9.5.3 –Lack of efficacy):
A 91 -year-old female subject , with hypertension, pulmonary
embolism, chronic bronchitis, and dementia, had a positive
SARS -CoV- 2 test 10 days after the second vaccine dose. Six
days later, the subject ’s condition deteriorated w ith a rapidly
settling hypoxia and she died within 15 -20 minutes.
A 69 -year-old m ale subject , with diabetes mellitus,
hypertension, dementia, coronary artery disease, and obesity,
had a positive SARS -CoV- 2 test 10 days after the second
vaccine dose. The subject experienced general physical health
deterioration, respiratory failure and w as hospitalised and put
on ventilation. The subject died 15 days after the second
vaccine dose.
An 81 -year-old female subject , with asthma, hypertension,
bronchitis, and arthralgia, experienced pneumonia and was
hospitalised; SARS -CoV -2 test w as found to be positive,
9 days after the second vaccine dose. The subject ’s condition
aggravated, and she was put on oxygen mask and
administered morphine for pain and antibiotics. The subject
died 17 days after the second vaccine dose.
A 93 -year-old m ale blind subject , with atrial fibrillation,
hypertension, myocardial ischaemia, diabetes mellitus,
coronary arterial stent, and hypothyroidism, had a positive
SARS -CoV- 2 test 13 days after the second vaccine dose. The
subject was hospitalis ed and lab investigations revealed
lymphopenia and thrombocytopenia. The subject was initially
treated w ith amoxicillin/clavulanic acid,
piperacillin/tazobactam, and prednisone but had a worsening
neurological condition with hypovigilance, diabetes
de-equilibrium, and hyperosmolar coma. Chest CT w as
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Total Number of Cases in the Reporting Period (N= 29750)
compatible with COVID -19 lung infection, moderate
involvement (25 -50%) and signs of associated bronchial
superinfection. The subject had unfavourable evolution with
worsening of the neurological state ,despite control of
glycaemia, and increase of pulmonary lesions of the COVID
leading to death.
A 92 -year-old m ale subject , with medical history including
COVID -19 (serological status unknown), atrial fibrillation,
cardiac failure, ischaemic stroke, liver injury, ne utropenia,
and thrombocytopenia, w as diagnosed with COVID -19
pneumonia 23 days after the second vaccine dose.
COVID -19 w as evolving into severe form, and the subject
was hospitalised with respiratory distress and oxygen support
was provided. Ventilation/perfusion scan indicated
COVID -19 involvement ofmore than 50% lung field. The
patient died 30 days after the second vaccine dose.
VAED may present as severe or unusu al clinical manifestations of
COVID -19. Overall, there were 7 5subjects with confirmed
COVID -19 following one or both doses of the vaccine; 51 of the
75cases w ere severe , resulting in hospitalisation, disability,
life-threatening consequences or death. No ne of the 7 5cases could be
definitively considered as having VAED/VAERD.
Conclusion: In this review of subjects with COVID -19 following
vaccination, based on the current evidence, VAED/VAERD remains a
theoretical risk for the vaccine .Surveillance will c ontinue.
a.Please note that this corresponds to evidence from post -EUA /conditional marketing authori sation
approval data sources;
b.As per both the EU RMP Version 1.0, dated 21 December 2020 and the US PVP, Version 0. 3, dated 20
January 2021 ;
c.Search criteria: Standard Decreased Therapeutic Response Search AND PTs Dysp noea; Tachypnoea;
Hypoxia; COVID 19pneumonia; Respiratory Failure; Acute Respiratory Distress Syndrome;
Cardiac Failure; Cardiogenic shock; Acute myocardial infarction; Arrhythmia; Myocarditis; Vomiting;
Diarrhoea; Abdominal pain; Jaundice; Acute hepatic failure; Deep vein throm bosis; Pulmonary embolism;
Peripheral Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness;
Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; Thrombocytopenia;
Disseminated intravascular coagulation; Chillblains; Erythema multiforme; Multiple organ
dysfunction syndrome; Multisystem inflammatory syndrome in children ;
d.Multiple episodes of the same PT event were reported w ith a different seriousness within some cases
hence the sum of the events seriousness exceeds the total number of PT events.
e.Multiple episodes of the same PT event were reported w ith a different clinical outcome within some
cases hence the sum of the events outcome exceeds the total number of PT events ;
f.Note that 6additional cases, retrieved with this search strategy , were excluded from the discussion
because, upon revie w, they were determined not to report lack of efficacy: in 1 case, unspecified drug
resistance reported w ith no COVID -19 infection and in 5 cases, the PT Drug ineffective was removed after
DLP as the p atients did not develop COVID -19 infection .
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Page 609.5.2.Evaluation of AESIs
Table 12 below presents the evaluation of new information received during the interval
reporting period from post -marketing data sources9with regard to the AESIs forBNT162b2 .
Where applicable, o bserved versus expected anal ysis is provided in Appendix 5.1.
Table 12.AESIsEvaluation for BNT162b2
AESIs32
CategoryPost-Marketing9CasesEvaluation
Total Number of Cases in the Reporting Period (N= 29750)
Anaphylactic Reactions
Search criteria: Anaphylactic
reaction SMQ (Narrow and
Broad, with the algorithm
applied),selecting relevant cases
according to BC criteriaPlease refer to the Risk ‘Anaphylaxis ’ inTable 11.
Cardiovascular AESIs
Search criteria: PTs Acute
myocardial infarction;
Arrhythmia; Cardiac failure;
Cardiac failure acute;
Cardiogenic shock; Coronary
artery disease; Myocardial
infarction; Postural orthostatic
tachycardia syndrome; Stress
cardiomyopathy; TachycardiaNumber of cases: 1000 (3.4% of the total PM dataset, compared to
3.9% in the previous reporting period), of w hich 7 29are medically
confirmed and 271are non -medically confirmed;
Country of incidence: France (167), Mexico (152), UK (132), Italy
(113), US (91), Germany (61), Netherl ands (31), Spain (27),
Portugal (24), Sw eden (20), Czech Republic (19), Finland (18),
Poland (17), Belgium and Japan (16 each), Greece (15), Austria
and Romania (11 each), Switzerland (9), Hungary, Israel, Norw ay
and Slovakia (6 each), Ireland (5), Croatia and Luxembourg (4
each); the remaining 13 cases were distributed among 9 other
countries;
Subjects’ gender: female (734), male (236) and unknown (30);
Subjects’ age (n = 942): ranged from 4 to 99 years (mean = 54.7
years, median = 51 years);
Subject s’ age group (n = 961): Adult33(670), Elderly34(290)and
Child35(1);
Number of relevant events: 1041, of which 744 serious, 297
non-serious; in the cases reporting relevant serious events,
subject’s age ranges from 4 to 99 years (mean = 59.5 years,
median = 56 y ears);
Reported relevant PTs: Tachycardia (654), Arrhythmia* (132),
Myocardial infarction* (108), Cardiac failure* (92), Acute
myocardial infarction* (27), Cardiogenic shock* (13), Postural
orthostatic tachycardia syndrome* (6), Stress cardiomyopathy (5),
Cardiac failure acute* (3) and Coronary artery disease* (1);
Relevant event onset latency (n = 872): Range from 24 hours to
62 days, median 1 day;
32For the complete list of the AESIs, please refer to Appendix 5 .
33Subjects w ith age ranged between 18 and 64 years .
34Subjects w ith age equal to or above 65 years .
35Subjects w ith age ranged between 2 and 11 years .
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Total Number of Cases in the Reporting Period (N= 29750)
Relevant event outcome: fatal (111), resolved/resolving (548),
resolved with sequelae (21), not resolved (130) and unknown
(231);
In 90 out of 1000 cases (involving 58 females ,31 m ales and 1
subject of unknown gender, with ages ranged from 31 to 98 years,
mean 73.2 years, median 80 years), 2 6of which had fatal outcome,
the subject’s medical history was significant for the specific events
of Cardiac failure (34), Arrhythmia (18), Coronary artery disease
(13), Myocardial infarction (12), Tachycardia (10), Acute
myocardial infarction and Postural orthostatic tachycardia
syndrome (4 each), Cardiac failure acute (1). More than 1 relevant
medical history event was reported in 6 cases;
Additionally, in 78 out of 1000 cases, the subject’s medical history
was significant for other cardiac disorders, with the following
conditions reported most frequently ( ≥3 cases): Atrial fibrillation
(25), Cardiac disorder (7), Supraventricular tachycardia (6),
Myocardial ischaemia (5), Atrial flutter (4), Cardiomyopathy,
Cardiovascular disorder, Hypertensive heart disease and
Ventricular extrasystoles (3 each);
In 58out of 1000 cases, the subjects’ medical history was
significant for COVID -19 or s uspected COVID -19.
* Observed/Expected analys is was performed for Acute myocardial
infarction /Myocardial infarction , Arrhythmia, Cardiac failure/Cardiac
failure acute, Cardiogenic shock, Coronary Artery disease and Postural
orthostatic tachycardia syndrome (see Appendix 5.1 ).
Conclusion: Nocardiovascular s ignals have emerged from the review
of post -authori sation data . The review of cases and O/E analysis do not
raise new concerns. Surveillance w ill continue .
