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PF-07302048 (BNT162b2) Reporting Period
Summary Monthly Safety Report ( SMSR) 3 01 February 2021 through 28 February 2021
CONFIDENTIAL
Page 1SUMMARY MONTHLY SAFETY REPORT 3
for
ACTIVE SUBSTANCE: PF-07302048 (BNT162b2)
ATC CODE: J07BX 031
AUTHORISATION PROCEDURE in the EU: Centralised
INTERNATIONAL BIRTH DATE (IBD):219 December 2020
EUROPEAN UNION REFERENCE DATE (EURD): 21 December 2020
INTERVAL COVERED BY THIS REPORT:
01 FEBRUARY 2021 through 28 FEBRUARY 2021
DATE OF THIS REPORT: 12MARCH 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 Pfizer and BioNTech , their Affiliates, their Licensees, or Regulatory
Agencies is stri ctly prohibited. Except as may be otherwise agreed to in writing, by accepting or reviewing these materials,
you agree to hold such information in confidence and not to disclose it to others (except where required by applicable law),
nor to use it for unau thorized purposes.
1Temporary ATC code.
2It corresponds to the earliest conditional approval date.
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Page 2EXECUTIVE SUMMARY
This is the 3rdSummary Monthly Safet y Report (SMSR) for PF-07302048 [Coronavirus
disease 2019 (COVID -19) mRNA Vaccine, hereafter referred to as BNT162b2) ], covering
thereporting interval 01February 2021 through 28 February 2021 .
BNT162b2 is a white to off -white frozen dispersion (pH: 6.9 - 7.9), provided as concentrate
for dispersion for injection (sterile concentrate) as multidose vial to be diluted before use.
The multidose vial contains 6 doses of 0.3 mL after dilution ; low dead -volume sy ringes
and/or needles should be used in order to extract 6 doses from a single vial. The low
dead -volume s yringe and needle combination should have a dead volume of no more than 35
microlitres. If standard sy ringes and needles a re used, there may not be sufficient volume to
extract a sixth dose from a single vial. Each dose contains 30 micrograms of BNT162b2
embedded in lipid nanoparticle s(LNPs ). The vaccine also contains
(4-hydroxybutyl)azanediy l)bis(hexane -6,1-diyl)bis(2 -hexyldecanoate) (ALC -0315), 2-
[(poly ethylene gl ycol) -2000] -N,N-ditetradecy lacetamide (ALC -0159), 1,2 -Distearo yl-sn-
glycero-3-phosphocholine (DSPC), cholesterol, potassium chloride, potassium dihy drogen
phosphate, sodium chloride, disodium hydrogen phosphate dih ydrate, sucrose and water for
injections as excipients.
BNT162b2 is highly purified single -stranded, 5’ -capped mRNA produced using a cell- free in
vitro transcription from the corresponding DNA templates, encoding the viral spike (S)
protein of severe acute respiratory syndrome coronavirus 2 ( SARS -CoV -2). The nucleoside -
modified mRNA is formulated in L NPs, which enable delivery of the RNA into host cells to
allow expression of the SARS- CoV -2 S antigen. The vaccine elicits both neutralizing
antibody and cellular immune responses to the spike (S) antigen, which may contribute to
protection against COVID-19.
BNT162b2 is indicated for active immunisation to prevent COVID -19 caused by
SARS -CoV -2 virus, in individuals 16 years of age and older. No dosage adjustment is
required in elderl y individuals ≥65 y ears of age. It is administered intramuscularly in the
deltoid muscle after dilution as a series of 2 doses (0.3 mL each) at greater than or equal to
21 day s(prefer ably 3 weeks) apart.
It is estimated that approximately 126,212,580doses of BNT162b2 were shipped worldwide
from the receipt of the first temporary authorisation for emergency suppl y on
01December 2020 through 28 February 2021 and that approximately 59,939,685doses of
BNT162b2 were shipped worl dwide during the current reporting interval from
01February 2021through 28 February 2021.
BNT162b2 has received temporary authori sation for emergency suppl y in28 countries and
conditional marketing authorisation approval in 39 c ountries globally .
The RSI for this SMSR is the BNT162b2 CDS Version 1.0, dated 12 February 2021, in effect
at the end of the reporting period. After the data -lock point of this SMSR , on 02 March 2021,
the CDS was updated with the following safet y-related changes: Diarrhoea, Pai n in extremity
(arm) and Vomiting were added as adverse reactions in Section 4.8 Undesirable effects.
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Page 3During the reporting period, the following safet y topics and signals were addressed:
Diarrhoea was evaluated and was added to the RSI as an adverse reaction;*
Vomiting was evaluated and was added to the RSI as an adverse reaction;*
Delay ed syncope was evaluated and determined not to be a risk;
Eye pain and Ey e swelling were evaluated and determined not to be risks;
Hearing loss and Tinnitus wereevaluated a nd determined not to be risks;
Dizziness was evaluat ed and subsequentl y subsumed in an evaluation of vaccine
stress --related responses that is ongoing ;
Immune thrombocy topenia was evaluated and determined not to be a risk;
Facial paral ysis was evaluated and determined not to be a risk at this time; but will be re-
evaluated once final safety data from the Study C4591001 is available in mid
-April 2021;
Herpes Zoster evaluation is ongoing;
Paraesthesia and Dy saesthesia were evaluated subsequently subsumed in an evaluation of
vaccine stress- related responses that is ongoing ;
Tach ycardia was subsumed in an evaluation of vaccine stress- related responses that is
ongoing ;
Guillain -Barre s yndrome was a safet y topic determined not to be a validated signal ;
Myocarditis and pericarditis were safety topic sdetermined not to be a validated signal;
Severe cutaneous adverse reactions were safety topic sdetermined not to be a validated
signal .
*Diarrhoea and Vomiting were determined as identified risks (not important for the purpose
of inclusion in the Risk Management Plans and Pharmacovigilance Plans) ; the related events
were added as adverse reactions to the RSIafter the data -lock point of this SMSR , on
02March 2021 .
Based on the new safet y and efficacy /effectiveness data from the reporting interval for
BNT162b2, the benefit -risk profile of BNT162b2 remains favorable.
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Page 4TABLE OF CONTENTS
EXECUTIVE SUMMARY ................................ ................................ ................................ .......2
LIST OF TABLES ................................ ................................ ................................ ..................... 5
LIST OF FIGURES ................................ ................................ ................................ ................... 5
APPENDI CES ................................ ................................ ................................ ........................... 6
LIST OF ABBREVIATION S................................ ................................ ................................ ....8
1. INTRODUCTION ................................ ................................ ................................ ............... 10
2. WORLDWIDE APPRO VAL OR AUTHORI SATION STATUS ................................ ......11
3. ACTIONS TAKEN IN THE REPORTING INTERV AL FOR SAFETY REASON S ....... 11
4. CHANGES TO REFERENCE SAFETY INFORMATI ON................................ ............... 11
5. ESTI MATED EXPOSUR E AND USE PATTERNS ................................ .......................... 11
5.1. Cumulative and I nterval Exposure Data ................................ ................................ .11
6. DATA IN SUMMARY T ABU LATIONS ................................ ................................ ........... 14
6.1. Reference Information ................................ ................................ ............................. 14
6.2. Cumulative and I nterval Summary Tabulations from Post -Marketing Data
Sources ................................ ................................ ................................ ...................... 15
7. MEDI CATION ERRORS ................................ ................................ ................................ ....17
8. GENERAL OVERVIEW ................................ ................................ ................................ .....25
9. SI GNAL AND RISK E VALUATION ................................ ................................ ................ 43
9.1. L iterature Review ................................ ................................ ................................ ....43
9.2. Overv iew of Signals During the Reporting Interval ................................ ............... 43
9.3. Summary of Safet y Concerns ................................ ................................ .................. 44
9.4. Summary of Adverse Events of Special Interest (AESIs) ................................ .......45
9.5. Evaluation of Safet y Concerns ................................ ................................ ................ 45
9.5.1. Evaluation of Important Identified and Important Potentia l Risks ............. 45
9.5.2. Evaluation of AESIs ................................ ................................ ................... 53
9.5.3. Evaluation of Special Situations ................................ ................................ .65
9.5.4. Evaluation of Missing Information ................................ ............................. 70
10. OVERALL BENEFIT- RISK EVALUATION ................................ ................................ ..76
10.1. Benefits ................................ ................................ ................................ .................. 76
10.2. Risks ................................ ................................ ................................ ...................... 77
10.3. Overall Benefit- Risk ................................ ................................ ............................. 78
11. CO NCL USION AND ACTIONS................................ ................................ ...................... 78
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Page 5LIST OF TABLES
Table 1. List of SMSRs ................................ ................................ ................................ .......10
Table 2. Cumulative Estimated Shipped Doses of BNT162b2 by Region Worldwide ......12
Table 3. Interval Estimated Shipped Doses of BNT162b2 by Region Worldwide ............ 13
Table 4. Interval/Cumulative Estimated Shipped Doses of BNT162b2 b y EU
Countries (30) ................................ ................................ ................................ .......14
Table 5. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval ................................ ................................ ........................... 25
Table 6. Events Reported in ≥2%* Cases ................................ ................................ ......... 31
Table 7. Overview of Signals ................................ ................................ ............................. 43
Table 8. Safety Concerns ................................ ................................ ................................ ....44
Table 9. Risks Evaluation for BNT162b2 ................................ ................................ .......... 45
Table 10. AESI s Evaluation for BNT162b2................................ ................................ ......... 53
Table 11. Evaluation of Special Situations for BNT162b2 ................................ .................. 65
Table 12. Evaluation of Missing Information for BNT162b2 ................................ .............. 70
Table 13. 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 ................................ .76
LIST OF FIGURES
Figure 1. Case Outcome b y Presence of Relevant Comorbidities ................................ .......26
Figure 2. Case Outcome b y Presence of Relevant Comorbidities, Gender and Age
Group ................................ ................................ ................................ .................... 27
Figure 3. Fatal Case Outcome b y Presence of Relevant Comorbidities and Age
Group ................................ ................................ ................................ .................... 29
Figure 4. General Overview: Total Number of Events by MedDRA SOC and Event
Seriousness ................................ ................................ ................................ ........... 30
Figure 5. Events Reported in ≥2%Cases in the Interval Period by Gender ...................... 33
Figure 6. PTReported in ≥2% in the I nterval Period -by SOC and Age Group ............... 34
Figure 7. Events Reported in ≥2% in the Interval Period by Age Group within
Gender ................................ ................................ ................................ ................... 41
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Page 6APPENDICES
APPENDIX 1 REFERENCE INFORMATIO N (CDS 12 FEBRUARY 202 1) ........................79
APPENDIX 2 INTERVAL NUMBER OF CASE REPOR TS [(SERIOUS AND NON -
SERI OUS, MEDICALLY C ONFIRMED AND NON -MED ICALLY CONFIRMED)
FROM POST-MARKETING DATA SOURCES, OVERALL, BY SEX, COUNTRY,
AGE GROUPS AND IN SPECIAL POPUL ATIONS ] AND SUMMARY TABULA TION
BY PREFERRED TERM AN D MEDDRA SYSTEM ORGA N CLASS .........................99
APPENDIX 2.1 CUMULAT IVE NUMBER OF CASE R EPORTS [(SERIOUS AND NON-
SERI OUS, MEDICALLY C ONFIRMED AND NON -MED ICALLY CONFIRMED)
FROM POST-MARKETING DATA SOURCES, OVERALL, BY SEX, CO UNTRY,
AGE GROUPS AND IN SP ECIAL POPULATIONS ] AND SUMMARY TABULA TION
BY PREFERRED TERM AN D MEDDRA SYSTEM ORGA N CLASS ........................155
APPENDIX 2.2 INTERVA L SUMMARY TABULATION OF CASE REPORTS WI TH DME
EVENTS FROM POST -MAR KETING DATA SOURCES ................................ ........... 219
APPENDIX 2.3 CUMULAT IVE AND INTERVAL SUMMARY TAB ULAT ION OF
SERI OUS AND NON -SERI OUS CASE REPORTS FRO M POST -MARKETING DATA
SOURCES BY MEDI CAL LYCONFI RMED AND NON -MEDICALLY CONFIRMED,
REGION AND COUNTRY ................................ ................................ .............................222
APPENDIX 2.4 CUMULAT IVE AND INTERVAL SUM MARY TABULATION OF F ATAL
CASE REPORTS FROM POST -MARKETING DATA SOURCES BY COUNTRY
................................ ................................ ................................ ................................ ......... 228
APPENDIX 2.5 CUMULAT IVE AND INTERVAL SUM MARY TABULATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY
PREFERRED TERM ................................ ................................ ................................ ........ 230
APPENDIX 2.5.1 CUMUL ATIVE AND INTERVAL SU MMARY TABULATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY
PREFERRED TERM PER C OUNTRY ................................ ................................ ........... 322
APPENDIX 2.5.2 CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF
SERI OUS A ND NON -SERI OUS ADVER SE REACTIONS FROM PO ST-MARKETING
DATA SOURCES ORGANIZED PER AGE GROUP BY PREFERRED TERM P ER
COUNTRY ................................ ................................ ................................ ......................1008
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 ................................ ................................ ................................ ......................1939
APPENDIX 2.5.4 CUMULATIVE AND INTERVAL SUMMARY TABULAT ION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PER PATIENTS WI TH RELEVA NT CO -
MORBIDIT IES BY PREFERRED TERM PER COUNTRY ................................ ......... 2600
APPENDIX 2.6 CUMULAT IVE AND INTERVAL SUM MARY TABULATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
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Page 7DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY HIGH
LEVE L TERM ................................ ................................ ................................ ................2818
APPENDIX 2.6.1 CUMUL ATIVE AND INTERVAL S UMMARY TABULATION OF
SERI OUS AND NON -SERI OUS ADVERSE REACTION S FROM POST- MARKETIN G
DATA SOURCES ORGANIZED PER MEDDRA SYSTEM ORGAN CLASS BY HIGH
LEVE L TERM PER COUNTRY ................................ ................................ ................... 2854
APPENDIX 3 TABULAR S UMMARY OF SAFETY TOPI CS AND SIGNAL SEVALUATED
DURING THE REPORTING PERIOD ................................ ................................ .........3327
APPENDIX 3.1 SUMMARY OF SAFETY TO PICS AND SI GNAL EVALUATIONS .......3324
APPENDIX 3. 2 SAFETY EVALUATION OF IMMUNE THROMBOCYT OPENIA
................................ ................................ ................................ ................................ .......3336
APPENDIX 3. 3 SAFETY EVALUATION OF HEARING LOSS AND TI NNITUS
................................ ................................ ................................ ................................ .......3343
APPENDIX 3. 4 SAFETY EVALUATION OF INSOMNIA ................................ ................. .3349
APPENDIX 3. 5 SAFETY EVALUAT ION OF DIZZIN ESS ................................................ .3351
APPENDIX 3. 6 SAFETY EVALUATION OF GUILLAIN -BARRE’ SYN DROME ........... 3356
APPENDIX 4 CUMULATIV E APPROVAL/AUTHORI SATION STATUS ....................... 3378
APPENDIX 5 LIST OF A DVERSE EVENTS OF SPECIAL INTEREST ............................ 3383
APPENDIX 5.1 OBSERVE D VERSUS EXPECTED AN ALYSIS FOR ADVERSE E VENTS
OF SPECI AL INTEREST ................................ ................................ .............................. 3392
APPENDIX 6 LITERATUR E REVI EW IN THE REPO RTING PERIOD (METHOD OLOGY)
................................ ................................ ................................ ................................ .......3409
APPENDIX 6.1 LITERATURE REVIEW IN THE REPORTI NG PERIOD (RETR IEVED
RESUL TS)................................................................ ................................ ........ NO DATA
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Page 8LIST OF ABBREVIATIONS
Acronym Term
AE adverse event
AESI adverse event of special interest
BC Brighton Collaboration
BMI body mass index
CDC Centers for Disease Control and Prevention
CDS core data sheet
CI confidence interval
COPD chronic obstructive pulmonary disease
COVAX COVID -19 Vaccines Global Access
COVID -19 coronavirus disease 2019
DLP data lock point
DME designed medicall y event
DNA deox yribonucleic acid
DSPC Distearo yl-sn-glycero-3-phosphocholine
EEA European Economic Area
EMA European Medicines Agency
EU European Union
EUA emergency use authori sation
EURD European Union Reference Date
HC Health Canada
HCP healthcare professional
HLGT (MedDRA ) High Group Level Term
HLT (MedDRA) High Level Term
HPRC Health Product Risk Communication
IBD international birth date
ICH International Conference on Harmonisation
LNP lipid nanoparticle
MAH marketing authorisation holder
MedDRA medical dictionary for regulatory activities
MHRA Medicines and Healthcare products Regulatory Agency
mRNA messenger ribonucleic acid
NAAT nucleic acid amplification tests
PCR Polymerase Chain Reaction
PI prescribing information
PRAC Pharmacovigilance Risk Assessment Committee
PT (MedDRA) Preferred Term
PVP pharmacovigilance plan
RMP risk management plan
RNA ribonucleic acid
ROW rest of world
RT-PCR Reverse Transcription -Polymerase Chain Reaction
RSI reference safet y information
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Page 9Acronym Term
TME targeted medically event
SAE serious adverse event
SARS -CoV -2 severe acute respiratory syndrome coronavirus 2
SmPC Summary of Product Characteristics
SMQ standardised MedDRA query
SMSR summary monthl y safety report
SOC (MedDRA) S ystem Organ Class
UK United Kingdom
US United States
VAED vaccine -associated enhanced disease
VAERD vaccine -associated enhanced respiratory disease
VAERS vaccine adverse event reporting s ystem
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Page 101.INTRODUCTION
This is the 3rdSMSR for PF-07302048 ( COVID -19 mRNA Vaccine , hereafter referred to as
BNT162b2), covering the reporting interval 01 February 2021 through 28 February 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 dilute d 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, there may not be sufficient volume to
extract a sixth dose from a single vial. E achdose contains 30 micrograms of BNT162b2
(embedded in LNPs ). The vaccine also contains ( (4-hydroxy butyl)azanedi yl)bis(hexane -6,1-
diyl)bis(2- hexy ldecanoate) (ALC -0315), 2- [(polyethy lene gl ycol) -2000]- N,N-
ditetradecy lacetamide (ALC -0159), 1,2 -Distearoy l-sn-glycero-3-phosphocholine (DSPC),
cholesterol, potassium chloride, potassium dihy drogen phosphate, s odium chloride, disodium
hydrogen phosphate dih ydrate, sucrose and water for injections as excipients.
