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PF-07302048 (BNT162b2) Reporting Period
Summary Monthly Safety Report (SMSR) 2 01 January 2021 through 31 January 2021
CONFIDENTIAL
Page 1SUMMARY MONTHLY SAFETY REPORT 2
for
ACTIVE SUBSTANCE: PF-07302048 (BNT162b2)
ATC CODE: J07BX031
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 JANUARY 2021through 31 JANUARY 2021
DATE OF THIS REPORT: 12FEBRUARY 2021
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 Pfizerand BioNTech , their Affiliates, their Licensees , or Regulatory
Agencies is strictly 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 unauthorized purposes.
1Temporary ATC code.
2It corresponds to the earliest conditional approval date.
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Page 2EXECUTIVE SUMMARY
This is the 2ndSummary Monthly Safet y Report (SMSR) for PF-07302048 ( COVID -19
mRNA Vaccine , hereafter referred to as BNT162b2) , covering the reporting interval
01January 2021through 31 January 2021.
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 syringes
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 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 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 phosphate dihy drate, sucrose and water for injec tions
as excipients.
BNT162b2 is 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. The
vaccine elicits both neutralizing antibody and cellular 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 y ears of age and older. No dosage adjustment is
required in elderl y individuals ≥65 y ears of age. It is administered intramuscularl y,
preferabl y in the deltoid muscle of the upper arm, after dilution as a course of 2 doses (0.3
mL each) at least 21 day s apart.
It is estimated that approximately 66,416,610doses of BNT162b2 were shipped worldwide
from the receipt of the first temporary authori sation for emergency suppl yon
01December 2020 through 31 January 2021 and that approximately 42,122,535 doses of
BNT162b2 were shipped worldwide during the current reporting interval from
01January 2021through 31 January 2021.
BNT162b2 has received tem porary authori sation for emergency suppl y in25 countries and
conditional marketing authorisation approval in 34 c ountries globally .
The Core Data Sheet (CDS) , currently in development, will be designated as the unique
reference safet y information ( RSI)for all the countries, once it isfinalized and effective.
For the European Union and other countries that use it as reference, the RSI for this SMSR is
the BNT162b2 EU S ummary of Product C haracteristics ( EU SmPC) ,dated 28 January 2021,
in effect at the end of the reporting period . Previous version sof the combined EU SmPC,
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Page 3dated 21 December 2020 and 08 January 2021 , werein effect during the reporting period ,
and they were updated respectively on 08 January 2021 and 28 January 2021 without
safet y-related changes .
For the U nited States and other countries that use it as reference, the RSI for this SMSR is
the BNT162b2 combined E mergency Use Authorisation (EUA) Fact Sheet for the Healthcare
Professional ( HCP )andFullEUA Prescribing Information ( PI), dated 25 January 2021, in
effect at the end of the reporting period . Previous versions of the combined EUA Fact Sheet
for the HCP and Full EUA PI , dated 23 December 2020 and 05 January 2021, were also in
effect during the reporting period , and they were respectivel yupdated on 05 January 2021
without safety -related changes and on 25 January 2021 to add ‘anaph ylaxis’ as an adverse
reaction.
During the reporting period, the following safet y signals were addressed:
1.Hypersensitivity reactions ( other than anaphy laxis )**were evaluated and
Hypersensitivity (e.g. rash, pruritus, urticaria, angioedema) was added to labelling as
an adverse reaction ;*
2.Pain in extremity ** was evaluated and will be added to labelling as an adverse
reaction;
3.Diarrhoea was evaluated and will be added to labelling as an adverse reaction; *
4.Vomiting was evaluated and will be added to labelling as an adverse reaction; *
5.Injection site pruritus ** was evaluated and determined not to be a risk;
6.Insomnia **was evaluated and determined not to be a risk;
7.Deaths including in elderly or frail individuals was evaluated and determined not to
be a risk;
8.Immune thrombocy topenia was evaluated and determined not to be a risk;
9.Overdose was evaluated and it was determined that no update to the Overdose section
of labelling was warranted;
10.Eye pain and Ey e swelling were evaluated and determined not to be risks;*
11. Dizziness evaluation is ongoing;
12.Facial paral ysis evaluation is ongoing ;
13.Paraesthesia evaluation is ongoing.
The events added to labeling as adverse reactions are considered to be identified risks (not
important for the purpose of inclusion in the Risk Management Plans and Pharmacovigilance
Plans).
*After the data -lock point of this SMSR.
**These events were included in the EU SmPC as adverse reactions at the request of the
EMA at the time of conditional approval of the vaccine.
Based on the new safet y and efficacy /effectiveness data from the reporting interval for
BNT162b2 , the benefit- risk profile of BNT16 2b2 remains favorable.
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Page 4TABLE OF CONTENTS
EXECUTIVE SUMMARY ................................ ................................ ................................ .......2
LIST OF TABLES ................................ ................................ ................................ ..................... 5
LIST OF FIGURES ................................ ................................ ................................ ................... 6
APPENDI CES ................................ ................................ ................................ ........................... 7
LIST OF ABBREVIATION S................................ ................................ ................................ ....9
1. INTRODUCT ION ................................ ................................ ................................ ............... 11
2. WORLDWIDE APPROVA L OR AUTHORI SATION S TATUS ................................ ......12
3. ACTIONS TAKEN IN THE REPORTING INTERV AL FOR SAFETY REASON S ....... 12
4. CHANGES TO REFERENCE SAFETY INF ORMATI ON................................ ............... 12
5. ESTI MATED EXPOSUR E AND USE PATTERNS ................................ .......................... 13
5.1. Cumulative and I nterval Exposure Data ................................ ................................ .13
6. DATA IN SUMMARY T ABU LATIONS ................................ ................................ ........... 16
6.1. Reference Information ................................ ................................ ............................. 16
6.2 Cu mulative and I nterval Summary Tabulations from Post -Marketing Data
Sources ................................ ................................ ................................ ...................... 16
7. MEDI CATION ERRORS ................................ ................................ ................................ ....18
8. OVERALL SAFETY EVALUATION ................................ ................................ ................ 27
8.1. General Overview ................................ ................................ ................................ ...27
9. SI GNAL AND RISK EVALUATION ................................................................................41
9.1. L iterature Review ................................ ................................ ................................ ....41
9.2. Overview of Signals During the Reporting Interval ................................ ............... 41
9.3. Summary of Safet y Concerns ................................ ................................ .................. 42
9.4. Summary of Adverse Events of Special Interest (AESIs) ................................ .......42
9.5. Evaluation of Safet y Concerns ................................ ................................ ................ 43
9.5.1. Evaluation of Important Identified and Important Potential Risks ............. 43
9.5.2. Evaluation of AESIs ................................ ................................ ................... 49
9.5.3. Evaluation of Special Situations ................................ ................................ .57
9.5.4. Evaluation of Missing Information ................................ ............................. 61
10. OVERALL BENEFIT- RISK EVALUATION ................................ ................................ ..68
10.1. Benefits ................................ ................................ ................................ .................. 68
10.2. Risks ................................ ................................ ................................ ...................... 69
10.3. Overall Benefit- Risk ................................ ................................ ............................. 70
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Page 511. CONCL USION AND A CTIONS ................................ ................................ ...................... 70
LISTOF TABLES
Table 1. List of SMSRs ................................ ................................ ................................ .......11
Table 2. Cumulative Estimated Shipped Doses of BNT162b2 by Region Worldwide ......13
Table 3. Interval Estimated Shipped Doses of BNT162b2 by Region Worldwide ............ 14
Table 4. Inter val/Cumulative Estimated Shipped Doses of BNT162b2 by EU
Countries (30) ................................ ................................ ................................ .......15
Table 5. Medication Errors of Special Interest Associated with Harm .............................. 22
Table 6. Preparation Errors of Special Interest with No Harm................................ ........... 23
Table 7. Administration Errors of Special Interest with No Harm ................................ .....25
Table 8. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval ................................ ................................ ........................... 27
Table 9. Events Reported in more than ≥2%* Cases ................................ .......................... 34
Table 10. Overview of Signals ................................ ................................ ............................. 41
Table 11. Safety Concerns ................................ ................................ ................................ ....42
Table 12. Risks Evaluation for BNT162b2 ................................ ................................ .......... 43
Table 13. AESI s Evaluation for BNT162b2................................ ................................ ......... 49
Table 14. Evaluation of Special Situations for BNT162b2 ................................ .................. 57
Table 15. Evaluation of Missing Information for BNT162b2 ................................ .............. 61
Table 16. 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 ................................ .68
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Page 6LIST OF FIGURES
Figure 1. Case Outcome b y Presence of Relevant Comorbidities ................................ .......29
Figure 2. Case Outcome b y Presence of Relevant Comorbidities, Gender and Age
Group ................................ ................................ ................................ .................... 30
Figure 3. Fatal Case Outcome b y Presence of Relevant Comorbidities and Age
Group ................................ ................................ ................................ .................... 32
Figure 4. General Overview: Total Number of Events by MedDRA SOC and Event
Seriousness ................................ ................................ ................................ ........... 33
Figure 5. Events Reported in more than ≥2% Cases in the Interval Period b y Gender .......36
Figure 6. PT Repor ted in more than ≥2% in the I nterval Period - by SOC and Age
Group ................................ ................................ ................................ .................... 37
Figure 7. Events Reported in more than ≥2% in the Interval Per iod by Age Group
within Gender ................................ ................................ ................................ .......40
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Page 7APPENDICES
APPENDIX 1REFERENCE INFORMAT ION ( EU SMPC 28 JANUARY 2021) ................71
APPENDIX 1. 1 REFERENCE INFORMAT ION (EUA FACT SHEET FOR THE H CP AND
FULL EUA PI 25 JANUARY 2021)................................ ................................ ............. 104
APPENDIX 1. 2SAFETY REL ATED CHAN GES TO EUA FACT SHEET FOR T HE HCP
AND FULL EUA PI ................................ ................................ ................................ ......134
APPENDIX 2 INTERVAL NUMBER OF CASE REPOR TS [(SERIOUS AND NON -
SERI OUS , MEDICALLY CONFIRMED AND NON -MEDI CALLY CONFIRMED )
FROM POST-MARKETING DATA SOURCES, OVERALL, BY SEX, COUNTRY,
AGE GROUP SAND INSPECIAL POPULATIONS ] AND SUMMARY TABULA TION
BY PREFERRED TERM AND M EDDRA SYSTEM ORGAN C LASS ...................... 138
APPENDIX 2.1 CUMULATIVE NUMBER OF CASE REPOR TS [(SERIOUS AND NON-
SERI OUS , MEDICALLY CONFIRMED AND NON -MEDI CALLY CONFIRMED )
FROM POST-MARKETING DATA SOURCES, OVERALL, BY SEX, COUNTRY,
AGE GROUP SAND INSPECIAL POPULATIONS ] AND SUMMARY TABULA TION
BY PREFERRED TERM AN D MEDDRA SYSTEM ORGA N CLASS ........................ 176
APPENDIX 2.2 INTERVA L SUMMARY TABULATION OF CASE REPORTS WI THDME
EVENTS FROM POST- MARKETING DATA SOURCES ................................ ...........216
APPENDIX 2. 3CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF
SERI OUS AND NON -SERI OUS CASE REPORTS FROM POST- MARKETING DATA
SOURCES BY MEDI CAL LY CONFI RMED AND NON -MEDICALLY CONFIRMED,
REGION AND COUNTRY ................................ ................................ .............................218
APPENDIX 2. 4CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF FATAL
CASE REPORTS FROM POST -MARKETING DATA SOURCES BY COUNTRY
................................ ................................ ................................ ................................ ......... 224
APPENDIX 2 .5CUMULATIVE AND INTER VAL SUMMARY TABULATI ON OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PE R MEDDRA SYSTEM ORGAN CLASS BY
PREFERRED TERM ................................ ................................ ................................ ........ 225
APPENDIX 2. 5.1 CUMULATIVE AND IN TERVAL SUMMARY TABUL ATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PE R MEDDRA SYSTEM ORGAN CLASS BY
PREFERRED TERM PER COUNTRY ................................ ................................ ...........284
APPENDIX 2.5.2 CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PER AGE GROUP BY PREFERRED TERM PER
COUNTRY ................................ ................................ ................................ .......................645
APPENDIX 2.5.3 CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PER GENDER BY PREFERRED TERM PER
COUNTRY ................................ ................................ ................................ ...................... 1091
APPENDIX 2.5.4 CUMULATIVE AND INTERVAL SUMMARY TABULATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
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Page 8DATA SOURCES ORGANIZED PER PATIENTS WI TH RELEVA NT CO -
MORBIDIT IES BY PREFERRED TERM PER COUNTRY ................................ ......1427
APPENDIX 2. 6CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF
SERI OUS AND NON -SERI OUS AD VERSE REACTIONS FROM POST -MARKETING
DATA SOURCES ORGANIZED PE RMEDDRA SYSTEM ORGAN CLASS BY HIGH
LEVE L TERM ................................ ................................ ................................ ............... 1529
APPENDIX 2. 6.1 CUMULATIVE AND IN TERVAL SUMMARY TABUL ATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED P ER MEDDRA SYSTEM ORGAN CLASS BY HIGH
LEVE L TERM PER COUNTRY ................................ ................................ ................... 1557
APPENDI X 3 TABULAR SUMMARY OF S AFETY SI GNA LS................................ ......... 1841
APPENDIX 3 .1EVALUATION OF SIGNAL S................................ ................................ .....1849
APPENDIX 3. 2EVALUATION OF FACIAL PARAL YSIS ................................ ................1852
APPENDIX 3. 3 EVALUATION OF IMMUNE THROMBOCYTOP ENIA ......................... 1860
APPENDIX 3. 4CUMULATIVE REVIEW O F DIARRHOEA AND VOMI TING.............. 1873
APPENDIX 3. 5CUMULATIVE REVIEW O F EYE PAIN AND EYE SWELLING ........... 1879
APPENDIX 3. 6CUMULATIVE REVIEW OF PARAESTHESI A AND DYSAESTESI A
................................ ................................ ................................ ................................ .......1881
APPENDIX 4 CUMULATIVE APPROVAL/ AUTHORI SATION STATUS ....................... 1884
APPENDIX 5 LIST OF A DVERSE EVENTS OF SPECIAL IN TEREST ............................ 1888
APPENDIX 5.1 OBSERVE D VERSUS EXPECTED AN ALYSIS FOR ADVERSE E VENTS
OF SPECI AL INTEREST ................................ ................................ ..............................1897
APPENDIX 6 LITERATUR E REVI EWIN THE REPORTI NG PE RIOD(METHODOLOGY)
................................ ................................ ................................ ................................ .......1915
APPENDIX 6.1 LITERAT URE REVIEW IN THE REPORTI NG PER IOD (RETRIEVED
RESUL TS)................................ ................................ ................................ ........ NO DATA
APPENDIX 7 TR ACEABILITY TOOLS (STICKERS) ................................ ........................1916
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Page 9LIST OF ABBREVIATIONS
Acronym Term
AE adverse event
AESI adverse event of special interest
BMI body mass index
CDS core data sheet
CI confidence interval
COPD chronic obstructive pulmonary disease
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
EMA European Medicines Agency
EU European Union
EUA emergency use authori sation
EURD European Union Reference Date
HCP healthcare professional
HLGT (MedDRA ) High Group Level Term
HLT (MedDRA) High Level Term
IBD international birth date
ICH International Conference on Harmonisation
LNP lipid nanoparticle
MAH marketing authorisation holder
MedDRA medical dictionary for regulatory activities
mRNA messenger ribonucleic acid
NAAT nucleic acid amplification tests
PI prescribing information
PT (MedDRA ) Preferred Term
PVP pharmacovigilance plan
RMP risk management plan
ROW rest of world
RT-PCR Reverse Transcription -Polymerase Chain Reaction
RSI reference safet y information
TME targeted medically event
SAE serious adverse event
SAR S-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 ) System Organ Class
UK United Kingdom
US United States
VAED vaccine -associated enhanced disease
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Page 10Acronym Term
VAERD vaccine -associated enhanced respiratory disease
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Page 111.INTRODUCTION
This is the 2ndSMSR for PF-07302048 ( COVID -19 mRNA Vaccine , hereafter referred to as
BNT162b2), covering the reporting interval 01 January 2021through 31 January 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 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 6doses 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 sy ringe and needle combination should have a dead volume of no more than 35
microlitres. If standard sy ringes and needles are used, t here may not be sufficient volume to
extract a sixth dose from a single vial (see Section 4). Eachdose contains 30 micrograms of
BNT 162b2 (embedded in 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), cho lesterol, potassium chloride, potassium dihy drogen
phosphate, sodium chloride, disodium phosphate dihy drate, sucrose and water for injections
as excipients.
BNT162b2 is 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. The
vaccine elicits both neutralizing antibody and cellular 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 y ears of age and older. No dosage adjustment is
required in elderl y individuals ≥ 65 y ears of age. It is administered intramuscularl y,
preferabl y in the deltoid muscle of the upper arm, after dilution as a course of 2 doses (0.3
mL each) ; it is recommended to admi nister the second dose 3 weeks after the first dose.
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 will be
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 P eriod
1 01 December 2020 Through 31 December 2020
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Page 122.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 authori sedfor emergency use in 25
countries.
BNT162b2 received first regulatory conditional marketing authorisation approval in
Switzerland on 19 December 2020 and is currently conditionall y approved in 34countries.
Details of the current authori sation/ approva lstatus are presented in Appendix 4 .
3.ACTIONS TAKEN IN THE REPORTING INTERVAL FOR SAFETY REASONS
On 1 5January 2021, f ollowing fatal events involving elderly patients vaccinated with
BNT162b2 in Norway ,the Norwegian Agency updated their guidance for vaccination,
advis ingthat caution and case -by-case judgement should be used when vaccinating frail,
elderl y subjects.
There were no withdrawals for safety reasons during the reporting interval.
4.CHANGES TO REFERENCE SAFETY INFORMATION
The CDS, currentl y in development, will be designated as the RSI for all countries, once it is
finalized and effective.
For the EU and other countries that use it as reference, the RSI for this SMSR is the
BNT162b2 EU SmPC, dated 28 January 2021, in effect at the end of the reporting period
which is located in Appendix 1 . Previous versions of the EU SmPC, respectively dated 21
December 2020 and 08 January 2021 , were also in effect during the reporting period . The EU
SmPC dated 21 December 2020 was updated without safet y-related changes, to indicate that
the use of 6 doses/vial in place of 5 doses/vial was approved , on 08 January 2021. It was
specified that 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 syringe and needle combination should have
a dead volume of no more than 35 microlitres. If standard s yringes and needles are used,
there may not be sufficient volume to extract a sixth dose from a single vial . The EU SmPC
dated 08 January 2021 was updated without safet y-related changes made on 28 January 2021.
For the US and other countries that use it as reference, the RSI for this SMSR is the
BNT162b2 combined EUA Fact Sheet for th e HCP and Full EUA PI , dated 25 January 2021,
in effect at the end of the reporting period which is located in Appendix 1.1. Previous
versions of the combined EUA Fact Sheet for the HCP and Full EUA PI, respectively dated
23 December 2020 and 05 January 2021, were also in effect during the reporting period. The
combined E UA Fact Sheet for the HCP and Full EUA PI dated 23 December 2020 was
updated on 05 January 2021 without safety -related changes to indicate that the use of 6
doses/vial was approved, while the combined EUA Fact Sheet for the HCP and Full EUA PI
dated 05 January 2021 was updated on 25 January 2021 to add ‘anaph ylaxis’ as an adverse
reaction. The summary of the safet y-related changes made is presented in Appendix 1.2.