COVID-19 AESIs
Search criteria: Covid -19 SMQ
(Narrow and Broad) OR PTs
Ageusia; AnosmiaNumber of cases: 1861 (6.3% of the total PM dataset, compared to
6.9% in the previous reporting period), of w hich 1050 are
medically confirmed and 811 are non -medically confirmed;
Country of incidence: US (625), UK (331), France (144), Italy
(122), Germany (116), Portugal (100), Belgium (52), Spain (45),
Mexico (33), Romania (32), Canada (31), Austria (22), Poland
(18), Czech Republic and Netherlands (17 each), Sweden (16),
Hungary (15), Greece (14), Israel (12), Sw itzerland (10); the
remaining 89 c ases were distributed among 29 other different
countries;
Subjects’ gender: female (1025), male (566) and unknown (270);
Subjects’ age group (n=1222): Adult33(713), Elderly34(509);
Number of relevant events: 1996, of which 1279 serious, 717
non-serious;
Most frequently reported relevant PTs (1 occurrence): COVID- 19
(1251), Suspected COVID -19 (147), SARS -CoV -2 test positive
(118), Ageusia* (111), Asymptomatic COVID -19 (92), SARS -
CoV- 2 antibody test negative (87), Anosmia* (84), COVID -19
pneumonia (55), SARS -CoV -2 antibody test positive (2 4),
Exposure to SARS -CoV -2 (14), Coronavirus infection, COVID -19
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Total Number of Cases in the Reporting Period (N= 29750)
immunisation and SARS -CoV -2 test negative (3 each), SARS -
CoV- 2 test false positive (2);
Relevant event onset latency (n=1255): Range from <24 hours to
82 days, median 8 days;
Relevant event outcome:36resolved/resolving (452), not resolved
(285), fatal (110), resolved w ith sequelae (11) and unknown
(1140).
* Observed/Expected analysis was performed for Ageusia and
Anosmia (see Appendix 5.1 )and as in the Feb 2021 SMSR, at least
one of the ris k periods or risk windows has a 95% CI greater than one,
although the ratios are lower overall.
Conclusion: Anosmia and ageusia cases were reviewed and determined
not to be a validated signal (see Appendix 3 , Appendix 3.1 and
Appendix 3. 4). No new issues are raised with the current O/E analysis .
Surveillance will continue.
Dermatological AESIs
Search criteria: PT Chillblains ;
Erythema multiformeNumber of cases: 30 cases (0.1% of the total PM dataset,
compared to 0.06% in the previous report ing period), of which 23
are medically confirmed and 7 are non -medically confirmed;
Country of incidence: UK (10), US (7), Italy (6) and France (3),
and the remaining 4 cases were distributed among 4 other different
countries;
Subjects’ gender: female (18) , male (11) and unknown (1);
Subjects’ age group (n=28): Adult33(22), Elderly34(6);
Number of relevant events: 30 events, 25 serious, 5 non -serious
Reported relevant PTs: Erythema multiforme* (20) and
Chillblains* (10)
Relevant event onset latency (n=23): Range from 24 hours to 33
days, median 1 day;
Relevant event outcome: not resolved (13), resolved/resolving
(10), fatal (1) and unknown (6).
* Observed/Expected analysis wasperformed for Chillblains and
Erythema multiforme (see Appendix 5.1 ).
Conclusion: No safety signals have emerged based on thereview of
these cases ,or of the Observed versus Expected analysis. Surveillance
will continue .
Haematological AESIs
Search criteria:37Leukopenias
NEC (HLT) OR Neutropenias Number of cases: 955(3.2% of the total PM dataset ,compared to
2.6 % in the previous reporting period ), of which 474 medically
confirmed and 481 non -medically confirmed;
36Multiple episodes of the same PT event w ere reported w ith a different clinical outcome within some
cases hence the sum of the events outcome exceeds the total number of PT events .
37To increase clinical relevance of the review, additional PTs included in the HLT/HLGT All Path w ere
reviewed for Haematological, Immune -Mediated, Other, Respiratory and Thromboembolic AESIs categories
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Total Number of Cases in the Reporting Period (N= 29750)
(HLT) OR PTs Immune
thrombocytopenia ,
Thrombocytopenia OR SMQ
Haemorrhage terms (excl
laboratory termsCountry of incidence: UK (309), US (192), France (84), Italy (51),
Netherlands (45), Germany (33), Spain (29), Mexico (26), Canada
and Portugal (16 each), Austria (15), Israel and Sw eden (14 each),
Czech Republic (12), Belgium (11), Finland and Norw ay (10
each), Denmark and Japan (8 each), Poland (7), Hungary (6),
Croatia and Ireland (5 ea ch), Australia, Greece and Switzerland (4
each), Cyprus (3), Latvia, Luxemburg and Romania (2 each); the
remaining 8 cases were distributed among 8 other countries;
Subjects’ gender: female (662), male (268) and unknown (25);
Subject s’ age group (n =890): Adult33(548), Elderly34(337),
Adolescent38(3), Infant39and Neonate40(1 each );
Number of relevant events: 1119, of which 788 serious, 331
non-serious;
Most frequently reported relevant PTs ( ≥15 occurrences) include:
Epistaxis (125), Contusion (121), Vaccination site bruising (66),
Haem orrhage* (55), Haematochezia (41), Thrombocytopenia*
(38), Vaccination site haematoma and Vaginal haemorrhage (36
each), Cerebral haemorrhage (35), Petechiae (32), Haematoma,
Immune thro mbocytopenia*, Menorrhagia (31 each), Conjunctival
haemorrhage (24), Rectal haemorrhage (23), Eye haemorrhage
(20), Metrorrhagia (19), Haematuria and Vaccination site
haemorrhage (18 each), Haematemesis and Neutropenia (16 each),
Lymphopenia and Purpura (1 5 each);
Relevant event onset latency (n = 816): Range from 24 hours to
61days, m edian = 2 days;
Relevant event outcome:36fatal (81),resolved/resolving ( 444),
resolved with sequelae (1 4), not resolved ( 237)and unknown
(347).
As per EMA PRAC assessment report received on the third SMSR, a
cumulative overv iew of all cases reporting Thromboembolic events,
including those associated with thrombocytopenia, was conducted and
included in Appendix 3. 2.This signal was determined to not be a risk.
* Observed/Expected analysis w as performed for Haem orrhage,
Immune thrombocytopenia, T hrom bocy topenia and TTP (see
Appendix 5.1 ).
Conclusion: No signals for the hematological AESIs have emerged
based on a review of these cases , or of the Observed versus Expected
analysis. Surveillance will continue.
(so reporting proportion of events reported for these Categories may vary compared to the previous reporting
period ).
38Subjects w ith age ranged between 12 and less than 18 years .
39Subjects w ith age ranged between 1 (28 days) and 23 months .
40Subjects w ith age below 28 day s.
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Total Number of Cases in the Reporting Period (N= 29750)
Hepatic AESIs
Search criteria: Liver related
investigations, signs and
symptoms (SMQ) (Narrow and
Broad) OR PT Liver injuryNumber of cases: 69cases (0.2% of the total PM dataset , as in the
previous reporting period), of which 53medically confirmed and
16 non- medicall y confirmed ;
Country of incidence: UK ( 19), US ( 11), France (9), Germany ,
Poland and Spain (4each), Canada, Greece, Israel, Netherlands,
Sweden and Switzerland (2 each); the remaining 6 cases originated
from 6 different countries;
Subject s’ gender: female (52), male (16)and unknown (1) ;
Subject s’ age group (n= 64): Adult33(39), Elderly34(25);
Number of relevant events: 91, of which 60serious, 31
non-serious;
Most frequently reported relevant PTs ( ≥2 occurrences) : Alanine
aminotransferase increased (13),Aspartate aminotransferase
increased, Blood bilirubin increased and Hepatic enzyme increased
(7 each), Liver function test abnormal and Transaminases
increased ( 6 each ), Gamma -glutamyltransferase increased and
Liver function test increased (5 each ), Blood alkaline phosphatase
increased , Hepatic pain and Liver injury * (4each), Ascites,
Hepatic function abnormal and Hypertransami nasaemia (3 each)
and Congestive hepatopathy, Hepatomegaly, Hyperbilirubinaemia
andHypoalbuminaemia (2each);
Relevant event onset latency (n = 49): Range from 24 hours to 36
days, median 4 days;
Relevant event outcome: fatal ( 1), resolved/resolving ( 22), not
resolved ( 23) and unknown ( 45).
* Observed/Expected analysis w as performed for Liver injury (see
Appendi x 5.1 ).
Conclusion: Hepatic events arean ongoing safety topic under
evaluation (see Appendix 3 and Appendix 3.1 ). No other safety signals
have emerged based on a review of th esecases , or of the Observed
versus Expected analysis. Surveillance will continue .
Facial Paralysis
Search criteria: PT sFacial
paralysis, Facial paresis ,
Oculofacial paralysisNumber of cases: 48841(1.6% of the total PM dataset , com pared to
1.4% of previous reporting period ), of which 288medically
confirmed and 200non-medically confirmed;
Country of incidence: UK ( 140), US ( 90), Italy ( 48), Germany
(37), France ( 35), Mexico (18), Spain (1 7), Belgium (13), Sweden
(9), Israel (8), Czech Republic, Ireland and Poland (6 each),
Canada , Finland and Norw ay (5 each), Greece, Lithuania, Portugal
and Romania (4 each), Australia and Netherlands (3 each) ,
Austria, Croatia, Japan and Switzerland (2 each) ; the remaining 10
cases originated from 10different countries;
Subject s’ gender: female (321), male ( 146), unknown ( 21);
41Twenty-fiveadditional cases were excluded from the analysis as they were not cases of peripheral facial
nerve palsy (BC Category 5) because they described other disorders ( cerebrovascular accident or transient
ischaemic attack) .