BNT162b2 is highly purified single -stranded, 5’ -capped mRNA produced using a cell -free in
vitro transcription from the corresponding DNA templates, encoding the viral spike (S)
protein of SAR S-CoV -2.The nucleoside -modified mRNA is formulated in LNPs, which
enable delivery of the RNA into host cells to allow expression of the SARS- CoV -2 S antigen.
Thevaccine elicits both neutralizing antibod y and cel lular 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 adjustme nt is
required in elderl y individuals ≥65 y ears of age. It is administered intramuscularly in the
deltoid muscle after dilution as a series of 2 doses (0.3 mL each) at greater than or equal to
21 day s(preferabl y 3 weeks) apart.
Pfizer is responsible for the preparation of the SMSR on behalf of the MAH BioNTech
according to the Pharmacovigilance Agreement in place . Data from BioNTech 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 Period
1 01 December 2020 Through 31 December 2020
2 01 January 2021Through 31 January 2021
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Page 112.WORLDWIDE APPROVAL OR AUTHORISATION STATUS
BNT162b2 received first temporary authori sation for emergency suppl yunder regulation 174
in the UK on 01 December 2020 and is currentl y authorised for emergency use in 28
countries.
BNT162b2 received first regulatory conditional marketing authorisation approval in
Switzerland on 19 December 2020 and is currently conditionall y approved in 39countries .
Details of the current authori sation/ approval status are presented in Appendix 4 .
3.ACTIONS TAKEN IN THE REPO RTING INTERVAL FOR S AFETY REASONS
On 05 February 2021 H ealth Canada requested to issue a joint Pfizer -Health C anada Health
Product R isk Communication to communicate revisions to Product Monograph (addition of
6-dose vial information and text on anaphy laxis). Final HPRC was approved on 08 February
2021.
There were no withdrawals for safety reasons during the reporting interval.
4. CHANGES TO REFERENCE SAFETY INFORMATION
The RSI for this SMSR is the BNT162b2 CDS Version 1.0, dated 12 February 2021, in effect
at the end of the reporting period which is located in Appendix 1 .
After the data -lock point of this SMSR, on 02 March 2021, the CDS was updated with the
following saf ety-related changes made: Diarrhoea, Pain in extremity (arm) and Vomiting
were added as adverse reactions from post -authorisation experience in Section 4.8
Undesirable effects .
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 subject exposure .
With these caveats in mind, it is es timated that :
approximately 126,212,580 doses of BNT162b2 were shipped worldwide from the
receipt of the first temporary authorisation for emergency suppl y on 01December 2020
through 28February 2021 ;
approximately 59,939,685doses of BNT162b2 were shipped worldwide during the
current reporting interval from 01 February 2021 through 28 February 2021.
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Page 12The estimated cumulative number of shipped doses of BNT162b2 by region3based on data
provided in the shipment tracker 4from the re ceipt of the first temporary
authorisation for emergency suppl y on 01 December 2020 through 28 February 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 Americad
Asia
Japana
Other Countriese
Oceania
Australia/New Zealanda
Other Countries
Africa
Total 100.0% 126212580
a. I n this Region BNT162b2 was 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 ;
d.In this Region BNT162 received authorisation for emergency supply; in Colombia B NT162b2 is also
shipped for COVAX;
e.In this Region BNT162b2 received authorization for emergency supply , except for South Korea w here
BN6162b2 is shipped for COVA X.
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 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 13The estimated interval number of shipped doses of BNT162b2 b y region5based on data
provided in the shipment tracker 6from 01 February 2021 through
28February 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 Americad
Asia
Japana
Other Countrie se
Oceania
Australia/New Zealanda
Other Countries
Africa
Total 100.0% 59939685
a. I n this Region BNT162b2 was conditionally approved;
b. I n this Region BNT162b2 received authorisation for emergency supply;
c.Includes: Armenia, Azerbai jan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan,
Turkmenistan, Ukraine, Uzbekistan ;
d.In this Region BNT162 received authorisation for emergency supply; in Colombia BNT162b2 is also
shipped for COVAX;
e.In this Region BNT162b2 received authorization for emergency supply, except for South Korea w here
BN6162b2 is shipped for COVAX .
Table 4 provides the estimated interval/cumulative number of shipped doses of BNT162b2
from the receipt of the first conditional marketing authorisation approval through
28 February 2021 for the 27 European Countries and for the 3 of the European Free Trade
Association.
5Currently there were no available data that a llow 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 14Table 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
Norw ay
Total
6.DATA IN SUMMARY TABU LATIONS
6.1.Reference Information
The MedDRA version 23.1 wasused to code adverse events /reactions in summary
tabulations.
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Page 156.2.Cumulative and Interval Summary Tabulations from Post -Marketing Data
Sources7
As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002 .1)
received on the second SMSR (01 Jan 2021 to 31 Jan 2021) , the MAH should specify the last
date that EudraVigilance data were accessed for the purposes of preparing future SMSR.
Cases from EudraVigilance are downloaded with a 3- day delay , therefore for example cases
with a Eudravigilance availability date of 28 February 2021 were accessed and downloaded
on 03 March 2021 . However ,among cases received or downloaded during the reporting
period, only those having a complete workflow cycle in the safety database (meaning they
progressed to Distribution or Closed workflow status) areincluded in that month’s SMSR .
This approach prevent s the inclusion of cases that are not full y processed hence not
accuratel y reflect ingfinal data. Each month, Pfizer applies a Late condition process that
retrieves cases received in the previous reporting period /sbut not included in that mo nth’s
SMSR due to lack of completeness , in order to include them in the current SMSR, therefore
ensuring that no cases are excluded from inclusion in the S MSR s.
Appendix 2 and Appendix 2.1 respectively provide interval and cumulative number sof
case reports (serious and non- serious, medicall y confirmed and non- medically confirmed)
received from post -marketing authoris ation data sources,7overall, b y sex, country , age
groups and in special populations, and summary tabulations of events by PT and SOC
respectivel y for the interval and cumulative periods.
The cumulative data i nclude all data up to 28February 2021 while the interval data are
for the peri od from 01 February 2021 to 28February 2021 .
Appendix 2 .2provide san interval summary tabulation of case reports with DMEs from
post-marketing data sources .7
Appendices 2.3 and2.4provide data stratified by country . In these appendices,
spontaneous cases (including regulatory authorit y and literature cases) are presented
separately from non-interventional cases :
oAppendix 2.3 provides a cumulative and interval summary tabulation of case sby
medically confirmed and non -medicall y confirmed status (fatal, serious and non -
serious).
oAppendix 2 .4provide sa cumulative and interval summary tabulation of fatal cases.
Appendix 2.58and Appendix 2.6 provide a cumulative and interval summary tabulation
of adverse reactions from post- marketing authori sation data sources7respectively by PT
7This refers to post-EUA/conditional marketing authorisation approval data sources.
8Due to a technical formatting issue, 1 blank page (92) appears in this Appendix; the total data are
however correctly displayed.
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Page 16and by HLT organized according to SOC. Please refer to Appendix 2.5.19and
Appendix 2.6.1 for data per country .
Adverse events totals presented in Appendix 2 , Appendix 2.1 and for safety topic evaluations
in Section 9.5may differ from those presented in Appendix 2.5 and Appendix 2.6, due to the
fact that Appendix 2.5 and Appendix 2.6 only display the number of serious and non- serious
reactions from spontaneous sources, serious reactions from non- interventional studies and
from solicited sources as described above, whereas Appendix 2 , Appendix 2.1 and the safety
topic evaluation s includes all reported events.
Appendix 2.5.2,10Appendix 2. 5.311and Appendix 2 .5.4were added to include a cumulative
and interval summary tabulation of adverse events from post -authori sation data sources7by
PT per country , stratified respectively for age, gender and relevant co -morbidities.
Available relevant information with regard to the differences in vaccination prioritization in
EU countries,12US13, UK and ROW14was taken into account in the evaluation of adverse
events trends, clusters or signals .
9Due to a technical formatting iss ue, 8 blank pages (154, 164, 200, 277, 531, 656, 672 and 686) appear in
this Appendix; the total data are how ever correctly displayed.
10Due to a technical formatting issue, 5 blank pages (1 42, 316, 785,801 and 931 ) appear in this
Appendix; the total data are how ever correctly displayed.
11Due to a technical formatting issue, 2 blank pages ( 68 and 177) appear in this Appendix; the total data
are how ever correctly displayed.
12Overview of the implementation of COVID -19 vaccination strategies and vaccine dep loyment plans in
the EU/EEA . ECDC, February 2021.
13https:// www.cdc.gov/vaccines/hcp/acip -recs/vacc- specific/covid -19/evidence -table -phase -1b-1c.html .
14WHO 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 177.MEDICATION ERRORS
Cases potentially indicative of medication errors15that occurred in the reporting period are
summarized below.
Number of cas es: 858 (3.6% of 23,558 cases, the total PM7dataset ) of which 644
(75.1%) are medically confirmed, compared to 872 ( 6%)in the second monthly report of
which 74.5% were medically confirmed). Out of the 858 cases, 13 cases describing
medication errors occurr ing in an unspecified number of individuals, and 3 additional
cases, describing medication errors occurr ingwith co -suspects were determined to be
non-contributory and are not included in the discussion.
Number of relevant medication e rror cases : 842
Number of relevant even ts: 1189 .
Number of medication errors b y country :
There were 393 cases describing medication errors, which occurred in the EU/EEA
countries [France (139), Czech Republic (87), Germany (50), Italy (25), Finland (21),
Portugal (18), Sweden (10), Austria (8), Greece, Spain and Poland (5 each), Norway
and Denmark (4 each), Romania (3), Belgium, Croatia and Slovakia (2 each),
Lithuania, Slovenia and Ireland (1 each)].
There were 449cases with medication errors from other countries [US (332 ), UK
(67), Canada ( 16), Puerto Rico (12), Chile (7), Mexico ( 4), Israel ( 3), Switzerland and
Norther Mariana islands (2 each), Angola, Costa Rica, Oman, Saudi Arabia (1 each) ].
15MedDRA (version 23.1) Higher Level Term s: Accidental exposures to product; Product administration
errors and issues; Product confusion errors and issues; Product dispensing errors and issues; Product label
issues; Product monitoring errors and issues; Product preparation errors and issues; Product selection errors and
issues; Product sto rage errors and issues in the product use system; Product transcribing errors and
communication issues , OR Preferred Terms: Accidental poisoning; Circumstance or information capable of
leading to device use error; Circumstance or information capable of leading to medication error;
Contraindicated device used; Deprescribing error; Device use error; Dose calculation error; Drug titration error;
Expired device used; Exposure via direct contact; Exposure via eye contact; Exposure via mucosa; Exposure via
skin c ontact; 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; Pr oduct 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; U nintentional medical device removal;
Unintentional use for unapproved indication; Vaccination error; Wrong device used; Wrong dosage form;
Wrong dosage formulation; Wrong dose; Wrong drug; Wrong patient; Wrong product procured; Wrong product
stored; Wrong rate; Wrong route; Wrong schedule; Wrong strength; Wrong technique in device usage process;
Wrong technique in product usage process.
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Page 18In some instances, clusters of medication errors wer e reported, generally by HCP s,
suggesting that rather than a sy stematic issue worldwide, these errors were repeated
mistakes at certain vaccination locales:
In the EU/EEA region there were 11 clusters, the largest in France (96 cases),
Czech Republic (83 c ases), German y (25 cases) and in Finland (12 cases);
In other countries there were 19 clusters, the largest in US (14 cases), Puerto Rico
(10 cases) ,Chile (7 cases) and in Canada (2 cases).
Medication error PTs in the EU and ex -EU16
In the EU/EEA countries, a total of 652 PTs indicative of medication errors were
reported; those events reported at least thrice included: Poor quality product
administered (243), Product temperature excursion issue (141), Product preparation
error (96), Incorrect route of product administration (69), Inappropriate schedule of
product administration (25), Underdose (22), Product preparation issue (21), Product
administered at inappropriate site (9), Wrong technique in product usage process (7),
Incorrect dose administered (5) and Circumstance or information capable of leading
to medication error (3).17
In other countries, a total of 537 medication errors were reported; those events
reported at least thrice included: Inappropriate schedule of product administr ation
(173), Underdose (53), Poor quality product administered (51), Product administered
to patient of inappropriate age (37), Incorrect route of product administration (31),
Product temperature excursion issue (24), Circumstance or information capable of
leading to medication error (22), Product preparation error (18), Product administered
at inappropriate site, Product preparation issue, and Wrong technique in product
usage process (14 each), Accidental exposure to product (13), Exposure via skin
contact (12), Incomplete course of vaccination (11), Accidental overdose and Wrong
product administered (8 each), Incorrect dose administered (7), Incorrect dosage
administered (5), Product dose omission issue and Product administration error (4
each), Product st orage error (3).
16As per EMA assessment received on the first SMSR, the MAH was requested to should keep
medication errors under close scr utiny 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.
17The PTs re ported less than 3 times included: Accidental overdose and Medication error (2 each) and
Accidental exposure to product, Exposure via skin contact, Intercepted product preparation error, Lack of
vaccination site rotation, Product administered to patient of inappropriate age, Product administration error and
Transcription medication error (1 each).
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Page 19Medication error sby seriousness:
Serious (24); out of these, 12 serious medication errors18were reported in EU/EEA
countries [Croatia, France, German y, Lithuania and Romania (2 each), and Denmark
and I taly (1 each)].
Seriousness criteri a were hospitalization and disability or permanent damage (1 event
each) and important medical events (10 events); all but 1 event were medically
confirmed.
Non-serious (1165 ).
Medication error case outcome s:
Fatal ( 5)19(cross -ref with Section 9.5.3 , Death ),
Resolved/resolving (167, of which 85 are serious),
Resolved with sequelae (3, of which 2 are serious)
Not resolved (90, of which 58 are serious),
Unknown (577, of which 21 are serious).
Medication Err ors Harm Analysis
Among the medication error cases, the following scenarios , categorized according to the
EMA guidance “Good practice guide on recording, coding, reporting and assessment of
medication errors” (EMA/762563/2014) were described :
Medication errors associated with harm [i.e., resulting in adverse reaction (s)] were
reported in 1720cases (15in the second SMSR) ;
18PTs: Incorrect route of product administration (3), Accidental overdose, Inappropriate schedule of
product administration, Incorrect dose administered, Incorrect route of product administration, Lack of
vaccination site rotation, Poor quality product administered, Product administration error, Product preparation
issue, Product temperature excursion issue, Underdose (1 each).
19As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002.1) , MAH should
provide details regarding the fatal cases of medication errors and more clearly indicate whether or not the
medication error caused or contributed to serious adverse event or outcome. All the medic ation errors reported
in these cases were assessed as non -serious occurrences with an unknown outcome; based on the available
information including the causes of death, the relationship betw een the medication error and the death is weak.
20Two cases reported both medication errors w ith harm and without harm.
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Page 20Medication errors without harm [i.e. not resulting in adverse reaction(s)]21were
reported in 774 cases (in 321 of them there were co -reported AEs) compared to 713
cases of which 288 included co -reported AEs in the second SMSR;
Intercepted medication errors were reported in 2 cases, compared to 2 cases in the
second SMSR;
Potentia l medication errors were reported in 51 cases, compared to 106 cases in the
second SMSR.
Medication errors associated with harm (21 medication errors in 17cases)
There were 8 cases from the EU/EEA area [Sweden (4), France (2), Germany and Italy (1
each)] and 9 from non- EU/EEA countries [US (7), UK (2)].
Serious medication errors
In 4 cases ( involving 5 medication error events), serious medication errors potentially
contribut edto the occurrence of serious adverse events.
Seizure, Circulatory collapse, Tachy cardia, Loss of consciousness, Presyncope, Somatic
symptom disorder, F acial paral ysis, Hypotension, Vertigo, and P araesthesia occurred ina
30-year-old woman 15 minutes after she received a dose of vaccine exposed to
temperature excursion (PTs Product temperature excursion issue, Poor quality product
administered). No antiepileptics treatment were administered since “s eizure self -limited
once the woman was in flat position with legs lifted ”. The events seizure, paraesthesia,
facial paral ysis, circulator y collapse, tach ycardia, and unconsciousness resolved after
treatment including fluid and electrol yte replacement solution and paracetamol ; the
outcome was unknow nfor the remaining events (cross -reference with Section 9.5.2 ).
Myositis, Vaccination sitepain, N euralgic amyotrophy and Backpain were reported in a
52-year-old man after receiving the vaccine (PT Lack of vaccination site rotation). The
events were con sidered complications from vaccine absorption by the allerg yand
toxicolog y specialists. The events (except vaccination site pain) were resolving after
treatment at the time of the report.
Pain/arthralgia accompanied by nausea and paraesthesia occurred to a 51-year-old
woman after she received the vaccine intramuscularly towards the humeral head and not
in the deltoid muscle (PT Product administration error); the events were resolving after
treatment.
The vaccine was administered 2 cm below the deltoid musc le (PT Product administered
at inappropriate site) inan adult woman who experienced “constantl y itching scabbing
21AEs may be co -reported in a case, but they are not considered to be a result of the medication error.
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Page 21over granulating and oozing 6 weeks post injection”. The outcome of the events was
unknown.
Non-serious medication errors
In 13 cases ( involving 16 medication error events), non- serious medication errors potentiall y
contribut edto the occurrence of non-serious adverse events.
Administration of undiluted vaccine (2 events, 1 case)
A 41 -year-old woman experienced anal incontinence the night after she received a dose
of undiluted vaccine. The subject recovered the following day ; it was unknown if
treatment was given.
Errors in the route of administration (11 events, 10 cases)
This error occurred in 5 cases in the EU/EEA area (4 from Sweden and 1 from France)
and in 5 US cases. The vaccine was administered subcutaneousl y (6 events); “not
intramuscularl y”(3 events), and through other routes (IV, oral, 2 events). Local
vaccination site reactions mainly included ery thema, swelling, pruritus, and warmth and
pain.
Errors of vaccination at the wrong anatomical site (3 events, 3 cases)
This error occurred in 3 cases (from the US). The vaccination was not administered in the
deltoid (PT Product administered at inappropriate site). Vaccination site erythema and
Pain in extremity (2 each), Skeletal injury and Contusion (1 each) were reported.