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Page 13After the data -lock point of this SMSR , on 04 February 2021 ,an update to include
Hypersensi tivity specific reactions (e.g. rash, pruritus, urticaria, angioedema) to the EUA
Fact Sheets and EUA PI was submitted to the FDA.
5. ESTIMATED EXPOSURE AND USE PATTERNS
5.1. Cumulative and Interval Exposure Data
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 patient exposure.
With these caveats in mind, it is estimated that approximately
66,416,610 doses of BNT162b2 were shipped worldwide from the receipt of the first
temporary authorisation for emergency suppl y on 01 December 2020 through 31
January 2021 and that
approximately 42,122,535 doses of BNT162b2 were shipped worldwide during the
current reporting interval from 01 January 2021 through 31 January 2021.
The estimated cumulative number of shipped doses of BNT162b2 by region3based on data
provided in the shipment tracker )4from the receipt of the first temporary
authorisation for emergenc y suppl y on 01 December 2020 through 31 January 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 Countries
Commonwealth of Independent Statesc
North Am ericab
US
Canada
Central and South America
Asia
Japan
Other Countries
3Currently there are no available data that allow to estimate exposure by gender andage group .
4The is the most accurate tracker of shipment used as data source for all the Regions and
Countries; US shipment data not available in the were taken from the
.
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(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Page 14Table 2.Cumulative Estimated Shipped Doses of BNT162b2 by Region Worldwide
Region/Country/Other % of Doses Total Number of Shipped
Doses
Oceania
Australia/New Zealand
Other Countries
Africa
Total 100.0% 66416610
a. I n this Region BNT162b2 w as conditionally approved;
b. I n this Region BNT162b2 received authorisation for emergency supply;
c.Includes: Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan , Kyrgyzstan, Moldova, Russia, Tajikistan,
Turkmenistan, Ukraine, Uzbekistan.
The estimated interval number of shipped doses of BNT162b2 b y region5based on data
provided in the shipment tracker )6from 01 January 2021 through 31 January
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 Countries
Commonwealth of Independent Statesc
North Am ericab
US
Canada
Central and South America
Asia
Japan
Other Countrie s
Oceania
Australia/New Zealand
Other Countries
Africa
Total 100.0% 42122535
5Currently there were no available data that allow to estimate exposure by gender andage group .
6The 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)
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Page 15Table 3.Interval Estimated Shipped Doses of BNT162b2 by Region Worldwide
Region/Country/Other % of Doses Total Number of Shipped
Doses
a. I n this Region BNT162b2 w as conditionally approved;
b. I n this Region BNT162b2 received authorisation for emergency supply;
c.Includes: Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan,
Turkmenistan, Ukraine, Uzbekistan.
Table 4 provides the estimated interval/cumulative number of shipped doses of BNT162b2
from the receipt of the first conditional marketing authorisation approval through 31 January
2021 for the 27 Eur opean Countries and for the 3 of the European Free Trade Association.
Table 4.Interval/Cumulative Estimated Shipped Doses of BNT162b2 by EU
Countries (30)
EU Country Total Number of Interval Shipped
DosesTotal Number of Cumulative Shipped
Doses
European Union
(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
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Page 16Table 4.Interval/Cumulative Estimated Shipped Doses of BNT162b2 by EU
Countries (30)
EU Country Total Number of Interval Shipped
DosesTotal Number of Cumulative Shipped
Doses
Norw ay
Total
6.DATA IN SUMMARY TABULATIONS
6.1.Reference Information
The MedDRA version 23.1 wasused to code adverse events /reactions in summary
tabulations.
6.2 Cumulative and Interval Summary Tabulations from Post -Marketing Data Sources
Appendix 2 and Appendix 2.1 respectively provide interval and cumulative number
of case reports (serious and non- serious, medically confirmed and non -medically
confirmed) received from post -marketing authorization data sources7, overall, by 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 i nclude all data up to 31 January 2021 while the interval data are
for the period from 01 January 2021 to 31 January 2021.
Appendix 2 .2provide san interval summary tabulation of case reports with DMEs
from post -marketing data sources .7
Appendices 2.3 and2.4are referred to data stratified by country . In these appendices,
spontaneous cases (including regulatory authorit y and literature cases) are presented
separately from non-interventional cases :
7This refers to post-EUA/conditional marketing authorisation approval data sources. Please note that in
the first SMSR, all cases received in the reporting period and uploaded in the safety database (as of date, 01
January 2021) w ere included, regardless of their position in the workflow process . Howe ver, for this and
subsequent monthly reports , only cases having a complete workflow cycle in the safety database (meaning that
they went to Distribution or Closed w orkflow status) have been included . This approach willprevent the
inclusion of cases initially received and not fully processed since cases in early steps of the w orkflow process
may still undergo changes and not accurately reflect final data . Each month, Pfizer applies a Late condition
process that retriev es cases received in the reporting per iod but not included due to lack of completeness ; this
ensures no cases will be missed for inclusion in monthly reports .
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Page 17oAppendix 2.3 provides a cumulative and interval summary tabulation of case s
organized as medicall y confirmed and non- medically confirmed (fatal, serious
and non- serious).
oAppendix 2 .4provide sa cumulative and interval summary tabulation of fatal
cases.
Appendix 2.5 and Appendix 2.68provide a cumulative and interval summary
tabulation of adverse reactions from post- marketing authorization data sources7
respectivel y by PTand by HLT organized according to SOC. Please refer to
Appendix 2.5.1 and Appendix 2.6.1 for data per country.
Adverse event stotals 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 spont aneous 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 includes all the reported events.
As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002)
received on the first SMSR :
Appendix 2.5.2,9Appendix 2. 5.3 and Appendix 2.5.410were added to include a
cumulative and interval summary tabulation of adverse events from
post-authorization data sources7by PT per country , stratified respectivel y for age,
gender and relevant co -morbidities.
Available relevant information with regard to the differences in vaccin ation
prioritization in EU countries,11US12, UK and ROW13was taken into account in the
evaluation of adverse events trends, clusters or signals .
8Due to a technical formatting issue, 1 blank page ( 5) appear sin this Appendix; the total data are how ever
correctly displayed.
9Due to a technical formatting issue, 7 blank pages ( 66, 100, 135, 306, 366, 408, 446 ) appear in this
Appendix; the total data are how ever correctly displayed.
10Due to a technical formatting issue, 1 blank page ( 102) appear sin this Appendix; the total dat a are
however correctly displayed.
11Overview of the implementation of COVID -19 vaccination strategies and vaccine deployment plans in
the EU/EEA . ECDC, February 2021.
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 Vaccines (Dec 01, 2020); JCVI updated interim
advice on priority groups for COVID -19 vaccination (Sept 25, 2020)
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Page 187.MEDICATION ERRORS
Cases potentially indicative of medication errors14that occurred in the reporting period are
summarized below.
Number of cases: 872 (6% of 14,52 5 cases, the total PM dataset ) of which 650 (74.5 %)
are medically confirmed , compared to 323 (8.9% in the first monthly report of which
87% medicall y confirmed). Out of the 872 cases, 3 3cases15were determined to be off
label use, reporting PTs including: Inappropriate schedule of product administration (28),
Incomplete course of vaccination (4), Incorrect route of product administration ( 3),
Product administratio n error and Wrong product administered (1 each); thus these are
excluded from discussion in this Section. Upon review , 316additional cases determined to
be non-contributory are not included in the discussion.
Number of relevant medication error cases : 836
Number of relevant even ts: 1067 .
Number of medication errors b y country :
There were 176 cases describing medication errors , which occurred in the EU /EEA
countries [ Sweden (39), German y (30), France (28), Romania (24), Ital y (16),
Norway (10), Spain (5), Poland and Denmark (4 each), Greece and Netherlands (3
each), Austria and Portugal (2 each) and Belgium, Estonia, Hungary , Lithuania,
Slovakia and Slovenia (1 each) ].
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 erro rs and issues; Product preparation errors and issues; Product selection errors and
issues; Product storage errors and issues in the product use system; Product transcribing errors and
communication issues , OR Preferred Terms: Accidental poisoning; Circumst ance 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 prescribing
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 unapproved indication; Vaccination error; Wrong device used; Wrong dosage form;
Wrong dosage fo rmulation; Wrong dose; Wrong drug; Wrong patient; Wrong product procured; Wrong product
stored; Wrong rate; Wrong route; Wrong schedule; Wrong strength; Wrong technique in device usage process;
Wrong technique in product usage process.
15In one case, the P T Product administration error w as determined to be off -label and w as excluded; the
second medication error PT ( Circumstance or information capable of leading to medication error ) included in
the same case, is evaluated as a medication error.
16One case was made i nvalid and in 2 cases the PTs Underdose and Incorrect dose administered,
respectively were removed.
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Page 19There were 660cases with medication errors from other countries [US (580 ), UK
(48), Canada (15), Israel ( 12), Andorra, Chile, Mexico ,United States minor outly ing
Islands and Qatar (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:
Sweden (2cluster sof 7 and 29 cases , respectivel y),
France (1cluster of 3 and 2 clusters of 5 cases),
Norway (1 cluster of 6 cases)
United Kingdom and Canada (2 clusters of 2 and 3cases ,respectivel y)
US (21 clusters, the largest one with 26cases ),
Romania - a dministration of the vaccine using syringes and needles for insulin
administration through incorrect route (subcutaneous) to 180 individuals was
described in a case.
Medication error PTs in the EU and ex -EU17
EU/EEA countries: There were 246 PTs indicative of medication errors Poor quality
product administered ( 49), Circumstance or information capable of leadin g to
medication error and Underdose (35 each),Product preparation issue ( 24), Incorrect
route of product administration (22), Wrong technique in product usage process ( 21),
Product preparation error ( 14), Inappropriate schedule of product administration,
Product temperature excursion issue and Product administered at inappropriate site (7
each), Accidental overdose and Incorrect dose administered (6 each), Product label
confusion and Medication error (3 each) , Product administ ration error (2), Drug
administered in wrong device, Exposure via skin contact, Intercepted medication
error, Intercepted product preparation error and Product administered to patient of
inappropriate age (1 each) .
In other countries ,a total of 821 medication errors were reported; th ose reported at
least thrice included :Inappropriate schedule of product administration (263), Poor
quality product administered (96), Underdose (77), Product preparation error (67),
Product preparation issue (61), Incorrect route of product administration (60),
17As per EMA assessment received on the first SMSR, the MAH was requested to should keep medication
errors under close scrutiny especially within the EU context and discuss whether the current product
information is sufficiently clear or whether there is room for improvement. The Rapporteurs should be notified
immediately in case of unexpected findings or trends.
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Page 20Circumstance or information capable of leading to medication error (40), Product
administered at inappropriate site and Wrong technique in product usage process (25
each) , Product temperature excursion issue (18), Product administered to patient of
inappropriate age (12), Incorrect dose administered (11), Accidental exposure to
product , Exposure via skin contact andProduct administration error (10 each) ,
Accidental overdose (9), Incomplete course of vaccination (7), Wrong product
administered (5) an d Contraindicated product administered (3).
Medication error by seriousness
Serious ( 13), out of these, 2 serious medication errors (PTs Product administered at
inappropriate site and Accidental overdose, 1 each) were reported in 1EU/EEA
countr y(German y).
Seriousness criteria18were life -threatening (1 event), hospitalization and disability or
permanent damage (3 events each) and important medical events (7 events); all
serious events, but 3, were medicall y confirmed.
Non-serious (1054 ).
Medication error outcome s:
Fatal (3),
Resolved/resolving ( 139, of which 29 serious ),
Not resolved ( 77, of which 23 serious ),
Unknown (612, of which 9 serious ).
Medication error sof special interest were:
a.The preparation and administration of undiluted vaccine (27 individuals, 31 events),
see Medication Error Harm Analy sis – Medication errors with no harm.
Country No. of Cases Medication Error Analysis (Number of Events)
Italy 1 With outharm –full undiluted vial (0.45 mL) (1, Administration)
US 4 Without harm – full undiluted vial (0.45 mL) (4, Preparation)
France 1 Without harm -undiluted dose (0.3mL) (1, Preparation)
Israel 2 Without harm -undiluted dose (0.3mL) (2, Preparation)
Qatar 1 Without harm -undiluted dose (0.3mL) (1, Preparation)
US 6 Without harm -undiluted dose (0.3mL) (7; Preparation 6, Administration 1)
UK 2 Without harm (volume unknown) (2, Preparation)
US 10 Without harm (volume unknown) (13; Preparation 9, Administration 4)
18One not medically confirmed ser ious case reported 2 different seriousness criteria.
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Page 21b.The administration of a “full diluted vial” (3individuals, 3 events ), see Medication
Error Harm Anal ysis –Medication errors associated with harm.
c.The administration of an erroneous third dose (1 individual) see Medication Error
Harm Anal ysis –Medication errors associated with harm.
The events above are further detailed in Table 5, Table 6and Table 7.
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 asse ssment of
medication errors” (EMA/762563/2014) were encountered:
Medication errors associated with harm [i.e., resu lting in adverse reaction (s)]were
reported in 15 cases (17 in the first SMSR) ;
Medication errors without harm [i.e. not resulting in adverse reaction (s)]19were
reported in 713 cases (in 288of them there were co -reported AEs) compared to 282
cases of which 59 included co-reported AEs in the firstSMSR ;
Intercepted medication errors were report ed in 2 cases , compared to no cases in the
firstSMSR ;
Potential medication errors were reported in 10 6cases , compared to 24 cases in the
firstSMSR .
Medication errors associated with harm (1 6medication errors in 1 5cases)
There were 6 cases from the EU/EEA area ( Germany ), and 9 from non-EU/EEA countries
[US (8) and the UK (1) ].
Medication error sof special interest (associated with harm )includ ing
the administration of a full diluted vial of vaccine (3 events) and
the administration of a n erroneous third dose of vaccine (1 event)
aredetailed in the table below.
19AEs may be co -reported in a case, but they are not considered as a result of the medication error.
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Page 22Table 5.Medication Errors of Special Interest Associated with Harm
Country/
Case
SeriousnessNumber of
Doses
AdministeredVolume of vaccine
administeredMedication Error
PTsAssociated Reaction(s)
Germany /
Serious1 2.25 mL
diluted vaccineAccidental overdose Pain in extremity, Headache,
Asthenia, Pain, Weight bearing
difficulty, Dizziness
Germany /
Non-serious1 2.25 mL
diluted vaccineAccidental overdose Body temperature increased,
Headache, Dizziness, Pain in
extremity, Fatigue, Local reaction
Germany /
Non-serious1 2.25 mL
diluted vaccineAccidental overdose Headache, Pain, Swelling, Asthenia,
Limb discomfort, Palpitations, Sense
of oppression, Dizziness
US / Serious 3 Unknown Incorrect dose
administeredSomnolence
Other medication error sassociated with harm
Medication error of unspecified overdose: this occurred in 1 individual in German y; the
associated non- serious reactions included Headache, Fatigue , Palpitations, Asthenia .
Medication error of vaccination atthe wrong anatomical site: This occurred in 8 cases (2
from German y and 6 from the US) , the vaccination was not administered in the deltoid ( PT
Product administered at inappropriate site) . Associated serious reactions (in 2 cases)
included: Pain (2), Mus culoskeletal d isorde r,Joint range of motion decreased,
Hypoaesthasia, Paraesthesia, Asthenia, Periarthritis (1 each) . Associated non -serious
reactions (in 6 cases) included: Vaccination sit e pain and Vaccination site vesicles (2 each),
Arthropath y,Constipation, Nerve compression , Vaccination site swelling (1 each).
In 2 UScases, the vaccine was not administered intramuscularl y; in the first one , serious, the
vaccine was also not administered in the deltoid (see above), in the second case, non -serious,
local vaccination site reactions (ery thema and pruritus) were reported.
In the last case from UK ,Anaph ylactic reaction (Section 9.5.1 ,Anaphylactic reaction ) and
Pulmonary oedema occurred ,on the same day of the vaccination, to an individual with
multiple allergies (PT Contraindicated product administered) .
Medication errors without harm19(941medication errors in 713 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
165cases from the EU/EEA area [Sweden (39), France (27), Germany (24), Romania
(23), Ital y (16) ,Norway (10), Spain (5), Denmark (4), Greece (3), Austria, Netherlands,
Poland and Portugal (2 each ), and Belgium, Estonia, Hungary , Lithuania, Slovakia,
Slovenia (1 each) ]and
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Page 23548from non- EU/EEA countries [ those with more than 1 medication error include d the
US (473), the UK ( 46), Canada (13) and Israel (11) ].
Vaccine preparation errors (259events ,all non- serious ): events mainly described errors in
storage conditions, during dilution before use.
oIncorrect t hawing procedure (34events) : 14 events described an inadvertent refreezing
of the vials after these were thawed ; a“slushy ” appear ance of the content of the vial
after diluent was added was reported in 5of them .There were 20 events describing the
vaccine was left at room temperature for a longer time than the one specified in the RSI ;
no events were reported upon v accine administ ration.
oIncorrect dilution ( 107events) :
Dilution was not performed (25 events); medication errors of special interest in the
dilution step includ ed:
dilution not performed and preparation of a 0.3 mL dose of undiluted vaccine (10
events) ,
dilution not performed and preparation of a 0.45 mL dose of undiluted vaccine (4
events) and
dilution not performed and preparation of a nunknown volume of undiluted vaccine
(11events) .
These events are detailed in the table below.
Table 6.Preparation Errors of Special Interest with No Harm
Country/
Case SeriousnessNumber
of CasesVolume of vaccine
administeredCo-Reported AEs (Relevant Medication Error
PTs)
France / Non -
serious1 0.3 mL undiluted vaccine Product preparation error, Overdose, Injection site
erythema
Israel / Non -serious 2 0.3 mL undiluted vaccine Product preparation error, Overdose
Qatar / Non -serious 1 0.3 mL undiluted vaccine Overdose, Product preparation error
US / Non -serious 1 0.3 mL undiluted vaccine Overdose, Product preparation error
US / Non -serious 3 0.3 mL undiluted vaccine Overdose, Product preparation issue
US / Non -serious 1 0.3 mL undiluted vaccine Product preparation error, Accidental overdose
US / Serious 1 0.3 mL undiluted vaccine Nausea,aFeeling abnormal, Pain, Pyrexia, Blood pressure
increased, Chest discomfort, Migraine, Peripheral
swelling, Vaccination site pain, Movement disorder,
Overdose , Product preparation error
US / Non -serious 4c0.45 mL undiluted vaccine Overdose ,Product preparation error
UK/ Non -serious 2b Unknown volume of
undiluted vaccineProduct preparation issue , Overdose
US / Non -serious 1 Unknown volume of
undiluted vaccineOverdose, Product preparation error
US / Non -serious 4 Unknown volume of
undiluted vaccineProduct preparation error, O verdose
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Page 24Table 6.Preparation Errors of Special Interest with No Harm
Country/
Case SeriousnessNumber
of CasesVolume of vaccine
administeredCo-Reported AEs (Relevant Medication Error
PTs)
US / Non -serious 3 Unknown volume of
undiluted vaccineProduct preparation error, Accidental overdose
US / Non -serious 1 Unknown volume of
undiluted vaccineProduct preparation error, Overdose, Pyrexia, Myalgia,
Headache, Pain in extremity
a.Only the PTs Nausea, Feeling abnormal and Pain, were reported as serious occurrences.
b.Cluster of 2 cases from the same reporter who suspected the vaccine might have been given undiluted, or
an incorrect amount of soluti on to dilute was used.
c.Cluster of 4 cases from the same reporter.