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Total Number of Cases in the Reporting Period (N= 29750)
Subject s’ age group (n= 441): Adult33(329), Elderly34(112);
Number of relevant events:42488, of w hich 450serious, 38
non-serious ;
Reported relevant PTs: Facial paralysis * (402), Facial paresis *
(86);
Relevant event onset latency (n = 397): Range from <24 hours to
56days, median 2 days;
Relevant event outcome: fatal (1) , resolved/resolving (1 99),
resolved with sequelae ( 2), not resolved ( 190) and unknown ( 96);
Duration of events till resolution was reported in 50out of 98
occurrences with outcome of resolved ;it ranged from 20 minutes
to 57 days, with a median value of 34 hours .
* Please see Appendix 5.1 for Observed versus Expected analysis of
Facial paralysis /Facial paresis (Bell’s palsy) .
Interval c onclusion: No ne w significant safety information was
identified based on a review of these cases, or of the Observed versus
Expected analysis . Surveillance w ill continue.
Overall Conclusion: Taking all available information into
consideration, including the unblinded clinical study C4591001 data
(DLP 14 November 2020), the post- authori sation data and the
comparison of observed case reports to the expected number of events
(O/E analyses), the available information does not support a conclusion
of a causal association between Bell’s palsy and the vaccine. This topic
will continue to be monitored. Causality assessment will be further
evaluated following availability of additional data from the remaining
clinical study C4591001, w hich will be unblinded for final analysis
approximately mid -April 2021. Additionally, non -interventional post -
authoris ation safety studies, C4591011 andC4591012 are expected to
capture data on a sufficiently large vaccinated population to detect an
increased risk of Bell’s palsy in vaccinated individuals . The timeline
for conducting these analyses will be established based on the size of
the vaccinated population captured in the study data sources by the first
interim reports (due 30 June 2021) . Study C4591021, pending protocol
endorsement by E MA, is also intended to inform this risk.
Immune-Mediated/Autoimmune
AESIs37
Search criteria: Immune-
mediated/autoimmune disorders
(SMQ) (Broad and Narrow) OR
Autoimmune disorders HLGT OR
PTs Cytokine release syndrome;
Cytokine storm; HypersensitivityNumber of cases: 866(2.9% of the total PM dataset, compared to
3.0% of the previous reporting period), of w hich 493medically
confirmed and 373non-medically confirmed ;
Country of incidence: UK (264), US (149), Italy (76), France (63),
Germ any (47), Spain (37), Poland (22), Japan (19), Czech
Republic (18), Israel (17), Belgium and Sweden (16 each),
Netherlands (14), Greece, Mexico and Switzerland (11 each),
Finland (10); the remaining 65 cases were distributed among 22
other countries;
42If a case included both PT Facial paresis and PT Facial paralysis, only the PT Facial paralysis was
considered in the descriptions of the events as it is most clinically important.
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Total Number of Cases in the Reporting Period (N= 29750)
Subjects’ gender: female (626), male (211) and unknown (29).
Subject s’ age group (n =796): Adul t33(583), Elderly34(209)
Adolescent38(3), Infant39(1)
Number of relevant events: 908, of which 720 serious, 188
non‑serious.
Most freq uently reported relevant PTs ( ≥5 occurrences):
Hypersensitivity (355), Pericarditis* (49), Myocarditis* (44),
Derm atitis and Neuritis (19 each), Psoriasis (17), Diabetes mellitus
(16), Myositis and Raynaud’s phenomenon (15 each),
Autoimmune disorder, Colit is ulcerative, Pancreatitis and Uveitis
(14 each), Polymyalgia rheumatica *(13), Systemic lupus
erythematosus (12), Dermatitis bullous (10), Hyperthyroidism,
Pemphigoid and Psoriatic arthropathy (9 each), Crohn's disease,
Diabetic ketoacidosis, Myasthenia gravis *and Radiculitis brachial
(8 each), Colitis, Encephalitis* and Hepatitis (7 each),
Autoimmune thyroiditis *, Dermatomyositis, Interstitial lung
disease and Vascular purpura (6 each), Ankylosing spondylitis,
Coeliac disease, Hypothyroidism, Sarcoidosi s and Type 1 diabetes
mellitus *(5 each).
Relevant event onset latency (n = 632): Range from <24 hours to
79 days, median 1 day.
Relevant event outcome:36resolved/resolving (392), not resolved
(203), fatal (13), resolved w ith sequelae (24) and unknown (278).
* Please see Appendix 5.1for Observed/Expected analysis performed
for Autoimmune thyroiditis, Encephal itis, Myasthenia gravis, Myelitis,
Myocarditis , Pericarditis , Polymyalgia rheumatica, Type 1 diabetes
mellitus .
Conclusion: Myasthenia gravis cases were individually reviewed
following O/E analyses in the Feb and March 2021 SMSRs with the
upper limit of the 95% CI exceeding one for at least one of the risk
windows. This safety topic was determined not to be a validated signal
(see Appendix 3 ,Appendix 3.1 and Appendix 3.8 ). Surveillance will
continue.
Musculoskeletal AESIs
Search criteria: PTs Arthralgia;
Arthritis; Arthritis bacterial ;43
Chronic fatigue syndrome;
Polyarthritis; Post viral fatigue
syndrome; Rheumatoid arthritisNumber of cases: 2946(9.9% of the total PM dataset , com pared to
9.1% of the previous reporting period ), of w hich 1466medically
confirmed and 1480non-medically confirmed;
Country of incidence: UK ( 1200 ), Italy ( 368),US (334 ),Mexico
(216), France ( 108), Netherlands (106), Belgium (99), Czech
Republic ( 76), Portugal (68), Spain (41), Finland (31), Germany
(29), Austria (28), Poland (27), Denmark (24), Sweden (18),
Latvia and Romania (17 each), Slovakia (15), Greece (14), Ireland
(12), Japan (11), Luxembourg (10), Bulgaria (9 ), Israel and
Norw ay (8each), Canada (7), Hungary (6), Cy prus and Lithuania
(5each), Costa Rica, Croatia , Slovenia and Switzerland (4each)
43This PT not included in the AESIs/TME list w as included in the review as relevant for ACCESS
protocol criteria.
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and Colombia and Estonia (3 each ); the remaining 7cases
originated from 5 different countries ;
Subject s’ gender (n= 2862): female ( 2291 ), male ( 571);
Subject s’ age group (n= 2751): Adult33(2259 ), Elderly34(488),
Adolescent38(3) and Infant39(1);
Number of relevant events: 2988, of which 1474 serious, 1515
non-serious;44
Reported relevant PTs: Arthralgia ( 2843), Arthritis ( 55),
Rheumatoid arthritis * (50), Post viral fatigue syndrome* (19),
Chronic fatigue syndrome * (11), Polyarthritis * (9) and Arthritis
bacterial (1);
Relevant event onset latency (n = 2376 ): Range from <24 hours to
51days, median 1 day ;
Relevant event outcome:36fatal (5), resolved/resolving (1 582),
resolved with sequelae ( 41), not resolved ( 750) and unknown
(630).
* Observed/Expected analysis was performed for Rheumatoid arthritis,
Polyarthritis, Chronic fatigue syndrome, and Post viral fatigue
syndrome (see Appendix 5.1 ).
Conclusion: No new s afety signals have emerged based on a review of
these cases , orof the Observed versus Expected analysis . Surveillance
will continue.
Neurological AESIs (including
demyelination)
Search criteria: Convulsion s
(SMQ) (Broad and Narrow) OR
Demyelination (SMQ) (Broad and
Narrow) OR PTs Ataxia;
Cataplexy; Encephalopathy ;
Fibromyalgia; Intracranial
pressure increased; Meningitis;
Meningitis aseptic; Narcolepsy ;
Neuropathy peripheral;
Polyneuropathy45Number of cases: 621(2.1% of the total PM dataset, compared to
1.7% of the previous reporting period), of w hich 417medically
confirmed and 204non-medically confirmed.
Country of incidence: UK (1 84), US ( 91), Mexico (50), France
(48), Italy (40), Germany (33), Spain (23), Poland (18), Japan (16),
Netherlands (1 4), Belgium ( 11), Sw eden (10), Switzerland (9),
Czech Republic (8), Norw ay (7), Austr iaand Portugal (6 each) ,
Lithuania (5) , Denmark and Greece (4 each), Finland, Hungary,
Ireland, Israel, Malaysia, Romania and Slovenia (3 each),
Australia , Chile and Estonia (2 each ); the remaining 7cases
originated from 7different countries ;
Subject s’ gender (n=600): female ( 414), male (1 86);
Subject s’ age group (n= 576): Adul t33(386), Adolescent38(12),
Elderly34(178);
Number of relevant events: 697, of which 655serious, 42
non‑serious ;
44Multiple episodes of the same PT event w ere reported w ith a different seriousness within 1 case hence
the sum of the events seriousness exceeds the total number of PT events.
45As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002.2) received on the
third SMSR, Polyneuropathy was moved under Neurological AESIs (including demyelination) category;
Neuropathy peripheral was also m oved under the same category for consistency.