Medication errors without harm20(1113 medication errors in 774 cases)
These m edication error PTs describe errors occurring during 1 or more steps of the
vaccination process: preparation, administration, or scheduling of seco nd dose.
Overall, t here were
381 cases from the EU/EEA area [France (137), Czech Republic (86), Germany (49),
Italy (24), Finland (21), Portugal (18), Austria (8), Sweden (6), Greece and Poland (5
each), Denmark and Spain (4 each), Norway and Romania (3 each), Belgium, Croatia and
Slovakia (2 each), Lithuania and Slovenia (1 each)] and
393 from non-EU/EEA countries [those with more than 1 medication error included the
US (285), the UK (64), Canada (14), Puerto Rico (12), Chile (7), Mexico (3) Northe rn
Mariana Islands, Israel and Switzerland (2 each)].
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Page 22Vaccine preparation errors (320 events, 2 of which were serious) : events mainly described
errors in storage conditions orduring dilution (before use ).
oTemperature excursion (167 events) : in the majority of the events, the vaccine was left
at room temperature or in the refrigerator for a longer time than specified in the RSI ; no
adverse events were reported upon vaccine administration.
oIncorrect dilution (1 38events): Dilution was performed either with a sm aller volume of
normal saline (8 events), or with a larger volume of normal saline (6 events) than
instructed ; dilution with improper volume was reported with a variable total number of
available doses after dilution from a single vial (15 events). There were 97 events of
dilution performed with a different solvent (water for injection for 96 events) rather than
normal saline . In another 12 events the vaccine was administered without performing the
dilution ; no adverse events were reported upon vaccine administration.
oOther preparation errors (15 events ).
Vaccine administration errors (793 events, 17 of which were serious) : events mainly
described errors in administration of vaccine dose not adequatel y prepared (see Preparation
subset), errors in the volume or dosage of the vaccine administered, errors in administering
the second dose in less than 21 day s or after m ore than 21 day s, and errors in route of
administration.
oAdministration after inadequate preparation (294 events, all non -serious) : these events
referred to vaccine administered after inadequate preparation: dilution performed with
water for injection instead of normal saline (95 events); vaccine administered incorrect
thawing procedure (left at room temperature for a longer time than the one specified in
the RSI ), or thawed and inadvertentl y refrozen (166 events); and other 33 errors including
presence of particulates [single black particles (4), small white floating particles (2),
piece of latex (1) and another not further detailed particle (1)] after vaccine
administration.
oIncorrect interval between doses (148 events, 2 of which serious22): the second do se of
the vaccine was administered at less than 21 day s of interval (98 events); interval
between the first and the second dose ranged between 0 day (3 events) and 18 day s, with
the majority of the second doses administered between the 15thand the 18thday after the
first dose (51 events); the second dose was administered after more than 21 day s (50
events).
22PTs Inappropriate schedule of product administration (2), Asthenia, Chills, COV ID-19, Diarrhoea, Drug
ineffective, Fatigue, Headache, Lymphadenopathy, Nausea, Off label use, Pain, Pyrexia, Vomiting (1 each) .
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Page 23oErrors in the route of administration (93 events, of which 4 serious23): the vaccine was
administered subcutaneously (55 events)24; intravenously (14 ev ents), parenterall y
without any further detail (9 events); and through other routes (15 events).
oErrors in the volume administered (78 events, of which 3 serious25): partial doses were
administered due to leakage, s yringe or needle malfunction ( 74events); higher volume of
right dose of vaccine was administered ( 4events).
oPaediatric Individuals <16 Years of Age (38 events, of which 3 serious26):the vaccine
was inadvertently administered to paediatric individuals below 16 years (see
Section 9.5.4 Use in Paediatric Individuals <16 Years of Age).27
oDose of vaccine not administered (33 events, of which 1serious28): the second dose was
not administered at the scheduled date. In 15 instances, the dose was not administered
either because the vaccinees were recovering from AEs occurred after first dose or they
became COVID -19 positive or due to the impossibility to attend at the scheduled date;
only saline was injected or the sy ringe was empty (2 each); in the remaining instances the
second dose was not administered for not further detailed causes (14 events).
oAccidental exposure to vaccine (27 events, all non- serious) : all involved skin exposure.
oErrors in vaccine dosage (25 events, of which 2 serious) : these errors include
administration of vaccine at higher concentration s(10 events) and at lower
concentration s(6 event s) than recommended and 7 events in which the vaccine was
administered undiluted ora third dose was administered (2 events, 1 case).
oVaccination site other than deltoid muscle (20 events, of which 1 serious29): the vaccine
was administered in the vaccinee’ s arm but not in the deltoid muscle (14 events); the
23PTs Chills, Deep vein thrombosis, Drug ineffective, Erythema, Fatigue, Feeling abnormal, Feeling hot,
Feeling of body temperature change, Gait disturbance, Headache, Hyperaemia, Lymphadenopathy, Malaise,
Myalgia, Pain in extremity, Rash pruritic, Suspected COVID -19, Vaccination site discolouration, Vaccination
site pain, Vaccination site thrombosis .
24In 1 case route w as reporte d as partly subcutaneous and partly intramuscular.
25PTs Accidental overdose and Product administration error (2 each), Cough, Fatigue, Headache,
Incorrect dose administered, Malaise, Pain in extremity, Pyrexia, Underdose, Vaccination site pain (1 each).
26PTs Headache (3), Product administered to patient of inappropriate age (3), Pyrexia and Pain in
extremity (2 each) , Arthralgia, Back pain, Chills, Mastitis, Myalgia, Peripheral sw elling, Swelling, Vertigo and
Wheezing (1 each).
27Out of these 38 cases, 1 8 were not further detailed in Section 9.5.4 as reporting information wasnot
consistent for paediatric subjects (e.g. age category of adult or medical history and medications clearly for
adults) .
28PTs Product dose omission issue, Drug ineffective, COVID -19.
29PTs Neurological symptom, Neuralgic amyotrophy, Pain in extremity, Paraesthesia, Joint dislocation,
Chest discomfort, Pain, Wrong technique in product usage process .
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Page 24administration site was in the leg, thigh or in the gluteus (4 events), in the hand and in
the abdomen (1 event each).
oWrong vaccine administered (10 events, all non -serious): the vaccinees received one
dose of Moderna vaccine and 1 dose of BioNTech -Pfizer vaccine (8 events); in 2
instances the vaccinees were told to receive one dose of Moderna vaccine, but the
vaccination card reported the BioNTech -Pfizer vaccine was administered.
oOther vaccine adminis tration errors (28 events, of which 1 serious30): the majority of the
events were indicative of issues with sy ringes and needles or related to the use of
concomitant drugs31(7 events each); expired vaccine (3events32) and not further detailed
in the 11 remaining one s.
Intercepted medication errors ( 2medication errors in 2 cases)
There were 2 cases of which 1 was from the EU/EEA area (Norway ) and 1 from non-
EU/EEA countries (US).
In the first case a woman of unknown age who had received her first dose in the morning,
was called in the afternoon of the same day for the second dose because her last name was
misspelt; her second dose was rescheduled. In the second case, a physician prepared a
syringe with a double amount of vaccine; the dose was not adminis tered.
Potential medication errors (53 medication errors in 51 cases)
There were 3 cases from the EU/EEA area [Czech Republic, Ireland and Spain (1 each)] and
50 from non- EU/EEA countries [US (43), Canada (2) and 1 case each from I srael, Mexico,
Oman, Saudi Arabia and the UK].
Potential dosing interval error (53 events, all non -serious) : events mainl y described
potential errors in the scheduling for the second dose not according to the 21 days
interval. In some instances, the scheduled date for the secon d dose is planned at 4 weeks
interval; in other instances, the planned date was scheduled at a different interval for
vaccine unavailability or for individual unavailability .
Some medication errors are expected to occur despite written instructions and edu cational
activities for HCPs administering the vaccine. The number and seriousness of the reported
medication errors do not indicate aneed for additional mitigation activity .
30PTsHeadache, Pyrexia, Fatigue, Vaccination site pain, Cough, Malaise, Pain in extremity, Incorrect
dose administered , Underdose (1 each).
31Co-suspect in 1 instance.
32Three events (in 2 cases) described administration of the vaccine after its expiry date; in the first case,
the vaccine was administered 5 days after the expiry date; no information was available for the second case.
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Page 258.GENERAL OVERVIEW
A total of 23,558 case reports (13,389medicall y confirmed and 10,169 non- medicall y
confirmed) containing 91,934 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
Table5. General Overview: Selected Characteristics of All Cases Received During
the Reporting Interval
Characteristics Relevant cases ( N=23558)
Gender: Female 17040
Male 5317
No Data 1201
Age range (years):
0.06 -107years
Mean = 52.6 years
n= 2043317
18-30
31-50
51-64
65-74
³75
Unknown91a
2654
7579
4526
2234
3544
2927b
Case outcome: Resolved/Resolving 11729
Resolve d with sequelae 329
Not re solved at the time of report 6403
Fatal 798
Unknown 4299
Presence of relevant
comorbiditiesYes 4953c
No 18605
a.Including 27 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 12, Use in Paediatric Individuals <16 Years of Age) and 17
breastfed babies for which paediatric age w as reported;
b.Including 14 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, Patien ts 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 12.One of these cases was made invalid hence excluded from the discussion in
Table 12below .
Case outcome b y age group, gender and presence of relevant comorbidities is presented in
Figure 1, Figure 2and Figure 3. Across all age groups, there were more females than males
reporting adverse events .The fatal cases reported m orecomorbidities , but this is expected
considering that the majority of fatal outcomes occurred in patients 75 years and older as
shown in Figure 2-B(please also see Death inTable 11and Frail patients with
co-morbidities e.g. COPD, diabetes, chronic neurological disease, cardiovascular disorders,
described as Missing Information in Table 12).
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Page 26Figure1.Case Outcome by Presence of Relevant Comorbidities
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Page 27Figure2.Case Outcome by Presence of Rel evant Comorbidities ,Gender and Age
Group
A. Case Outcom e by Presence of Relevant Com orbidities and Gender
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Page 28B. Outcom e by Presence of Relevant Com orbidities and Age Group
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Page 29Figure3.Fatal Case Outcome by Presence of Relevant Comorbidities and Age Group
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Page 30ADVERSE EVENT DATA
As shown in Figure 4, the MedDRA SOCs containing the greatest number of events ( ≥2%)
were General disorders and administration site conditions ( 28,420 ),Nervous sy stem
disorders ( 15,446 ), Musculoskeletal and connective tissue disorders ( 9872 ), Gastrointestinal
disorders ( 8274 ), Skin and subcutaneous tissue disorders (4919 ), Respiratory , thoracic and
mediastinal disorders ( 5574 ),Infections and inf estations ( 2879), Injury , poisoning and
procedural complications (2722), Investigations ( 2120) andCardiac disorders (1918) . Of
note, multiple adverse events may be reported in a single case.
Figure4. General Overview: Total Number of Events by MedDRA SOC and Event
Seriousness
The overall safet y evaluation includes a review of the most frequentl y reported events b y
SOC and by the PT for events reported in (≥2%) of all cases during the reporting interval as
compared to the cumulative period since the first temporary authorisation for emergency
supply on 01 December 2020 .050001000015000200002500030000
General disorders
Nervous system
Musculoskeletal
Gastrointestinal
Respiratory
Skin
Infections
Injury/procedural complications
Investigations
Cardiac
Vascular
Psychiatric
Blood & lymphatic
Eye
Immune
Ear & labyrinth
Metabolism & nutrition
Renal & urinary
Reproductive & breast
Product issues
Social circumstances
Hepatobiliary
Neoplasms
Pregnancy
Endocrine
Congenital & genetic
Surgical & medical procedures NONSERIOUS
SERIOUS
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Page 31Table6.Events Reported in ≥2%*Cases
01 February 2021 Through
28 February 2021Cumulatively Through 28
February 2021
MedDRA SOC
MedDRA PTAEs (AERP%)
N = 23558AEs (AERP%)
N = 42086
Blood and lymphatic system disorders
Lymphadenopathya 1101 (4.67%) 1972 (4.69%)
Cardiac disorders
Tachycardia 713 (3.03%) 1098 (2.61%)
Gastrointestinal disorders
Nauseaa 2946 (12.51%) 5182 (12.31%)
Diarrhoeab 1132 (4.81%) 1880 (4.47%)
Vom itingb 1037 (4.40%) 1698 (4.03%)
General disorders and administration site conditions
Pyrexiaa 4272 (18.13%) 7666 (18.22%)
Fatiguea 4226 (17.94%) 7338 (17.44%)
Chillsa 2899 (12.31%) 5514 (13.10%)
Vaccination site paina 2584 (10.97%) 5181 (12.31%)
Paina 1825 (7.75%) 3691 (8. 77%)
Malaisea 1697 (7.20%) 2897 (6.88%)
Astheniaa 1549 (6.58%) 2285 (5.43%)
Drug ineffectivec 1032 (4.38%) 2201 (5.23%)
Chest pain 475 (2.02%) 722 (1.72%)
Vaccination site erythemaa 471 (2.00%) 930 (2.21%)
Infections and infestations
COVID -19c 1092 (4.64%) 1927 (4.58%)
Injury, poisoning and procedural complications
Off label usec 508 (2.16%) 880 (2.09%)
Product use issuec 474 (2.01%) 828 (1.97%)
Musculoskeletal and connective tissue disorders
Myalgiaa 2903 (12.32%) 4915 (11.68%)
Arthralgiaa 2101 (8.92%) 3525 (8.38%)
Pain in extremityb 2058 (8.74%) 3959 (9.41%)
Back paina 473 (2.01%) 809 (1.92%)
Nervous system disorders
Headachea 5699 (24.19%) 10131 (24.07%)
Dizziness 2200 (9.34%) 3720 (8.84%)
Paraesthesia 875 (3.71%) 1500 (3.56%)
Syncope 540 (2.29%) 710 (1.69%)
Hypoaesthesia 531 (2.25%) 999 (2.37%)
Respiratory, thoracic and mediastinal disorders
Dyspnoead 1406 (5.97%) 2057 (4.89%)
Coughd 676 (2.87%) 1146 (2.72%)
Oropharyngeal pain 551 (2.34%) 948 (2.25%)
Skin and subcutaneous tissue disorders
Pruritusa 813 (3.45%) 1447 (3.44%)
Rasha 784 (3.33%) 1404 (3.34%)
Erythemaa 642 (2.73%) 1044 (2.48%)
Hyperhidrosis 529 (2.25%) 900 (2.14%)
Total number of events 52814 93104
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Page 32Table6.Events Reported in ≥2% *Cases
01 February 2021 Through
28 February 2021Cumulatively Through 28
February 2021
MedDRA SOC
MedDRA PTAEs (AERP%)
N = 23558AEs (AERP%)
N = 42086
a.Listed or consistent with listed AEs in current RSI;
b.Added to the CDS after the data -lock point of this SMSR, on 02 March 2021;
c.Listed per case processing conventions; fordiscussion of relevant cases of Drug ineffective/COVID -19
see Table 11, Lack of Efficacy subsection;
d.Consistent with anaphylactic reactions listed in the current RSI ;
* Reporting proportion (% of total cases) in the current reporting period.
Most of the frequently reported events are listed or consistent with listed event s as per the
current RSI. Of note, the frequentl y reported events Dizziness ,Paraes thesia , Syncope and
Tach ycardia , not listed as per the current RSIs, aresignals addressed during the reporting
period (see Section 9.2).
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.
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Page 33Figure5.Events Reported in ≥2%Cases in the Interval Period by Gender
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Page 34Figure6.PTReported in ≥2% in the Interval Period - by SOCand Age Group
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Page 41Figure7.Events Reported in ≥2% in the Interval Period by Age Group within
Gender
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Page 42As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002 .1)
received on the second SMSR , the MAH was requested to discuss the findings regarding side
effects (particularly fever and muscle ache) reported more frequent and severe:
a.following the 1st dose;
b.following the 2nd dose;
in vaccinees that previously had a (PCR confirmed) COVID- 19 infection, including any
implications for the product information.
MAH Response
The available data on subjects in the Phase 2/3 portion of Study C4591001 with evidence of
prior infection with SARS- CoV -2 as determined by NAAT or N -binding assay (at Visit 1)
suggest no clinically meaningful difference with regard to clinical profile of the reported
events . Out of a total safety population of approximately 44,000 subjects of both arms at the
time of the anal yses (14 November 2020), 545 BNT162b2 -vaccinated subjects and 580
placebo recipients, were identified as baseline SARS -CoV -2 positive at Visit 1 and had
safet y data available for anal ysis.
Overall, there w ere no meaningful differences in the incidences or severity of reactogenicit y,
or incidences of AEs or SAEs between the baseline positive and negative subject groups. For
any systemic reactions across all the measured reactions and doses, in the same
react ogenicity baseline SARS -CoV -2 status subsets, 70.1% compared to 77.7% reported at
least 1 sy stemic event in those positive or negative at baseline, respectively .
In participants positive at baseline for SARS -CoV -2, the reactogenicit y reported at the first
dose was generall y higher than after the second dose. Fever was reported in 12.3% and 7.5%
after Dose 1 and Dose 2, respectively, and muscle pain was reported 29.9% and 27.8% after
Dose 1 and Dose 2, respectively . Overall, the rate of reactogenicit y for e ach event measured
was comparable to the rates for those negative at baseline for SARS -CoV -2. For example,
muscle pain after any dose in baseline SARS -CoV -2 positive participants was 39.6%
compared to 38.2 % in individuals negative for SARS -CoV -2 at baseli ne, while fever after
any dose in baseline SARS -CoV -2 positive participants was 16.9% as compared to 14.1% in
baseline negative participants. Hence, for s ystemic events the rate of reactogenicity was
higher after Dose 1 than Dose 2, but the overall rate wa s similar to the reactogenicit y rates
observed in participants negative for SARS -CoV -2.
With regard to the AE profile, among the safety data of ~38,000 participants33with AEs
collected from Dose 1 to 1 month after Dose 2 and for which a median of 2 months of
follow -up after Dose 2 was conducted , the frequency of AEs were 22.0% and 27.1% in those
who were positive (n=545 BNT162b2, n=580 placebo) and negative (n=17,841 BNT162b2,
n=17,808 placebo) at baseline, respectively . Of the AEs reported, 16.5% and 21.0% were
related AEs in those positive and negative at baseline, respectively . Most of these events
33Population that met the requirement for the US EUA.