Other incorrect dilution errors
Dilution was performed either with a smaller volume of normal saline (10 events), or
with a larger volume of normal saline (19 events) than instructed anddilution with
improper volume was reported with a variable total number of available doses after
dilution from a single vial (16 events) . There were 37 events indicative of dilution
performed with sterile water rather than normal saline; no adverse events were reported
upon vaccine administration.
oVaccine appearance after dilution ( 57 events) :there were 29 cases , all from Sweden, in
which the color of the vaccine aft er dilution was transparent instead of off-white ; no
events were reported after thevaccine was administered .
oLack of vial inversion (31 events) : inversion of the vial after dilution was not performed
in accordance to instructions.
oOther preparation errors (30events).
Vaccine a dministration errors (679even ts, 7of which were serious) : events mainly described
errors in administration of vaccine dose not adequately prepared (see Preparation subset),
errors in the volume or dosage of the vaccine admini stered, error sin administering the
second dose in less than 21 day s or after more than 21 day s,and errors in route of
administration.
oIncorrect i nterval between doses(188events, all non- serious) : the second dose of the
vaccine was administered at less than 21 day s of interval (16 6events); interval between
the first and the second dose ranged between 1 day and 20 day s, with the majority of the
second doses administered between the 17thand the 20thday after the first dose (11 4
events) ; the second dose was administered after more than 21 day s (22 events) .
oAdministration after inadequate preparation (116events,all non-serious) : these events
referred to vaccine administered after inadequate preparation :dilution performed with
sterile wat er instead of normal saline (42 events) ; vaccine administered incorrect thawing
procedure (left at room temperature for a longer time than the one specified in the RSI ),
or thawed and inadvertently refrozen (40 events) ; inver sion after dilution not performed
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Page 25(27events );and other errors including reconstitution before vaccine was fully thawed (7
event s).
oErrors in the volume administered ( 116events,all non-serious) : partial doses were
administered due to leakage, s yringe orneedle malfunction (100 events); larger volume
of vaccine was administered (15 events) , and accidental overdose (1event ).
oErrors in the route of administration ( 79events, of which 2 serious20): the vaccine was
administered subcutaneously (65events)21; parenteral lywithout any further detail (11
events) ; and through other routes (3 events).
oVaccination site other than deltoid muscle ( 30events, of which 2 were serious22):the
vaccine was administered in the vaccinee’s arm but not in the deltoid muscle (24 events) ;
the administration site was in the leg or in the gluteus (5 events) and not specified (1
event).
oErrors in vaccine dosage (2 4events,all non-serious) :
Wrong dosage of vaccine was administered (6 events ); medication errors of special
interest in dosing the vaccine included :
administration of a 0.3 mL dose of undiluted vaccine (1 event),
administration of a 0.45 mL dose of undiluted vaccine ( 1 event) and
administration of an unknown volume of undiluted vaccine ( 4events) .
These events are detailed in the tabl e below.
Table 7. Administration Errors of Special Interest with No Harm
Country/
Case
SeriousnessNumber
of CasesVolume of vaccine
administeredCo-Reported AEs
(Relevant Medication Error PTs )
Italy /Non -serious 1 0.45 mL undiluted vaccine Hypotension, Pruritus, Anaphylactic shock,
Bradycardia, Incorrect dose administered
US / Non -serious 1 0.3 mL undiluted vaccine Product preparation error, Accidental overdose
US / Non -serious 1 Unknown volume of
undiluted vaccineProduct preparation error, Overdose, Vaccination site
reaction
US / Non -serious 3 Unknown volume of
undiluted vaccineProduct preparation error, Accidental overdose
20PT Incorrect route of product administration (2).
21One of these cases with a fatal case outcome is referenced in Death subsection in Table 14.
22PTs Wrong technique in product usage process and Product administered at inappropriate site (1 each).
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Page 26Other wrong dosage errors
Dilution performed with a larger volume of normal saline than recommended le adingto
lower concentration (15 events), 2 doses at the same date (3 events) .
oAccidental exposure to vaccine (22 events , of which 2 serious23): all but 2 (eye) involved
skin exposure.
oDose of vaccine not administered (21 events, all non-serious) : the second dose was not
administered (12 events); presence of air orempt y syringe (8events); or diluent was
administered (1 event).
oPaediatric Individuals <16 Years of Age (13 events, of which 1 serious24):the vaccine
was inadvertently administered to paediatric individuals below 16 y ears (Section 9.5.3
Table 15, Use in Paediatric Individuals <16 Years of Age ).25
oWrong vaccine administered (12events, all non- serious): the Moderna vaccine was
administered to individuals who received the first dose of BioNTech -Pfizer vaccine (8
even ts); it was unknown if the BioNTech- Pfizer or Moderna vaccine were administ ered
(3 events) and adose of BioNTech - Pfizer vaccin e was administered as first dose instead
of a dose of Moderna (1 event) .
oVaccination card errors (3events, all non-serious):there were 2 errors in the date
planned for the second dose (wrong date or not filled in) andin 1 case the card was not
given to the vaccinee.
oOther vaccine administration errors ( 55events, all non-serious) : the majority of the
events were indicative of administration of the vaccine using syringes and needles for
insulin administration or in order to avoid repeated puncture of the diluted viala needle
was left in the vial to which all thesyringes were subsequently attached (31events );
some doses were administered after collection of residual vaccine from different vials (5
events) ; the presence of “ an object ”or “1-2black object s” were noted in the vial after the
first dose of the vial was administered26and was notified through product complaint
reports (3 events for lot EJ6795 ), and expir ed vaccine (2 events) .
Scheduling (3 events ,all non-serious ): the second dose of the vaccine was notscheduled
according to the 21 day s interval (3 events) .
23One case reported Accidental exposure to product and Exposure via skin contact (1 each).
24PT Product administered to patient of inappropriate age (1). Co -reported AES included Rash pruritic,
Renal failure, Blood urine present, Pyrexia, Hyperhidrosis .
25Out of these 13 cases, 11 are cross -referenced in Section 9.5.4 ; for the remaining 2 cases, follow -up
information has been requested after data -lock point.
26Only o ne dose w as adm inistered (w ith no events) and the vaccine in the vial was discarded.
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Page 27Intercepted medication errors ( 2medication errors in 2 cases)
There were 2 cases from the EU/EEA area [France andRomania (1 each)] and none from
non-EU/EEA countries .
A vial,reconstituted with a larger volume of diluent ,was not used (1 ev ent); an insulin
needle w as removed from the sy ringe and another needle suitable for intramuscular injection
was used (1 event).
Potential medication errors (108 medication errors in 106 cases)
There were 3 cases from the EU/EEA area [Poland (2), and Netherlands (1)] and 103from
non-EU/EEA countries [ US (99), Canada (2) and 1 case each from the UK and Israel] .
Potential vaccine p reparation error (5events ,all non -serious) : events mainly described
product label confusion ( 5events).
Potential dosing interval error (103 events , all non -serious) : events mainly described
potential error s in the scheduling for the second dose not according to the 21 days
interval.
Some medication errors are expected to occur despite written instructions and educational
activities for HCPs ad ministering the vaccine. The number and seriousness of the reported
medication errors do not indicate aneed for additional mitigation activity .
8.OVERALL SAFETY EVALUATION
As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002) received
on the first SMSR, the MAH was requested to add a summary overview of the presented
adverse events which highlights the main (safety) findings from the case reports in the
section.
8.1.General Overview
A total of 14,525 adverse event reports (9193 medically confi rmed and 5332 non-medicall y
confirmed) containing 51,765 events fulfilled criteria for inclusion in this SMSR . Refer to
Appendix 2 for the summary tabulations of all cases received during the current reporting
period.
PRESENTATION OF CASE CHARACTERISTICS
Table8. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval
Characteristics Relevant cases ( N=14525)
Gender: Female 10011
Male 3093
No Data 1421
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Page 28Table8. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval
Characteristics Relevant cases ( N=14525)
Age range (years):
0.01-104years
Mean = 49.1 years
n= 1129417
18-30
31-50
51-64
65-74
75
Unknown70a
1764
4809
2552
686
1473
3171b
Case outcome: Resolved/Resolving 6134
Resolve d with sequelae 141
Not re solved at the time of report 3907
Fatal 410
Unknown 3933
Presence of relevant
comorbiditiesaYes 2535
No 11990
a.Including 13 cases for which a paediatric age w as initially reported but that they re -evaluated as not
consistent with this age upon review (see Table 15, Use in Paediatric Individuals <16 Years of Age );) and 33
breastfed babies for which paediatric age w as reported;
b.Including 37 breastfed 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) described as
Missing Information in Table 15.
Case outcome b y age group, gender and presence of relevant comorbidities is presented in
Figure 1, Figure 2and Figure 3.The fatal cases reported more comorbidities , but this is
expected considering that the ma jority of fatal outcome soccurred in patients 75 years and
older as shown in Figure 2(please also see Death inTable 14 and Frail patients with
co-morbidities e.g. COPD, diabetes, chronic neurological disease, cardiovascular disorders ,
described as Missing Information in Table 15).
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Page 29Figure1.Case Outcome by Presence of Relevant Comorbidities
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Page 30Figure2.Case Outcome by Presence of Relevant Comorbidities ,Genderand Age
Group
A. Case Outcom e by Presence of Relevant Com orbidities and Gender
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Page 31B. Outcom e by Presence of Relevant Com orbidities and Age Group
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Page 32Figure3.Fatal Case Outcome by Presence of Relevant Comorbidities and Age Group
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Page 33ADVERSE EVENT DATA
As shown in Figure 4, the MedDRA SOCs containing the greatest number of events (≥2%)
were General disorders and administration site conditions ( 18,136), Nervous sy stem
disorders ( 8114), Musculoskeletal and connective tissue disorders (5 896), Gastrointestinal
disorders ( 4389), Skin and subcutaneous tissue disorders (2 672),Respiratory, thoracic and
mediastinal disorders ( 2408 ),Injury , poisoning and procedural complications (2 125),
Infections and infestations
(1390) and Investigations ( 1173). 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 firsttemporary authorisation for emergency
supply on 01 December 2020.
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Page 34Table9.Events Reported in more than ≥2%*Cases
01 January 2021 Through
31 January 2021Cumulatively Through 31
January 2021
MedDRA SOC
MedDRA PTAEs (AERP%)
N = 14525AEs (AERP%)
N = 18061
Blood and lymphatic system disorders
Lymphadenopathya 711 (4.90%) 832 (4.61%)
General disorders and administration site conditions
Pyrexiaa 2773 (19.09%) 3281 (18.17%)
Fatiguea 2401 (16.53%) 2984 (16.52%)
Chillsa 2087 (14.37%) 2529 (14.00%)
Vaccination site paina 2018 (13.89%) 2532 (14.02%)
Paina 1454 (10.01%) 1797 (9.95%)
Drug ineffectiveb 1046 (7.20%) 1233 ( 6.83%)
Malaisea 924 (6.36%) 1141 (6.32%)
Astheniaa 597 (4.11%) 704 (3.90%)
Vaccination site erythemaa 364(2.51%) 448 (2.48%)
Vaccination site swellinga 350 (2.41%) 430 (2.38%)
Influenza like illnessa 344 (2.37%) 398 (2.20%)
Feeling abnormala 295 (2.03%) 376 (2.08%)
Gastrointestinal disorders
Nauseaa 1722 (11.86%) 2140 (11.85%)
Diarrhoea 574 (3.95%) 711 (3.94%)
Vom iting 509 (3.50%) 633 (3.50%)
Infections and infestations
COVID -19b 688 (4.74%) 789 (4.37%)
Injury, poisoning and procedural complications
Inappropriate schedule of product
administrationb297 (2.04%) 304 (1.68%)
Musculoskeletal and connective tissue disorders
Myalgiaa 1628 (11.21%) 1949 (10.79%)
Pain in extremitya 1472 (10.13%) 1817 (10.06%)
Arthralgiaa 1173 (8.08%) 1382 (7.65%)
Nervous system disorders
Headachea 3512 (24.18%) 4269 (23.64%)
Dizziness 1107 (7.62%) 1461 (8.09%)
Paraesthesia 445 (3.06%) 590 (3.27%)
Hypoaesthesia 332 (2.29%) 440 (2.44%)
Respiratory, thoracic and mediastinal disorders
Dyspnoeac 497 (3.42%) 612 (3.39%)
Coughc 350 (2.41%) 444 (2.46%)
Skin and subcutaneous tissue disorders
Rashd 471 (3.24%) 596 (3.30%)
Pruritusd 460 (3.17%) 607 (3.36%)
Urticariad 311(2.14%) 403 (2.23%)
Erythemad 296 (2.04%) 371(2.05%)
Total number of events 31208 38203
a.Listed or consistent with listed AEs in current RSIs ;
b.Listed per case processing conventions ;
c.Consistent with anaphylactic reactions listed in the current RSIs;
d.Consistent with hypersensitivity reactions listed in the current RSIs ;an update to include
Hypersensitivity specific reactions (e.g. rash, pruritus, urticaria, angioedema) to the EUA Fact Sheets and
EUA PI w assubm itted to the FDA after the data- lock point of this SMSR ;
* Reporting proportion (% of total cases) in the current reporting period.
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Page 35Most of the frequently reported events are listed or consistent with listed AEs as per the
current RSIs. Of note, the most frequentl y reported events Diarrhoea, Vomiting, Di zziness
and Paraes thesia , not listed as per the current RSIs, were signals under evaluation (see
Section 9.2).After the data -lock point of this SMSR, the signals Diarrhoea and Vomiting
were evaluated as adverse reactions that will be added to labelling and closed as identified
risks (not important). Dizziness and Paraesthesia are still under evaluation.
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 showe d in Figure 6and Figure 7. The largest number of events is reported overall in the
31-50 years age group and within this group, there were more female sthan males. This
difference may reflect the vaccination campaigns worldwide which mainl y prioritizes
healthcare professionals.11,12,13
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Page 36Figure5.Events Reported in more than≥2%Cases in the Interval Period by Gender
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Page 37Figure6.PTReported in more than ≥2% in the Interval Period - by SOCand Age
Group
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Page 38
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Page 39
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Page 40Figure7.Events Reported in more than ≥2% in the Interval Period by Age Group
within Gender
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Page 419.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 were no literature articles identify ing
new safety topics that would represent signals for BNT162b2 during the reporting interval.
9.2.Overview of Signals During the Reporting Interval
Signals addressed during the reporting interval are presented below in Table 10.
Table 10.Overview of Signals
Signal Status Category
Hypersensitivity reactions (other
than anaphylaxis)Closed Identified Risk (Not Important)
Insomnia Closed NoRiska
Injection site pruritus Closed NoRiska
Pain in extremity Closed Identified Risk (Not Important)
Facial paralysis Ongoing Under evaluation
Vom itingClosedb Identified Risk (Not Important)
Diarrh oeaClosedb Identified Risk (Not Important)
Overdose Closed No Risk
Paraesthesia and Dysaesthesia Ongoing Under evaluation
Dizziness Ongoing Under evaluation
Immune thrombocytopenia Closed No Risk
Eye pain and Eye swellingClosedb No risk
Deaths including in elderly or frail
individualsClosed No Risk
a.Insomnia and Injection site pruritus were included in the EU SmPC as adverse reaction s at the
request of the EMA at the time of conditional approval of the vaccine , how ever based on evaluation of
available clinical and post -authorization data, they were determined not to be risks for inclusio n in the
company CDS or, therefore, in the US EUA Fact Sheet for the HCP and Full EUA PI ;
b.After the data-lock of this SMSR.
Appendix 3 provides a summary of the safet y signals during the reporting interval. Please
refer to Appendix 3.1 for evaluation of signals during the reporting interval , toAppendix 3.2
for specific evaluation of Facial paral ysis and to Appendix 3.3 for specific evaluation of
Immune thrombocy topenia .
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Page 42As per EMA PRAC assessment report received on the first SMSR ,the following cumulative
overviews were performed on :
Case reports of Diarrhoea and Vomiting (Appendix 3. 4);
Case reports of Eye pain and Ey e swelling (Appendix 3. 5);
Case reports of Paraesthesia and Dysaesthesia (Appendix 3. 6).
9.3.Summary of Safety Concerns
Table 11 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 11.Safety Concerns
Important Identified Risk Anaphylaxisa,d
Important Potential Risk Vaccine- Associated Enhanced Disease (VAED), Including
Vaccine -Associated Enhanced Respiratory Disease (VAERD)b
Missing Information Use in Pregnancy and While Breast Feedingb
Use in Immunocompromised Patientsa
Use in Frail Patients With Co-M orbidities (e.g. COPD, Diabetes,
Chronic Neurological Disease, Cardiovascular disorders)a
Use in Patients With Autoimmune or Inflammatory Disordersa
Interaction With Other Vaccinesa
Long -Term Safety D ataa
Use in Paediatric Individuals <16 Years of Agec
Vaccine Effectivenessc
a.As per the EU RMP Version 1.0, dated 21 December 2020;
b.As per both the EU RMP Version 1.0, dated 21 December 2020 and the US PVP, Version 0.2, dated 05
December 2020;
c.As per the US PVP, Version 0.2, dated 05 December 2020 ;
d.The US PVP was updated during the reporting period w ith the finalization of the US PVP, Version 0.3,
dated 20 January 2021, to include Anaphylaxis as an Important identified risk.
9.4. 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 analysis for AESIs.
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 AESI 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.
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Page 43The 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 sources7for 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 andSection 9.5.4 .
9.5.1.Evaluation of Important Identified and Important Potential Risks
Table 12 below presents the e valuation of new information received during the interval
reporting period from post -marketing data sources7for the important identified and important
potential risks of BNT162b2.
Table 12.Risks Evaluation for BNT162b2
SafetyRisk Post-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
Important Identified Risk
Anaphylaxisf
Note: 2 database search strategies
were applied. First a broad and
narrow search of PTs in the
Anaphylactic reaction SMQ
(Narrow and Broad) , with the
algorithm applied, then a focused
search of narrow PTs in the
Anaphylactic SMQ with the
algorithm appliedSearch strategy #1
Number of cases from the Anaphyla ctic reaction SMQ (Broad
and Narrow ) search strategy , applying the MedDRA algorithm
based on all terms in the SMQ : 497(3.4%of the total PM
dataset ), of which 397were medically confirmed and 100 were
non-medically confirmed ;
Number of events: 1183;
Country of incidence: US (185), UK (159) , Germany (26), Ital y
(25), Denmark andIsrael (11each) , Greece (10) , Mexico (9),
Spain (8), Portugal and Sweden (6 each), Singapore (5), Canada ,
Czech Republic, Finland, France andRom ania (4 each) ,
Netherlands (3), Croatia and Switzerland (2 each) andAustria,
Belgium, Bulgaria, Chile, Hungary, Iceland, Malta, Norw ay and
Serbia (1 eac h);
Patients’ gender: female ( 400), male (63) and unknown ( 34);
Patients’ age (n = 450): ranged from 18 to 98 years ( mean = 49.3
years, median = 46 years);
Most frequently reported individual PTs ( ≥2%): Anaphylactic
reaction ( 162), Dyspnoea (123), Pruritus (72), Urticaria (64),
Cough and Rash (55 each), Erythema (45), Chest discomfort and
Swollen tongue (43 each), Throat tightness (42), Flushing (40),
Lip swelling (33), Hypotension (31), Anaphylactic shock and
Pharyngeal swelling (30 each), Circulat ory collapse (28),
Swelling face (27), Swelling (23), Wheezing (22), Angioedema
(20), Rash erythematous (16), Blood pressure decreased ( 13) and
Eye swelling (10);
Relevant event seriousness: serious ( 820), non- serious (363);
Relevant event outcome:efatal ( 28), resolved/resolving ( 700),
resolved with sequelae ( 18), not resolved ( 151), unknown ( 288).