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Most frequently reported relevant PTs ( ≥5occurrences) included:
Seizure* ( 211), Epilepsy ( 69), Neuropathy peripheral *(62),
Generalised tonic -clonic seizure * (43), Febrile convulsion *(38),
Guillain -Barre syndrome *(29), Multiple sclerosis *(28), Petit mal
epilepsy (21), Status epilepticus (18), Fibromyalgia* (17),
Multiple sclerosis relapse* ( 16), Trigeminal neuralgia (14),
Myelitis transverse *and Partial seizures *(13 each), Optic
neuritis* (11), Ataxia (10), Polyneuropathy *(9), Meningitis
aseptic *(8), Tonic clonic movements (7) andDemyelination,
Meningitis *and Tonic convulsion * (5 each);
Relevant event onset latency (n =528 ): Range from <24 hours to 57
days, median 1 day ;
Relevant events outcom e:36fatal (1 2), resolved/resolving ( 365),
resolved with sequelae ( 24), not resolved ( 111) and unknown
(188);
A relevant medical history was reported in 207 out of 621 cases
with the m ostfrequently reported relevant medical history (> 2
occurrence s)terms coded to :Epilepsy ( 103), Seizure ( 38),
Multiple sclerosis (24), Fibromyalgia ( 15), Neuropathy peripheral
(11), Polyneuropathy and Partial seizures (8 each), Trigeminal
neuralgia ( 6), Petit mal epilepsy (5), Generalised tonic -clonic
seizure (4), Relapsing -remitting multiple sclerosis, Menin gitis,
Guillain -Barre syndrome and Temporal lobe epilepsy (3 each).
* Observed/Expected analysis was performed for Encephalopa thy,
Guillain -Barre syndrom e, Fibromyalgia, Meningitis , Multiple sclerosis,
Myelitis transverse, Narcolepsy, Optic neuritis , Polyneuropathy and
Seizure /Seizure disorders (see Appendix 5.1 ).
Conclusion: Transverse myelitis, Peripheral neuropathy and Meningitis
cases were individually reviewed following O/E analyses in the Feb
2021 SMSR w ith the upper limit of the 95% CI exceedi ng one for at
least one of the risk windows. These safety topics were determined not
to be validated signals (see Appendix 3 and Appendix 3.1 ) and the
current O/E analyses for these events raise no new issues .Additionally,
polyneuropathy cases were reviewed following the March 2021 O/E
analysis with a ratio >1 for the interval risk windows; based on case
review, it was determined to be a non -validated signal. Surveillance
will continue for all of these events.
Other AESIs
Search criteria:37Herpes viral
infections (HLT) OR PTs Adverse
event following immunisation;
Inflammation; Manufacturing
laboratory analytical testing issue;
Manufacturing materials issue;
Manufacturing production issue;
MERS-CoV test; MERS-CoV test
negative; MERS-CoV test positive;
Middle East respiratory
syndrome; Multiple organ Number of cases: 6174 (20. 8% of the total PM dataset, compared
to 19.5% of the previous reporting period), of which 3720 were
medically confirmed and 2454 non -medically confirmed;
Country of incidence :UK (1907), Italy (977), US (740), France
(371), Mexico (239), Belgium (206), Spain (185), Portugal (171),
Germ any (164), Netherlands (137), Czech Republic (128), Sweden
(98), Finland (86), Poland (77), Denmark (74), Japan (71), Austria
(70), Greece (63), Ireland (48), Romania (39), Hungary (35), Israel
(34), Latvia (32), Norw ay (30), Slovakia (24), Sw itzerland (22),
Croatia (21); the remaining 125 cases w ere distributed among 24
other countries;
Subjects’ gender: female (4575), male (1372), unknown (227);
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dysfunction syndrome;
Occupational exposure to
communicable disease; Patient
isolation; Product availability
issue;Product distribution issue;
Product supply issue; Pyrexia;
Quarantine; SARS-CoV-1 test;
SARS-CoV-1 test negative; SARS-
CoV-1 test positiveSubject s’ age group (n =5733 ): Adult33(4672 ), Elderly34(1043),
Adolescent38(14), Infan t39(4);
Number of relevant events: 629 0, of which 2852 serious, 3441
non‑serious;44
Most frequently reported relevant PTs ( ≥5 occurrences) included:
Pyrexia (5507), Herpes zoster* (456), Inflammation (154), Oral
herpes (69), O phthalmic herpes zoster* (17), Herpes simplex (16),
Multiple organ dysfunction syndrome* (13), Herpes ophthalmic
(12), Herpes virus infection (11), Herpes Zoster oticus *and
Herpes zoster reactivation* (5 each);
Relevant event onset latency (n = 5282): Ran ge from <24 hours to
81 days, median 1 day;
Relevant events outcome:36fatal ( 70), resolved/resolving ( 4071 ),
resolved with sequelae (5 9), not resolved ( 998) and unknown
(1136 ).
* Amo ng multiple different events grouped under this Other AESIs
category, Observed/Expected analysis was performed on specific PTs
relevant for Herpes zoster disorders andMultiple organ dysfunction
syndrome (see Append ix 5.1 ).
Conclusion: Herpes Zoster is an ongoing signal under evaluation (see
Appendix 3 and Appendix 3.1 ). No other safety signals have emerged
based on a review of these cases , or of the Observed versus Expected
analysis .Surveillance will continue .
Pregnancy Related AESIs
Search criteria: PTs Amniotic
cavity infection; Caesarean
section;Congenital anomaly;
Death neonatal; Eclampsia;
Foetal distress syndrome; Low
birth weight baby; Maternal
exposure during pregnancy;
Placenta praevia; Pre-eclampsia;
Premature labour; Stillbirth;
Uterine rupture; Vasa praeviaFor relevant cases ,please refer to the subsection Use in Pregnancy and
While Breast Feeding inTable 14.
Renal AESIs
Search criteria: PTs Acute kidney
injury;Renal failure.Number of cases: 69cases (0. 2% of the total PM dataset, as in the
previous reporting period), of which 57medically confirmed, 12
non-medically confirmed;
Country of incidence: UK (17), France (1 3), Germany and US (8
each), Denmark (5), Czech Republic, Spain and Switzerland (3
each), Netherlands ,Poland and Sw eden (2each) and Australia,
Belgium and Italy (1 each);
Subject s’ gender (n=68) : female ( 41), male ( 27);
Subject s’ age group (n= 66): Adult33(10), Elderly34(56);
Number of relevant events: 69, all serious;
Reported relevant PTs: Acute kidney injury * (40) and Renal
failure * (29 );
Relevant event onset latency (n = 42): Range from 24 hours to 35
days, median 4days;
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Relevant event outcome: fatal (17), resolved/ resolving ( 15),
resolved with sequelae (1), not resolved (11) and unknown ( 25).
* Observed/Expected analysis performed for Acute kidney injury and
Renal failure (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , or of the Observed versus Expected analysis performed .
Surveillance will continue .
Respiratory AESIs37
Search criteria: Lower respiratory
tract infections NEC (HLT) OR
Respiratory failures (excl
neonatal) (HLT) OR Viral lower
respiratory tract infections (HLT)
OR PTs: Acute respiratory
distresssyndrome; Endotracheal
intubation; Hypoxia; Pulmonary
haemorrhage; Respiratory
disorder; Severe acute respiratory
syndromeNumber of cases: 389 cases (1.3% of the total PM dataset
compared to 0.4% of the previous reporting period), of which 248
medically confirmed.
Count ryof incidence: UK (70), France (62), US (60), Belgium
(26), Italy, Netherlands (21 each), Germany (20), Spain (17),
Australia, Norway (10 each), Sweden (8), Austria, Finland,
Mexico, Poland (7 each), Denmark (6); t he remaining 30 cases
originated from 14 different countries.
Subjects’ gender (n=383): male (167).
Subject s’s age group (n= 357):Elderly34(222),Adul t33(135).
Number of relevant events: 404 serious events, 22 non -serious.
Reported relevant PTs: Pneumonia (160), Respiratory disorder
(63), Respiratory failure (53), Hypoxia (35), Cardio -respiratory
arrest, Low er respiratory tract infection (34 each), Bronchitis (26),
Acute respiratory distress syndrome (10), Pulmonary sepsis (3),
Atypical pneumonia, Pneumonia viral (2 each), Chronic
respirat ory failure, Lower respiratory tract infection viral,
Pulmonary haemorrhage, and Severe acute respiratory syndrome
(1 each).
Relevant event onset latency (n=289): range from < 24 hours to
62days.
Relevant events outcome: fatal (119), resolved/resolving (1 22), not
resolved (57), resolved w ith sequelae (7) and unknown (121).
Out of these 389 cases, 12 cases (8 fatal, 1 life -threatening, and
3hospitalisation) in which the PTs Respiratory failure (7), Acute
respiratory distress syndrome *, Bronchitis (2 each), Hypoxia,
Pneumonia, Respiratory disorder, and Severe acute respiratory
syndrome (1 each) w ere reported in a context of vaccine lack of
efficacy (PTs Drug ineffective or Vaccination failure), were also
reviewed among the potential relevant cases for the Ri sk ‘VAED
Including VAERD’ in Table 11.
* Observed/Expected analysis performed for Acute respiratory distress
syndrome (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , orof the Observed versus Expected analysis performed
Surveillance will continu e.