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Page 43were local and s ystemic reactogenicity . SAEs were reported in 4 participants (0.7%) in the
BNT162b2 recipients positive a t baseline compared to 97 participants (0.5%) in participants
negative at baseline.
The safet y profile (ie, reactogenicity and AEs) did not show a clinically meaningful
difference on the basis of baseline SARS- CoV -2 status and did not suggest any clinical
concern about BNT162b2 vaccination in individuals previously exposed to SARS -CoV -2. As
demonstrated b y the data included in the MAA, overall Dose 2 had a higher frequency of
systemic reactogenicity across all participants. Based on this analy sis, the MAH did not
recommend an update to the EU SmPC.
9.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 7.
Table 7.Overview of Signals
Signal Status Category
Vom iting Closed Identified Risk (Not Important)
Diarrh oea Closed Identified Risk (Not Important)
Eye pain/Eye swelling Closed No Risk
Delayed Syncope Closed NoRisk
Hearing Loss and Tinnitus Closed No Risk
Immune thrombocytopenia Closed No Risk
Dizziness Ongoing Under evaluation
Facial paralysis Ongoing Under evaluation
Paraesthesia Ongoing Under evaluation
Herpes Zoster Ongoing Under evaluation
Tachycardia Ongoing Under evaluation
Vaccine stress -related responses Ongoing Under evaluation
Appendix 3 provides a summary of the safet ytopics and signals addressed during the
reporting interval and Appendix 3.1 an evaluation of these safet y topics and signals .
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Page 44As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002 .1)
received on the second SMSR, the following cumulative overviews wereperformed for:
Safety evaluation of Immune thrombocy topenia (Appendix 3.2);
Safety evaluation of Hearing loss and Tinnitus ( Appendix 3.3 );
Safety evaluation of Insomnia with discussion on duration ( Appendix 3.4);
Safety evaluation of Dizziness ( Appendix 3.5);
Safety evaluation of Guillain -Barré s yndrome (Appendix 3. 6).
9.3.Summary of Safety Concerns
Table 8 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 pe riod. The pharmacovigilance and risk management activities
implemented for the safety concerns by Pfizer on behalf of BioNTech are global.
Table 8.Safety Concerns
Important Identified Risk Anaphylaxisa
Important Potential Risk Vaccine- Associated Enhanced Disease (VAED), Including
Vaccine -Associated Enhanced Respiratory Dise ase (VAERD)a
Missing Information Use in Pregnancy and While Breast Feedinga
Use in Immunocompromised Patientsb
Use in Frail Patients With Co-M orbidities (e.g. COPD, Diabetes,
Chronic Neurological Disease, Cardiovascular disorders)b
Use in Patient s With Autoimmune or Inflammatory Disordersb
Interaction With Other Vaccinesb
Long -Term Safety D atab
Use in Paediatric Individuals <16 Years of Agec
Vaccine Effectivenessc
a.As per both the EU RMP Version 1.0, dated 21 December 2020 and the US PVP Version 0. 3, dated 20
January 2021;
b.As per the EU RMP Version 1.0, dated 21 December 2020 ;
c.As per the US PVP Version 0. 3, dated 20 January 2021 .
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Page 45
9.4. Summary of Adverse Events of Special Interest (AESIs)
Please refer to Appendix 5 for the list of the company’s AESIs for BNT162b2 . Please refer to
Appendix 5 .1 for the observed versus expected analysis for AESIs.34,35
The company’s AESI list takes into consideration the lists of AESIs 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 term s are incorporated into a TME list and include events of interest due to their
association with severe COVID -19 and events of interest for vaccines in general.
The AESI list includes MedDRA PTs, HLTs , HLGTs or MedDRA SMQs and can be
changed as appropriate based on the evolving safety profile of the vaccine.
9.5. Evaluation of Safety Concerns
Evaluation of new information collected from post -marketing data sources7 for BNT162b2
during the interval reporting period for important identified and important potential risks ,
AESIs , special situations and missing information is provided below in Section 9.5.1 ,
Section 9.5.2 , Section 9.5.3 and Section 9.5.4 .
9.5.1. Evaluation of Important Identified and Important Potential Risks
Table 9 below presents the e valuation of new information received during the interval
reporting period from post -marketing data sources7 for the important identified and
important potentia l risks of BNT162b2 .
Table 9. Risks Evaluation for BNT162b2
Safety Risk Post-Marketing Case s Evaluationa
Total Number of Cases in the Reporting Period (N= 23558 )
Important Identified Risk
Anaphylaxise
Search criteria: Anaphylactic
reaction SMQ (Narrow and Broad,
with the algorithm applied),
selecting relevant cases according
to BC criteria
Number of cases from the Anaphylactic reaction SMQ ( Narrow and
Broad) search strategy, applying the MedDRA algorithm based on all
terms in the SMQ: 115636 (4.9% compared to 3.4% of the total PM
dataset of the previous SMSR), of which 907 were medically
confirmed and 249 were non -medically con firmed;
• Number of events: 2868;
34 It shou ld be noted that for the O/E analyses, the numbers of doses of vaccine administrated had been
estimated based on publicly available data from health authorities in various regions.
35 As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002.1) sSpecific O/E
analysis for arrythmias, deafness, hypertension, tinnitus, sudden hearing loss were also included in
Appendix 5.1.
36 One additional case was made invalid after the DLP due to lack of minimum valid criteria to process the
case.
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Page 46Table 9.Risks Evaluation for BNT162b2
SafetyRisk Post-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
Country of incidence ( 2%): UK (257), Mexico (138), US (135),
Italy (105), Germany (103), France (51), Spain (49), Greece (35),
Sweden (28), Austria and Portugal (25 each);
Subject s’ gender: female (976), male (150) and unknown (30);
Subject s’ age (n = 1100): ranged from 4 years (2 subject s) to 100
years (mean = 48.1 years, median = 46 years);
Most frequently reported individual PTs (≥2%): Dyspnoea (365),
Anaphylactic reaction (360), Rash (189), Pruritus (172),
Erythema ( 145), Cough (126), Respiratory distress (124),
Urticaria (100), Hypotension (78), Sw ollen tongue (74), Sw elling
face (72), Anaphylactic shock (71), Lip sw elling (69), Chest
discomfort (66), Oedema (64), Flushing (56), Throat tightness
(49), Pharyngeal swel ling (48), Circulatory collapse (45),
Swelling (40), Angioedema and Wheezing (38 each) and
Bronchospasm (35) , Blood pressure decreased (28), Type I
hypersensitivity (27), Tongue oedema (25) and Face oedema (24 );
Relevant event seriousness: serious (2203), non-serious (665);
Relevant event outcome:dfatal (46), resolved/resolving (1741),
resolved with sequelae (30), not resolved (203), unknown (857).
Cases (1156) w ere individually reviewed and assessed according to
Brighton Collaboration (BC) case definition and level of diagnostic
certainty as show n in theTable below .
Brighton Collaboration Level Number of cases
BC 1 212
BC 2 225
BC 3 7
BC 4 296
BC 5 416
Total 1156
Level 1 indicates a case with the highest level of diagnostic certainty
of anaphylaxis, whereas the diagnostic certainty is low est for Level 3.
Level 4 is defined as “reported event of anaphylaxis, with insufficient
evidence to meet the case definition” and Level 5 as not a case of
anaphylaxis.
BC Level 1 and 2 cases:
Number of cases : 437 (1467 events of interest)
Medical history (n=239): the most frequently ( ≥2%) reported medical
conditions included Hypersensitivity (51), Asthma (46), Food allergy
(44), Drug hypersensitivity (40) , Hypertension (22) , Anaphylactic
reaction (17), Seasonal allergy (16), Allergy to animal and C OVID -19
(10 each) and Urticaria (9 ).
Number of vaccine doses administered at the time of the event onset:
1 dose in 248 cases, 2 doses in 51 cases and number of doses w as not
specified in 138 cases.
Relevant PTs (2%): Dyspnoea (215), Rash (130), Erythema (103),
Pruritus (102), Anaphylactic reaction (87), Respiratory distress (78),
Urticaria (68), Cough (56), Hypotension (52), Sw elling face (43),
Swollen tongue (40), Throat tightness (33), Oedema (32), Pharyngeal
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Page 47Table 9.Risks Evaluation for BNT162b2
SafetyRisk Post-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
swelling (31), Lip swelling (30), Wheezing (29), Angioedema and
Bronchospasm (27 each), Chest discomfort (24), Blood pressure
decreased (20), Sw elling (18), Anaphylactic shock (17), Flushing and
Tongue oedema (15 each), Laryngeal oedema (14) , Face oedema (13),
Mouth swe lling and Stridor (11 each), Rash pruritic (10), Sensation of
foreign body and Type I hypersensitivity (9 each ).
Relevant event outcome: fatal (6), resolved/resolving (874), resolved
with sequelae (9), not resolved (84), unknown (497).
Fatal cases: 2
1.Coun try: US;
Subject ’s gender and age: female subject aged 58 years;
Medical history: hypersensitivity to penicillin, hypertension,
obesity, sleep apnoea syndrome and type 2 diabetes mellitus;
Vaccine dose: 1
Lot Number: EL9263
Event onset date: Day 0; ( 1 hou r after receiving the vaccine);
PTs: Acute pulmonary oedema, Anaphylactic reaction, Vomiting,
Dyspnoea, Flushing and Illness . Acute pulmonary oedema and
Anaphylactic reaction are reported with fatal outcome.
Treatments: diphenhydramine hydrochloride, epine phrine, oxygen
and cardiopulmonary resuscitation was performed.
Autopsy :not performed.
2.Country: Belgium
Subject ’s age and gender: female subject aged 69 years;
Medical history: Appendicitis, Cholecystectomy, Dementia with
Lewy bodies; Urinary incontinence, Urinary tract infection and
Vertigo positional
Concomitant medications: enoxaparin, donepezil,
benserazide/levodopa, melatonin, ascorbic acid/ ferrous
sulfate,estriol and pantoprazole/sesquihydrate
Vaccine dose: 1
Lot number: EM0477
Event ons et date: Day 0 (1 hour after receiving the vaccine);
PTs: Dyspnoea, Hypotension, Malaise, Anaphylactic reaction,
COVID -19 pneumonia, Acute respiratory failure and Cardio -
respiratory arrest. All events reported a fatal outcome.
Treatments: adrenaline
Autopsy: not specified if it was performed.
Discussion
Anaphylaxis is anadverse reaction in Section 4.8 of the EU SmPC , in
the CDS and local labels/fact sheets . It is also included as an Important
identified risk in the EU RMP and inthe US PVP.eBased upon review
ofthe available information, no additional change to the RSI is
warranted at this time.
On 08 February 2021, a cumulative revie w of all cases reporting
serious hypersensitivity reactions suggestive of anaphylaxis using the
Brighton Collaboration criteria and inclusive of Observed versus
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Expected analysis was submitted to EMA in a LEG procedu re as per
EMA PRAC assessment report (Product No.
EMEA/H/C/005735/MEA/002) received on the first SMSR. Follow ing
EMA feedback, the response to the Post -Authori sation Measure LEG -
022 Assessment will be submitted in conjunction with the current
SMSR.
Conclusion: Evaluation of BC cases Level 1 and 2 as well as 3 and 4
did not reveal any significant new safety information. Anaphylaxis is
appropriately described in the product labeling as are non -
anaphylactic hypersensitivity events . Surveillance will con tinue.
Important Potential R isk
Vaccine- Associated Enhanced
Disease (VAED) Including
Vaccine- Associated Enhanced
Respiratory Disease (VAERD)b,cVAED is a m odified and/or severe presentation of an infectious
disease affecting individuals exposed to the wild -type pathogen after
having received vaccine designed to prevent infection.37
As noted by the Brighton Collaboration, there is currently no
uniform ly accepted definition of VAED (or VAERD) and the BC
working group considers that a definitive case of VAED (Level 1
diagnostic certainty) cannot be ascertained with current knowledge of
the mechanisms of pathogenesis of the condition ; they have provided
guidance onlevels of diagnostic certainty of VAED cases based on
various laboratory and clinical findings .
No post -authorized AE reports have been identified as cases of
VAED/VAERD, therefore, there is no observed d ataat this time. An
expected rate of VAED is difficult to establish so a meaningful
observed/expected analysis cannot be conducted at this point based on
available data. The feasibility of conducting such an analysis w ill be
re-evaluated on an ongoing basis as data on the virus grows and the
vaccine safety data continues to accrue.
The search criteria utilised to identify potential cases of VAED for this
SMSR include sPTs indicating a lack of effect of the vaccine and
medical disorders chosen because they are PTs potentially indicative
of severe or atypical COVID- 19.
Overview
Number of cases based on search strategy: 73(0.3% of the total
PM dataset , compared to 0.4% ofthe previous reporting period ),
all serious (of which 44are medically confirmed )h;
Country of incidence: UK(38), US ( 8), Germany ( 7), France,
Spain ( 4 each ), Italy (3 ), Denmark (2);the remaining 7cases
originated from 7different countries.
Gender: female ( 40), males ( 26),unknown ( 7).
37Flor 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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Age: 23to 100 years (n = 71), mean = 63.8,
median = 68.0;
Respiratory system PTs: Dyspnoea ( 23), COVID -19 pneumonia
(15), Respiratory failure (5), Hypoxia, Pulmonary embolism ,(3
each), Tachypnoea (1 ).
Gastrointestinal system PTs:Diarrhoea ( 14), Vomiting ( 11),
Abdominal pain ( 2);
Nervous system PTs :Seizure (6), Encephalopathy (1) ;
Other systems , relevant PTs :Arrhythmia , Cardiac failure, Acute
kidney injury, Renal failure, Thrombocytopenia, Shock (1 each) .
Case outcome: fatal ( 20), not resolved ( 34), resolved/resolving
(14), unknown at the time of the reporting ( 4), resolved w ith
sequelae (1 ).
COVID-19 positivity and severity of events
Suspected COVID -19 infection (test not performed or negative or
inconclusive) : 21.
Confirmed COVID -19 infection : 52(test positive).
Seriousness criteria for the total 73cases :
oMedically significant: 34(of which 5serious also for
disability);
oHospitalization required (non-fatal/non -life threatening) :
11;
oLife threatening: 8 ;
oDeath: 20 (All subject s had COVID- 19 test positive) .
Seriousness criteria: m edically significant (34)
In 15,out of 3 4cases where the seriousness criteria was
“medically significant”, it was reported that the subject s had a
COVID-19 positive test after vaccination , while 19subject shad
unconfirmed suspected COVID -19. These 34subject s didnot
require hospitalization .
Age: 25 to 96 ( n=15), Mean=56 .3, Median=51.
Among the 15COVID -19 positive subject s:
3received the 1stvaccine dose. Latency to COVID -19was
15, 16 and 50days respectively .
o5 received the 1stand the 2ndvaccine doses . Latency to
COVID -19 ranged from 1 to 15 days; in 1 case the
subject tested positive for COVID -19 on the same day of
the 2nddose administration and 19 days after the 1stdose
o7 case s did not indicate the number of doses the subject
had received . Latency to COVID 19 w as reported for 6
subject sand ranged from 5to 17days post-vaccination.
The PTs reported more than twice in these 15 cases were: Drug
ineffective (15), COVID -19 (13), Cough (7), Dyspnea, Pyrexia (6
each), Diarrhoea (5), Chest pain, Vomiting (4 each) , Dizziness,
Myalgia, SAR -CoV- 2 test positive, and Tachy cardia (2 each).
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COVID -19 infection outcome :resolved/resolving (7), not resolved (4),
unknown (4).
Seriousness criteria: hospitalization (non-fatal, non -life
threatening) (11)
Hospitalization occurred in 10subject s, for 1 of them COVID- 19
was not confirmed (inconclusive test).
Age: 30 to 100 ( n=9), Mean=63 .9, Median=67:
Among the 10 COVID- 19 positive subject s
o3 received the 1stvaccine dose. Latency to COVID -19
was reported for 1 subject (17 days).
o2 received the 1stand the 2ndvaccine doses . Latency to
COVID -19 w as reported for 1 subject (10 days).
o5 cases did not indicate the number of doses thesubject s
had received . Latency to COVID -19 w as reported in all
cases and ranged from 2 to 14 days post -vaccination.
The PTs reported more than twi ce in these 10 cases were: Drug
ineffective (10), COVID -19 (8), Dyspnoea (4), Cough, COVID -19
pneumonia, Diarrhoea, Oxygen saturation decreased, Pneumonia (2
each).
Covid -19 infection’s outcome: resolved/resolving (3), not resolved (3),
unknown (4).
Seriousness criteria: life threatening (8)
Hospitalization occurred in 3 of the 8 cases characterized as
life-threatening ;COVID -19 was suspected for 1 of the 8 subject s.
Age: 52 to 88 ( n=7), Mean=74 .9, Median=81
Among the 7 positive COVID -19 subject s:
o2 received the 1stvaccine dose. Latency to COVID -19
was reported for 1 subject (18 days).
o1 received the 1stand the 2ndvaccine doses . Latency to
COVID -19 unknown.
o4 cases did not indicate the number of doses the subject s
hadreceived. Latency to COVID -19 was reported in 3
cases and ranged from 5 to 17 days post -vaccination.
The PTs reported more than twice in these 8 cases were : Drug
ineffective (8), COVID -19 (5), COVID- 19 pneumonia (4), Dyspnoea
(2); Suspected COVID -19 (1) was the other term associated t o the
LOE PT.
COVID -19 infection outcome: not resolved (6), resolved w ith sequelae
(1), and unknown (Suspected COVID -19).
Seriousness criteria: death(20)
Twenty (20) subject sdied, all had a COVID -19 positive test after
vaccination :
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oAge: 63to 92years (n = 20), mean = 8 4.2,
median = 85.
oCountries of incidence : UK ( 5), Germany ( 4), Denmark ,
France, Spain, andUS (2 each) , Belgium, Czech
Republic, and Italy ( 1 each).
oGender : female ( 9), male (1 1).
oMedical history (n=16)of clinical significance included
PTs in the following SOCs :
Nervous system disorders: 11 ( 55.0%) [Cerebral
infarction, Cerebrovascular accident, Cognitive
disorder, Dementia, Dementia Alzheimer’s type (2
each), Cerebral thrombosis, Facial paralysis,
Ischaemic stroke, Parkinson's disease, Vascular
dementia (1 each)];
Cardiac disorders : 9 (45.0%) [Atrial fibrillation ( 5),
Cardiac failure ( 2)Acute myocardial infarction,
Angina pectoris, Bundle branch block left,
Cardiomyopathy, Cardiovascular disorder, Coronary
artery disease, Myocardial infarction (1 each) ];
Metabolism and nutrition disorders: 9 (45.0%) [Type
2 diabetes mellitus (5), Diabetes mellitus (3),
Dyslipidemia (2), Hypercalcemia, Insulin -requiring
type 2 diabetes mellitus , Vitamin B12 deficiency (1
each)] ;
Renal and urinary disorders: 7 (35.0%) [Chronic
kidney disease (5), Renal impairment (2 each), Renal
cyst (1);
Vascular disorders: 7 (35%) [Hypertension ( 7), Deep
vein thrombosis (1);
Latency of COVID -19 occurrence was reported for allcases and
ranged from 2 to 41 days after vaccination:
o14to 25 days after dose 1 (12);
o8 to 14 days after dose 2 (2);
o10 days after dose 2 ( 1);
o2 to 41 days after vaccination (dose number not reported )
(6).