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Page 44Table 12.Risks Evaluation for BNT162b2
SafetyRisk Post-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
Search strategy #2
Number ofcases retrieved using the Anaphylaxis SMQ (Narrow )
search strategy , applying the MedDRA algori thmbased on all
terms in the SMQ: 226cases (1.6%of the total PM dataset ), of
which 198 are medically confirmed and 28 non -medically
confirmed;
Patients’ gen der: female ( 182), male ( 27) and unknown ( 17);
Patients’ age (n = 196): ranged from 18 to 98 years (mean = 49.3
years, median = 46 years);
Patient’s age group (n = 198): Adultsg(168), Elderlyh(30), no
cases involving Paediat ric patients;
Events: 229 events, all serious, except 1 non -serious;
Relevant reported PTs :Anaphylactic reaction ( 162), Anaphylactic
shock ( 30), Circulatory collapse (28), Anaphylactoid reaction ( 7),
and Shock symptom and Ty pe I hypersensitivity (1 each) ;
Relevant event onset latency (n = 17 6): Most of the events (153)
occurred the same day of the vaccination, for the remaining 23
events for which a latency was reported ,it range dfrom 1to 24
days;
Relevant event outcome: fatal (5), resolved/resolving (154), not
resolved (16), resolved w ith sequelae (2) and unknown ( 52);
Of note in 143out of these 226cases, thepatients had a medical
history of allergies ; the most frequently reported relevant medica l
histories ( ≥20) included Drug hypersensitivity (174), Asthma
(161), Hypersensitivity (89), Season allergy (55), Anaphylactic
reaction (54), Respiratory distress (31), Contrast media allergy
(27), Iodine allergy (23) and Rhinitis allergic (20).
Anaphylaxis is anadverse reaction in Section 4.8 of the EU SmPC , in
the US combined EUA Fact Sheet for the HCP and Full EUA PI and it
was added to the CDS. It is also included as an Important identified
risk in the EU RMP and inthe US PVP.fBased upon review of the
available information, no additional change to the RSIs is warranted at
thistime.
After the data -lock point of this report, on 08 February 2021 , a
cumulative review of all cases reporting serious hypersensitivity
reactions suggestive of anaphylaxis using the Brighton Collaboration
criteria and inclusive of Observed versus Expected analysis was
submitted to EMA in a LEG proced ureas per EMA PRAC assessment
report (Product No. EMEA/H/C/005735/MEA/002) received on the
first SMSR .
Conclusion: Anaphylaxis is appropriately specified in the product
labeling. No ne w significant safety information was identified based
on a review of these cases. Surveillance will continue.
Important Potential R isk
Vaccine- Associated Enhanced
Disease (VAED) Including
Vaccine- Associated Enhanced
Respiratory Disease (VAERD)b,cAs noted by the Brighton Collaboration, there is currently no
uniformly accepted definition of VAED (or VAERD) and the w orking
group considers that a definitive case of VAED (Level 1 diagnostic
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Page 45Table 12.Risks Evaluation for BNT162b2
SafetyRisk Post-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
certainty) cannot be ascertained w ith current knowledge of the
mechanisms of pathogenesis of the condition.27
Given this, identifying an individual case as a case of VAED/VAERD
is currently not possible and, therefore, observed data is not available
at this time. An expected rate of VAED is also difficult to establish so
a meaningful observed/expected analysis cannot be conducted at this
point based on available data. The feasibility of conducting such an
analysis will 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 PTs 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 casesdbased on search strategy: 63(0.4% of the total
PM dataset , compared to 0.1% of the previous reporting period ),
all se rious (of which 45 medically confirmed );
Country of incidence: UK(33), US (16), Germany ( 9), Mexico
(2), Israel, Bulgaria and Denmark (1 each) ;
Gender: female ( 37), males ( 26);
Age: 21to 97 years (n = 60), mean = 57.5,
median = 58.5;
Respiratory system PTs: Dyspnoea ( 28), COVID -19 pneumonia
(8), Hypoxia , Respiratory failure, and Tachypnoea (2 each) ;
Gastrointestinal system PTs:Diarrhoea (18), Vomiting (9),
Abdominal pain (1);
Cardiovascular system PTs:Cardiac failure (3) , Acute myocardial
infarction and Myoca rditis (1each);
Other systems , relevant PTs :Multiple organ dysfunction
syndrome, Cerebrovascular accident, Deep vein thrombosis (1
each).
Case outcome: fatal (1 7), not resolved ( 28), resolved/resolving
(13), unknown at the time of the reporting (5).
COVID-19 positivity and severity of events
Suspected COVID -19 infection (test not performed or negative or
inconclusive) : 22.
COVID -19 positive test: 41.
Seriousness criteria for the 63 cases :
oMedically significant: 37 (of which 3 serious also for
disability a nd1 for life threatening) ;
oHospitalization required : 9(of which 3 serious also for
life threatening) ;
oDeath: 17.
27Flor M Munoz, et al. Vaccine -associated Enhanced Disease: Case Definition and Guidelines for Data
Collection, Analysis, and Presentation of Immunization Safety Data. Brighton Collaboration. September 2020,
Vaccine Journal Draft Manuscript.
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Seriousness criteria: m edically significant
In 18cases ,out of 37 reporting “medically significant” as
seriousness criteria, it was reported that the patients had a
COVID-19 positive test after vaccination , while 19patients had
unconfirmed suspected COVID -19. These 37 patients didnot
require hospitalization .
Among the 18 COVID -19 positive patients:
o11received the 1stvaccine dose. Latency to COVID 19
wasreported for 10/11 and ranged from 0 to 14 days.
o7patients did not indicate if they had taken the first or
second dose. Latency to COVID 19 w as reported for all
patients and ranged from 0 to 11 days .
One of these 18 cases refers toa60-year-old paramedic (medical
history not provided) w ho developed life- threatening COVID -19
on the same day of vaccination. He had fever, myalgia, cough
and shortness of breath, gradually worsened to hypoxia. He had
not recovered at the time of the reporting.
Seriousness criteria: hospitalization
Hospitalization occurred in 9 patients :
o27-year-old w oman with an anaphylactic reaction following
vaccine;
o81-year-old woman and a 90 -year-old manwith unconfirmed
COVID -19;
o21-year-old female, with a history of COVID -19 infection
prior to vaccination, was hospitalized for 1 day after having a
COVID -19 test the day following her vaccination;
oThe remaining patients had a positive test for COVID -19 with
a latency (n= 4) betw een 0 and 9days after vaccine
administration :
a43-year-oldwoman, with a history of hypertension, had
mild dyspnea and COVID- 19 related symptoms 1 day
after the 1stvaccine dose and was hospitalized 10 day s
later due to increased systolic blood pressure;
67-year-old manwith CABG x 4was admitted to the
hospital with fever and diarrh oea9 days after vaccination ;
Male patient of unspecified age w ith tachypnoea w as
hospitalized;
84-year-old manwho tested positive for COVID -19 1
week after vaccination and w as hospitalized 5 day s later
with pneumonia and acute myocardial infarctio n. At the
time of the reporting he was not recovered from COVID -
19and the outcome of the cardiac event was not
provided.
34-year-old manwho tested p ositive for COVID -19 the
day after his 2ndvaccination and developed myocarditis 3
days after the vaccination .He w as hospitalized for anST
segment elevat edmyocardial infarction andwas
improving at the time of the reporting .
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Seriousness criteria: death
Seventeen (17) patients died:
oAge: 65 to 97 years (n = 17), mean = 83.9,
median = 85.
oCountries of incidence : UK (8), Germany (7) , Denmark
andUS (1 each).
oGender : female (5), male (12) .
oMedical history was provided for11 patients :
Cardiac conditions: 6(54.5%) [atrial fibrillation (4),
hypertension (4), Cardiac failure (3), Coronary artery
disease (3) , Cardiovascular disorder (1), myocardial
infarction (1) ];
Other significant medical histories: 5 (45.5%) [diabetes
mellitus (2), COVID -19(2), chronic kidney disease, dem entia ,
duodenal ulcer, haemochro matosis, obesity (1 each)] .
Sixteen (16) patients had a COVID -19 positive test after
vaccination, while 1 patient had unconfirmed suspected
COVID -19.
Latency of COVID -19 occurrence was reported for 12of the 1 6
COVID -19 positive fatal cases and ranged from the dat eof the
vaccination to 15days after vaccination:
o0to 4days after dose 1 (5);
o15 days after dose 1 (1);
o10 days after dose 2 ( 1);
o1 to 7 days after vaccination (dose number not reported )
(5).
Cause of death was reported for all the 1 6 fatal COVID- 19
positive cases:
o3patients died from COVID -19 associated cardiac events
and/or respiratory events;
o10cases reported the following cause of death: COVID -
19,COVID -19 pneumonia (2each), Death , Cardiac
failure , , Hypoxia, Pneumonia aspiration , Respiratory
failure, Severe acute respiratory syndrome and Sudden
death (1each);and in 3 cases there were different causes
of death:
o87-year-oldmandied due to COVI D-19 and
cerebrovascular accident thatoccurred 3 days after the
vaccination; the patient’s medical history was not
provided;
o89-year-old m ale, with a medical history ofhypertension,
atrial fibrillation , heart failure, and bladder cancer , who
had a positive to COVID -19 1 day after vaccination ,was
admitted to the hospital the follow ing day with low
oxygen saturation (87%) ; he died on the same date due to
cardiac failure, chronic kidney disease, COVID -19
pneumonia, and tachya rrhythmia.
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o74-year-old m ale patient (medical history not provided) ,
developed COVID- 19 pneumonia (revealed by autopsy)
on the same day of vaccination , with pulmonary sepsis
and multi organ failure; he died 6 days later.
Because VAED may present as severe or unusual c linical
manifestations of COVID -19,cases resulting from the search strategy
are review ed for severity. Symptoms of COVID -19, not necessitating
hospitalization ,were reported for 3 7patients and 9 patients were
hospitalized however they did not present wi th signs that appeared to
be atypical COVID -19 or more severe COVID -19 than anticipated .
Conclusion: No new significant safety information was identified
based on a review of these cases. VAED/VAERD continues to be a
theoretical risk for the vaccine, rather than an identified safety
concern. Surveillance will continue.
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 0.2, dated 05
December 2020 ;
c.Search cri teria: Standard Decreased Therapeutic Response Search AND PTs Dyspnoea; Tachypnoea;
Hypoxia; COVID 19pneumonia; Respiratory Failure; Acute Respiratory Distress Syndrome;
Cardiac Failure; Cardiogenic shock; Acute myocardial infarction; Arrhythmia; Myocardi tis; 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; Menin gitis; Cerebrovascular accident; Thrombocytopenia;
Disseminated intravascular coagulation; Chillblains; Erythema multiforme; Multiple organ
dysfunction syndrome; Multisystem inflammatory syndrome in children ;
d.One additional case retrieved in the reporting period has been invalidated in the safety database after
data-lock point .
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.As per the EU RMP Version 1.0, dated 21 December 20 20; the US PVP w as updated during the
reporting period w ith the finalization of the US PVP, Version 0.3, dated 20 January 2021, to include
Anaphylaxis as an Important identified risk.
g.Patients with age ranged between 18 and 64 years;
h.Patients with age equal to or above 65 years.
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Page 499.5.2.Evaluation of AESIs
Table 13 below presents the evaluation of new information received during the interval
reporting period from post -marketing data sources7with regard to the AESIs forBNT162b2 .
Where applicable, o bserved versus expected anal ysis is provided in Appendix 5.1.
Table 13.AESIsEvaluation for BNT162b2
AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
Anaphylactic Reactions
Search criteria: Anaphylactic
reaction SMQ (Narrow and
Broad, with the algorithm applied,please refer to the Risk ‘Anaphylaxis ’ inTable 12.
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: 344(2.4 %of the total PM dataset , as in the
previous reporting period ), of which 274are medically confirmed
and 70non-medically confirmed;
Country of incidence: UK (102),US (101), Germany (34), Italy
(30), Mexico (11) , Greece (10), Israel (9), France (6), Canada,
Portugal and Romania (5 each), Denmark, Iceland, Poland and
Sweden (3 each) andNorw ay and Spain (2 each) ; the remaining 10
cases were distributed among 10other countries ;
Patients’ gender: female (254), male ( 72) and unknown ( 18);
Patients’ age (n = 314): ranged from 18 to 104years (mean = 49. 4
years, median = 4 5years);
Patients’ age group (=320): Adultf(264), Elderlyg(56);
Number of relevant events: 349, of which 202 serious, 147
non-serious ;in the cases reporting relevant serious events,
patient’s age range sfrom 18 to 104 years (mean = 55.9 years,
median = 49.5 years);
Reported relevant PTs :Tachycardia ( 272), Myocardial infarction *
(25), Acute myocardial infarction *(18),Cardiac failure (16),
Arrhythmia (14), Coronary artery disease (2) and Cardiogenic
shock and Postural orthostatic tachycardia syndrome (1 each);
Relevant event onset latency (n = 278): Range from 24 hours to
18 days, median 1 day;
Relevant event outcome:cfatal ( 38), resolved/resolving ( 178),
resolved with sequelae ( 7), not resolved ( 39)andunknown ( 88);
Of note ,in29 cases out of 344 cases (involving 13 female and 16
male patien ts with age ranged from 23 to 100 years, median 73.4
years, median 83 years) , 19 of which had fatal outcome, the
patient’s medical history was significant for the specific events
Myocardial infarction ( 10), Cardiac failure (8), Coronary artery
disease ( 7), Acute myocardial infarction , Postural orthostatic
tachycardia syndrome and Tachycardia (2 each) and Arrhythmia
(1). There w ere 3 cases reporting 2 relevant medical history terms
each;
In additional 29 cases out o f 344 cases , the patient’s medical
histor y was significant for other cardiac disorders , with the
following conditions reported more than once: Myocardial
ischaemia (6), Atrial fibrillation (5), Mitral valve prolapse,
Extrasystoles, Pericarditis, Cardiac disorder and Supraventricular
tachycardia ( 2 each);
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
In 40 out of 344 cases, the patients’ medical history was
significant for COVID -19 or suspected COVID -19.
* Observed/Expected analysis performed for Acute myocardial
infarction and Myocardial infarction.
Conclusion: No cardiovascular s ignals have emerged from the review
of post -authorization data. The review of cases and O/E analysis do not
raise new concerns. Surveillance w ill continue (see Appendix 5.1 ).
Covid-19 AESIs
Search criteria: Covid -19 SMQ
(Narrow and Broad)Number of cases: 1111(7.6% of the total PM dataset , com pared to
5.4% of the previous reporting period ), of w hich 751medically
confirmed and 360non-medically confirmed;
Country of incidence: U S (604), UK (235 ), Germany ( 125),
Rom ania (19), Portugal (18), Israel (16), Italy and Poland (13
each), Mexico (11), France (10), Spain (8), Canada (7), Slovakia
(6), Belgium and Latvia (5 each), Bulgar ia, Czech Republic and
Hungary (3 each) and the remaining 7cases were distributed
among 7other diffe rent countries;
Patients’ gender: female ( 539), male ( 295) and unknown ( 277);
Patients’ age group (n= 582): Adultsf(450), Elderlyg(131),
Adolescent (1);
Number of relevant events: 1150 , of which 1074 serious, 76
non-serious ;
Most frequently reported relevant PTs (1 occurrence): COVID -19
(688), SARS- CoV -2 test positive (252), Suspected COVID- 19
(115), Exposure to SARS -CoV -2 (38),COVID -19 pneumonia and
SARS -CoV- 2 antibody test negative (12each),SARS -CoV -2
antibody test positive ( 10),Occupational exposure to SARS -CoV-
2(6), Asymptomatic COVID -19 and SARS- CoV -2 test false
positive ( 5 each ), Coronavirus infection and Coronavirus test
positive (3 each);
Relevant event onset latency (n = 635): Range from 24 hours to
40days, m edian 6 days;
Relevant event outcome: fatal (29), not resolved ( 123),
resolved/resolving ( 130), resolved with sequ elae (1 )and unknown
(867).
Conclusion: No safety signals have emerged based on a review of these
cases .Surveillance will continue .
Dermatological AESIs
Search criteria: PT ChillblainsNumber of cases: 2 cases (0.0 1% of the total PM dataset , in the
previous reporting period there w ere no relevant cases ), 1 of which
wasmedically confirmed and 1 non-medically confirmed ;
Country of incidence: UK and US (1 each) ;
Patients’ gender: female and unknown (1 each );
Patients’ age group (n= 1): Adultf(1);
Number of relevant events: 2 events , 1 serious, 1 non -serious
(relevant PT: Chillblains);
Relevant event onset latency ( n = 1): 3 days;
Relevant event outcome: not resolved and unknown (1 each).
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
Conclusion: No safety signals have emerged based on a review of these
cases. Surveillance will continue .
Haematological AESIs
Search criteria: Leukopenias NEC
(HLT) (Primary Path) OR
Neutropenias (HLT) (Primary
Path) OR PTs Haemorrhage;
Haemorrhagic disorder;
ThrombocytopeniaNumber of cases: 19(0.1% of the total PM dataset , compared to
0.08% of the previous reporting period ), of which 14medically
confirmed and 5 non- medically confirmed;
Country of incidence: US (7), UK (6) , France (2), Belgium,
Hungary, Israel and Mexico (1 each);
Patients’ gender (n=17) : female (7)andmale (10 );
Patients’ age group (n= 15): Adultf(7), Elderlyg(8);
Number of relevant events: 20, of which 19serious, 1 non- serious;
Reported relevant PTs: Thrombocytopenia (10), Haemorrhage (5),
Lymphopenia (3) and Febrile neutropenia and Neutropenia (1
each);
Relevant event onset latency (n = 11): Range from 24 hours to 12
days, median = 5 days;
Relevant event outcome: fatal and resolved/resolving (4 each),
resolved with sequelae (1), not resolved ( 3)and unknown ( 8).
A cumulative review of all cases reporting thrombocytopenia w as
submitted to FDA and SwissMedic (see Appendix 3.3 ),respectively
during this reporting period and just after the data-lock point .
Conclusion: Thrombocytopenia was determined to not be a risk f or the
vaccine. No other signals for the hematological AESIs have emerged
based on a review of these cases.