Thromboembolic Events
Search criteria:37Embolism and
thrombosis (HLGT) ,excluding
PTs reviewed as Stroke AESIs, OR Number of cases: 392(1.3% of the total PM dataset, compared to
0.5% of the previous reporting period), of w hich 219medically
confirmed and 173non-medically confirmed;
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PTs Deep vein thrombosis;
Disseminated intravascular
coagulation; Embolism; Embolism
venous;Pulmonary embolismCountry of incidence: UK ( 127), US (79), France ( 38), Germany
(25),Sweden (24), Italy (14), Austria and Netherlands (13 each),
Norw ay and Spain (10 each), Poland (6), Belgium (5), Ireland (4),
Canada, Denmark and Israel (3 each), Croatia, Czech Republic and
Finland ( 2 each) ; the remaining 9cases originated from 9different
countries;
Subjects’ gender (n=386): female ( 246), male ( 140);
Subject s’ age group (n= 371): Adult33(152), Adolescent38(1),
Elderly34(218);
Number of relevant events: 458, of w hich 451serious, 7
non-serious;
Most frequently reported relevant PTs ( 1occurrence) included:
Pulmonary embolism * (178), Thrombosis (109), Deep vein
thrombosis * (80), Pulmonary thrombosis (13), Embolism and
Thrombo phlebitis superficial (7 each ), Arterial thrombosis (6),
Retinal vein occlusion and Thrombo phlebitis (5 each), Retinal
artery occlusion and Venous thrombosis (4 each), Blue toe
syndrome and Venous thrombosis limb (3 each) and Coronary
artery thrombosis, Disseminated intravascular coagulation,
Embolism venous, Mesenteric ve in thrombosis, Pelvic venous
thrombosi s, Subclavian vein thrombosis and Thrombosis
mesenteric vessel (2 each) ;
Relevant event onset latency (n = 343): Range from <24 hours to
83days, m edian 7 days;
Relevant event outcome:36fatal ( 43), resolved/resolving ( 166),
resolved with sequelae ( 19), not resolved (119)and unknown
(115).
* Observed/Expected analysis performed for Deep vein thrombosis and
Pulmonary embolism (see Appendix 5.1 ).
As per EMA PRAC assessment report received on the third SMSR, a
cumulative overview of all cases reporting Thromboembolic events,
including those associated with thrombocytopenia, was conducted and
included in Appendix 3.2 . This signal was determined to no t be a risk.
Conclusion: Noother safety signals have emerged based on a review of
these cases and of the Observed versus Expected analysis performed .
Surveillance will continue .
Stroke
Search criteria: HLT Central
nervous system haemorrhages and
cerebrovascular accidents
(Primary Path) OR HLT
Cerebrovascular venous and sinus
thrombosis (Primary Path)Number of cases: 391(1.3% of the total PM dataset , com pared to
0.8% of the previous reporting period ), of w hich 230medically
confirmed and 161non-medically confirmed;
Country of incidence: UK ( 78), US (62 ), France ( 57), Germany
(41), Netherlands (29), Italy (17), Norw ay (15), Sweden ( 12),
Czech Republic (7), Austria, Belgium, Finland and Spain (6 each) ,
Israel, Japan and Sw itzerland (5 each), Australia, Denmark,
Greece and Hungary (4 each), Mexico, Poland and Portugal (3
each) and Romania (2) ;the remaining 7cases originated from 7
different countries;
Subject s’ gender (n= 380): female ( 226), male ( 154);
Subject s’ age group (n= 365): Adult33(84), Elderly34(281);
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Number of relevant events: 430,all serious ;
Most frequentl y reported relevant PTs ( 1 occurrence) included:
oPTs indicative of Ischaemic stroke: Cerebrovascular
accident *(207), Ischaemic stroke * (51),Cerebral
infarction * (33), Ischaemic cerebral infarction ( 12),
Cerebral thrombosis *(10), Cerebral ischaemia (7),
Cere bellarstroke ( 5), Cerebral venous sinus thrombosis *
and Embolic stroke ( 4 each) and Basilar artery
thrombosis *and Cerebral venous thrombosis (2 each) ;
oPTs indicative of Haemorrhagic stroke: Cerebral
haemorrhage * (35), Subarachnoid haemorrhage *(13),
Haem orrhagic stroke * (10), Cerebral haematoma * (6) ,
Ruptured cerebral aneurysm (4), Haemorrhage
intracranial *(3), Basal ganglia haemorrhage, Brain stem
haemorrhage *and Putamen haemorrhage (2 each) ;
Relevant event onset latency (n =323): Range from <24 hours to 52
days, median 3days;
Relevant event outcome: fatal (96), resolved/resolving ( 111),
resolved with sequelae ( 33), not resolved ( 73) and unknown ( 117).
* Observed/Expected analysis was performed for Ischemic strokes and
Hem orrhagic strokes (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , or of the Observed versus Expected analysis performed .
Surveillance will continue.
Vasculitic Events
Search criteria: Vasculitides HLTNumber of cases: 38cases (0.1% of the total PM dataset, as in the
previous reporting period ), of which 23medically confirmed and
15 non -medically confirmed ;
Country of incidence: UK(14), Germany (8 ), France ( 6), US (3),
Belgium and Italy (2 each) and Austria, Netherlands and Sweden
(1 each) ;
Subject s’ gender: female (2 3), male (15);
Subject s’ age group (n= 34): Adult33(14), Elderly34(20);
Number of relevant events: 39, of which 35serious, 4 non- serious ;
Reported relevant PTs: Vasculitis *(14),Giant cell arteritis *(6),
Hypersensitivity vasculitis ( 5),Peripheral ischaemia *and
Vasculitic rash *(3each), Henoch -Schonlein purpura (2) and Anti-
neutrophil cytoplasmic antibody positive vasculitis, Behcet's
syndrome *, Microscopic polyangiitis, Palpable purpura,
Pulmonary vasculitis and Renal vasculitis (1 each) ;
Relevant event onset latency (n = 2 7): Range from 24 hours to 21
days, median 2days;
Relevant event outcome: fatal (3), resolved/resolving (12), not
resolved ( 10) and unknown ( 14).
* Observed/Expected analysis was performed for Vasculitis and
Cutaneous vasculitis disorders (see Appendix 5.1 ).
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No new significant safety information was identified based on a review
of these cases, or of the Observed versus Expected analysis .
Surveillance will continue.
9.5.3.Evaluation of Special Situations
Table 13 below presents the evaluation of new information received during the current
reporting period from post -marketing data sources for BNT162b2 in relation to special
situations (Death, Lack of Ef ficacy and Vaccine Interactions).
Table 13.Evaluation of Special Situations for BNT162b2
Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 29750)
Death Overview
Number of fatal cases: 97346(3.3% of the total PM dataset ,compared to 3.4% of the
total PM cases received in the previous reporting period ) of which 750were
medically confirmed and 223 non-medically confirmed;
Country of incidence: the majority were from France (174), Germany (161),
Netherlands (110), UK (94), US (55), Israel (4 1), Sw eden (36), Spain (35), I taly
(34), and Austria (26) ; the remaining 207cases occurred in 28other countries ;
Subject Gender: females ( 492), males ( 453), unknown ( 28);
Subject s’ Age: 18 to 105 years (n = 910), mean = 81.7, median = 85;
Adults ( 87), Elderly ( 839), subject s with unknown age ( 47);
Causes of death most frequently reported ( >2%of total fatal cases ): Death (296),
COVID -19 (77), Dyspnoea (56), Pyrexia, Sudden death (55 each), Cardiac arrest
(54), Malaise, Pneumonia (42 each), Cardiac failure (40), General physical health
deterioration (39), Myocardial infarction (36), Drug ineffective (34), Cardio -
respiratory arrest (28), Cerebrovascular accident, Vomiting (27 each), Oxygen
saturation decreased (25), Fatigue (24), Cerebral haemorrhage (22), andRespiratory
failure ( 19).
PTs most frequently reported ( 2%events ): Death (2 97),Dyspnoea, Pyrexia (98
each), COVID -19 (9 6),Malaise (71), and Fatigue (6 2).
Concomitant medications were reported in 386out of 973cases and the most
frequently present ( >2%of total fatal cases ) are listed below:
furosemide (69), paracetamol (67), colecalciferol (57), acetylsalicylic acid (49),
omeprazole (42), pantoprazole (35), simvastatin (33), atorvastatin, levothyroxine
46During the current re porting interval, there were 4 additional cases reporting subjects’ death that were
excluded from further analysis in this subsection as the death w as mentioned as an incidental information only
in 4 cases, with none of the reported events presenting a fat al outcome. Another 6 cases were excluded as these
cases reported foetal death and are review ed in Table 14under Use in Pregnancy and While Breast Feeding .
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 29750)
sodium (32 each), amlodipine, apixaban (30 each), bisoprolol (29), riva roxaban (26),
allopurinol, oxazepam (25 each), metformin (24), spironolactone (23), bisoprolol
fumarate, calcium carbonate/colecalciferol, zopiclone (20 each), and ramipril (19).