Cause of death (n=20)reported more than once were: Drug
ineffective (9), COVID -19 , COVID- 19 pneumonia (8 each),
Respiratory failure (4), Acute respiratory failure, Confusional
state, Dyspnoea, Oxygen saturation decreased, Pulmonary
embolism (2 each).
In 2 fatal cases, vaccination failure was reported (cross ref. with
Section 9.5.3 –Lack of efficacy ):
A63-year-old female subject , with type 2 diabetes, arterial
hypertension, chronic renal failure a ndrecent closed fracture
of multiple cervical vertebrae, was admitted to intensive care
unit for acute respiratory failure (onset of symptoms 5 days
before) caused by untyped bacterial pneumonia; on the same
day, 14 days after the 2ndvaccine dose, she had a positive
SAR -CoV -2 PCR rapid test ; how ever, chest X -Ray was not
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suggestive of COVID -19 pneumonia; she died within 24
hours due to septic shock and multi -organ failure.
Vaccination failure was coded in this case due to coding
convention criteria.
An 85 -year-old female subject , with unspecified thyroid
disorder andon psychotropic drugs for unspecified diagnosis
and food supplements, developed vomiting and “aggravated
food intake”, 7 day s after the 2nddose. S he w as transferred to
the hospital, where she was diagnosed with massive
pulmonary embolism with saturation 50%; the day after, she
had a positive PCR COVID -19 test and she died on the same
day. Pulmonary embolism in this COVID -19 positive subject
may be due to COVID -19 or to an unspecified or unknown
underlying medical condition.
VAED may present as severe o r unusual clinical manifestations of
COVID -19. Overall, there were 52 subject s with test -confirmed
COVID -19 following one or both doses of the vaccine. 33 of the 52
cases were severe, resulting in hospitalization or death. None of the 52
cases could be definitively considered as having VAED/VAERD .
Conclusion: In this review of subject s with COVID -19 following
vaccination, based on the current evidence, VAED/VAERD remains a
theoretical risk for the vaccine 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. 3, dated 20
January 2021 ;
c.Search criteria: 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; Myocarditis; Vomiting;
Diarrhoea; Abdominal pain; Jaundice; Acute hepatic failure; Deep vein throm bosis; Pulmonary embolism;
Peripheral Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness;
Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; Thrombocytopenia;
Disseminated intrav ascular coagulation; Chillblains; Erythema multiforme; Multiple organ
dysfunction syndrome; Multisystem inflammatory syndrome in children ;
d.Multiple episodes of the same PT event were repo rted w ith a different clinical outcome within some
cases hence the sum of the events outcome exceeds the total number of PT events.
e.As per the EU RMP Version 1.0, dated 21 December 2020 ; 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.
f.Subject s with age ranged between 18 and 64 years;
g.Subject s with age equal to or above 65 years.
h.Note that 24 additional cases, retrieved w ith this search strategy, have been excluded from the discussion
because, upon revie w, they cannot be considered true lack of efficacy cases: 23 cases, where the PT Drug
ineffective was coded, reported that the subject s deve loped SARS -CoV- 2 infection during the early days
from the first dose (days 1 –13); the vaccine has not had sufficient time to stimulate the immune system and,
consequently, the development of a vaccine preventable disease during this time is not considere d a potential
lack of effect of the vaccine; in 1 case the PT Drug ineffective has been removed after DLP because the
subject experienced COVID -19 like symptoms but the COVID -19 test (PCR) w as negative.
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Table 10 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 10.AESIsEvaluation for BNT162b2
AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 23558)
Anaphylactic Reactions
Search criteria: Anaphylactic
reaction SMQ (Narrow and
Broad, with the algorithm
applied),selecting relevant cases
according to BC criteriaPlease refer to the Risk ‘Anaphylaxis ’ inTable 9.
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: 924 (3.9% of the total PM dataset, compared to
2.4% in the previous reporting period), of w hich 768 are medically
confirmed and 156 are non -medically confirmed;
Country of incidence: Mexico (185), UK (128), France (121), Italy
(109), Germany (65), US (56), Spain (43), Greece (33), Portugal
(32), Ireland (17), Sw eden (15), Poland (13), Netherlands (11),
Austria and Finland (10 each), Belgium (9), Czech Republic,
Hungary and Norw ay (8 each), Croatia and Romania (7 each),
Latvia (4), Canada, Denmark and Israel (3 each); the remaining 16
cases were distributed among 12 other countries;
Subject s’ gender: female (717), male (193) and unknown (14);
Subject s’ age (n = 88 6): ranged from 17to 102 years (mean = 50. 4
years, median = 47 years);
Subject s’ age group (n = 89 4): Adultc(703), Elderlyd(190) and
Adolescente (1);
Number of relevant events: 956, of which 677 serious, 279
non-serious; in the cases reporting relevant serious events,
subject ’s age ranges from 17to 102 years (mean = 54. 5years,
median = 49 .5years);
Reported relevant PTs: Tachycardia (713), Arrhythmia *(83),
Cardiac failure *(61), Myocardial infarction* (55), Acute
myocardial infarction* (19), Cardiac failure acute *(10),
Cardiogenic shock *and Postural orthostatic tachycardia
syndrome *(6 each) and Coronary artery disease *(3);
Relevant event onset latency (n = 826): Range from 24 hours to
21 days, median <24 hours;
Relevant event outcome:ffatal ( 83), resolved/resolving ( 515),
resolved with sequelae ( 11), not resolved ( 89)andunknown ( 260);
In 73 cases out of 924 cases (involving 41 female and 32 male
subject s with ages ranged from 35 to 97 years, mean 76.8 years,
median 81 years), 34 of which had fatal outcome, the subject ’s
medical history was significant for the specific events of Cardiac
failure (34), Myocardial infarction (17), Coronary artery disease
(11), Arrhythmia (9), Tachycardia (4), Acute myocardial infarction
and Postural orthostatic tachycardia syndrome (3 each),
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CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 23558)
Cardiogenic shock and Stress cardiomyopathy (1 each). More
than 1 relevant medical history event was reported in 9 cases;
Additionally, in 94 out of 924 cases, the subject ’s medical history
was significant for other cardiac disorders, with the following
conditions reported most frequently (>2 cases): Atrial fibrillation
(40), Myocardial ischaemia (14), Cardiovascular disorder (6),
Angina pectoris (5), Hypertensive heart disease (4), Cardiac
disorder, Palpitations and Supraventricular tachycardia (3 each);
In 65 out of 924 cases, the subject s’ medical history was
significa nt for COVID -19 or suspected COVID -19.
* Observed/Expected analysis was performed for Acute myocardial
infarction /Myocardial infarction , Arrhythmia, Cardiac failure/Cardiac
failure acute, Cardiogenic shock, Coronary Artery disease and Postural
orthostatic tachycardia syndrome (see Appendix 5.1 ).
Conclusion: Tachy cardia is an ongoing signal (see Appendix 3 and
Appendix 3.1 ). No other cardiovascular signals have emerged from the
review of post -authori sation data . The review of cases and O/E
analysis do not raise new concerns. Surveillance will continue .
COVID-19 AESIs
Search criteria: Covid -19 SMQ
(Narrow and Broad) OR PTs
Ageusia; AnosmiaiNumber of cases: 1630 (6.9% of the total PM dataset, compared to
7.6% in the previous reporting period), of w hich 1067 are
medically confirmed and 563 are non -medically confirmed;
Country of incidence: US (412), UK (323), Germany (233), France
(153), Italy (76), Spain (62), Romania (41), Belgium (37), Poland
(35), Mexico and Portugal (32 each), Sw eden (29), Austria (25),
Greece (23), Israel (22), Denmark (17), Czech Republic (14),
Hungary (13), Ireland (11), Canada (5), Netherlands, Switzerland
and United Arab Emirates (4 each), Costa Rica, Slovakia and
Slovenia (3 each); the remaining 14 cases were distributed among
10 other different countries;
Subject s’ gender: female (874), male (468) and unknown (288);
Subject s’ age group (n= 1039 ): Adultc(645), Elderlyd(390),
Infantg(2), Adolescenteand Childh(1 each);
Number of relevant events: 1760, of which 1325 serious, 435
non-serious;
Most frequently reported relevant PTs ( 1 occurrence): COVID- 19
(1092), Suspected COVID -19 (142), Ageusia *and SARS -CoV -2
test positive (114 each), Anosmia *(91), SARS -CoV- 2 antibody
test negative (67), COVID -19 pneumonia and SARS -CoV -2
antibody test positive (38 each), Asymptomatic COVID -19 (22),
Exposure to SARS -CoV -2 (18), Coronavirus infection (10 ),
Coronavirus test positive (4), Occupational exposure to SARS -
CoV- 2 (3), SARS -CoV -2 antibody test and SARS -CoV -2 test
negative (2 each);
Relevant event onset latency (n = 1115): Range from <24 hours to
50 days, median 6 days;
Relevant event outcome: fatal (98), not resolved ( 312),
resolved/resolving ( 333), resolved with sequ elae (4)and unknown
(1014 ).
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CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 23558)
* Observed/Expected analysis was performed for Ageusia and
Anosmia (see Appendix 5.1 ).
Conclusion: No safety signals have emerged based on a review of these
cases ,however the lower level of the confidence interval exceeds 1 for
the cumulative and interval risk periods in the Observed versus
Expected analysis. Anosmia and ageusia will be reviewed and
discussed in the next SMSR .
Dermatological AESIs
Search criteria: PT Chillblains ;
Erythema multiformejNumber of cases: 15 cases (0.06% of the total PM dataset,
compared to 0.01% in the previous reporting period), of w hich 12
are medically confirmed and 3 are non -medically confirmed ;
Country of incidence: UK (5), France and Poland (2 each), and the
remaining 6 cases were distributed among 6 other different
countries;
Subject s’ gender: female (14) and unknown (1);
Subject s’ age group (n= 15): Adultc(14), Elderlyd(1);
Number of relevant events: 15 events, 13 serious, 2 non -serious
Reported relevant PTs: Erythema multiforme *(11) and
Chillblains *(4)
Relevant event onset latency (n = 14): Range from 24 hours to 17
days, median 4 days;
Relevant event outcome: resolved/r esolving (6), not resolved and
unknown (5 each).
* Observed/Expected analysis wasperformed for Chillblains and
Erythema multiforme (see Appendix 5.1 ).
Conclusion: No safety signals have emerged based on a review of these
cases ,or of the Observed versus Expected analysis. Surveillance will
continue
Haematological AESIs
Search criteria: Leukopenias NEC
(HLT) (Primary Path) OR
Neutropenias (HLT) (Primary
Path) OR PTs Immune
thrombocytopenia ,j
Thrombocytopenia OR SMQ
Haemorrhage terms (excl
laboratory termskNumber of cases: 612 (2.6% of the total PM dataset ),kof which
330medically confirmed and 282non-medically confirmed;
Country of incidence: UK ( 229), US (149 ), France ( 45), Italy (35),
Germ any (30), Spain (23), Mexico (12), Poland ( 9), Netherlands
(8), Ireland, Portugal and Sweden (7 each), Denmark and Finland
(6 each), Austria, Israel and Norw ay (5 each), Croatia (4), Greece
(3), Belgium, Cyprus, Hungary and Latvia (2 each); the remaining
9 cases originated from 9 different countries;
Subject s’ gender (n=592): female (442)andmale (1 50);
Subject s’ age group (n= 555): Adultc(339), Elderlyd(216);
Number of relevant events: 721, of w hich 519serious, 202
non-serious;
Most frequently reported relevant PTs ( ≥15 occurrences) include :
Epistaxis (75), Contusion (71), Vaccination site bruising (46),
Haem orrhage * (34), Petechiae ( 33), Vaccination site haemorrhage
(31), Haematochezia and Vaccination site haematoma (26 each),
Conjunctival haemorrhage and Thrombocytopenia *(24 each),
Haem atoma (20), Menorrhagia (19), Rectal haemorrhage (18),
Immune thrombocytopenia *and Vaginal haemorrhage (17 each),
Haem atemesis, Haemoptysis and Neutropenia (15 each);
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CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 23558)
Relevant event onset latency (n = 534): Range from 24 hours to
33days, m edian = 1 day;
Relevant event outcome:ffatal (16), resolved/resolving ( 268),
resolved with sequelae (1 4), not resolved ( 174)and unknown
(251).
As per EMA PRAC assessment report received on the second SMSR, a
cumulative overv iew of all cases reporting Immune
thrombocytopenia/T hrombocytopenia , using Search strategy of HLT
Thrombocytopenias and SMQ Haematopoietic thrombocytopenia
(narrow and broad), w as conducted and included in Appendix 3. 2.
* Observed/Expected analysis w as performed for Haem orrhage,
Immune thrombocytopenia and Thrombocytopenia (see Appendix 5.1 ).
Conclusion: No other signals for the hematological AESIs have
emerged based on a review of these cases , or of the Observed versus
Expected analysis. Surveillance w ill continue.
Hepatic AESIs
Search criteria: Liver related
investigations, signs and
symptoms (SMQ) (Narrow and
Broad) OR PT Liver injuryNumber of cases: 52 cases (0.2% of the total PM dataset ,
compared to 0. 1% of the previous reporting period), of w hich 38
medically confirmed and 14 non -medically confirmed ;
Country of incidence: UK ( 11), US ( 9), France (7), Italy (5),
Germ any (4), Mexico and Spain (3 each), Austria, Belgium and
Iceland (2 each) and Denmark, Greece, Ireland and Slovakia (1
each);
Subject s’ gender: female ( 35), male (16)and unknown (1) ;
Subject s’ age group (n= 47): Adultc(28), Elderlyd(19);
Number of relevant events: 69, of which 36serious, 33
non-serious;
Reported relevant PTs: Alanine aminotransferase increased (11),
Transaminases increased (8), Hepatic pain (7), Liver function test
increased (6), Aspartate aminotransferase increased, Gamma -
glutamyltransferase increased and Liver function test abnormal (5
each), Hepatic enzyme increased (4), Blood alkaline phosphatase
increased , Blood bilirubin increased andHypertransaminasaemia
(3 each), Ascites and Liver injury *(2each) and Deficiency of bile
secretion, Hepatic function abnormal, Hepatomegaly,
Hyperbilirubinaemia and Liver tenderness (1 each);
Relevant event onset latency (n = 46): Range from 24 hours to 20
days, median 3 days;
Relevant event outcome: fatal ( 2), resolved/resolving ( 15),
resolved with sequelae (1), not resolved ( 11) and unknown ( 40).
* Observed/Expected analysis w as performed for Liver injury (see
Appendix 5.1 ).
Conclusion: No safety signals have emerged based on a review of th ese
cases , or of the Observed versus Expected analysis. Surveillance will
continue .
Facial Paralysis As per EMA PRAC assessment report (Product No.
EMEA/H/C/005735/MEA/002.1) received on the second SMSR, the
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Total Number of Cases in the Reporting Period (N= 23558)
Search criteria: PT sFacial
paralysis, Facial paresisMAH was requested to thoroughly follow -up cases reporting facial
paralysis including the outcome and if recovered the days till recovery
to estimate the total durat ion of this ADR. Once a reliable estimate of
duration is available from case reports, the MAH is requested to
include information of duration of facial paralysis complaints in the
product information. The MAH was also requested to indicate when the
resultsof the assessments of the facial paralysis cases in the clinical
study data will be available.
A cumulative case series evaluation of this topic , with cases assessed
according to BC case definition and criteria, was included in the second
SMSR (reporting period 01 -31 January 2021) and w ill be repeated as
warranted.
A review of the interval cases reported during the current reporting
period follows.
Number of cases: 323l(1.4% of the total PM dataset , com pared to
0.7% of previous reporting period ), 228medically confirmed and
95 non- medically confirmed;
Country of incidence: UK (83 ), US (65), I taly(37), France ( 27),
Spain (1 7), Germany (1 1), Sweden (1 0), Ireland (9), Israel (8),
Austria (7), Finland (6), Cyprus , Hungary and Portugal (5 each ),
Mexico (4), Canada andCroatia (3 each), Malta, Netherlands ,
Norw ay, Poland and Romania (2 each) ; the remaining 8cases
originated from 8different countries;
Subject s’ gender: female ( 209), male ( 103), unknown ( 11);
Subject s’ age group (n= 304): Adultc(221), Elderlyd(82), Infant
(1);g,n
Number of relevant events:m323, of which 319serious, 4
non-serious ;
Reported relevant PTs: Facial paralysis (283), Facial paresis (40);
Relevant event onset latency (n = 286): Range from <24 hours to
29days, median 2 days;
Relevant event outcome: resolved/resolving ( 138), resolved with
sequelae ( 1), not resolved ( 129) and unknown ( 55);
Duration of events till resolution was reported in 39 out of 6 7
occurrences with outcome of resolved ;it ranged from 10 minutes
to 1 month and 3 days, with a median value of 1 day.
* Please see Appendix 5.1 for Observed versus Expected analysis of
Facial paralysis /Facial paresis (Bell’s palsy) .
Interval c onclusion: No ne w significant safety information was
identified based on a review of these cases, or of the Observed versus
Expected analysis . Surveillance w ill continue.