Hepatic AESIs
Search criteria: Liver related
investigations, signs and
symptoms (SMQ) (Narrow and
Broad) OR PT Liver InjuryNumber of cases: 14 cases (0.1% of the total PM dataset ,
compared to 0.03% of the previous reporting period), of w hich 12
medically confirmed and 2 non -medically confirmed ;
Country of incidence: UK (8), US (3) and Belgium, Costa Rica
andRom ania (1 each) ;
Patients’ gender: f emale ( 6), male ( 8);
Patients’ age group (n=1 3): Adultf(7), Elderlyg(6);
Number of relevant events: 20, of which 12 serious, 8 non -serious;
Reported relevant PTs: Alanine aminotransferase increased (5),
Hepatic enzyme increased (3), Aspartate aminotransferase
increased, Blood alkaline phosphatase increased , Liver function
test abnormal and Liver function test increased (2 each)and
Bilirubin urine present, Gamma -glutamyltransferase increased,
Hepatic pain and Transaminases increased (1 each);
Relevant event onset latency (n = 9): Range from 24 hours to 1 4
days, median 5 days ;
Relevant event outcome: fatal ( 1), resolved/resolving ( 10), not
resolved (3) and unknown ( 6).
Conclusion: No safety signals have emerged based on a review of th ese
cases.Surveillance will continue .
Facial Paralysis
Search criteria: PT sFacial
paralysis, Facial paresisNumber of cases: 98e(0.7% of the total PM dataset , com pared to
0.6% of previous reporting period ), of which 71medically
confirmed and 27 non-medically confirmed;
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CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
Country of incidence: US (4 4), UK (31),Israel (9), Romania (3) ,
Cyprus (2); the remaining 9 cases originated from 9 different
countries;
Patients’ gender: female ( 65), male ( 25) and unknown ( 8);
Patients’ age group (n=82): Adultf(71), Elderlyg(11);
Number of relevant events: 102, of w hich 98serious, 4non-
serious .
Relevant event onset latency (n = 71): Range from 24 hours to 1 6
days, median 2days;
Relevant event outcome: resolved/resolving ( 31), resolved with
sequelae (1), not resolved ( 45) and unknown ( 25).
The evaluation of facial paralysis *cases was made using the Brighton
Collaboration criteria for individual case assessment:
4 cases were assessed as B righton Collaboration criteria Level 1 and
they involved respectively:
A 35 -year-old female patient who developed Facial paralysis
(left sided facial palsy) , Hypoaesthesia oral, Paraesthesia oral,
Pain in extremity, Tachycardia, Blood pressure increased on
the same day as vaccination ; she was treated with steroids and
valacyclovir ( outcome of not resolved at the time of the
report);
A 61 -year-old m ale patient who experienced Facial paralysis
(left side of face) , Lacrimation increased, Vision blurred 5
days following the vaccination ; hewas trea ted w ith steroid s,
acyclovir and tetracycline (outcome of not resolved at the
time of the report);
A 23-year-old female patient who experienced Facial
paralysis (right side) , Pain in extremity on the same day of her
first vaccination ; she was treated w ith steroids and eye
ointment (outcome of unknown);
A 26 -year-old female patient who experienced Facial
paralysis (right side), Facial paresis, Ear pain, Disease
recurrence, Headache, Hypoaesthesia 8 days following the
first dose of vaccine ; she was treated w ith steroids, acyclovir
and eye drops and had full resolution after 11 -12 days .
1 case w as assessed as Brighton Collaboration criteria Level 2 and it
involved:
a43-year-old female patient who experienced Fatigue,
Nausea, Facial paralysis (mild facial pals y), Vaccination site
pain, Vaccination site swelling, Headache, Pyrexia,
Palpitations, Myalgia, Vaccination site erythema, Spinal pain,
Sensory disturbance, Pyrexia on the same day of vaccination
with influenza vaccine and BNT162b2 ; the facial palsy
resolv ed within 2 days;
The remaining 93 cases were assessed as Category 4 because they
report facial nerve palsy without provision of enough detail to exclude
known causes by clinical history, physical exam, labs or imaging.
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
Relevant events: 96, of which 9 2serious, 4 non -serious;
Relevant reported PT s: Facial paralysis ( 87), Facial paresis ( 9);
Relevant event onset latency (n = 67): Range from <24 hours to 16
days, median = 1 day ;
Relevant event outcome: not resolved ( 43), resolved/resolving ( 28),
resolved with sequelae (1) and unknown ( 24).
* Please see Appendix 5. 1 for Observed versus Expected analysis of
Facial paralysis /Facial paresis (Bell’s palsy) . No ne w significant safety
information was identified based on a review of these cases, of the
Observed versus Expected analysis (see Appendix 5.1 ) and of the
cumulative review of Facial paralysis case (see Appendix 3.2 ).
Immune-Mediated/Autoimmune
AESIsd
Search criteria: Immune-
mediated/autoimmune disorders
(SMQ) (Broad and Narrow) OR
Autoimmune disorders HLGT
(Primary Path) OR PTs Cytokine
release syndrome; Cytokine storm;
HypersensitivityNumber of cases: 364 ( 2.5% of the total PM dataset , as well as in
the previous reporting period ), of which 251medically confirmed
and 113 non- medically confirmed;
Country of incidence: US (166), UK (101), Germany (17), Israel
(11), Greece (10), Italy (8), Portugal (7), Poland (6), Canada,
Denmark, Mexico and Romania (5 each), Chile and Serbia (3
each), Czech Republic and France (2 each) ; the remaining 8 cases
were from 8 different countries ;
Patients’ gender (n=333): female ( 260), male ( 73);
Patients’ age group (n= 300): Adultf(246), Elderlyg(54);
Number of relevant events: 371, of w hich 186serious, 185
non-serious;
Most frequent ly reported relevant PTs (2occurrence s):
Hypersensitivity (161), Anosmia ( 70), Arthritis (26), Dermatitis ,
Neuropathy peripheral (13each), Pericarditis *(7), Myocarditis *,
Neuritis andRheumatoid arthritis *(5each), Diabetes mellitus * (4)
andHypothyroidism, Immune thrombocy topenia, Neuralgic
amyotrophy, Pancreatitis (3 each).
Relevant event onset latency (n = 236): Range from 24 hours to
21days, m edian 1 day ;
Relevant event outcome:cresolved/resolving ( 136), not resolved
(83), fatal (6), resolved w ith sequelae ( 5)andunknown (14 2).
* Please see Appendix 5.1 forObserved/Expected analysis performed
for Diabetes mellitus, Pericarditis ,Myocarditis , Rheumatoid arthritis .
Conclusion: No new s afety signals have emerged based on a review of
these cases and of the Observed versus Expected analysis (see
Appendix 5.1 ).Surveillance will continue .
Musculoskeletal AESIs
Search criteria: PTs Arthralgia;
Arthritis; Chronic fatigue
syndrome; Polyarthritis;
Polyneuropathy; Post viral fatigue
syndromeNumber of cases: 1191 (8.2% of the total PM dataset , com pared to
5.7% of the previous reporting period ), of w hich 743 medically
confirmed and 448 non -medically confirmed;
Country of incidence (>2%): US (498), UK (496), Italy (40) and
Mexico (36) ;
Patients’ gender (n=1130): female (905), male (225 );
Patients’ age group (n=1096): Adultf(977), Elderlyg(117) and
Adolescent (2).
Number of relevant events: 1204, of whi ch 392 serious, 812
non-serious;
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
Reported relevant PTs: Arthralgia (1173), Arthritis (26), Post viral
fatigue syndrome (3) and Polyneuropathy (2);
Relevant event onset latency (n = 962): Range from <24 hours to 2 2
days, median 1 day ;
Relevant event outcome:cresolved/resolving (582), resolved with
sequelae (16), not resolved (353) and unknown (265).
Conclusion: No new s afety signals have emerged based on a review of
these cases. 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; Cerebrovascular
accident; Fibromyalgia;
Intracranial pressure increased;
Meningitis; Meningitis aseptic;
NarcolepsyNumber of cases: 130(0.9% of the total PM dataset , com pared to
0.5% of the previous reporting period ), of w hich 79medically
confirmed and 51 non- medically confirmed;
Country of incidence: UK ( 61), US (28), Germany ( 9),Mexico (8) ,
Israel (7), Italy (4), France (3), Norw ay and Sweden (2 each); the
remaining 6 cases originated from 6 different countries ;
Patients’ gender (n=123): female (85), male (38);
Patients’ age group (n=121): Adultf(68), Elderlyg(53);
Number of relevant events: 136, of w hich 127serious, 9
non-serious;
Most frequently reported r elevant PTs(1 occurrence) included :
Cerebrovascular accident * (41), Seizure* (38), Epilepsy (8), Aura
(7), Fibromyalgia *, Generalised tonic -clonic seizure *and Multiple
sclerosis relapse *(5 each), Guillain -Barre syndrome *, Multiple
sclerosis *, Petit mal epilepsy *and Trigeminal neuralgia (3 each)
and Acute disseminated encephalomyelitis *, Demyelination and
Optic neuritis *(2 each);
Relevant event onset latency (n = 102): Range from 24 hours to
16days, m edian 1 day ;
Relevant event soutcome: fatal (7), resolved/resolving (5 7),
resolved with sequ elae (3) ,not resolved ( 34) and unknown ( 35);
In 30cases, the patient ’s medical history was relevant for Epilepsy
(9), Multiple sclerosis (6), Fibromyalgia and Cerebrovascular
accident (5 each), Generalised tonic- clonic seizure ( 3), Partial
seizures and Se izure (2 each) and Myoclonic epilepsy (1).
* Observed/Expected analysis performed for Cerebrovascular accident,
Guillain -Barre syndrom e, Multiple sclerosis, Multiple sclerosis relapse ,
Optic neuritis and Seizure/Seizure disorders. No new significant safet y
information was identified based on a review of these cases and of the
Observed versus Expected analysis (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged from review of the
cases or of the O/E analyses. Surveillance will continue .
Other AESIs
Search criteria: Herpes viral
infections (HLT) (Primary Path)
OR PTs Adverse event following
immunisation; Ageusia;
Inflammation; Manufacturing
laboratory analytical testing issue;
Manufacturing materials issue;
Manufacturing production issue;Number of cases: 2953 (20.3% of the total PM dataset , compared
to 15.3% of the previous reporting period ), of which 1905
medically confirmed and 1 048non-medically confirmed;
Country of incidence: US ( 1309 ), UK ( 1079 ), Italy (111),
Germ any (58), Spain (46), Israel and Poland (41each), Romania
(34), Mexico (32), Denmark (31), Canada (19), Serbia and Sweden
(17 each), Iceland (15), Hungary (14), Greece (13), Portugal (12),
France (8), Croatia, Lithuania and Norw ay (6 each), Puerto Rico
(5), Czech Republic and Slovakia (4each), Chile, Costa Rica ,
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
MERS-CoV test; MERS-CoV test
negative; MERS-CoV test positive;
Middle East respiratory
syndrome; Multiple organ
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 positiveLatvia and Saudi Arabia (3 each), Bulgaria, Finland and United
Arab Emirates (2 each) and the remainin g 7 cases were distributed
among 7 other countries;
Patients’ gender (n=2817) : female (2110), male (707);
Patients’ age group (n= 2627): Adultf(2341 ), Elderlyg(277), Child,
Infant (see Table 15, respectively infant breastfeeding patients and
children below 16 who experienced Pyrexia) and Adolescent ( 3
each);
Number of relevant events: 2986 , of which 899serious, 2087
non-serious;
Most frequently reported relevant PTs ( 1 occurrence) included:
Pyrexia ( 2773), Ageusia ( 79), Herpes zoster (64), Inflammation
(27), Oral herpes ( 21), Herpes virus infection ( 8), Multiple organ
dysfunction syndrome (5) and Genital herpes and Herpes simplex
(2each);
Relevant event onset latency (n = 2405 ): Range from 24 hours to
28days, median 1 day;
Relevant events outcome:cfatal (23), resolved/resolving ( 1727 ),
resolved with sequ elae (34),not resolved ( 572) and unknown
(655).
Conclusion: No new safety signals have emerged based on a review of
these cases. 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 15.
Renal AESIs
Search criteria: PTs Acute kidney
injury;Renal failure.Number of cases: 19 cases (0.1% of the total PM dataset, in the
previous reporting period there w ere no relevant cases), of which
16medically confirmed, 3non-medically confirmed;
Country of incidence: UK (7), Germ any (6)and Belgium, France,
Italy, Norw ay, Sweden and US (1 each);
Patients’ gender: female ( 14), male ( 5);
Patients’ age group (n=1 8): Elderlyg(17), Infant (1, relevant PT
Renal failure, see Table 15, Use in Paediatric Individuals <16
Years of Age );
Number of relevant events: 19, all serious;
Reported relevant PTs: Acute kidney injury *(13) and Renal
failure (6);
Relevant event onset late ncy (n = 1 3): Range from 1to 9 days ,
median 2 days ;
Relevant event outcome: fatal (7), resolving (3), not resolved (5)
and unknown ( 4).
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
* Observed/Expected analysis performed for Acute kidney injury.
Conclusion: No new safety signals have emerged based on a review of
these cases and of the Observed versus Expected analysis performed
(see Appendix 5.1 ).Surveillance w ill continue .
Respiratory AESIs
Search criteria: Lower respiratory
tract infections NEC (HLT)
(Primary Path) OR Respiratory
failures(excl neonatal) (HLT)
(Primary Path) OR Viral lower
respiratory tract infections (HLT)
(Primary Path) OR PTs: Acute
respiratory distress syndrome;
Endotracheal intubation;
Hypoxia; Pulmonary
haemorrhage; Respiratory
disorder; Severe acute respiratory
syndromeNumber of cases: 31cases ( 0.2% of the total PM dataset,
compared to 0.06% of the previous reporting interval) , of which
26medically confirmed;
Countr iesof incidence: UK (10), Spain ( 5), Belgium, Germany (3
each), Denmark, France, Greece, US (2 each), Italy and
Switzerland (1 each).
Patients’ gender (n=31): male (16), female (15).
Patients’s age group (n= 29):Elderlyg(22), Adultf(7).
Number of relevant events: 31serious event s, 1 non -serious .
Reported relevant PTs:Acute respiratory failure (10), Respiratory
failure (7), Respiratory disorder (6 , of whic h 1 non -serious ),
Hypoxia (5), Acute respiratory distress syndrome * (2), Severe
acute respira tory syndrome ( 2).
Relevant event onset latency (n=31): range from < 24 hours to 19
days.
Relevant events outcome:cfatal (19), Resolved/resol ving (4), not
recovered (4) and unknown (5).
Four (4) of these 31cases [3with fatal and 1 life threating ; PTs:
Respiratory failure (1), Hypoxia (2), Respiratory failure (1),
Severe acute respiratory syndrome (1)] , werealso reviewed among
thepotential relevant cases for the Risk ‘VAED Including
VAERD’ in Table 12.
* Observed/Expected analysis performed for Acute respiratory distress
syndrome.
Conclusion: No new safety signals have emerged based on a review of
these cases and of the Observed ver sus Expected analysis performed
(see Appendix 5.1 ).Surveillance w ill continu e.
Thromboembolic Events
Search criteria: Embolism and
thrombosis (HLGT) (Primary
Path) OR PTs Deep vein
thrombosis; Disseminated
intravascular coagulation;
Embolism; Embolism venous;
Pulmonary embolismNumber of cases: 33(0.2% of the total PM dataset, compared to
0.03% of the previous reporting period), of which 22medically
confirmed and 11non-medically confirmed;
Country of incidence: US ( 12), UK ( 10), Germany (4), Israel ( 3)
and Austria, Belgium, Italy and Portugal (1 each);
Patients’ gender (n= 29): female (1 9), male ( 10);
Patients’ age group (n=27): Adultf(11), Elderlyg(16);
Number of relevant events: 36, of which 35serious, 1 non -serious;
Reported relevant PTs: Deep vein thrombosis *(12), Thrombosis
(11), Pulmonary embolism (9)and Embolism, Microembolism,
Peripheral embolism and Vena cava thrombosis (1 each);
Relevant event onset latency (n = 27): Range from 24 hours to 1 1
days, median 3 days ;
Relevant event outcome: fatal (4), resolved w ith sequelae ( 2)and
resolved/resolving, not resolved and unknown ( 10 each ).
* Observed/Expected analysis performed for Deep vein thrombosis.
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 14525)
Conclusion: No new safety signals have emerged based on a review of
these cases and of the Observed versus Expected analysis performed
(see Appendix 5.1 ). Surveillance w ill continue .
Vasculitic Events
Search criteria: Vasculitides HLT
(Primary Path) OR PTs
Kawasaki'sdisease;
Microangiopathy; Peripheral
ischaemiaNumber of cases: 2 cases (0.01% of the total PM dataset, in the
previous reporting period there were no relevant cases), both
medically confirmed;
Country of incidence: Spain and UK(1 each);
Two female elderlygpatients experienced Peripheral ischaemia ,
serious, 3 day safter the vaccination ;
Relevant event outcome: fatal and unknown (1 each).
Conclusion: No new safety signals have emerged based on a review of
these cases. Surveillance will continue.
a.For the complete list of the AESIs, please refer to Appendix 5;
b.Please note that this corresponds to evidence from post -EUA/conditional marketing authorisation
approval data sources;
c.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;
d.Cases reporting the PTsDemyelinating polyneuropathy, Demyelination, Guillain -Barre syndrome,
Multiple sclerosis, Multiple sclerosis relapse, Myelitis transverse, Narcolepsy and Optic neuritis overlapping
in this category were described in the Neurological category ;
e.Fifteen additional cases were excluded from the analysis of facial paralysis because they were assessed
as Categ ory 5 according to Brighton collaboration criteria (i.e., not cases of facial paralysis ); 1 case was
excluded from the analysis because it was invalid due to an unidentifiable reported ;
f. P atients with age ranged between 18 and 64 years;
g.Patients with age equal to or above 65 years.
9.5.3.Evaluation of Special Situations
Table 14 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 14.Evaluation of Special Situations for BNT162b2
Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N=14525)
Death Overview
Number of fatal cases: 40928(2.8 % of the total PM dataset ,compared to 0.3% of the
total PM cases received in the previous reporting period ) of which 340 w ere
medically confirmed and 69 non -medically confirmed;
28During the current reporting interval there were 2 additional cases reporting patients’ death. How ever,
they were excluded from further analysis in this subsection as the death was mentioned as an incidental
information only in these 2 cases, with none of the reported events presenting a fatal outcome. A third
additional case was excluded as it was made invalid based on the follow up information received.
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N=14525)
Country of incidence: the majority were from UK (115), Germany (83), the US (47),
Norw ay (30), Sweden (24), France (18), Israel (14), Denmark and Spain (12 each)
and Italy (11); the remaining 43 cases occurred in other 10 countries.
Patients ’Gender: females ( 204), males ( 176), unknown ( 29);
Patients’ Age: 27to 104 years (n = 363), mean = 83.6, median = 85;
Adults ( 29), Elderly ( 350), patients with unknown age (30);
Causes of death most frequently reported (≥2%): Death (167), Sudden death (32),
Cardiac arrest (27), COVID- 19 (22), General physical health deterioration and
Dyspnoea (16 each), Drug ineffectiv e (15), Myocardial infarction (13), Pneumonia
and Pyrexia (12 each), Cardiac failure (11), Vomiting and Acute respiratory failure
(8 each).