Lot/Batch Number (#) information by Country wasavailable in 5 80cases w ith no
related quality issues identified during investigations of the impacted lot/batch
number s. The list of Lot /Batch #smostfrequently reported ( >2% of total fatal cases)
is presented hereinafter:
oLot # E J6788 in 53cases from France (4 8)andGermany ( 5).
oLot # EP9598 in 52cases from Netherlands (12), Spain (8), France, Italy (7
each), Poland (5), Norw ay (4), Germany, Portugal (3 each), Belgium (2),
and Slovenia (1).
oLot # EM0477 in 51cases from France (13), Germany, Netherlands (12
each), B elgium (7), Norw ay (3), Denmark (2), Spain, and Switzerland (1
each).
oLot/Batch # EK9788 in 42cases from France (15), Germany (9), Spain (7),
Netherlands (3), Denmark, Norw ay (2 each), Austria, Belgium, Czech
Republic, and Italy (1 each).
oLot # EJ6789 in 33 cases from France (15), Germany (7), Norw ay (5),
Netherlands (4), and Belgium (2).
oLot # EL1491 in 30cases from Austria (17), Germany (7), Finland (4),
Poland, and Romania (1 each).
oLot # EP2166 in 28cases from Italy (8), France (6), Sw eden ( 4), Norw ay
(2), Austria, Czech Republic, Lithuania, Netherlands, Poland, Portugal,
Slovenia, Spain, and Sw (1 each).
oLot # EJ6795 in 26cases from France (16), Netherlands (5), Finland,
Norw ay (2 each), and Sweden (1).
oLot # EP2163 in 22cases from Germ any (6), Spa in, Sw eden (4 each),
Australia (3), Austria, Japan (2 each), and France (1).
oLot # EJ6790 in 19 cases from Netherlands (7), Italy (4), Sweden (3),
Hungary (2), Austria, Czech Republic, and France (1 each).
Time to onset of fatal events was reported for 755subject s and ranged from the day
of vaccination to 59days after vaccination:
oSame day to 3 days after vaccination: 3 53cases
o4-7 days after vaccination: 154cases
o8-14 days after vaccination: 134cases
o15-59days after vaccination: 114cases
Number of vaccine doses administered at the time of the subject s’ death: in 426
cases the death occurred after the administration of the first dose, in 309cases the
fatal outcome was observed after the administration of the second dose w hereas in
the rema ining cases ( 238) it was not specified if the subject s received the first or the
second vaccine dose at the time of the fatal events.
Test for COVID- 19 w asreported for 257subject s as follows: in 107cases subject s
tested positive (64after 1st vaccine do se, 29after 2nd vaccine dose and in 14there
was no informatio navailable about the dose they received) , in 134were negative, 7
cases reported prior history of positive COVID -19 test, and in 9cases test results
were unknown .
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 29750)
Analysis
Most of the cases reporting a fatal outcome (7 5.2%) w ere in subjects over 75 years of
age. This reflects one of the priority groups targeted for vaccination by many regions and
countries, including Europe and the US , that is, elderly (with various lower age cut -offs
across countries), because of their higher risk of severe disease and mortality if infected
with SARS -CoV-2.11,12
Among the total of 973cases with a fatal outcome, when the medical history was
provided (in 738cases), the majority had multiple concomitant comorbidities. The most
frequently reported medical conditions included cardiac and vascular disorders (eg
Hypertension, Atrial fibrillation, Cardiac failure, Cerebrovascular accident, Myocardial
ischaemia ). Other frequently reported significant medical histories included
Dem entia/Dementia Alzheimer's type, Chronic kidney disease, Renal failure, Diabetes
mellitus /Type 2 diabetes mellitus, and Chronic obstructive pulmonary disease . Some of
the subject s (6.1%) who received the vaccine already had general physical deterioration,
were bedridden, w ere living in residential institutions, or on palliative care . No specific
pattern regarding underlying condition sor cause of death have been identified. Further
reports w ill continue to be closely monitored.
Please see Appendix 5.1 for Observed versus Expected analysis of Death.
Conclusion: No new risks were identified following review of the signal of death,
particularly in the comorbid elderly population.
Lack of Efficacy Company conventions for coding cases indicative of lack of efficacy :
The coding conventions for lack of efficacy in the context of administration of
the COVID- 19 vaccine was revised on 12 February 2021, as shown below: PT
“Vaccination failure” is coded when ALL of the following criteria are met:
oThe subject has received the appropriate series of tw o doses based on
the labeling.
oAt least 7 days have elapsed since the second dose of vaccine has been
administered.
oThe subject experiences SARS -CoV- 2 infection (confirmed laboratory
tests).
PT “Drug ineffective” is coded w hen either of the following applies:
oThe infection is not confirmed as SARS -CoV -2 through laboratory
tests (irrespective of the vaccination schedule). This includes scenarios
where LOE is stated or implied, e.g., “the vaccine did not work”, “I got
COVID -19”.
oIt is unknown:
Whether the subject has received the appropriate series of two
doses in correct timing based on the labeling instructions;
How many days have passed since the first do se (including
unspecified number of days like “ a few days”, “some days”,
etc.);
If 7 days have passed since the second dose of the vaccine
administration
oThe subject experiences a vaccine preventable illness 14 days after
receiving the first dose up to and through 6 days after receipt of the
second dose.
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Note: after the immune system has had sufficient time (14 days) to respond to the
vaccine, this is considered a potential lack of efficacy even if the vaccination course is
not complete.
This is the summa ry of the coding conventions for onset of vaccine preventable disease
versus the vaccination date:
1stdose (day 1 -13) From day 14 post 1stdose
to day 6 post 2nddoseDay 7 post 2nddose
Code only the events
describing the SARS -CoV -
2 infectionCode “Drug ineffective” Code “Vaccination failure”
Scenario Not considered
LOEScenario considered LOE
as “Drug ineffective”Scenario considered LOE as
“Vaccination failure”
Lack of efficacy cases
Number of cases47: 934 (3.1% of the total PM dataset, compared to 3.6% of the
previous reporting period) of which 546were medically confirmed and 388
non-medically confirmed .
Number of lack of efficacy events: 934 (PT: Drug ineffective [726]and Vaccination
failure [208]).
Country of incidence: US(332), U K(86), France (80), Portugal (73), Italy (69),
Germ any (63), Belgium (44), Canada (31), Romania, Spain (21 each), Poland (14),
Austria (12), Hungary (9), Czech Republic, Israel, Sweden (8 each), Greece, Malta,
Mexico, Netherlands (6 each) ; the remaining 31cases originated from 18different
countries.
COVID -19 infection was confirmed in 900cases andsuspected in 34cases .
Outcome was reported as resolved/resolving ( 163), resolved with sequelae (2), not
resolved ( 89), or unknown ( 622) at the time of the reporting ;there were 58 cases
where a fatal outcome was reported (see also Death section above in this table).
Drug ineffective cases ( 726)48
Drug ineffective seriousness: all serious ( 726)49
Lack of efficacy term was reported:
oafter the firstdose in 477cases
oafter the second dose in 163cases
47Thirty si x (36) additional cases retrieved in this dataset were excluded from the analysis ; upon review,
6cases cannot be considered true lack of efficacy cases because the subjects developed SARS -CoV -2 infection
during the early days from the first dose (days 1 –13); the vaccine has not had sufficient time to stimulate the
immune system and, consequently, the development of a vaccine preventable disease during this time is not
considered a potential lack of effect of the vaccine; 22 cases were identified as not t o report lack of efficacy,
these patients did not develop COVID -19 infection ; in 3 cases, the lack of efficacy PT did not refer to
BNT162b2 vaccine; 5 cases were invalidated in the safety database after DLP.
48There w ere 723 PTs Drug ineffective; in 4additional cases the LOE PT has been reco ded from
Vaccination failure (3) or Therapeutic product ineffective (1) toDrug ineffective after DLP ; in 1 additional case
that recorded both Drug ineffective and Vaccination failure, Drug ineffective was removed after DLP .
49Includes 3 cases where e vent seriousness captured as non -serious was upgraded to serious after DLP.
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oin 86cases it was unknown after w hich dose the lack of efficacy occurred
Latency of lack of efficacy term reported after the first dose was known for
191cases:
oday 14 to ≤ 30 days : 173 subjects
o≥ 31 days to ≤ 60days: 18 subjects
Latency of lack of efficacy term reported after the second dose w as known for
60cases:
obefore day 7: 47subject s
oday 7 to ≤ 30 days : 9subject s
o≥ 31days to ≤ 60 days : 4subject s
Latency of lack of efficacy term reported in cases where the number of doses
administered w as not provided, w as known in 40cases:
obefore day 7: 3subjects
oday 7 to ≤ 30 days: 32subjects
o≥ 31 days to ≤ 60 days: 5subjects
According to the RSI, individuals may not be fully protected until 7 days after their
second dose of vaccine, therefore for the above 726cases where lack of efficacy was
reported after the first dose or the second dose, the reported events may represent s igns
and symptoms of intercurrent or undiagnosed COVID -19 infection or infection in an
individual who was not fully vaccinated, rather than vaccine ineffectiveness.
Vaccination failure cases ( 208)
Vaccination failure seriousness: all serious50
Lack of efficacy term was reported in all cases after the second dose
Latency of lack of efficacy term was known for all cases:
oday 7 to ≤ 30 days: 160subjects
o≥ 31 days to ≤ 60 days: 46subjects
o61 days and65 days: 2 subjects
COVID -19 (156), Asymptomat ic COVID -19 (39), SARS -CoV -2 test positive (11),
COVID -19 pneumonia (7), and Suspected COVID -19 (1) were the reported vaccine
preventable infections in these 208cases.
South African variant (2 cases)
In 2of the 934cases ,South African variant COVID -19infection was reported . Both
the cases were received from thesame nursing home in France .
Latency: 3 days (PT Drug ineffective ) and 33 days (Vaccination failure) after dose 2.
COVID -19 infection ouctome: not resolved (1) and fatal (1) .
Conclusion: No new safety signals have emerged based on a review of these cases.