Update to case series review presented in the second SMSR (reporting
period 01 -31 January 2021): The 139 spontaneous reports resulting
from the MedDRA version 23.1 search of the MAH safety database for
PTs Facial paralysis or Facial paresis were reviewed for any updates
in outcome resulting from follow -up activi ty through 26 Feb ruary 2021
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Total Number of Cases in the Reporting Period (N= 23558)
(As-of date 27 Feb ruary 2021). Thirty of the 139 reports w ere
reversioned due to updates and 2 reports w ere made invalid. The 30
reversioned reports w ere reviewed to understand the nature of the
updates. Of the 30 reversioned reports, 4 reports had a change in
outcome:
AER , PT Facial paralysis was changed to Facial paresis
and outcome changed from Not recovered to Recovering
AER , PT Facial paralysis outcome changed from Not
recovered to Recovering
AER , PT Facial paralysis outcome changed from
Unknown to Not recovered
AER PT Facial paralysis outcome changed from Not
recovered to Unknown
These updates based on follow -up do not substantially change the
MAH’s evaluation or conclusion. Follow-up efforts to obtain detail,
including outcome for AEs, especially AESIs, reported for the vaccine
are in place. Evaluations of facial palsy will continue to consider
duration of facial paresis/paralysis and will propose updates to labeling
language regarding facial palsy if warranted.
Overall Conclusion: Taking all available information into
consideration, including the unblinded clinical study C4591001 data
(DLP 14 November 2020), the post- authori sation data and the
comparison of observed case repor ts to the expected number of events
(O/E analyses), the available information does not support a conclusion
of a causal association between Bell’s palsy and the vaccine. This topic
will continue to be monitored. Causality assessment will be further
evaluated following availability of additional data from the remaining
clinical study C4591001, w hich will be unblinded for final analysis
approximately mid -April 2021. Additionally, non -interventional post -
authoris ation safety studies, C4591011 andC45910 12 are expected to
capture data on a sufficiently large vaccinated population to detect an
increased risk of Bell’s palsy in vaccinated individuals . The timeline
for conducting these analyses will be established based on the size of
the vaccinated populati on captured in the study data sources by the first
interim reports (due 30 June 2021) . Study C4591021, pending protocol
endorsement by EMA , is also intended to inform this risk.
Immune-Mediated/Autoimmune
AESIs
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: 710 (3.0% of the total PM dataset, compared to
2.5% of the previous reporting period), of w hich 518 m edically
confirmed and 192 non -medically confirmed ;
Country of incidence (>10 cases): UK (174), US (107), France
(68), Italy (63), Germany (48), Sw eden (33), Spain (31), Mexico
(30), Greece (22), Austria (16), Czech Republic (14), Denmark
(11). The remaining 93 cases were from 25 different countries.
Subject s’ gender (n=682): female (526), male (156).
Subject s’ age group (n=664): Adul tc(510), Elderlyd(152
Adolescente(2).
Number of relevant events: 730, of which 582 serious, 148
non‑serious.
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(b) (6)
(b) (6)
(b) (6)
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Most frequently reported relevant PTs (>10 occurrences):
Hypersensitivity (374), Neuropathy peripheral *(35), Pericarditis *
(23), Myocarditis *(20), Encephalitis *(16), Dermatitis Bullous
(12), Dermatitis, Psoriasis (11 each) ;
Relevant event onset latency (n = 580): Range from <24 hours to
30 days, median 1 day.
Relevant event outcome:fresolved/resolving (359), not resolved
(166), fatal (7), resolved w ith sequelae (15) and unknown (184).
* Please see Appendix 5.1for Observed/Expected analysis perfor med
for Autoimmune thyroiditis, Encephal itis, Myasthenia gravis, Myelitis,
Myocarditis , Neuropathy peripheral, Pericarditis , Type 1 diabetes
mellitus .
Conclusion: No new s afety signals have emerged based on a review of
these cases . The low er level of the confidence interval exceeds 1 for
the cumulative and interval risk periods in the Observed versus
Expected analysis for Myasthenia gravis and Peripheral neuropathy
and these events will b e reviewed and discussed in the next SMSR .
Surveillance will continu e.
Musculoskeletal AESIs
Search criteria: PTs Arthralgia;
Arthritis; Arthritis bacterial ;o
Chronic fatigue syndrome;
Polyarthritis; Polyneuropathy;
Post viral fatigue syndrome ;
Rheumatoid arthritisjNumber of cases: 2151 (9.1% of the total PM dataset , com pared to
8.2% of the previous reporting period ), of w hich 1121 medically
confirmed and 1030 non-medically confirmed;
Country of incidence: UK ( 827), US (340 ), Italy ( 241),Mexico
(201), Portugal ( 70), Germany (54), France (46) ,Greece (44) ,
Czech Republic ( 30), Latvia (28), Poland (27), Spain and Sweden
(20 each), Ireland (19), Austria, Belgium and Finland (18 each),
Israel (15), Netherlands (14), Denmark (13), Romania (10),
Bulgaria and Croatia (9 each), Cyprus (8), Canada, Hungary and
Norw ay (6 each), Estonia and Serbia (5 each), Iceland, Puerto
Rico and Slovakia ( 3 each), Costa Rica, Lithuania, Malta, Saudi
Arabia a nd Slovenia (2 each); the remaining 5 cases originated
from 5 different countries ;
Subject s’ gender (n= 2089 ): female ( 1653 ), male ( 436);
Subject s’ age group (n= 2027): Adultc(1656 ), Elderlyd(371);
Number of relevant events: 2173 , of which 1179 serious, 994
non-serious;
Reported relevant PTs: Arthralgia ( 2101 ), Arthritis ( 40),
Rheumatoid arthritis *(20), Polyarthritis* (5), Chronic fatigue
syndrome *(3), Polyneuropathy *(2)and Arthritis bacterial and
Post viral fatigue syndrome * (1 each);
Relevant event onset latency (n = 1798 ): Range from <24 hours to
32days, median 1 day ;
Relevant event outcome:fresolved/resolving ( 1103 ), resolved w ith
sequelae ( 27), not resolved ( 533) and unknown ( 522).
* Observed/Expected analysis was performed for Rheumatoid arthritis,
Polyarthritis, Chronic fatigue syndrome, Polyneuropathy and Post viral
fatigue syndrome (see Appendix 5.1 ).
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Total Number of Cases in the Reporting Period (N= 23558)
Conclusion: No new s afety signals have emerged based on a review of
these cases , orof the Observed versus Expected analysis .Surveillance
will continue.
Neurological AESIs (including
demyelination)
Search criteria: Convulsion s
(SMQ) (Broad and Narrow) OR
Demyelination (SMQ) (Broad and
Narrow) OR PTs Ataxia;
Cataplexy; Encephalopathy ;j
Fibromyalgia; Intracranial
pressure increased; Meningitis;
Meningitis aseptic; NarcolepsyNumber of cases: 394 ( 1.7% of the t otal PM dataset, compared to
0.9% of the previous reporting period), of w hich 296 medically
confirmed and 98 non -medically confirmed.
Country of incidence (>10 cases): UK (110), US (41), Germany
(40), Italy (28), Mexico (26), France (24), Spai n (18), Polan d (17),
Netherlands (15), Israel (11). The remaining 64 cases were from
23 different countries.
Subject s’ gender (n=377): female (253), male (124).
Subject s’ age group (n=378): Adul tc(256), Elderlyd(122);
Number of relevant events: 42 6, of which 409 serious, 17
non‑serious.
Most frequently reported relevant PTs ( ≥2occurrences) included:
Seizure* (159), Epilepsy (7 3), Generalised tonic -clonic seizure *
(26), Guillain -Barre syndrome *(20), Febrile convulsion *,
Trigeminal neuralgia (14), Fibromyalgia *(12), Status epilepticus
(11), Myelitis transverse *and Tonic convulsion *(9 each), Optic
neuritis *(8), Ataxia (7), Encephalopathy *, Petit mal epilepsy and
Tonic clonic movements (6 each) ,Multiple sclerosis relapse *(5),
Foam ing at mouth (4 ), Aura, Narcolepsy *, Partial seizures and
Tongue biting (3 each) and Bad sensation, Clonic convulsion,
Leukoencephalopathy , Meningitis *, Meningitis aseptic *,
Myokymia, Postictal state and Seizure like phenomena (2 each) ;
Relevant event onset latency (n = 342): Range from <24 hours to
48 days, median 1 day ;
Relevant events outcom e: fatal (13), resolved/resolving (211),
resolved with sequelae (8), not resolved (71) and unknown (125) ;
upon review, in the 11 cases reporting overall 13 neurological
events with fatal outcome , the outcome of these neurological
events was not relevant as the subjects died due to multiple or
different causes ;
Most frequently reported relevant medical history (> 1 occurrence)
Epilepsy (39), Seizure (14), Cer ebrovascular accident (8),
Fibromyalgia (7), Trigeminal neuralgia (4), Cerebral haemorrhage,
Cerebral infarction (3 each), Cerebral palsy, Generalised tonic -
clonic seizure, Myoclonus, Partial seizures, Petit mal epilepsy,
Transient ischaemic attack (2 each ).
* Observed/Expected analysis was performed for Encephalopahty,
Guillain -Barre syndrom e, Fibromyalgia, Meningitis , Multiple sclerosis,
Myelitis transverse, Narcolepsy, Optic neuritis and Seizure/Seizure
disorders (see Appendix 5.1 ). A safety evaluation of Guillain -Barre
syndrome was also conducted (see Appendix 3.6) .
Conclusion: No new safety signals have emerged from review of the
cases . The low er level of the confidence interval exceeds 1 for the
cumulative and interval risk periods in the Observed versus Expected
analysis for Meningitis and Transverse myelitis and these event swill
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be review ed and discussed in the next SMSR . Surveillance will
continue.
Other AESIs
Search criteria: Herpes viral
infections (HLT) (Primary Path)
OR PTsAdverse event following
immunisation; Inflammation;
Manufacturing laboratory
analytical testing issue;
Manufacturing materials issue;
Manufacturing production issue;
MERS-CoV test; MERS-CoV test
negative; MERS-CoV test positive;
Middle East respiratory
syndrome;Multiple organ
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 positiveNumber of cases: 4597 ( 19.5% of the total PM dataset, compared
to 20.3% of the previous reporting period ), of which 2650 were
medically confirmed and 1947 non -medically confirmed ;
Country of incidence (> 20 occurrences): UK (1475), US (716),
Italy (586), Portugal (198), Mexico (191), France (176), Germany
(145), Spain (135), Sw eden (117), Denmark (92), Greece (82),
Poland (79), Czech Republic (72), Finland (49), Austria (47),
Latvia , Norw ay (45 each), Belgium (40), Israel (38), Hungary
(36), Croatia (34), Ireland (32), Romania (24) Netherlands (22).
The remaining 121 cases were from 21 different countries ;
Subject s’ gender (n=4441): female (3427), male (1014) ;
Subject s’ age group (n= 4312): Adultc(3496), Elderlyd(803),
Adolescente, Childh(5 each), Infantg(3);
Number of relevant events: 4666, of which 2691 serious, 1975
non‑serious ;
Most frequently reported relevant PTs ( ≥5 occurrences) included:
Pyrexia (4 272), Herpes zoster *(179), Inflammation (93), Oral
herpes (50), Multiple organ dysfunction syndrome *(12),
Ophthalmic herpes zoster *(10), Herpes simplex (8), Herpes virus
infection (7), Herpes ophthalmic (6), Herpes zoster reactivation *
(5);
Relevant event onset latency (n = 2498 ): Range from <24 hours to
32 days, median 1 day ;
Relevant events outcome:ffatal (69), re solved/resolving (2953),
resolved with sequelae (50), not resolved (752) and unknown
(877).
* Amo ng multiple different events grouped under this Other AESIs
category, Observed/Expected analysis was performed on specific PTs
relevant for Herpes zoster disorders andMultiple organ dysfunction
syndrome (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , or of the Observed versus Expected analysis .Surveillance
will continue .
Pregnancy Related AESIs
Search criteria: PTs Amniotic
cavity infection; Caesarean
section;Congenital anomaly;
Death neonatal; Eclampsia;
Foetal distress syndrome; Low
birth weight baby; Maternal
exposure during pregnancy;
Placenta praevia; Pre-eclampsia;
Premature labour; Stillbirth;
Uterine rupture; Vasa praeviaFor relevant cases ,please refer to the subsection Use in Pregnancy and
While Breast Feeding inTable 12.
Renal AESIs
Search criteria: PTs Acute kidney
injury;Renal failure.Number of cases: 45cases (0. 2% of the total PM dataset,
compared to 0.1% of the previous reporting period), of w hich 36
medically confirmed, 9non-medically confirmed;
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Total Number of Cases in the Reporting Period (N= 23558)
Country of incidence: France (12), Germany (10), UK (6), Spain
(4), Belgium and US (3 each), Italy (2) and Austria, Canada,
Denmark, Finland and Luxembo urg (1 each);
Subject s’ gender: female ( 29), male (16);
Subject s’ age group (n= 45): Adultc(6), Elderlyd(39);
Number of relevant events: 45, all serious;
Reported relevant PTs: Acute kidney injury * (24) and Renal
failure * (21);
Relevant event onset latency (n = 28): Range from 24 hours to 15
days, median 4days;
Relevant event outcome: fatal (15), resolved/ resolving ( 7), not
resolved (11) and unknown ( 12).
* Observed/Expected analysis performed for Acute kidney injury and
Renal failure (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , or of the Observed versus Expected analysis performed .
Surveillance will continue .
Respiratory 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: 100cases ( 0.4% of the total PM dataset,
compared to 0.2% of the previous reporting interval) , of which 82
medically confirmed;
Countr iesof incidence: France (17), Germany (12), United
Kingdom (12), Spain (11), Italy (8), Belgium, United States (7
each), Denmark 6), Norw ay (5), Czech Republic, Iceland (3 each);
the remaining 9 cases originated from 6 different countries.
Subject s’ gender (n= 60):male ( 40).
Subject s’s age group (n= 97):Elderlyd(63), Adultc(33),
Adolescente(1).
Number of relevant events: 100serious event s, 6non-serious .
Reported relevant PTs:Hypoxia, Respiratory failure ( 35 each),
Respiratory disorder (26), Acute respiratory distress syndrome (7),
Chronic respiratory syndrome (2 ), Severe acute respira tory
syndrome ( 1).
Relevant event onset latency (n=80): range from < 24 hours to 1 8
days.
Relevant events outcome: fatal (30), Resolved/resol ving (4 1), not
recovered ( 11)and unknown ( 24).
Out of these 100 cases, only2 (1 fatal and 1 medically significant )
in which the PT Respiratory failure (2)was reported in a context
of vaccine lack of efficacy (PT: Drug ineffective) , were also
reviewed among thepotential relevant cases for the Risk ‘VAED
Including VAERD’ in Table 9.
* Observed/Expected analysis performed for Acute respiratory distress
syndrome (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , orof the Observed versus Expected analysis performed
Surveillance will continu e.
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Total Number of Cases in the Reporting Period (N= 23558)
Thromboembolic Events
Search criteria: Embolism and
thrombosis (HLGT) (Primary
Path),excluding PTs reviewed as
Stroke AESIs, OR PTs Deep vein
thrombosis; Disseminated
intravascular coagulation;
Embolism; Embolism venous;
Pulmonary embolismNumber of cases: 114(0.5% of the total PM dataset, compared to
0.2% of the previous reporting period), of w hich 86medically
confirmed and 28non-medically confirmed;
Country of incidence: UK ( 23), France (20), US (18 ), Germany
(11), Spain (6), Denmark ,Italy and Sweden (5 each), Belgium,
Canada, Cyprus and Netherlands (2 each) ; the remaining 13 cases
originated from 13 different countries;
Subject s’ gender (n= 112): female ( 69), male ( 43);
Subject s’ age group (n= 106): Adultc(55), Elderlyd(51);
Number of relevant events: 127, of w hich 125serious, 2
non-serious;
Most frequently reported relevant PTs ( 1 occurrence) included:
Pulmonary embolism *(48), Thrombosis (28), Deep vein
thrombosis * (23), Thrombo phlebitis superficial (6), Venous
thrombosis limb (4), Thrombo phlebitis and Venous thrombosis (3
each) and Blue toe syndrome and Microembolism (2 each);
Relevant event onset latency (n = 95): Range from <24 hours to 28
days, median 5 days;
Relevant event outcome: fatal ( 9), resolved/resolving (44),
resolved with sequelae ( 4),not resolved (41) and unknown ( 29).
* Observed/Expected analysis performed for Deep vein thrombosis and
Pulmonary embolism (see Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases and of the Observed versus Expected analysis performed
Surveillance will continue .
Strokep
Search criteria: HLT Central
nervous system haemorrhages and
cerebrovascular accidents
(Primary Path) OR HLT
Cerebrovascular venous and sinus
thrombosis (Primary Path)Number of cases: 1 93(0.8% of the total PM dataset) )p, of which
120medically confirmed and 73non-medically confirmed;
Country of incidence: US ( 46), U K (42), France (2 8), Germany
(16), Norway (12), Netherlands and Spain (11 each), Sweden (6),
Italy (3), Belgium, Denmark, Finland and Poland (2 each); the
remaining 1 0cases originated from 10 different countries;
Subject s’ gender (n= 1 91): female ( 133), male ( 58);
Subject s’ age group (n=1 86): Adultc(38), Elderlyd(147), Childh,q
(1);
Number of relevant events: 209,all serious ;
Most frequently reported relevant PTs ( 1 occurrence) included:
oPTs indicative of Ischaemic stroke: Cerebrovascular
accident (111), Ischaemic stroke (30),Cerebral infarction
(12), Cerebral thrombosis and Ischaemic cerebral
infarction (3 each) and Basal ganglia stroke, Cerebral
ischaemia, Cerebral venous sinus thrombosis and
Thrombotic stroke (2 each);
oPTs indicative of Haemorrhagic stroke: Cerebral
haemorrhage (19), Haemorrhagic stroke (7), Cerebral
haematoma and Subarachnoid haemorrhage (4 each);
Relevant event onset latency (n = 164): Range from <24 hours to
41days, median 2days;
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Relevant event outcome: fatal and resolved/resolving (44 each),
resolved with sequelae ( 7), not resolved (4 9) and unknown ( 65).
* Observed/Expected analysis was perfo rmed for Stroke disorders (see
Appendix 5.1 ).
Conclusion: No new safety signals have emerged based on a review of
these cases , or of the Observed versus Expected analysis performed .
Surveillance will continue.