PTs most frequently reported ( 2%): Death (166), Drug ineffective (46), COVID- 19
(40), Sudden death (39), Malaise (35), Dyspnoea (33), Pyrexia (32), Cardiac arrest
(29), Vomiting (27), General physical health deterioration (25), Fatigue (15), Fall
(14), Diarrhoea, Myocardial infarction and Pneumonia (13 each), Oxygen saturation
decreased (12), Cardiac failure (11), Circulatory collapse, Confusional state, Cough,
Hypotension (10 each), Acute respiratory failure, Asthenia and Nausea (9 each).
Concomitant medications were reported in 165 out of 409 cases and the most
frequently present (≥2%) are listed below :
paracetamol (53), furosemide (32), acetylsalicylic acid (31), omeprazole (23),
atorvastatin and levothyroxine sodium (22 each), apixaban (21), colecalciferol (20),
macrogol 3350 /potassium chloride/sodium bicarbonate/sodium chloride and ramipril
(17 each), bisoprolol (16), oxazepam (14), amlodipine, folic acid and lactulose (13
each), mirtazapine, simvastatin and zopiclone (12 each), bisoprolol fumarate and
salbutamol (10 each), calcium carbonate/colecalciferol, glyceryl trinitrate and
lansoprazole (9 each), metformin, metoprolol, pantoprazole, prednisolone, pregabalin
and sodium picosulfate (8 each).
Lot/Batch Number (#) information by Country are available in 2 36cases w ith no
related quality issues identified during investigations of the impacted lot/batch
number. The list of Lot # more frequently reported ( >2% of total fatal cases) is
presented hereinafter:
oLot # EJ6796 in 58 cases from Germany ( 19),Spain (10), Sweden (9),
Iceland (6), Norw ay and Austria (5 each), Slovenia (2), Switzerland and
Denmark (1), respectively
oLot # EM0477 in 30 cases from Germ any (12), France (8) , Belgium (6),
Denmark (3) and Ireland (1) , respectively
oLot # EJ6795 in 30 cases from Norw ay (19), Sw eden (4), France (3),
Germ any (2) and Greece (1) , respectively
oLot # EJ1688 in 20 cases from UK
oLot # EJ6797 in 17 cases from Denmark (8), Germany (6), Austria (2) and
Italy (1), respectively
oLot # EJ0553 in 15 cases from UK
Time to onset of fatal events was reported for 305 patients and ranged from the day
of vaccination to 23 days after vaccination:
oSame day to 3 days after vaccination: 208 cases,
o4-7 days after vaccination: 54 cases
o8-14 days after vaccination: 28 cases
o15-23 days after vaccination: 15 cases
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N=14525)
Number of vaccine doses administered at t he time of the patients’ death: in 167 cases
the death occurred after the administration of the first dose, in 23 cases the fatal
outcome was observed after the administration of the second dose w hereas in the
remaining cases (219) it w as not specified if the patients received the first or the
second vaccine dose at the time of the fatal events.
Test for COVID- 19 w ere reported for 10 5patients as follows: in 4 1cases patients
tested positive (18after 1stvaccine dose, 2 after 2ndvaccine dose and in 21there w as
no informatio navailable about the dose they received) , in 58were negative and in 6
cases test results were unknown.
Analysis
Most of the cases reporting a fatal outcome (77.3 %) w ere in subjects over 75 years of
age. This reflects one of the priority groups targeted for vaccination by many countries
including Europe and the US , that is, elderly (with various low er age cut -offs across
countries), because of their higher risk of severe disease and mortality if infected w ith
SARS -CoV-2.11,12
Among the total of 409 cases with a fatal outcome, when the med ical history was
provided (in 310 cases), the majority had multiple concomitant comorbidities. The most
frequently reported medical conditions included cardiac and vascular disorders (eg
Hypertension, Atrial fibrillation, Cardiac failure, Cerebrovascular a ccident, Myocardial
ischaemia, Coronary artery disease, Myocardial infarction). Cases not describing cardiac
conditions reported other significant medical histories that included Dementia, Diabetes
mellitus, Chronic kidney disease, Chronic obstructive pulm onary disease and Renal
failure. In some individuals, palliative care had already been initiated before vaccination.
No specific pattern regarding underlying condition or cause of death have been
identified. Further reports w ill continue to be carefully mo nitored.
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 Number of cases29: 1043 (7.2 % of the total PM dataset, compared to 3.7% of the
previous reporting period) of which 705 w ere m edically confirmed and 338 non -
medically confirmed;
Country of incidence: US (563), UK (226), Germany (113), Romania (19), Portugal
(18), Israel (14), Poland (13), Italy and Mexico (11 each); the remaining 55 cases
originated from 16 different countries.
COVID -19 infection (suspected or confirmed) outcome was reported as
resolved/resolving (111), not resolved (116) or unknown (787) at the time of the
reporting, resolved with sequelae (1); there w ere 28 cases where a fatal outcome was
reported (see also Death section above in this table).
Number of lack of efficacy events: 1043 (PT: Drug ineffective);
29Four (4) additional cases retrieved in this dataset were excluded from the analysis because they were
invalid (2 cases, accordingly invalidated in the safety database after DLP ) or not LOE cases (2 cases, LOE PT
removed after DLP).
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N=14525)
Drug ineffective seriousness: serious (1040), non -serious (3)30; seriousness criterion
(more than 1 in some cases) was important medical event (1012), death (28),
hospitalization (25), life threatening (15), and disability or permanent damage (14);
Lack of efficacy term was reported:
oafter the 1stdose in 65 2cases
oafter the 2nddose in 19 cases
oin 372 cases it was unknown after which dose the lack of efficacy occurred.
Latency of lack of efficacy term reported after the first dose was known for 383
cases:
oWithin 0 and 7 days: 190 patients.
oWithin 8 and 14 days 1: 155 patients.
oWithin 15 and 20 days: 33 patients.
oWithin 21 and 40 days: 5 patients (in these cases it was not reported
whether a second dose was administered in the meantime).
Latency lack of efficacy term reported after the second dose was known for 16
cases:
oWithin 0 and 4 days: 13 patients.
oWithin 8 and 16 days: 3 patients (in 1 case the 1stand the 2nddose w ere not
properly spaced, in the 2ndand the 3rdcase the interval betw een the 1stand
the 2nddose w as not provided).
Latency of lack of efficacy term reported in cases where the number of doses
administered w as not provided, w as known in 187 cases:
oWithin 0 and 7 days after vaccination : 136 patients.
oWithin 8 and 14 days after vaccination: 39 patients.
oWithin 15 and 31 day after vaccination: 12 patients.
According to the RSI, individuals may not be fully protected until 7 days after their
second dose of vaccine, therefore for the above 670 cases where lack of efficacy was
reported after the 1stdose or the 2nddose, the reported events may represent signs and
symptoms of intercurrent or undiagnosed COVID -19 infection or infection in an
individual who was not fully vaccinated, rather than vaccine ineffectiveness.
Conclusion: No new safety signals have emerged based on a review of these cases.
Com pany conventions for coding cases indicative of lack of efficacy:
PT “Vaccination failure” is coded when ALL of the following criteria are met:
oThe patient has received the appropriate series of tw o doses based on
thelabeling.
oAt least 7 days have elapsed since the second dose of vaccine has been
administered.
oThe patient experiences COVID -19 infection (confirmed laboratory
tests).
PT “Drug ineffective” is coded when a reporter states orimplies LOE in a patient
who experiences a potential/confirmed COVID -19 infection and either of the
following applies:
30Event seriousness of PTs , indicative o f possi ble lack of therapeutic effect captured at the DLP, w as
upgraded to serious as per case processing convention at completion of the case.
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N=14525)
oThe patient has not received the appropriate series of tw o doses based
on the labeling or it is unknown;
oIt has NOT been 7 days since the second dose of the vaccine has been
administered or the time since the last dose is unknown;
oThe infection is not confirmed as COVID 19 through laboratory tests.
Vaccine
InteractionsNumber of cases: 12 (0.08% of the total PM dataset , com pared to 0.03% of the
previous reporting period ) of which, 6 cases were medically confirmed and 6 cases
were non -medically confirmed.
Country of incidence: US (8), Denmark, Germany, Greece, and Spain (1 each).
Patient Gender: Female (6), Male (5), and Unknown (1);
Patien ts’ Age: 36 to 86 years; (n=10); mean=54.5; median 49.0;
Relevant reported interaction PTs: Drug interaction (11) and Inhibitory drug
interaction (1);
Relevant event seriousness: Serious (2) and Non -serious (10);
Relevant event outcome: Resolved (2) and Un known (10);
Co-reported events coded to the PTs (>1 event): Headache (4), Malaise, Pain (3
each), Dizziness, Fatigue, and Pyrexia (2 each);
Reported Interacting Agents: montelukast sodium (2), amfetamine
aspartate/amfetamine sulfate/dexamfetamine saccharat e/dexamfetamine sulfate,
apixaban, diphtheria vaccine toxoid/pertussis vaccine acellular 5 -component/polio
vaccine inact 3v (vero)/tetanus vaccine toxoid, famotidine, fexofenadine
hydrochloride, guselkumab, ibuprofen, lithium, oxycodone hydrochloride,
paroxetine, piroxicam, prednisone, sulfamethoxazole/trimethoprim, and ustekinumab
(1 each);
Of the 12 cases, 1 case reported a potential interaction with another vaccine
(increased react ogenicity to diphtheria vaccine toxoid, pertussis vaccine acellular 5 -
component, polio vaccine inact 3v (vero), tetanus vaccine toxoid) (see also Ta ble 15,
Interaction With Other Vaccines ).
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.Please note that this corresponds to evidence from post -EUA/conditional marketing authorisation
approval data sources.
9.5.4.Evaluation of Missing Information
Table 15 below summari ses the evaluation of new information received during the current
reporting period from post -marketing data sources7in relation to the Missing information
associated with the use ofBNT162b2 .
Table 15.Evaluation of Missing Information for BNT162b2
Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
Use in Pregnancy and
While Breast
FeedingbNumber of cases: 199c(1.4% of the total PM dataset , com pared to 1.9% of the
previous reporting period )of which 1 29medically confirmed and 7 0 non-
medically confirmed;
Country of incidence: US (110), Canada (23), Germany (16), UK (14), Poland
(11), Estonia, Portugal (4 each), Romania (3), France, Israel, Spain (2 each),
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
Chile, Greece, Hungary, Italy, Mexico, Netherlands, Puerto Rico, and Slovakia
(1 each).
Pregnancy cases: 124 mother cases including:
115 cases indicative of exposure to vaccine during pregnancy [relevant PT
events Maternal exposure during pregnancy (87), Exposure during pregnancy
(23) and Maternal exposure timing unspecified (5)], of which:
78 cases re ported exposure in utero only without the occurrence of any
clinical event; trimester of exposure was reported in 9 of these cases: 1st
trimester (7 cases), 2ndtrimester (2 cases);
37 cases, 24 non -serious and 13 serious, reported additional clinical even ts,
which occurred in the vaccinated mothers; the events which occurred more
than once encoded to the PTs Vaccination site pain (11), Fatigue (8),
Headache, Myalgia, Pain in extremity, Pyrexia (7 each), Chills (6),
Lymphadenopathy (5), Drug ineffective, Na usea, Pain (4 each), Arthralgia,
Chest pain, Dizziness, (3 each), COVID -19, and Oropharyngeal pain (2
each); trimester of exposure was reported in 21 of these cases: 1sttrimester
(13 cases), 2ndtrimester (3 cases), 3rdtrimester (5 cases).
8 serious case s reported the PT Spontaneous abortion (note that 1 of these cases
reported an exposure term and w as also counted in the 115 cases above). No
other pregnancy outcomes were reported in any of the other pregnancy cases.
Trim ester of exposure was reported as 1sttrimester in 4 of these cases.
1 case reported the PT Morning sickness; however, pregnancy was not
confirmed in this case.
1 case reported that a pregnant w oman was scheduled to receive the vaccine;
however, the vaccine had not been administered at the time of reporting.
Breast Feeding baby cases : 70, of which:
63 cases reporting exposure to vaccine during breastfeeding without the
occurrence of any clinical event;
7 cases, all non -serious, reporting overall 15 additional clinical events
occurred, in t he subjects exposed to vaccine via breastfeeding; these events
encoded to the PTs: Pyrexia (3), Rash (2), Agitation, Anxiety, Crying,
Diarrhoea, Eructation, Increased appetite, Infant irritability, Infantile
Vom iting, Insomnia, and Poor quality sleep.
Lactation mother cases : 5, of which:
1 case w as serious and reported clinical events that encoded to the PTs:
Paresis, Pyrexia, and Suppressed lactation
4 cases w ere non -serious and reported clinical events that encoded to the
PTs: Suppressed lactation (3), Arthralgia, Breast milk discolouration,
Breast pain, Chills, Fatigue, Headache, Menstruation irregular, Migraine,
Myalgia, Nausea, Pain in extremity, Pyrexia, Scar pain, Vomiting (1 each)
Conclusion: There w ere no safety signals that emerged from the review of these
cases of pregnancy, lactation and breast -feeding babies.
Use in
Immunocompromised
PatientsdNumber of cases: 299(2.1% of the total PM dataset , com pared to 1.7 %of the
previous reporting period ) of which 172were medically confirmed and 127
non-medically confirmed;
Case Seriousness: Serious (1 54), Non -Serious ( 145);
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
Country of incidence: US ( 127), UK (1 22), Israel ( 9), Canada (6), Germany and
Italy (5 each), Denmark (4), France and Spain (3 each), Greece, Norw ay and
Portugal (2 each) ; the remaining 9 cases originated from 9 different countries ;
Gender: females ( 230), males ( 66)and unknown (3) ;
Age (n = 280) ranged from 18to 94 years, mean = 5 6.7, median = 54;
Relevant patients’ medical histories most frequently reported ( 10cases) coded
to the PTs: Breast cancer ( 36), Hysterectomy (24), Immunodeficiency (22),
Thyroid cancer and Thyroidectomy ( 18 each), Neoplasm malignant (16),
Prostate cancer (13) and Splenectomy (1 1);
Of the 1296 clinical events overall reported, the most frequent ( >20
occurrences) coded to the PTs: Headache ( 77), Fatigue ( 63), Vaccination site
pain (48), Pyrexia (46), Nausea (39), Chills (37), Dizziness (34), Arthralgia and
Myalgia (32 each), Pain (28), Malaise and Pain in extremity (26each)and
Diarrhoea (23);
Case outcome: fatal (1 4, see Table 14, Death ), resolved/resolving ( 140),
resolved with sequelae ( 6), not resolved ( 104)andunknown ( 35).
Conclusion: All the most frequently reported events observed in
immunocompromised patients w ere consistent with those observed in the overall
population. The reporting proportion of cases reporting outcome sof fatal (4.7%),
not resolved (3 4.8%) and resolved with seque lae (2%) in immunocompromised
patients is similar to the reporting proportion sobserved in the overall population
(2.8% for fatal outcome, 26.9% for outcome of not resolved and1% for outcome of
resolved with sequelae). No safety signals have emerged that w ould be considered
specific to this population
Use in Patients With
Autoimmune or
Inflammatory
DisordersdNumber of cases: 893(6.1% of the total PM dataset , com pared to 6.5 %of the
previous reporting period ) of which 584were medically confirmed and 309
non-medically confirmed;
Case Seriousness: Serious ( 345), Non -Serious ( 548);
Country of incidence: US ( 477), UK ( 297), Israel (20), Italy (18), Canada and
Germ any (15 each), Portugal (6), Spain (5), France (4), Denmark, Finland,
Greece, Hungary and Romania (3 each) and Bulgaria, Chile, Iceland, Poland ,
Puerto Rico and Sw eden (2 each); the remaining 9 cases originated from 9
different countries;
Gender: Females ( 773), Males ( 112) and Unknown ( 8);
Age (n = 854) ranged from 17to 98years, mean = 4 9years ,
median = 4 8years ;
Relevant patients’ medical histories most frequently reported ( 15cases) coded
to the PTs: Hypothyroidism ( 214), Rheumatoid arthritis ( 71), Arthritis (68),
Autoimmune thyroiditis ( 53), Psoriasis (51), Type 1 diabetes mellitus ( 42),
Coeliac disease ( 37), Thyroid disorder (35), Croh n’s disease (32), Multiple
sclerosis (30), Systemic lupus erythemato sus (28), Basedow’s disease (27),
Autoimmune disorder (26), Raynaud's phenomenon ( 25), Colitis ulcerative
(24),Psoriatic arthropathy ( 22);
Of the 4027 events overall reported, the most frequent (>4 0 occurrences) coded
to the PTs: Headache ( 284), Fatigue ( 205), Pyrexia ( 184), Chills ( 154), Pain
(151), Nausea (142), Pain in extremity ( 131),Vaccination site pain ( 123),
Myalgia ( 116), Arthralgia (107), Dizziness (83), Malaise ( 66),
Lymphadenopathy (51), Paraesthesia ( 50), Dysp noea, Influenza like illness and
Rash (42 each) ;
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
Case outcome: fatal (5 seeTable 14, Death ), resolved/resolving ( 452), resolved
with sequelae ( 15), not resolved ( 313) and unknown ( 108).
The reporting proportion of outcomes of “not resolved ” (33.2% in the previous
reporting period and 35.1%in the current reporting period ) and of “resolved with
sequelae ” (0.9% in the previous reporting period and 1.7%in the current reporting
period ) in patients with autoimmune or inflammatory disorders is similar to the
reporting proportion observed in the overall population (26.9% for outcome of not
resolved and 1% for outcome of resolved with sequelae). There w ere no cases with
fatal outcomes involving patients with autoimmune and inflammatory disorders in
the prev ious reporting period, and the reporting proportion of cases with fatal
outcome in patients with autoimmune or inflammatory conditions (0.6%) for this
reporting period is below the reporting proportion of cases with fatal outcome in
the overall population (2.8%).
Per company procedures, there is a minimum of 2 follow -up attempts for all
non-clinical study cases, regardless of product ,event orpopulation involved. The
MAH acknowledge sthat quality and completeness of information obtained is
important for individual case assessment and critical for signal detection and
evaluation. Reports should contain information on demographics, vaccine brand,
batch number, vaccination and adverse event dates, outcome, concomitant drugs,
etc. When contact with the reporter has been successfully established, if the reported
event has not resolved at the time of the initial report, follow up attempts are
pursued until the outcome has been established or the condition has stabilized.