Vaccine
InteractionsNumber of cases: 17(0.06% of the total PM dataset , com pared to 0.0 3% of the
previous reporting period ) of which, 4cases were medically confirmed and 13cases
were non -medically confirmed.
Country of incidence: US ( 8),UK (6), Cyprus, Germany, and Norw ay (1 each).
Subject Gender: Female ( 9)andMale ( 8);
50Includes 1 case where e vent seriousness captured as non -serious was upgraded to serious after DLP.
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Subject s’ Age: 3 6to 86 years; (n= 14); mean= 64; median 63.5;
Relevant reported interaction PTs: Drug interaction ( 14), Potentiating drug
interaction (2), and Inhibitory drug interaction (1);
Relevant event seriousness: Serious ( 6) and Non -serious ( 11);
Relevant event outcome: Resolved /Resolving (4), Not resolved (1), and Unknown
(12);
Co-reported events c oded to the PTs (>1 event): Fatigue, Headache, International
norm alised ratio increased, Pyrexia (3 each), and Dizziness (2).
Reported Interacting Agents: warfarin (2), acetaminophen/aspirin/caffeine,
acetylsalicylic acid/oxycodone hydrochloride/oxycodone terephthalate, alprazolam,
budesonide/formoterol fumarate/glycopyrronium bromide, bupropion, denosumab,
fludricortisone, interferon beta -1b, lamotrigine, lithium, meclozine, methotrexate,
phenprocoumon, prednisone, quetiapine, tadalafil, unspecified antibi otic,
unspecified local anaesthetic (1 each).
Conclusion: There is no indication of a safety signal of interference of immune response
of vaccines noted based on a review of these cases.
a. P lease note that this corresponds to evidence from post -EUA/conditional marketing authorisation
approval data sources.
9.5.4.Evaluation of Missing Information
Table 14 below summari ses the evaluation of new information received during the current
reporting period from post -marketing data sources9in relation to the Missing information
associated with the use ofBNT162b2 .
Table 14.Evaluation of Missing Information for BNT162b2
Missing Inform ationPost-Marketing9CasesEvaluation
Total Number of Cases in the Reporting Period (N= 29750)
Use in Pregnancy and
While Breast
Feeding51Number of cases: 26352(0.9% of the total PM dataset, compared to 0.6% of the
previous reporting period) of which 138 w ere m edically confirmed and 125
were non -medically confirmed;
Country of incidence: UK (113), US (38), Canada (18), Italy (15), Spain (12),
Germ any (11), Irela nd, Portugal (8 each), France, Mexico (6 each), Israel (5),
Netherlands, Norw ay (3 each), Czech Republic, Serbia (2 each), Belgium,
Chile, Costa Rica, Denmark, Greece, Hungary, Latvia, Poland, Romania,
Singapore, Slovakia, Sweden, and United Arab Emirates (1 each).
Pregnancy cases: 178 cases including:
51Missing information as per both the EU -RMP Version 1.0, dated 21 December 2020 and the US PVP,
Version 0.3, dated 20 January 2021 .
52Eighteen cases were excluded from the analysis because pregnancy was not confirmed, or the case did
not involve breast feeding .
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Total Number of Cases in the Reporting Period (N= 29750)
168 mother cases and 10 foetus/baby cases representing 171 unique
pregnancies (2 cases [a mother case and a foetus/baby case] were created for 7
pregnancies) ;
Pregnancy outcomes for the 171 pregnancies were reported as spontaneous
abortion53(38), spontaneous abortion with intrauterine death (5), spontaneous
abortion w ith neonatal death (4), intrauterine death (3), premature birth,
premature birth of normal neonate (2 each), congenital anomaly, intrauterine
death, intrauterine/neonatal death (1 each), and no outcome was provided for
115 pregnancies ;
55 mother cases ( all non -serious54) reported exposure to vaccine in utero
without the occurrence of any clinical event. The exposure PTs coded to the
PTs Maternal exposure during pregnancy (38), Exposure during pregnancy (9),
Maternal exposure timing unspecified (5), Maternal exposure before pregnancy
(2), and Off label use (1). Trimester of exposure was reported in 12 of these
cases: 1sttrimester (10 cases), 2ndtrimester (2 cases) ;
113 mother cases, 15 non -serious and 98 serious, reported additional clinical
events, which occurred in the vaccinated mothers. Pregnancy related events
reported in these cases coded to the PTs Abortion spontaneous (45), Abortion,
Abort ion missed (4), Ectopic pregnancy, Preterm premature rupture of
membranes (2 each), Foetal grow th restriction, Gestational diabetes,
Oligohydramnios, Pregnancy, Premature delivery, Premature labour, and
Uterine contractions during pregnancy (1 each). Other clinical events which
occurred in more than 5 cases coded to the PTs Headache (22), Fatigue (17),
Vaccination site pain (12), Pain in extremity, Pyrexia (11 each), Chills (10),
Myalgia (8), Dizziness (7), and Pain (6). Trimester of exposure w as reported in
42 of these cases: 1sttrimester (33 cases), 2ndtrimester (5 cases), 3rdtrimester (4
cases) ;
10 serious foetus/baby cases reported the PTs Maternal exposure during
pregnancy (5), Foetal death, Foetal heart rate abnormal, Premature baby (3
each), Exposure during pregnancy, Foetal exposure during pregnancy (2 each),
Ductus arteriosus premature closure, Foetal cystic hygroma, Foetal movement
disorder, Neutropenia neonatal, Pulmonary arterial pressure abnormal,
Syndactyly, Tachycardia foetal, and Vent ricular hypertrophy (1 each).
Trim ester of exposure was reported for 4 cases: 1sttrimester (1 case), 2nd
trimester, 3rdtrimester (1 case each).
Breast feeding baby cases : 78, of which:
59 cases reported exposure to vaccine during breastfeeding (PT Expos ure
via breast milk) without the occurrence of any clinical events;
19 cases, 11 serious and 8 non -serious, reported clinical events that
occurred in the infant/child exposed to vaccine via breastfeeding (PT
Exposure via breast milk); these events coded to the PTs Pyrexia (4), Infant
irritability (3), Crying, Rash (2 each), Abnormal faeces, Angioedema,
53Birth type of spont aneous abortion w as added to 16 cases after the data -lock point.
54One case reporting exposure to vaccine in utero without the occurrence of any clinical event was
downgraded to non -serious after the data -lock point .
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Total Number of Cases in the Reporting Period (N= 29750)
Feeling hot, Flushing, Illness, Infantile vomiting, Limb mass,
Lymphadenopathy, Malaise, Nasopharyngitis, Pharyngeal leukoplakia,
Restlessness, Rhinorrhoea, Roseola, Skin exfoliation, Sleep disorder,
Somnolence, Throat tightness, Tonsillar hypertrophy, and Viral infection
(1 each).
Breast feeding mother cases : 7, of which
6 were serious and 1 w as non -serious ;
Of the 7 cases that reported clinical events in mo thers who were breast
feeding, 4 cases reported lactation issues that coded to the PTs Suppressed
lactation (2), Breast milk discolouration, Lactation disorder (1 each);
The other clinical events reported in these cases coded to the PTs Chills (2)
Allergy to vaccine, Anxiety, Axillary pain, Cold sweat, Eye inflammation,
Eyelid ptosis, Eye pain, Eye pruritus, Facial paralysis, Headache, Heart
rate abnormal, Lacrimation increased, Loss of consciousness, Myalgia,
Ocular discomfort, Pain, Peripheral coldness, P yrexia, Syncope,
Vaccination site pain, Vision blurred (1 each).
Conclusion: Whether the frequency of pregnancy outcomes, pregnancy related
events, and ne wborn events is consistent with expectation cannot be evaluated based
on the spontaneous reports. Thenumber of pregnant w omen who have received the
COVID -19 vaccine is unknown. Additionally, the COVID -19 vaccine is currently
not indicated for use in pregnancy, therefore most pregnant women exposed to the
vaccine are assumed to have been exposed early in pregnancy prior to know ledge of
the pregnancy. Most such pregnancies will not yet have completed as vaccine has
only been available since December 2020. The MAH is conducting study
C4591015 to study the safety of vaccine in pregnancy as well as within Pos t-
Authorization Safety studies. There w ere no safety signals that emerged from the
review of these cases of use in pregnancy and while breast feeding.
Use in
Immunocompromised
Patients55Number of cases: 1298 (4.4% of the total PM dataset, compared to 4.0% of the
previous reporting period) of which 506 w ere m edically confirmed and 792
non-medically confirmed;
Case Seriousness: Serious (1007), Non -Serious (291);
Country of incidence: UK (629), US (263), France (147), Italy (38), Czech
Republic (26), Germ any (25), Spain (21), Netherlands (16), Sweden (15),
Belgium and Switzerland (13 each), Denmark (12), Japan (10), Israel (8),
Austria and Greece (7 each), Ireland and Norw ay (5 each), Poland (4),
Australia, Finland, Malta and Mexico (3 each), Canada, Colom bia, Hungary,
Portugal, Romania and Slovakia (2 each); the remaining 10 cases originated
from 10 different countries;
Gender: females (919), males (355) and unknown (24);
Age (n = 1209) ranged from 16 to 105 years, mean = 59.8 years, median = 60
years;
Relevant subjects ’ medical histories most frequently reported ( ≥20 cases) coded
to the PTs: Immunodeficiency (361), Breast cancer (157), Thyroidectomy (71),
Neoplasm malignant and Chemotherapy (62 each), Radiotherapy (61),
55Missing information as per the EU -RMP Version 1.0, dated 21 December 2020 .