Vasculitic Events
Search criteria: Vasculitides HLTNumber of cases: 26 cases (0.1% of the total PM dataset,
compared to 0.01% of the previous reporting period ), of w hich 21
medically confirmed and 5 non -medically confirmed ;
Country of incidence: UK(10), France (4), Portugal (3), Spain and
US (2 each) and Cyprus, Germany, Hungary, Italy and Slovakia (1
each);
Subject s’ gender: female (21), male (5);
Subject s’ age group (n=25): Adultc(13), Elderlyd(12);
Number of relevant events: 28, of which 21 serious, 7 non -serious ;
Reported relevant PTs: Vasculitis *(12), Cutaneous vasculitis *(4),
Vasculitic rash *(3), Behcet’s syndrome , Giant cell arteritis and
Hypersensitivity vasculitis (2 each) and Palpable purpura,
Peripheral ischaemia *and Takaya su’s arteritis (1 each);
Relevant event onset latency (n = 2 0): Range from 24 hours to 1 9
days, median 3days;
Relevant event outcome: resolved/resolving ( 12), not resolved ( 9)
and unknown ( 7).
* Observed/Expected analysis was performed for Vasculitis and
Cutaneous vasculitis disorders (see Appendix 5.1 ).
No new significant safety information was identified based on a review
of these cases, or of the Observed versus Expected analysis .
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 authoris ation
approval data sources;
c.Subject s with age ranged between 18 and 64 years;
d.Subject s with age equal to or above 65 years;
e.Subject s with age ranged between 12 and less than 18 years;
f.Multiple episodes of the same PT event were reported w ith a differ ent clinical outcome within some
cases hence the sum of the events outcome exceeds the total number of PT events;
g.Subject s with age ranged between 1 (28 days) and 23 months ;
h.Subject s with age ranged between 2 and 11 years;
i.To increase clinical relevance of the revie w, com pared to previous SMSR these PTs w ere m oved t o
COVID -19 category;
j.To increase clinical relevance of the revie w, com pared to previous SMSR this PT w as moved from the
Immune -mediated/Autoimmune Category to its appropriate specific body system category;
k.As per EMA PRAC assessment report received on the second SMSR, EMA has reques ted ananalysis of
haemorrhagic disorders through review of PTs present in a specific SMQ query in addition to the PTs
Haem orrhage and Haemorrhagic disorder already included in the AESIs/TME list; comparison with reporting
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AESIsa
CategoryPost-Marketing Case sEvaluationb
Total Number of Cases in the Reporting Period (N= 23558)
proportion of Haematological eve nts reported in the previous reporting period is therefore not applicable for
this Category ;
l.Twenty-four additional cases were excluded from the analysis as they were not cases of peripheral facial
nerve palsy (BC Category 5) because they described other disorders (stroke, cerebral haemorrhage or
transient ischaemic attack ); 1 case w as excluded from the analysis because it was invalid due to an
unidentifiable reporter;
m.If a case included both PT Facial paresis and PT Facial paralysis, only the PT Facial paralysis was
considered in the descriptions of the events as it is most clinically important;
n.This UK case report received from the UK MHRA described a 1-year-old subject who received the
vaccine, and had left postauricular ear pain that progressed to left -sided Bell’s palsy 1 day following
vaccination that had not resolved at the time of the report ;
o.This PT not included in the AESIs/TME list w as included in the review as relevant for ACCESS
protocol criteria;
p.New search strategy was implemented since this third SMSR for Stroke to include, in addition to the PT
Cerebrovascular accident already included in the AESIs/TME List, other reported PTs that are indicative of
stroke and were not in t he previous search strategy, and to differentiate betw een ischemic and hemorrhagic
strokes; for this reason the comparison with the reporting proportion of previous reporting period is not
applicable for this AESI category ;
q.This UK case report received from the UK MHRA described a 7 -year-old female subject who received
the vaccine and had stroke (unknown outcome); no follow -up is possible for clarification.
9.5.3.Evaluation of Special Situations
Table 11 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 11.Evaluation of Special Situations for BNT162b2
Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 23558)
Death Overview
Number of fatal cases: 79438(3.4% of the total PM dataset ,compared to 2.8% of the
total PM cases received in the previous reporting period ) of which 652were
medically confirmed and 142 non- medically confirmed;
Country of incidence: the majority were from France (140), Germany (132), UK
(99), Norw ay (65), Sw eden (56), US (48), Netherlands (44), Belgium (41), Denmark
(29), Spain (23) ; the remaining 117cases occurred in 21other countries.
Subject Gender: females ( 423), males ( 303), unknown ( 68);
38During the current re porting interval there were 8 additional cases reporting subjects’ death. How ever,
they were excluded from further analysis in this subsection as the death was mentioned as an incidental
information only in 3 cases, with none of the reported events present ing a fatal outcome; 2 cases were excluded
as it was made invalid; and 3 cases reported foetal death and are review ed in Table 12under Use in Pregnancy
and While Breas t Feeding .
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 23558)
Subject s’ Age: 19to 103 years (n = 722), mean = 82.7, median = 86;
Adults ( 68), Elderly ( 672), subject s with unknown age ( 54);
Causes of death most frequently reported ( ≥2%of total fatal cases ): Death (239),
COVID -19 (70), Sudden death (68), General physical health deterioration (63),
Pyrexia (51), Dyspnoea (42), Drug ineffective (37), Cardiac failure (35), Card iac
arrest, Pneumonia (26 each), Oxygen saturation decreased (25), Myocardial
infarction (23), Cerebrovascular accident (20), Respiratory failure, Vomiting (19
each), Malaise (18), and COVID -19 pneumonia (16).
PTs most frequently reported ( 2%events ): Death (240), COVID- 19 (94), Pyrexia
(85), Sudden death (73), Dyspnoea, General physical health deterioration (70 each),
and Drug ineffective (68).
Concomitant medications were reported in 343out of 794cases and the most
frequently present ( ≥2%) are listed below :
Paracetamol (97), Furosemide (71), Acetylsalicylic acid (52), Oxazepam (41),
Apixaban (38), Macrogol 3350/Potassium Chloride/Sodium Bicarbonate/Sodium
Chloride (34), Atorvastatin, Mirtazapine (31 each), Omeprazole (29), Bisoprolol
Fumarate (27), Bis oprolol, Colecalciferol (26 each), Pantoprazole, Ramipril (24
each), Amlodipine, Levothyroxine Sodium, Potassium Chloride, Zopiclone (23
each), Pantoprazole Sodium Sesquihydrate (22), Calcium Carbonate/Colecalciferol
(21), Folic Acid, Lansoprazole (20 each ), Risperidone (19), and Fentanyl (16) .
Lot/Batch Number (#) information by Country wasavailable in 514 cases w ith no
related quality issues identified during investigations of the impacted lot/batch
number s. The list of Lot /Batch #smostfrequently repo rted ( >2% of total fatal cases)
is presented hereinafter:
oLot # EM0477 in 130 cases from France (41), Germany (32), Netherlands
(19), Norw ay (16), Belgium (12), Spain (6), Ireland (3), and Denmark (1) .
oLot # EJ6795 in 70 cases from France (29), Norw ay (22), Sweden (11),
Netherlands (3), Germany, Finland (2 each), and Poland (1) .
oLot # EJ6796 in 49cases from Germ any (20), Norw ay (7), France (6),
Sweden (5), Austria (4), Spain (3), Belgium, Finland, Hungary, and Iceland
(1 each) .
oLot/Batch # EJ6788 in 41cases from France (38), Germany (2), and
Netherlands (1).
oLot # EJ6797 in 29cases from Denmark (14), Austria, Italy (5 each),
Germ any (3), Slovakia, and Slovenia (1 each) .
oLot # EJ6134 in 26cases from Sweden (7), Denmark (4), Netherlands,
Finland (3 eac h), Hungary, France, Belgium (2), Slovenia, Slovakia, and
Austria (1 each) .
oLot # EK9788 in 21 cases from Germany (9), Denmark (5), France (3),
Poland (2), Belgium, and Italy (1 each) .
oLot # EL1484 in 21 cases from Sweden (12), Italy (6), Portugal (2), and
Hungary (1) .
oLot # EL1491 in 17 cases from Germany (5), Austria (3), Croatia, Poland,
Spain (2 each), Czech Republic, Finland, and Greece (1 each) .
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 23558)
Time to onset of fatal events was reported for 602subject s and ranged from the day
of vaccination to 41days after vaccination:
oSame day to 3 days after vaccination: 327 cases
o4-7 days after vaccination: 155 cases
o8-14 days after vaccination: 83cases
o15-41days after vaccination: 37cases
Number of vaccine doses administered at the time of the subject s’ death: in 390
cases the death occurred after the administration of the first dose, in 108cases the
fatal outcome was observed after the administration of the second dose w hereas in
the remaining cases (2 96) it was not specified if the subject s received the first or the
second vaccine dose at the time of the fatal events.
Test for COVID- 19 w asreported for 234 subject s as follows: in 118cases subject s
tested positive (72after 1st vaccine dose, 7after 2nd vaccine dose and in 39there
was no informatio navailable about the dose they received) , in 107were negative, 2
cases reported prior history of positive COVID -19 test, and in 7cases test results
were unknown.
Analysis
Most of the cases reporting a fatal outcome (7 4.9%) w ere in subjects over 75 years of
age. This reflects one of the priority groups targeted for vaccination by many regions and
countries, including Europe and the US , that is, elderly (with various lower age cut -offs
across countries), because of their higher risk of severe disease and mortality if infected
with SARS -CoV-2.12,13
Among the total of 794cases with a fatal outcome, when the medical history was
provided (in 624cases), the majority had multiple concomitant comorbidities. The mos t
frequently reported medical conditions included cardiac and vascular disorders (eg
Hypertension, Atrial fibrillation, Cardiac failure, Cerebrovascular accident, Myocardial
ischaemia, Myocardial infarction ). Other frequently reported significant medical histories
included Dem entia/Dementia Alzheimer's type, Chronic kidney disease, Renal failure,
Diabetes mellitus /Type 2 diabetes mellitus, and Chronic obstructive pulmonary disease .
Some of the subject s (16.5%) who received the vaccine a lready had general physical
deterioration, w ere bedridden, w ere living in residential institutions, or on palliative care .
No specific pattern regarding underlying condition sor cause of death have been
identified. Further reports w ill continue to be close ly monitored.
Please see Appendix 5.1 for Observed versus Expected analysis of Death.
Conclusion: No new risks were identified following review of the signal of death,
particularly in the comorbid elderly population.
Lack of Efficacy Company conventions for coding cases indicative of lack of efficacy :
The coding conventions for lack of efficacy in the context of administration of
the COVID- 19 vaccine was revised on 12 February 2021, as shown below: PT
“Vaccination failure” is coded when ALL of the following criteria are met:
oThe subject has received the appropriate series of tw o doses based on
the labeling.
oAt least 7 days have elapsed since the second dose of vaccine has been
administered.
oThe subject experiences SARS -CoV- 2 infection (confirmed laboratory
tests).
PT “Drug ineffective” i s coded when e ither of the following applies:
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Total Number of Cases in the Reporting Period (N= 23558)
o The infection is not confirmed as SARS-CoV -2 through laboratory tests
(irrespective of the vaccination schedule). This includes scenarios where LOE
is stated or impl ied, e.g., “the vaccine did not work”, “I got COVID-19”.
oIt is unknown:
Whether the subject has received the appropriate series of two
doses in correct timing based on the labeling instructions;
How many days have passed since the first dose (including
unspecified number of days like a”a few days”, “some days”,
etc.);
If 7 days have passed since the second dose of the vaccine
administration;
oThe subject experiences a vaccine preventable illness 14 days after
receiving the first dose up to and through 6 days after receipt of the
second dose.
Note: after the immune system as had sufficient time (14 days) to respond to the vaccine,
this is considered a potential lack of efficacy even if the vaccinati on course is not
complete.
This is the summary of the coding conventions for onset of vaccine preventable disease
versus the vaccination date:
1stdose (day 1 -13) From day 14 post 1stdose
to day 6 post 2nddoseDay 7 post 2nddose
Code only the events
describing the SARS -CoV -
2 infectionCode “Drug ineffective” Code “Vaccination failure”
Secenario Not considered
LOEScenario considered LOE
as “Drug ineffective”Scenario considered LOE as
“Vaccination failure”
Lack of efficacy cases
Number of cases39: 856 ( 3.6% of the total PM dataset, compared to 7 .2% of the
previous reporting period) of which 572were medically confirmed and 284
non - medically confirmed;
Number of lack of efficacy events: 8 56[PT: Drug ineffective (840) and Vaccination
failure (16) ].
Country of incidence: US ( 233), UK ( 180), Germany (1 20), France (8 0), Italy (52),
Belgium, Romania ( 28 each), Poland (20), Spain ( 19), Austria , Israel (16 each),
Greece (14), Portugal ( 9), Denmark (7), Mexico ( 6), Czech Republic, Sweden (4
each); the remaining 20cases originated from 11different countries.
39One hundred and ninety -six(196) additional cases retrieved in this dataset were excluded from the
analysis ; upon review, 188 cases cannot be considered true lack of efficacy cases because the PT Drug
ineffective was coded but the subjects dev eloped SARS -CoV -2 infection during the early days from the first
dose (days 1 –13); the vaccine has not had sufficient time to stimulate the immune system and, consequently,
the development of a vaccine preventable disease during this time is not consider ed a potential lack of effect of
the vaccine; in 5 cases the PT Drug ineffective was removed after DLP because the subjects did not develop
COVID -19 infection ; in 1 case, reporting Treatment failure and Transient ischaemic attack, the Lack of efficacy
PT did not refer to BNT162b2 vaccine; 2 cases have been invalidated in the safety database after DLP.
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Topic Post-Marketing Cases Evaluationa
Total Number of Cases in the Reporting Period (N= 23558)
COVID -19 infection was confirmed in 79 1cases, suspected in 6 4cases, in 1 case it
was reported that the first dose was no effective (no other information).
COVID -19 infection (suspected or confirmed) outcome was reported as
resolved/resolving ( 100), not resolved (1 21) or unknown ( 591) at the time of the
reporting ;there were 44cases where a fatal outcome was reported (see also Death
section above in this table).
Drug ineffective cases (8 40)40
Drug ineffective seriousness: serious ( 833), non -serious ( 7)41;
Lack of efficacy term was reported:
oafter the 1stdose in 427cases
oafter the 2nddose in 106cases
oin 307cases it w as unknown after which dose the lack of efficacy occurred.
Latency of lack of efficacy term reported after the first dose was known for 119
cases:
oWithin 0 ad7 days: 1 subject ;
oWithin 14and 21days: 1 04subject s;
oWithin 23and 50days: 14subject s;
Latency lack of efficacy term reported after the second dose was known for 50
cases:
oWithin 0 and 7days: 28subject s;
oWithin 8 and 21days: 17subject s;
oWithin 23 and 36 days: 5 subject s.
Latency of lack of efficacy term reported in cases (307) where the number of doses
administered w as not provided, w as known in 1 94cases:
oWithin 0 and 7 days after vaccination: 1 21subject s.
oWithin 8 and 14 days after vaccination: 46subject s.
oWithin 15 and 44daysafter vaccination: 27 subject s.
According to the RSI, individuals may not be fully protected until 7 days after their
second do se of vaccine, therefore for the above 840 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.
Vaccination failure cases (16)
Vaccination failure seriousness: all serious;
Lack of efficacy term was reported in all cases after the 2nddose:
Latency of lack of efficacy term was known for all cases:
oWithin 7 and 14 days: 1 0subject s;
oWithin 1 5and 2 9days: 6subject s.
COVID -19 (10) and Asymptomatic COVID -19 (6) were the r eported vaccine
preventable infections occurred in these 16 cases.
40There w ere 837 PTs Drug ineffective; in 3 additional cases the LOE PT has been reco ded from
Vaccination failure t oDrug ineffective after DLP.
41Event seriousness of PTs , indicative o f possible 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= 23558)
Conclusion: No new safety signals have emerged based on a review of these cases.
Vaccine
InteractionsNumber of cases: 7(0.03% of the total PM dataset , compared to 0.0 8% of the
previous reporting period ) of which, 4cases were medically confirmed and 3cases
were non -medically confirmed.
Country of incidence: US ( 3), Portugal , Spain , Switzerland, UK (1 each).
Subject Gender: Female ( 4)andMale ( 3);
Subject s’ Age: 3 2to 80 years; (n=7); mean=5 0.6; median 49.0;
Relevant reported interaction PTs: Drug interaction ( 6) and Alcohol interaction (1);
Relevant event seriousness: Serious ( 4) and Non -serious ( 3);
Relevant event outcome: Resolved /Resolving (2), Not resolved (1), and Unknown
(4);
Co-reported events coded to the PTs (>1 event): Headache , Off -label use, and
Product use issue (2).
Reported Interacting Agents: adalimumab, alcohol, clozapine, insulin, lamotrigine,
ocrelizumab, paroxetine, PEG, and w arfarin.
Conclusion: there is no indication of a safety signal of interference of immune response
of va ccines 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 12 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 12.Evaluation of Missing Information for BNT162b2
Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
Use in Pregnancy and
While Breast
FeedingbNumber of cases: 153c(0.6% of the total PM dataset, compared to 1.4% of the
previous reporting period) of which 74 w ere m edically confirmed and 79 w ere
non-medically confirmed;
Country of incidence: UK (50), US (38), Germany (15), Canada (8), Italy (7),
Israel (6), Ireland, Mexico (5 each), Hungary (4), Portugal (3), Czech Republic,
Poland (2 each), Belgium, Denmark, Estonia, Finland, Latvia, Lithuania,
Rom ania, and Spain (1 each ).
Pregnancy cases: 121 cases including:
117 mother cases and 4 foetus/baby cases representing 117 unique pregnancies
(the 4 foetus/baby cases were linked to 3 mother cases; 1 mother case involved
twins)
Pregnancy outcomes for the 117 pregnancies were re ported as spontaneous
abortiond(18), spontaneous abortion w ith intrauterine death, premature birth
with neonatal death (2 each ), spontaneous abortion w ith neonatal death (1), and
no outcome was provided for 95 pregnancies (note that 2 different outcomes
were reported for the tw ins and both w ere counted)
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
47 non -serious mother cases reported exposure to vaccine in utero w ithout the
occurrence of any clinical event. The exposure PTs coded to the PTs Maternal
exposure during pregnancy (35), Exposure during pregnancy (11), and Maternal
exposure timing unspecif ied (1). Trimester of exposure was reported in 7 of
these cases: 1st trimester (5 cases), 2nd trimester, and 3rd trimester (1 case
each)
70 mother cases, 15 non -serious and 55 serious, reported additional clinical
events, which occurred in the vaccinated m others. Pregnancy related events
reported in these cases coded to the PTs Spontaneous abortion (17), Abortion,
Abortion missed, and Foetal death (1 each). Other clinical events which
occurred in more than 5 cases coded to the PTs Headache (24), Pain in
extremity (13), Fatigue (12), Nausea, Pyrexia, Vaccination site pain (8 each),
Chills, Myalgia, Pain (7 each), Arthralgia, and Asthenia (6 each). Trimester of
exposure was reported in 17 of these cases: 1sttrimester (13 cases), 2ndtrimester
(3 cases), 3rdtrimester (1 case).