Conclusion: The most freq uently reported events observed in patients with
autoimmune or inflammatory disorders w ere consistent with those observed in the
overall population. No safety signals have emerged that would be considered
specific to this population
Use in Frail Patients
With Co -morbidities
(e.g. COPD,
Diabetes, Chronic
Neurological Disease,
Cardiovascular
Disorders)dNumber of cases: 1343 (9.2%of the total PM dataset , com pared to 7.6 %of the
previous reporting period ) of which 903were medically confirmed and 440
non-medically confirmed;
Case Seriousness: Serious ( 787), Non -Serious ( 556);
Country of incidence: UK ( 523), US (497 ), Germany (74), Sweden (36),
Norw ay (29), Italy (25), Denmark (23), Spain (20), France (19), Israel (17),
Iceland (11), Austria and Belgium (8 each), Portugal (6), Canada, Greece and
Switzerland (5 each), Croatia, Czech Republic and Romania (3 each), Bulgaria,
Finland, Hungary, Latvia, Puerto Rico, Saudi Arabia and Slovenia (2 each); the
remaining 9 cases originated from 9 different countries ;
Gender: Females ( 960), Males ( 371) and Unknown ( 12);
Age (n = 1303) ranged from 2 months to 100 years, mean = 60.4,
median = 57;
Relevant patients’ medical histories most frequently reported ( 20cases) coded
to the PTs: Asthma ( 609),Diabetes mellitus ( 229), Type 2 diabetes mellitus
(137),Dementia ( 118), COPD ( 95),Cardiac failure ( 63), Chronic kidney
disease ( 54), Dementia Al zheimer ’s type (43), Renal failure (24), Parkinson’s
disease (23) andVascular dementia ( 22);
Of the 5649 events overall reported, the most frequent (> 60 occurrences) coded
to the PTs: Headache ( 310), Pyrexia (287), Fatigue ( 248), Chills (191), Nausea
(170), Vaccination site pain (168), Myalgia (153), Pain (151), Arthralgia,
Malaise and Pain in extremity (115 ea ch), Dizziness (103), Dyspnoea (108) ,
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Total Number of Cases in the Reporting Period (N= 14525)
Drug ineffective (85), Asthenia (77), Vomiting (76), Death (71), Cough (68)
and Diarrhoea (62) ;all these events were consistent with the most frequent
events observed in the overall population except for Death;
Case outcome: fatal ( 219, see Table 14Death ), resolved/resolving ( 535),
resolved with sequelae ( 18), not resolved ( 424) and unknown ( 147).
The reporting proportion of “not resolved” cases (31.6%) and cases resolved with
sequelae ( 1.3%) in frail patients is similar to the reporting proportion observed in
the overall population (26.9% for outcome of not resolved, 1 % for outcome of
resolved with sequelae).
The reporting proportion of cases reporting fatal outcome ( 16.3% ) in frail patients is
higher than the reporting proportion of cases reporting fatal outcome in the overall
population ( 2.8% ).This isexpected, considering that m ost of the cases reporting a
fatal outcome ( 87.7%) were in subjects 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.
Conclusion: Overall, no risks based on patient frailty have been identified for the
vaccine.
With regard to follow -up activities in place please see subsection Use in Patients
With Autoimmune or Inflammatory Disorders above in this Table.
Interaction With
Other VaccinesdThere was 1 case reporting an interaction with other vaccines during the reporting
interval (plea se refer to Table 14,Vaccine Interactions).
Long -Term Safety
DatadNot applicable
Use in Paediatric
Individuals <16
Years of AgeeNumber of cases: 15f(0.1% of the total PM dataset , compared to 0.08% of the
previous reporting period ), of which 9 w ere medically confirmed and 6 w ere
non-medically confirmed , and indicative of erroneous administration in
paediatric subjects <16 years of age (relevant PT Product administered to
patient of inappropriate age,gsee Section 7 Medication Errors );
Country of incidence: UK (8), US (5), Andorra and Italy (1 each);
Cases Seriousness: Serious (7), Non -Serious (8);
Gender: Females (9), Males (5) and Unknown (1);
Age (n =15) ranged from 2 months to 15 years, mean = 6.2, median = 5;
Of the 40 reported events,
oThe most frequently reported AEs (>1 case) w ere coded to the PTs
Product administered to patient of inappropriate age (11)g, Off label
use and Pyrexia (3 each).
oThe remaining 23 AEs were single occurrences and coded to the PTs
Abdominal pain upper, Blood pressure increased, Blood urine pres ent,
Cough, Decreased appetite, Dizziness exertional, Dyspnoea,
Exertional headache, Feeling abnormal, Headache, Hyperhidrosis,
Illness, Lethargy, Malaise, Myalgia, Nausea, Oropharyngeal pain,
Product use issue, Rash, Rash pruritic, Renal failure, Vaccinat ion site
pain and Vomiting;
oUnlisted AEs were reported in 2 cases:h
Limited information was provided in the case involving renal
failure (serious) blood in urine (non -serious) and
hyperhidrosis (non -serious) in a female patient of 1 years of
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 14525)
age(as reported) with suspected COVID -19 infection. A
meaningful medical assessment of causality cannot be made
as clinical details, complete medical history and concomitant
medications were not reported.
A male patient of 2 months of age (as reported) with a history
of hypertension experienced serious increase in blood
pressure (serious; blood pressure not reported). The patient
received treatment (unspecified), and the SAE was recovering
at the time of the report.
Case outcome: resolved/resolving and not resolved (4 each) and unknown (7).
No new significant safety information was identified based on a review of these cases.
Vaccine
effectivenesseRelevant cases for vaccine effectiveness during the reporting interval are reviewed in
Table 14, Lackof Efficacy .
a.Please note that this corresponds to evidence from post -EUA/conditional marketing authorisation
approval data sources;
b.Missing information as per both the EU -RMP Version 1.0, dated 21 December 2020 and the US PVP,
Version 0.2, dated 05 December 2020;
c.One case was excluded from the analysis as it did not involve pregnancy;
d.Missing information as per the EU -RMP Version 1.0, dated 21 December 2020;
e.Missing information as per the US PVP, Version 0.2, dated 05 December 2020;
f.Upon review, 1 3cases were excluded from analysi s as the data reported (e.g., clinical details, height,
weight, etc.) w ere not consistent for paediatric patients;
g.Applicable Medication Error PT Product administered to patient of inappropriate agewas added to 4of
the 1 5cases after the data -lock point ;
h.Details provided in these 2 individual case safety reports received from the UK MHRA seem
incongruent with a pediatric age, but no follow -up is possible for clarification .
Search Criteria for the Search and Inclusion of the R eports in the Special Population s
of Immunocompromised Patients, Patients With Autoimmune or Inflammatory
Disordersand Frail Patients With Co-Morbidities
As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002) received
on the first SMSR, the MAH was asked to clarify the criteria for the search and inclusion of
the reports in the special population of immunocompromised subjects to ensure proper
evaluation of the vaccine safety profile.
Criteria for the search and inclusion of the reports in the special population of
Immunocompromised Patients
Patients with Medical history ofPTs included in SMQ Malignancy related conditions
(Narrow and Broad); SMQ Malignancy related therapeutic and diagnostic procedures; SMQ
Malignant or unspecified tumours; HL GT Immunodeficiency syndromes (Primary Path);
HLT Retroviral infections (Primary Path); or of PTs Heart transplant; Pancreas islet cell
transplant; Small intestine transplant; Allogenic bone marrow transplantation therap y;
Allogenic stem cell transplantation; Autologous bone marrow transplantation therap y;
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Page 67Autologous haematopoietic stem cell transplant; Cord blood transplant therapy ; Bone
marrow transplant; Stem cell transplant; L iver transplant; Renal transplant; Lung transplant.
Criteria for the search and inclusion of the reports in the special population of Patients with
Autoimmune or Inflammatory Disorders
Patients with Medical history of PTs included in HLGT Autoimmune disorders (Primary
Path); I mmune disorders NEC (Primary Path); in HL T Neuromuscular junction dy sfunction
(Primary Path); in SMQ Immune -mediated/autoimmune disorders (N arrow and Broad).
Criteria for the search and inclu sion of the reports in the special population of Frail Patients
With Co -Morbidities
Patients with Medical history of PTs included in HLGTs (Primary Path when applicable)
Bronchial disorders (excl neoplasms), Heart failures, Mental impairment disorders,
Movement disorders (incl parkinsonism), Nephropathies, Pulmonary vascular disorders and
Renal disorders (excl nephropathies) and in HLTs (Pri mary Path when applicable)
Autonomic nervous s ystem disorders, Diabetes mellitus (incl subty pes), Hepatic failure and
associated disorders, Hepatic fibrosis and cirrhosis, Motor neurone diseases, Muscle tone
abnormal, Neuromuscular disorders NEC, Pulmonary hypertensions, Respiratory failures
(excl. neonatal) .
Criteria for Inclusion of Reports Overlapping Among Different Categories
(Immunocompromised Patients, Patients with Autoimmune or I nflammatory , Frail Patients
with Co -morbidities)
Frail patients of 70 years of age and older were considered frail even if they had also
an autoimmune/inflammatory or immunocompromised condition;
Any immunocompromised condition outweighed an autoimmune/inflammatory
condition if both were present and the patient was below the age of 70 years;
For any frail patient below the age of 70 years, medical histories conditions were
reviewed to evaluate which condition was the most relevant between theautoimmune
conditions or other co -morbidities .
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Page 6810.OVERALL BENEFIT -RISK EVALUATION
10.1.Benefits
BNT162b2 is indicated for active immunisation to prevent COVID -19 caused by
SARS -CoV -2 virus, in individuals 16 years of age and older.
In the Phase 2/3 portion, approximately 44,000 participants were randomised equall y and
were to receive 2 doses of COVID -19 mRNA Vaccine or placebo (normal saline) separated
by 21 day s. The efficacy anal yses included participants that received their second vaccination
within 19 to 42 day s after their first vaccination. Participants are planned to be followed for
up to 24 months after Dose 2, for assessments of safet y and efficacy against COVI D-19.
The population for the analy sis of the primary efficacy endpoint included 36,621 participants
12 years of age and older (18 ,242 in the COVID -19 mRNA Vaccine group and 18,379 in the
placebo group) who did not have evidence of prior infection with SARS -CoV -2 through 7
days after the second dose. In addition, 134 participants were between the ages of 16 to 17
years of age (66 in the COVID -19 mRNA Vaccine group and 68 in the placebo group) and
1616 participants 75 years of age and older (804 in the COVID -19 mRNA Vaccine group
and 812 in the placebo group).
At the time of the primary efficacy anal ysis, participants had been followed for symptomatic
COVID -19 for in total 2,214 person- years for the COVID -19 mRNA Vaccine and in total
2,222 person- years in the placebo group. There were no meaningful clinical differences in
overall vaccine efficacy in participants who were at risk of seve re COVID -19 including those
with 1 or more comorbidities that increase the risk of severe COVID -19 (e.g. asthma, bod y
mass index (BMI) ≥ 30 kg/m2, chronic pulmonary disease, diabetes mellitus, hy pertension).
The vaccine efficacy information is presented in Table 16.
Table 16.Vaccine efficacy –First COVID -19 occurrence from 7 days after Dose 2,
by age subgroup –participants witho ut evidence of infection prior to 7
days after Dose 2 –evaluable efficacy (7 days) population
First COVID -19 occurrence from 7 days after Dose 2 in participants without evidence of
prior SARS -CoV-2 infection*
Subgroup COVID-19 mRNA
Vaccine
Na=18,198
Cases
n1b
Surveillance timec
(n2d)Placebo
Na=18,325
Cases
n1b
Surveillance timec
(n2d)Vaccine efficacy
% (95% CI)f
All subjectse8
2.214 (17,411)162
2.222 (17,511)95.0 (90. 0, 97.9)
16 to 64 years 7
1.706 (13,549)143
1.710 (13,618)95.1 (89.6, 98.1)
65 years and older 1
0.508 (3848)19
0.511 (3880)94.7 (66.7, 99.9)
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Page 69Table 16.Vaccine efficacy –First COVID -19 occurrence from 7 days after Dose 2,
by age subgroup –participants witho ut evidence of infection prior to 7
days after Dose 2 –evaluable efficacy (7 days) population
First COVID -19 occurrence from 7 days after Dose 2 in participants without evidence of
prior SARS -CoV-2 infection*
Subgroup COVID-19 mRNA
Vaccine
Na=18,198
Cases
n1b
Surveillance timec
(n2d)Placebo
Na=18,325
Cases
n1b
Surveillance timec
(n2d)Vaccine efficacy
% (95% CI)f
65 to 74 years 1
0.406 (3074)14
0.406 (3095)92.9 (53.1, 99.8)
75 years and older 0
0.102 (774)5
0.106 (785)100.0 ( -13.1, 100.0)
Note: Confirmed cases were determined by Reverse Transcription -Polymerase Chain Reaction (RT -PCR)
and at least 1 symptom consistent with COVID -19 [* Case definition: (at least 1 of) fever, new or increased
cough, new or increased shortness of breath, chills, ne w or increased muscle pain, new loss of taste or smell,
sore throat, diarrhoea or vomitin g.]
*Participants who had no serological or virological evidence (prior to 7 days after receipt of the last dose)
of past SARS -CoV -2 infection (i.e., N -binding antibody [serum] negative at Visit 1 and SARS -CoV -2 not
detected by nucleic acid amplification tests (NAAT) [nasal swab] at Visits 1 and 2), and had negative NAAT
(nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
a. N = number of participants in the specified group.
b.n1=Number of participants meeting the endpoint definition.
c.Total surveillance time in 1000 person -years for the given endpoint across all subjects w ithin each group
at risk for the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the
surveillance period.
d.n2=Number of subjects at risk for the endpoint.
e.No confirmed cases were identified in participants 12 to 15 years of age.
f.Confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method
adjusted to the surveillance time. CI not adjusted for multiplicity.
In the second primary analy sis, compared to placebo, efficacy of COVID -19 mRNA Vaccine
in participants from first COVID- 19 occurrence from 7 day s after Dose 2 compared to
participants with or without evidence of prior infection with SARS -CoV -2 was 94.6% (9 5%
credible interval of 89.9% to 97.3%) in participants 16 y ears of age and older.
Additionally , subgroup analy ses of the primary efficacy endpoint showed similar efficacy
point estimates across genders, racial and ethnic groups, and participants with med ical
comorbidities associated with high risk of severe COVID -19.
10.2.Risks
As per the EU RMP Version 1.0, dated 21 December 2020 , traceabilit yis part of the routine
pharmacovigilance activities in place. During the reporting period i mproving ofthe design of
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Page 70traceability tools upon EMA request was implemented with the first pre -printed stickers with
batch/lot information delivered to 8 European markets (see Appendix 7 ).
Based on pharmacovigilance monitoring activities, since first authoris ation, anaphy laxis has
been recognised as an important identified risk. Facial paral ysis, pain in extremity , insomnia,
injection site pruritus and hy persensitivity (less severe than anaph ylaxis) were included in the
EU SmPC as adverse reactions in Section 4.8 at the request of the EMA at the time of
conditional approval of the vaccine. T he relevant signals , except for Facial paral ysis that it is
still under evaluation, were evaluated and closed during the reporting period ;according to the
Core Position, Hy persensitivity reactions (not Anaphy laxis) wasalso included after the data -
lock point of this SMSR as adverse reaction in the EUA Fact Sheet for the HCP and Full
EUA PI and is to be added in the CDS , Pain in extremity will be added to the EUA Fact
Sheet for the HCP and Full EUA PI and to the CDS , while Injection site pruritus and
Insomnia were considered as no risks with no further action warranted. Diarrhoea and
Vomiting were re -opened and evaluated as signals during the reporting period , they were
closed after the data -lock point of this SMSR and according to the Core Position they will be
added to labelling as adverse reaction s.
Based on all available safety and efficacy data for BNT162b2 the benefit-risk profile of the
vaccine remains favorable.
10.3.Overall Benefit -Risk
The identified risksassociated with the use of BNT162b2 are minimized through provision
of relevant product information in the RSI to support safe use of the product. Risks have been
evaluated in the context of the enumerated benefits of the product. Based on the available
safet y and efficacy data for BNT162b2, the overall benefit -risk profile of BNT162b2 remains
favourable.
11.CONCLUSION AND ACTIO NS
The MAH will continue to review the safet y of BNT162b2, including al l reports of adverse
experiences and will revise the product documents if an evaluation of the safety data yields
significant new information.
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1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
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2 This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Comirnaty con
centrate for dispersion for injec tion
COVID -19 mRNA Vaccine (nucleoside modified)
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
This is a m
ultidose vial and must be diluted before use.
One vial (0.45 mL) contains 6 dose
s of 0.3 mL after dilution , see section s 4.2 and 6.6.
1 dose (0.3 mL) contains 30 mi crograms of COVID-19 mRNA V accine (embedded in lipid
nanoparticles).
Single-stranded, 5’-capped messenger RNA (mRNA) produced using a cell- free in vitro trans
cription
from the corresponding DNA templates, encoding the viral spike (S) protein of SARS -CoV -2.
For the full list of excipien ts, see secti on 6.1.
3. PHARMACEUTICAL FORM
Concentrate f
or dispersion for injection (st erile concentrate) .
The vaccine is a white to off- white frozen dis persion ( pH: 6.9 - 7.9).
4. C LINICAL PARTICULARS
4.1 Therapeutic indications
Comirnaty is
indicated for a ctive immunisatio n to prevent COVID-19 caused by SARS -CoV-2 virus,
in individuals 16 years of age and older .
The use of this vaccine should b
e in accordance with o fficial recommendations.
4.2 Posology and method of administratio n
Posology
Individuals 16 years of age and older
Comirnaty is administered intramuscularly after dilution as a course of 2 doses (0.3 mL each). It is
recommended to administer the second dose 3 weeks after the first dose (see sections 4.4 and 5.1).
There are no data available on the interchangeability of Comirnaty with other COVID- 19 vaccines to
complete the vaccination course. Individuals who have received 1 dose of Comirnaty should receive a
second dose of Co mirnaty to complete the vaccination course.
Paediatric population The safety and efficacy of Comirnaty in children and adolescents
aged less than 16 years of age have
not yet been established. Limited data are available.
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3
Elderly population
No dosage adjustment is required in elderly individuals ≥ 65 years of ag e.
Method of administration
Comi rnaty should be administered intramuscularly after dilution (see section 6.6).
After dilution, vials of Comirnaty contain six doses of 0.3 mL of vaccine. In order to extract six doses
from a singl
e vial, low dead -volume syringes and/or needles should be used . The low dead -volume
syringe and needle combination should have a dead volume of no more than 35 microlitres . If standard
syringes and needles are used, there may not be sufficient volume to extract a sixth dose from a single
vial. Irrespective of the type of syringe and needle:
• Each dose must contain 0.3 mL of vaccine.
• If the amount of vaccine remaining in the vial cannot provide a full dose of 0.3 mL, discard the
vial and any excess volume.
• Do not pool excess vaccine from multiple vials.
The prefer
red site is the deltoid muscle of the upper arm.
Do not inject the vaccine intravascularly, sub cutaneously or intradermally.
The vaccine should not be mixed in the same syringe with any other vaccines or medicinal produc
ts.
For precautions to be taken before administering the vaccine, see section 4.4.
For instructions regarding thawing, handling and disposal of the vaccine, see section 6.6.
4.3 Contraindications
Hypersensit
ivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceabili ty of biological medicinal products, the name and the batch number
of the administered product should be clearly recorded.
General recommendations
Hypersensitivity and anaphylaxis
Events of anaphylaxis have been reported. Appropriate medical treatment and supervision should
always be readi
ly available in case of an anaphylactic reaction following the administration of the
vaccine.
Close observation for at least 15 minutes is recommended following vaccination. A second dose of t he
vaccine should not be given to those who have experienced anaphylaxis to the first dose of Comirnaty. Anxiety -related reactions
Anxiety-rel
ated reactions, including vasovagal reactions (syncope), hyperventilation or stress ‐related
reacti
ons may occur in association with vaccination as a psychogenic response to the needle injection.
It is important that precautions are in place to avoid injury from fainting.
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4 Concurrent illness
Vaccination should be postponed in individuals suffering from acute severe febrile illness or acute
infection. The
presence of a minor infection and/or low -grade fever should not delay vaccination.