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Total Number of Cases in the Reporting Period (N= 29750)
Neoplasm (54), Hysterectomy (48), Pr ostate cancer (40), Splenectomy (31),
Breast cancer female (29), Renal transplant (28), Chronic lymphocytic
leukaemia and Lung neoplasm malignant (23 each), Lymphoma (22),
Mastectomy (21) and Thyroid cancer (20);
Of the 5848 events overall reported, the mo st frequent clinical events ( ≥60
occurrences) coded to the PTs: Headache (309), Fatigue (272), Pyrexia (186),
Pain in extremity (158), Nausea (154), Arth ralgia (146), Myalgia (139), Chills
(132), Malaise (124), Vaccination site pain (117), Dizziness (103 ), Pain (101),
Asthenia (95), Lymphadenopathy (83), Dyspnoea (82) and Diarrhoea (76);
Case outcome: fatal (71, see Table 13, Death ), resolved/resolving (568),
resolved with sequelae (33), not resolved (509) and unknown (117).
Conclusion: The most frequently reported clinical events observed in
immunocompromised subjects w ere consistent with those observed in the overall
population. The reporting proportion of cases with fatal outcome (5.5%), unresolved
cases (39.2%) and cases r esolved with sequelae (2.5%) in immunocompromised
subjects is slightly higher compared to the reporting proportion observed in the
overall population ( 3.3% for fatal outcome, 28.2% for outcome of not resolved,
1.5% for outcome of resolved with sequelae) , but this is expected considering that
underlying comorbidities are likely to be contributory to delayed events recovery or
to subjects ’death .
No safety signals have emerged that w ould be considered specific to this population.
Use in Patients With
Autoimmune or
Inflammatory
Disorders55Number of cases: 2036 (6.8% of the total PM dataset, compared to 6.3% of the
previous reporting period) of which 891 w ere medically confirmed and 1145
non-medically confirmed;
Case Seriousness: Serious (1422), Non -Serious (614);
Country of incidence: UK (857), US (450), France (165), Italy (131), Germany
(44), Czech Republic and Spain (40 each), Belgium (29), Japan (28), Au stria
(25), Portugal (22), Denmark (21), Sw eden (19), Netherlands (18), Canada (16),
Finland and Greece (14 each), Ireland and Norw ay (12 each), Romania (10),
Israel and Mexico (9 each), Hungary (8), Croatia and Poland (6 each),
Switzerland (5), Bulgaria a nd Latvia (4 each), Slovakia (3), Malta and New
Zealand (2 each); the remaining 11 cases originated from 11 different countries;
Gender: Females (1681), Males (325) and Unknown (30);
Age (n=1928) ranged from 16 to 97 years, mean = 53.4 years,
median=53 years;
Relevant subjects’ medical histories most frequently reported ( ≥40cases) coded
to the PTs: Hypothyroidism (375), Rheumatoid arthritis (244), Arthritis (152),
Autoimmune thyroiditis (148), Type 1 diabetes mellitus (116), Colitis
ulcerative (101), Mu ltiple sclerosis (93), Crohn’s disease (89), Thyroid disorder
(82), Psoriasis (81), Coeliac disease (75), Inflammatory bowel disease (67),
Psoriatic arthropathy (51), Diabetes mellitus (49), Systemic lupus
erythematosus (45), Autoimmune disorder (44) and Sjogren's syndrome (40);
Of the 9389 events overall reported, the most frequent ( ≥100 occurrences)
coded to the PTs: Headache (540), Fatigue (449), Pyrexia (348), Nausea (278),
Chills (248), Myalgia (247), Arthralgia (246), Pain in extremity (236),
Dizzines s (194), Pain and Vaccination site pain (185 each), Malaise (177),
Asthenia (137), Diarrhoea (120), Dyspnoea (108) and Lymphadenopathy (100);
Case outcome: fatal (31, see Table 13, Death ), resolved/resolving (1066),
resolved with sequelae (37), not resolved (735) and unknown (167).
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Conclusion: The most frequently reported clinical events observed in subjects w ith
autoimmune or inflammatory disorders w ere consistent with those observed in the
overall population. The reporting proportion of unresolved cases (36.1%) is slightly
higher compared to the reporting proportion observed in the overall population
(28.2%) w hile reporting proportion of cases resolved with sequelae (1 .8%) is similar
to that in the overall population (1.5%). Of note, the reporting proportion of cases
with fatal outcome in subjects with autoimmune or inflammatory conditions (1.5%)
is below the reporting proportion of cases with fatal outcome in the overa ll
population (3.3%).
No safety signals have emerged that w ould be considered specific to this population.
Use in Frail Patients
With Co -morbidities
(e.g. COPD,
Diabetes, Chronic
Neurological Disease,
Cardiovascular
Disorders, Active
tuberculosis)56Num ber of cases: 3258 (11.0% of the total PM dataset, compared to 10.7% of
the previous reporting period) of which 1839 w ere medically confirmed and
1419 non -medically confirmed;
Case Seriousness: Serious (2471), Non -Serious (787);
Country of incidence: UK (1096), US (572), France (436), Germany (115),
Italy (104), Japan (102), Sw eden (99), Spain (98), Netherlands (93), Denmark
(52), Finland (45), Czech Republic (44), Norw ay (42), Portugal (40), Belgium
(39), Israel (36), Switzerland (34), Austria (33), Mexi co (25), Ireland (23),
Hungary (19), Greece (15), Australia (13), Romania (12), Poland (11), Canada
(9), Slovenia (8), Croatia and Estonia (6 each), Luxembourg (5), Chile and
Costa Rica (3 each), Iceland, Latvia, Lithuania and Puerto Rico (2 each); the
remaining 12 cases originated from 12 different countries;
Gender: Females (2209), Males (1008) and Unknown (41);
Age (n=3111) ranged from 13 to 101 years, mean = 63.5 years,
median = 66 years;
Relevant subjects’ medical histories most frequently reported ( 30 cases) coded
to the PTs: Asthma (1240), Diabetes mellitus (562), Type 2 diabetes mellitus
(430), COPD (261), Cardiac failure (181), Dementia (169), Chronic kidney
disease (145), Dementia Alzheimer’s type (117), Parkinson’s disease (97),
Pulmonary emboli sm (91), Cognitive disorder (88), Renal failure (82) and
Bronchiectasis (36);
Of the 14055 events overall reported, the most frequent ( .130 occurrences)
coded to the PTs: Headache (647), Fatigue (622), Pyrexia (523), Nausea (393),
Chills (329), Dyspnoea a nd Pain in extremity (301 each), Malaise (281),
Myalgia (271), Vaccination site pain (255), Dizziness (250), Arthralgia (244),
Pain (241), Asthenia (197), Vomiting (183), Diarrhoea (157), Death (135) and
Pruritus (132); all these events w ere consistent wit h the most frequent events
observed in the overall population except for Death;
Case outcome: fatal (470, see Table 13, Death ), resolved/resolving (1483),
resolved with sequelae (71), not resolved (1008) and unknown (226).
Conclusion: The reporting proportion of not resolved cases (30.9%) and cases
resolved w ith sequelae (2.2%) in frail subjects is similar to the reporting proportion
56Missing information as per the EU -RMP Version 1.0, dated 21 December 2020; as per the South Africa
RMP, Version 1.0, dated 24 March 2021, active tuberculosis is included as an additional co -morbidity .
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Total Number of Cases in the Reporting Period (N= 29750)
observed in the overall population (2 8.2% for outcome of not resolved, 1.5% for
outcome of resolved with sequelae).
The reporting proportion of cases reporting fatal outcome (14 .4%) in frail subjects is
higher than the reporting proportion of cases reporting fatal outcome in the overall
population (3.3%). This is expected, considering that m ost of the cases reporting a
fatal outcome (82.3%) among the frail subjects involved subje cts over 75 years of
age who, due to their advanced age and underlying comorbidities, are more likely to
die than younger individuals. Underlying comorbidities are likely to be contributory
to their deaths.
No safety signals have emerged that w ould be c onsidered specific to this population.
Interaction With
Other Vaccines55There w ere no cases reporting an interaction with other vaccines during the reporting
interval (please refer to Table 13, Vaccine Interactions ).
Long -Term Safety
Data55Not applicable
Use in Paediatric
Individuals < 16
Years of Age57Number of cases: 1958(0.06% of the total PM dataset, compared to 0.1% of
the previous reporting period), of which 12 w ere m edically confirmed and
7 were non -medically confirmed, and indicative of administration in
paediatric subjects <16 years of age;
Country of incidence: UK (10), Iceland (4), US (2), Austria, Israel, Japan
(1 each);
Cases Seriousness: Serious (4), Non -Serious (15);
Gender: Females (11), Males (7), Unknown (1);
Age (n=10) ranged from 3 weeks to 15 years, mean = 8.3, median = 11;
Case outcome: resolved/resolving (7), not resolved (3), and unknown (9).
Of the 64 reported events,
oThe most frequently reported events (>1 case) w ere coded to the
PTs Off label use (11), Product administered to patient of
inappropriate age (9, see Section 7 Medication Errors ), Product
use issue (8), Pyrexia (4), Chills, Pain in extremity, Palpitations,
Product use in unapproved indication (2 each) ;
oThere w ere 17 unlisted events reported in 7 cases. These events
coded to the PTs Palpitations (2), Abdomina
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