Thrombocytopenia and coagulation disorders
As with other intramuscular injections , the vaccine shoul d be given with caution in individ uals
receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as
haemophilia) because bleeding or bruising may occur following an intramuscular administration in
these individuals.
Immunocompromised individuals
The efficacy, safety and immunogenicity of the vaccine has not been assessed in immunocompromised
individuals
, including those receiving immunosuppressant therapy. The efficacy of Comirnaty may be
lower in immunosuppressed individuals.
Duration of protection
The duration of protection afforded by the vaccine i s unknown as it is still being determined by
ongoing clinical trials.
Limitations of vaccine effectiveness
As with any vaccine, vaccination with Comirnaty may not prot ect all vaccine recipients. Individuals
may not be fully protected until 7 days after their second dose of vaccine.
Excipient s
This vaccine contains less than 1 mmol potass ium (39 mg) per dose, that is to say essentially
‘potassium- free’.
This vaccine contains less than 1 mmol sodium (
23 mg) per dose, that is to say essentially
‘sodium -free’.
4.5 Interaction with other medicinal products and other forms of interaction
No interact
ion studies have been performed.
Concomitant administration of Comirnaty with other vaccines has not been studied.
4.6 Fertility, p regnancy and l actation
Pregnancy
There is limited experience with use of Comirnaty in pregnant women. Animal studies do not indicate
direct or indir
ect harmful effects with respect to pregnancy, embryo/foetal development, parturition or
post-natal development (see section 5.3). Administration of Comirnaty in pregnancy should only be
considered when the potential benefits outweigh any potential risks for the mother and f oetus.
Breast -feeding
It is unknown whether Comirnaty is excreted in human milk.
Fertility
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
(see section 5.
3).
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5 4.7 Effects on ability to drive and use machines
Comirnaty has no or negligible influence on the ability to drive and use machines. However, some of
the effects men
tioned under section 4.8 may temporarily affect the ability to drive or use machines.
4.8 Undesirable effects
Summary of safety profile
The safety of Comirnaty was evaluated in participants 16 years of age and older in 2 clinical studies
that included 21,744 participants that have received at least one dose of Comirnaty.
In Study 2, a total of 21,720 participants 16 years of age or older received at least 1 dose of Comirnaty
and a total of 21,728 participants 16 years of age or older received placebo (including 138 and
145 adolescents 16 and 17 years of age in the vaccine and placebo groups, respectively). A total of
20,519 participants 16 years of age or older received 2 doses of Comirnaty.
At the time of the analysis of Study 2, a total of 19,067 (9,531 Comirnaty and 9,536 placebo)
participants 16 years of age or older were evaluated for safety for at least 2 months after the second
dose of Comirnaty. This included a total of 10,727 (5,350 Comirnaty and 5,377 placebo) participants
16 to 55 years of age and a total of 8,340 ( 4,181 Comirnaty and 4,159 placebo) participants 56 years
and older.
The most frequent adverse reactions in participants 16 years of age and older were injection site pain
(> 80% ), fatigue ( > 60% ), headache ( > 50%), myalgia and chills ( > 30%), arthralgia (> 20 %), pyrexia
and injection site swelling (> 10%) and were usually mild or moderate in intensity and resolve d within
a few days after vaccination. A slightly lower frequency of reactogenicity events was associated with
greater age.
Tabulated list of a dverse reactions from clinical studies
Adverse reactions observed during clinical studies are listed below according to the following
frequency cat
egories:
Very common (≥ 1/10),
Common (
≥ 1/100 to < 1/ 10),
Uncommon (≥ 1/1,000 to < 1/100),
Rare (≥ 1/10,000 to < 1/1,000),
Very rare (< 1
/10,000),
Not
known (cannot be estimated from the available data).
Table 1: Adverse reaction s from Comirnaty c linical t rials
System Organ
Class Very
common
(≥ 1/10) Com mon
(≥ 1/100
to
< 1/10) Uncomm
on
(≥ 1/1,000 to
< 1/100) Rare
(≥ 1/ 10,000
to < 1/1,000) Not known
(cannot be
estimated from
the available
data)
Blood and
lymphatic
system disorders Lymphadenopathy
Immune system
disorders Anaphylaxis;
hypersensitivity
Psychiatric
disorders Insomnia
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6 System Organ
Class Very
common
(≥ 1/10) Com mon
(≥ 1/100
to
< 1/10) Uncomm
on
(≥ 1/1,000 to
< 1/100) Rare
(≥ 1/ 10,000
to < 1/1,000) Not known
(cannot be
estimated from
the available
data)
Nervous system
disorders Headache Acute
peripheral
facial
paralysis†
Gastrointestinal
disorders Nausea
Musculoskeletal
and connective
tissue disorders Arthralgia;
myalgia Pain in extremity
General
disorders and
administration site conditions Injection
site pain ;
fatigue;
chills;
pyrexia*;
injection site
swelling Injection
site redness Malaise; injection
site pruritus
* A higher frequency of pyrexia was observed after the 2nd dose.
† Throughout the safety follow -up period to date, acute peripheral facial paralysis (or palsy) was reported by
four participants in the COVID -19 mRNA Vaccine group. Onset was Day 37 after Dose 1 (participant did not
receive Dose 2) and Days 3, 9, and 48 afte r Dose 2. No cases of acute peripheral facial paralysis (or palsy)
were reported in the placebo group.
The safety profile in 545 subjects rec eiving Comirnaty, that were seropositive for S ARS -CoV-2 at
baseline, was similar to that seen in the general population.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal pr oduct. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V and include batch /Lot number if available.
4.9 Overdose
Overdose data
is available from 52 study participants included in the clinical trial that due to an error
in dilution rec
eived 58 micrograms of Comirnaty . The vaccine recipients did not report an increase in
reactogenicity or adverse reactions.
In the event of overdose, monitoring of vital functions and possible symptomatic treatment is
recommended.
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7 5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacothe
rapeutic group: vaccines, other viral vaccines, ATC code: J07BX03
Mechanism of action
The nucleoside -modified messen ger RNA in Comirnaty is formulated in lipid nanoparticles, which
enable delivery of the non replicating RNA into host cells to direct transient expression of the
SARS -CoV -2 S antigen. The mRNA codes for me mbrane -anchored, full -length S with two point
mutations within the central helix. Mutation of these two amino acids to proline locks S in an
antigenically preferred prefusion conformation. The vaccine elicits both neutralizing antibody and
cellular immune responses to the spike (S) antigen, which may contribute to protection against
COVID -19.
Efficacy
Study 2 is a multicent re, multinat ional, Phase 1/2/3 randomised, placebo -controlled , observer-blind
dose-finding, vaccine candidate selection and efficacy study in participants 12 years of age and older. Randomisation was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or
56 years of age and older, with a minimum of 40% of participants in the ≥ 56-year stratum. The study
excluded participants who were immunocompromised and those who had previous clinical or
microbiological diagnosis of COVID-19. Participants with pre- existing stable disease, defined as
disease not requiring significant chan ge in therapy or hospitalization for worsening disease during the
6 weeks before enrolment, were included as were participants with known stable infection with human
immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV). At the time of the analysis of Study 2, information presented is based on participants 16 years and older.
Efficacy in participants 16 years of age and older
In the Phase 2/3 portion, approximately 44,000 participants were randomised equally and were to
receive 2 dose
s of COVID-19 mRNA Vaccine or placebo separated by 21 days. The efficacy analyses
included participants that received their second vaccination within 19 to 42 days after t heir first
vaccination. The majority ( 93.1%) of vaccine recipients received the second dose 19 days to 23 days
after Dose 1. Participants are planned to be followed for up to 24 months after D ose 2 , for assessments
of safety and efficacy against COVID-19. In the clinical study, participants were required to observe a minimum interval of 14 days before and after administration of an influenza vaccine in order to receive either placebo or COVID -19 mRNA Vaccine. In the clinical study, participants we re required
to observe a minimum interval of 60 days before or after receipt of blood/plasma products or
immunoglobulins within through conclusion of the study in order to receive either placebo or COVID -19 mRNA Vaccine.
The population for the analysis of the primary efficacy endpoint included, 36,621 participants 12 years
of age and older
(18,242 in the COVID-19 mRNA Vaccine group and 18,379 in the placebo group)
who did not have evidence of prior infection with SARS- CoV -2 through 7 days after the second dose.
In addition, 134 participants were between the ages of 16 to 17 years of age (66 in the COVID-19 mRNA Vaccine group and 68 in the placebo group) and 1,616 participants 75 years of age and older
(804 in the COVID-19 mRNA Vaccine group and 812 in the placebo group).
Efficacy against COVID -19
At the time of the primary e fficacy analysis , participants had been followed for symptomatic
COVID -19 for in total 2,214 person-years for the COVID -19 mRNA Vaccine and in total
2,222 person- years in the placebo group.
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8 There were no meaningful clinical differences in overall vaccine efficacy in participants who were at
risk of severe COVID -19 including those with 1 or more comorbidities that increase the risk of severe
COVID -19 (e.g. asthma, body mass index ( BMI ) ≥ 30 kg/m2, chronic pulmonary disease, diabetes
mellitus, hypertension).
The vaccine efficacy information is presented in Table 2.
Table 2: Vaccine efficacy – F irst COVID -19 occurrence from 7 days after Dose 2, by age
subgroup – participants without evidence of infection prior to 7 days after Dose 2 –
evaluable efficacy (7 days) population
First COVID -19 occurrence from 7 days after Dose 2 in participants without evidence of prior
SARS -CoV -2 infection*
Subgroup COVID -19 mRNA
Vaccine
Na = 18,198
Cases
n1b
Surveillance timec (n2d) Placebo
Na = 18,325
Cases
n1b
Surveillance timec (n2d) Vaccine efficacy
% (95% CI)f
All subjectse 8
2.214 (17,411) 162
2.222 (17,511) 95.0 (90.0, 97. 9)
16 to 64 years 7
1.706 (13,549) 143
1.710 (13,618) 95.1 (89.6, 98.1)
65 years and older 1
0.508 (3848) 19
0.511 (3880) 94.7 (66.7, 99.9)
65 to 74 years 1
0.406 ( 3074) 14
0.406 (3095) 92.9 (53.1, 99.8)
75 years and older 0
0.102 (774) 5
0.106 (785) 100.0 (-13.1, 100.0)
Note: Confirmed cases were determined by Reverse Transcription -Polymerase Chain Reaction (RT -PCR) and
at least 1 symptom consistent with COVID -19 [*Case definition: (at least 1 of) fever, new or increased cough,
new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore
throat, diarrhoea or vomiting. ]
* Participants who had no serological or virological evidence (prior to 7 days after receipt of the last dose) of
past SARS -CoV -2 infection (i.e., N -binding antibody [serum] negative at Visit 1 and SARS -CoV -2 not
detected by nucleic acid amplification tests (NAAT ) [nasal swab] at Visits 1 and 2), and had negative
NAAT (nasal swab) at any unscheduled v isit prior to 7 days after Dose 2 were included in the analysis.
a. N = number of participants in the spec ified group.
b. n1 = Number of participants meeting t he endpoint definition.
c. Total surveillance time in 1000 person -years for t he given endpoint across all subjects within each group at
risk for the endpoint. Time period for COVID -19 case accrual is from 7 days after Dose 2 to the end of the
surveillance period.
d. n2 = Number of subjects at risk for the endpoint.
e. No confir
med cases wer e identi fied in participants 12 to 15 years of age.
f. Confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson method adjusted
to the surveillance time. CI not adjusted for multiplicity .
In the second primary analysis, compared to placebo, efficacy of COVID- 19 mRNA Vaccin e in
participants from first COVID -19 occurrence from 7 days after Dose 2 compared to participants with
or without evidence of prior infection with SARS- CoV -2 was 94.6% (95% credible interval of 89.9%
to 97.3%) in participants 16 years of age and older.
Additionally, subgroup analyses of the primary efficacy endpoint showed similar efficacy point
estimates across ge
nders, ethnic groups, and participants with medical comorbidities associated wi th
high risk of severe COVID -19.
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9 Paediatric population
The European Medicines Agency has deferred the obligation t o submit the results of studies with
Comirnaty in the paediatric population in prevention of COVID-19 (see section 4.2 for information on
paediatric use).
This medicinal product has been authorised under a so- called ‘condi tional approval’ scheme. This
means that further evidence on this medicinal product is awaited. The European Medicines Agency
will review new information on this medicinal product at least every year and this SmPC will be
updated as necessary.
5.2 Pharmacokinetic properties
Not applicab
le.
5.3 Preclinical safety data
Non-clinical
data reveal no special hazard for humans based on conventional studies of repeat dose
toxicity and r
eproductive and developmental toxicity.
General toxicity
Rats intramuscularly administered Comirnaty (receiving 3 full human doses once weekly , generating
relatively higher levels in rats due to body weight differences) demonstrated some injection site
oedema and erythema and increases in white blood cells (including basophils and eosinophils)
consistent with an inflammatory response as well as vacuolation of portal hepatocytes without evidence of liver injury. All effects were reversible.
Genotoxicity /Carcinogenicity
Neither genotoxicity nor carcinogenicity studies were performed. The components of the vaccine (lipids
and mRNA) ar
e not expected to have genotoxic potential.
Reproductive toxicity
Reproductive and developmental toxicity were investigat ed in rats in a combined fertility and
developmental toxicity study where female rats were intramuscularly administered Comirnaty prior to
mating and during gestation (receiving 4 full hu man doses that generate relatively higher levels in rat
due to body weight differences, spanning between pre-mating day 21 and gestational day 20).
SARS -CoV -2 neutralizing antibody responses were present in maternal animals from prior to mating
to the end of the study on postnatal day 21 as well as in foetuses and offspring . There were no
vaccine- related effects on female fertility, pregnancy, or embryo-foetal or offspring development. No
Comirnaty data are available on vaccine placental transfer or excretion in milk.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
((4-hydroxybuty
l)azanediyl)bis(hexane-6,1- diyl)bis (2-hexylde canoate) (ALC -0315)
2-[(polyethylene glycol)-2000]-N,N- ditetradecy lacetamide (ALC -0159)
1,2-Distearoyl -sn-glycero -3-phosphoc holine (DSPC)
Cholesterol
Potassium chloride
Potassium dihydrogen phosphate
Sodium chlor
ide
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10 Disodium phosphate dihydrate
Sucrose
Water for injections
6.2 Incompatibilities
This medicin
al product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Unopened vial
6 months at -90 °C to -60 °C.
Once removed
from the freezer, the unopened vac cine can be stored for up to 5 days at 2 °C to 8 °C,
and up to 2 hours at temperatures up to 30 °C, prior to use.
Once thawed, the vaccine should not be re-frozen.
Closed -lid vial trays containing 195 vials removed from frozen storage (< -60 °C) may b
e at room
temperature (< 25 °C) for up to 5 minutes for transfer between ultra-low- temperature environments.
After vial trays are returned to frozen storage following room temperature exposure, they must remain
in frozen storage for at least 2 hours before they can be removed again.
Diluted medicinal product
Chemical and physical in-use stabil ity has been demonstrated for 6 hours at 2 ºC to 30 ºC after dilution
in sodium chloride 9 mg/mL (0.9%) solution for injection. From a microbiological point of view, the
product should be used immediately. If not used immediately, in-use storage times and conditions are
the responsibility of the user.
6.4 Special precautions for storage
Store in a
freezer at -90 °C to -60 °C.
Store in the original package in order to protect from light.
During storage, minimise exposure to room light, and avoid exposure to direct sunlight and ultraviolet
light.
Thawed vi
als can be handled in room light conditions.
When you are ready to thaw or use the vac cine
• Open -lid vial t rays, or vial trays containing less than 195 vials removed from frozen storage
(< -60 °C) may be at room temperature (< 25 °C) for up to 3 minutes to remove vials or for
transfer between ultra-low-temperature environments.
• Once a vial is removed from the vial tray, it should be thawed for use.
• After vial trays are returned to frozen storage following room temperature exposure, they must
remain in f
rozen storage for at least 2 hours before they can be removed again.
For storage conditions after thawing and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container
2 mL clear mul
tidose vi al (type I glass) with a stopper ( synthetic bromobutyl rubber ) and a flip -off
plastic cap with aluminium seal. Each vial contains 6 doses, see section 6.6 .
Pack size: 195 vials
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11
6.6 Special precautions for disposal and other handling
Handling instructions
Comirnaty should be prepared by a healthcare professional using aseptic technique to ensure the
sterility o
f the prepared dispersion .
THAWING PRIOR TO DILUTION
• The multidose vial is stored frozen and
must be thawed prior to dilution.
Frozen vials should be transferred to an
environment of 2 °C to 8 °C to thaw; a
195 vial pack may take 3 hours to thaw.
Alternatively, frozen vials may also be thawed for 30 minutes at temperatures
up to 30 °C for immediate use.
• Allow the thawed vial to come to room
temperature and gently invert it 10 times prior to dilution. Do not shake.
• Prior to dilution, the thawed dispersion
may contain white to off-white opaque
amorphous particles.
DILUTION
• The thawed vaccine must be diluted in
its original vial with 1.8 mL sodium
chloride 9 mg/mL (0.9%) solution for
injection, using a 21 gauge or narrower
needle and aseptic techniques.
No more than
2 hours at
room
temperature
(up to 30 °C)
1.8 mL of 0.9% sodium chloride
injection
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12
• Equalise vial pressure before removing
the needle from the vial stopper by
withdrawing 1.8 mL air into the empty
diluent syringe.
• Gently invert the diluted dispersion
10 times. Do not shake.
• The diluted vaccine should present as an off- white dispersion with no
particulates visible. Discard the diluted vaccine if particulates or discolouration are present.
Pull back plunger to 1.8 mL to
remove air from vial
Gently x 10
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13
• The diluted vials should be marked
with the appropriate date and time.
• Do not freeze or shake the diluted
dispersion. If refrigerated, allow the diluted dispersion to come to room
temperature prior to use.
PREPARATION OF INDIVIDUAL 0.3 mL DOSES OF COM IRNATY
• After dilution, the vial contains
2.25 mL from which 6 doses of 0.3 mL
can be extracted .
• Using aseptic technique, cleanse the vial stopper w
ith a single- use antiseptic
swab.
• Withdraw 0.3 mL of Comirna ty.
Low dead-volume syringes and/or
needles should
be used in order to
extract 6 doses from a single vial. The
low dead-volume syringe and needle
combination should have a dead volume of no more than 35 microlitres.
If standard syringes and needles are
used, there
may not be sufficient
volume to extract a sixth dose from a
single vial.
• Each dose must contain 0.3 mL of vaccine.
• If the
amount of vaccine remaining in
the vial ca
nnot provide a full dose of
0.3 mL, discard the vial and any excess
volume.
• Discard any unused vaccine within
6 hours after di
lution.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local
requirement
s.
Record appropriate date and time.
Use within 6 hours after dilution
0.3 mL diluted
vaccine
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14 7. MARKETING AUTHORISATION HOLDER
BioNTech Manufacturing GmbH
An der Goldgrube 12 55131 Mainz Germany
Phone: +49 6131 90840 Fax: +49 6131 9084390
info@bionte ch.de
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/20/1528
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of firs
t authorisation: 21 December 2020
10. DATE OF REVISION OF THE TEXT
Detailed
information on this medicinal product is available on the website of the European Medicines
Agency http
://www.ema.europa.eu .
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