4 serious foetus/baby cases reported the PTs Exposure during pregnancy, Foetal
grow th restriction, Maternal exposure during pregnancy, Premature baby (2
each), and Death neonatal (1). Trimester of exposure was reported for 2 cases
(twins) as occurring during the 1sttrimester.
Breast feeding baby cases : 31, of which:
25 cases reported exposure to vaccine during breastfeeding (PT Exposure
via breast milk) without the occurrence of any clinical events;
6 cases, 3 serious and 3 non -serious, reported 7 additional clinical events
that occurred in the infant/child exposed to vaccine via breastfeeding; these
events coded to the PTs Illness (2), Diarrhoea, Pain, Pyrexia, Rash, and
Urticaria (1 each).
Breast f eeding mother cases :
1 serious case reported 3 clinical events that occurred in a mother during
breast feeding (PT Maternal exposure during breast feeding); these events
coded to the PTs Chills, Malaise, and Pyrexia.
Conclusion: There w ere no safety sign als that emerged from the review of these
cases of use in pregnancy and while and breast feeding.
Use in
Immunocompromised
PatientseNumber of cases: 941(4.0% of the total PM dataset, compared to 2.1% of the
previous reporting period) of which 369were medically confirmed and 572
non-medically confirmed;
Case Seriousness: Serious ( 758), Non -Serious ( 183);
Country of incidence: UK ( 534), US (175 ), France (78), Italy (18), Germany
(15), Denmark and Spain (11 each), Norw ay and Sweden (10 each), Austria and
Portugal (9 each), Belgium (7), Czech Republic, Israel and Netherlands (6
each), Greece (5), Ireland (4), Estonia, Finland and Slovakia (3 each), Bulgar ia,
Hungary, Malta, Mexico and Poland (2 each); the remaining 8cases originated
from 8different countries;
Gender: females ( 705), males ( 221) and unknown ( 15);
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
Age (n = 891) ranged from 18 to 100years, mean = 5 7.7years , median = 5 7
years ;
Relevant patients’ medical histories most frequently reported ( ≥20 cases) coded
to the PTs: Immunodeficiency (273), Breast cancer (119), Neoplasm malignant
(58), Chemotherapy (56), Neoplasm (51), Radiotherapy (42), Prostate cancer
(34), Hysterectomy (33), Thyroidectomy (32), Splenectomy (31), Lymphoma
(24), Chronic lymphocytic leukaemia (23) and Renal transplant (20);
Of the 4561events overall reported, the most frequent clinical events (≥60
occurrences) coded to the PTs: Headache ( 241), Fatigue ( 225), Pyrexia ( 145),
Nausea ( 141), Myalgia and Pain in extremity ( 112 each), Chills ( 106),
Dizziness ( 102), Malaise (98), Vaccination site pain (87), Pain (85), Arthralgia
(69), Dyspnoea (66) and Diarrhoea ( 60);
Case outcome: fatal ( 36, see Table 11, Death ), resolved/resolving ( 442),
resolved with sequelae ( 23), not resolved ( 359) and unknown ( 81).
Conclusion: The most frequently reported clinical events observed in
immunocompromised subject s were consistent with those observed in the overall
population. The reporting proportion of unresolved cases (3 8.2%) and cases
resolved with sequelae (2. 4%) in patients in immunocompromised subject sis
slightly higher compared to the reporting proportion observed in the overall
population (27.2% for outcome of not resolved, 1.4% for outcome of resolved with
sequelae), while the re porting proportion of cases with fatal outcome in
immunocompromised subject s (3.8%) is similar to the reporting proportion of cases
with fatal outcome in the overall population (3.4%).
No safety signals have emerged that w ould be considered specific to thi s population .
Use in Patients With
Autoimmune or
Inflammatory
DisorderseNumber of cases: 1490 (6.3% of the total PM dataset, compared to 6.1% of the
previous reporting period) of which 721 w ere m edically confirmed and 769
non-medically confirmed;
Case Seriousness: Serious (1009), Non -Serious (481);
Country of incidence: UK (586), US (403), France (84), Italy (76), Sw eden
(35), Germany (32), Portugal (31), Spain (27), Austria (26), Denmark (21),
Czech Republic (19), Croatia (17), Ireland (15), Finland (14), Greece (13),
Hungary and Israel (12 each), Norw ay (7), Canada and Romania (6 each),
Belgium, Malta and Netherlands (5 each), Cyprus, Mexico and Poland (4 each),
Bulgaria, Estonia, Slovakia and Slovenia (3 each) and Iceland and Latvia (2
each); the r emaining 5 cases originated from 5 different countries;
Gender: Females (1269), Males (195) and Unknown (26);
Age (n = 1416 ) ranged from 1 8to 104 years, mean = 52. 9years,
median = 51 .5years;
Relevant subject s’ medical histories most frequently reported (20cases) coded
to the PTs: Hypothyroidism (295), Rheumatoid arthritis (209), Arthritis (120),
Autoimmune thyroiditis (105), Crohn’s disease (74), Colitis ulcerative (69),
Thyroid disorder (67), Inflammatory bowel disease (65), Multiple sclerosis
(59), Type 1 diabetes mellitus (58), Coeliac disease (53), Psoriasis (48),
Systemic lupus erythematosus (41), Psoriatic arthropathy (39), Autoimmune
disorder (31), Sjogren's syndrome and Raynaud's phenomenon (28 each) and
Ankylosing spondylitis (24);
Of the 681 9 events overall reported, the most frequent ( ≥65 occurrences) coded
to the PTs: Headache (434), Fatigue (357), Pyrexia (247), Nausea (232),
Arthralgia (214), Vaccination site pain (197), Chills (196), Myalgia (174),
Dizziness (163), Pain in extremity (160 ), Pain (134), Malaise (111), Diarrhoea
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Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
(109), Asthenia (99), Paraesthesia (76), Lymphadenopathy (75), Dyspnoea (66)
and Vomiting (65);
Case outcome: fatal (13 see Table 11, Death ), resolved/resolving (76 5),
resolved with sequelae (34), not resolved (555) and unknown (123).
Conclusion: The most frequently reported clinical events observed in subject s with
autoim mune or inflammatory disorders w ere consistent with those observed in the
overall population. The reporting proportion of unresolved cases (37.2%) and cases
resolved with sequelae (2.3%) in subject s with autoimmune or inflammatory
disorders is slightly higher compared to the reporting proportion observed in the
overall population (27.2% for outcome of not resolved, 1.4% for outcome of
resolved with sequelae), while the reporting proportion of cases with fatal outcome
in subject s with autoimmune or inflammat ory conditions (0.9%) is below the
reporting proportion of cases with fatal outcome in the overall population (3.4%).
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)eNumber of cases: 252 1f(10.7% of the total PM da taset, compared to 9.2% of
the previous reporting period) of which 1602 were medically confirmed and
919non-medically confirmed;
Case Seriousness: Serious ( 2008 ), Non -Serious (5 13);
Country of incidence: UK (735), US (49 2), France (337), Sweden (149),
Germ any (126), Spain (113), Italy (80), Norw ay (76), Denmark (63), Finland
(40), Netherlands (37), Austria (36), Ireland and Portugal (35 each), Belgium
(33), Greece (18), Czech Republic (17), Canada and Switzerland (10 each) ,
Israel (9), Hungary (8), Croatia, Iceland and Romania (7 each), Malta and
Mexico (6 each), Estonia (5), Cyprus and Latvia (4 each), United Arab
Emirates (3), Luxembourg and Serbia (2 each); the remaining 9 cases originated
from 9 different countries;
Gender: Females (17 19), Males (774) and Unknown (28);
Age (n = 245 7) ranged from 5 to 106 years, mean = 66.5 years ,
median = 72 years ;
Relevant subject s’ medical histories most frequently reported ( 20 cases) coded
to the PTs : Asthma (880), COPD (242), Dementia (240), Cardiac failure (179),
Dem entia Alzheimer’s type (151), Chronic kidney disease (125), Cognitive
disorder (90), Parkinson’s disease (73), Pulmonary embolism (63), Renal
failure (59), Vascular dementia (45), Cardia c failure congestive (28) and
Bronchiectasis (26);
Of the 103 17events overall reported, the most frequent ( ≥100 occurrences)
coded to the PTs: Pyrexia (430), Headache (427), Fatigue (390), Dyspnoea
(284), Nausea (268), Chills (225), Malaise (20 1), Dizzin ess (19 4), Myalgia
(189), Vaccination site pain (167), Pain in extremity (15 7), Pain (152),
Vom iting (147), Arthralgia (143), Asthenia (142 ), Diarrhoea (118), Death (10 7)
and Cough (100); all these events were consistent with the most frequent events
obser ved in the overall population except for Death;
Case outcome: fatal (43 8, see Table 11, Death ), resolved/resolving (1158),
resolved with sequelae (47), not resolved (693 ) and unknown (185).
Conclusion: The reporting proportion of not resolved cases (27.5%) and cases
resolved with sequelae (1.9%) in frail subject s is similar to the reporting proportion
observed in the overall population (27.2% for outcome of not resolved, 1.4% for
outcome of resolved with sequelae).
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Page 74Table 12.Evaluation of Missing Information for BNT162b2
Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
The reporting proportion of cases reporting fatal outcome (17.4%) in frail subject s is
higher than the reporting proportion of cases reporting fatal outcome in the overall
population (3.4%). This is expected, considering that m ost of the cases reporting a
fatal outcome (8 2.9%) among the frail subject s involved subjects over 75 years of
age who, due to their advanced age and underlying comorbidities ,are m ore likely to
die than younger individuals. Underlying comorbidities are likely to be contributory
to their deaths.
As per EMA PRAC assessment report (Product No. EMEA/H/C/005735/MEA/002.1)
received on the second SMSR, t he MAH was requested to discuss if there is a higher
risk on worsened outcome in the particularly frail or elderly patients with
underlying morbidities, who are reporting diarrhoea and/or vomiting .
The reporting proportion of cases reporting Diarrhoea and/or Vomiting ( 9.4%) in
these frail or elderly subject s with underlying morbidities is similar to the reporting
proportion observed in the overall population ( 8.2%); there was no difference in the
incidence of serious occurrences (63.8% in frail or elderly subject s with und erlying
morbidities versus 61.3% of serious occurrences in the overall population) and in
the reporting proportion of cases in which these events had an outcome of not
resolved or resolved w ith sequelae, respectively 16.4 % and 1. 3% in frail subject s,
versus 18. 3% and 1.6% in the overall population. The reporting proportion of cases
in which Diarrhoea and/or Vomiting had a fatal outcome is higher (10.1%) in frail
subject s than in the overall population (1.7%) ;the cases with fatal outcome involved
24 su bjects w ith age ranged from 74 to 96 years (me an87.5 years, median 89 years)
and they had multiple underlying co -morbidities that are likely to be contributory to
their deaths.
Conclusion: Overall, no risks based on subject frailty have been identified for the
vaccine. Pfizer recognizes that severe vomiting and diarrhea may have negative
clinical consequences, especially in medically frail subject s. As with all
vaccinations, the full safety and efficacy profile of the vaccin e should be considered
in the context of the health of the individual subject when determining the benefit
risk of vaccination.
Interaction With
Other VaccineseThere w ere no cases reporting an interaction with other vaccines during the reporting
interval (please refer to Table 11, Vaccine Interactions ).
Long -Term Safety
DataNot applicable
Use in Paediatric
Individuals <16
Years of AgegNumber of cases: 26h(0.1% of the total PM dataset, as in the previous
reporting period), of which 11 w ere m edically confirmed and 15 w ere non -
medically confirmed, and indicative of administration in paediatric subjects
<16 years of age;
Country of incidence: UK (19), US (4), Germany (2), Israel (1);
Cases Seriousness: Serious (16), Non -Serious (10);
Gender: Females (20), Males (3), Unknown (3);
Age (n=26) ranged from 2 months to 15 years, mean = 6.2, median = 5;
Case outcome: resolved/resolving (10), not resolved, and unknown (8
each).
Of the 92 reported events,
oThe most frequently reported event s (>1 case) w ere coded to the
PTs Product administered to patient of inappropriate age (20 , see
Section 7Medication Errors ), Off label use (12), Product use
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Page 75Table 12.Evaluation of Missing Information for BNT162b2
Missing Inform ationPost-Marketing Case sEvaluationa
Total Number of Cases in the Reporting Period (N= 23558)
issue (4), Fatigue, Nausea, Pyrexia (3 each), COVID -19, Facial
paralysis, Headache, Lymphadenopathy, Swelling, and
Vaccination site pain (2 each)
oThere w ere 26 unlisted event s reported in 9cases:
These events coded to the PTs Facial paralysis, Swelling
(2 each), Blepharospasm, Cellulitis, Cerebrovascular
accident, C hest discomfort, Diarrhoea ,iExternal ear pain,
Feeling hot, Hypertension, Mastitis, Muscle spasms,
Myoclonus, Neuralgia, Pain in extremity,iPain in jaw ,
Paraesthesia, Paraesthesia oral, Peripheral sw elling, Poor
quality sleep, Post laminectomy syndrom e, Rhinorrhoea,
Vaccination site pruritus, and Wheezing (1 each).
All of these cases were received from the MHRA and
provided limited information (i.e., medical history,
concomitant medications, actions taken, or clinical
outcome not provided).
No new significant safety information was identified based on a review of these cases.
Vaccine
effectivenessgRelevant cases for vaccine effectiveness during the reporting interval are reviewed in
Table 11, 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. 3, dated 20 January 2021;
c.Five cases were excluded from the analysis; pregnancy was not confirmed in 4 cases and 1 case w as
invalid for unidentifiable reporter ;
d.Birth type of spontaneous abortion was added to 7 cases after the data -lock point;
e.Missing information as per the EU -RMP Version 1.0, dated 21 December 2020;
f.One additional case was excluded from the discussion as found as invalid upon review;
g.Missing information as per the US PV P, Version 0. 3, dated 20January 2021;
were excluded from analysis as the data reported (e.g., clinical details, height, w eight, etc.) w ere not
consistent for paediatric subjects;
h. Upon rev iew, 27 cases were excluded from analysis as the data reported (e.g. clinical details, height,
weight, etc.) w ere not consistent with paediatric subject s;other paediatric cases, including the one involving
a 2-month-old subject, might be reported w ith a miscoded pediatric age however, since they reported limited
details and no follow -up is possible for clarification, they were conservatively discussed in this section;
i.Added to the CDS af ter the data -lock point of this SMSR, on 02 March 2021.
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Page 7610.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 par ticipants 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 s ymptomatic
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 severe 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, hypertension).
The vaccine efficacy information is presented in Table 13.
Table 13.Vaccine efficacy –First COVID -19 occurrenc e 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=18,198Cases
n1b
Surveillance timec
(n2d)Placebo
Na=18,325Cases
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)
65 to 74 years 1
0.406 (3074)14
0.406 (3095)92.9 (53.1, 99.8)
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Page 77Table 13.Vaccine efficacy –First COVID -19 occurrenc e 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=18,198Cases
n1b
Surveillance timec
(n2d)Placebo
Na=18,325Cases
n1b
Surveillance timec
(n2d)Vaccine efficacy
% (95% CI)f
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 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 S ARS -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 adju sted 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 wi th SARS -CoV -2 was 94.6% (95%
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 medical
comorbidities associated with high risk of severe COVID -19.
10.2.Risks
Based on phar macovigilance monitoring activities, since first authorisation , anaphy laxis has
been recognised as an important identified risk.Hypersensitivity reactions ( other than
Anaph ylaxis) Diarrhoea, Pain in extremity (arm) and Vomiting were also assessed as
ident ified risks (not important for the purpose of inclusion in the Risk Management Plans and
Pharmacovigilance Plans) and added as adverse reactions to the labeling.
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Page 78Based on all available safety and efficacy data for BNT162b2 the benefit-risk profile of the
vaccine remains favourable .
10.3.Overall Benefit -Risk
The identified risksassociated with the use of BNT162b2 are mitigated 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 b enefit -risk profile of BNT162b2 remains
favourable.
11.CONCLUSION AND ACTIO NS
The MAH will continue to review the safet y of BNT162b2, including 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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1PREPARED BY PFIZER I NC
CDS EFFECTIVE DATE: 12-FEB -2021
Date of Superseded CDS: NA
COVID -19 mRNA Vaccine
CORE DATA SHEET
VERSION 1
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21. NAME OF THE MEDICINA L PRODUCT
COVID -19 mRNA Vaccine (nucleoside modified) and COMI RNATY are called
TRADENAME.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION1,2
This is a multidose vial and must be diluted before use.
One vial (0.45 mL) contains 6 doses of 0.3 mL after dilution, see Section 6.6.
One dose (0.3 mL) contains 30 micrograms of COVID -19 mRNA Vaccine (embedded in lipid
nanoparticles).
TRADENAME is highl y purified single -stranded, 5’ -capped messenger RNA (mR NA) produced
using a cell -free in vitro transcription from the corresponding DNA templates, encoding the viral
spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS -CoV -2).
For the full list of excipients, see Section 6.1.
3. PHARMACEUTICAL FORM2,3
Concentrate for solution for injection.
The vaccine is a white to off- white frozen solution.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
The following is a representative indication. Locally approved indications may differ.
Active immuniz ation to prevent coronavirus disease 2019 ( COVID -19)disease caused by
SARS -CoV -2 virus, in individuals 16 years of age and older.4
4.2. Posology and method of administration
Posology
Individuals 16 years of age and older
TRADENAME is administered intramuscularly after dilution as a series of 2doses (0.3 mL
each) at greater than or equal to 21 days(preferably 3weeks) apart .5
There are no data available on the interchangeability of TRADENAME with other COVID -19
vaccines to comple te the vaccination series. Individuals who have received 1dose of
TRADENAME should receive a second dose of TRADENAME to complete the vaccination
series.
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3Individuals may not be protected until at least 7 days after their second dose of the vaccine.6
For further information on efficacy , see Section 5.1.
Pediatric population
The safet y and efficacy of TRADENAME in individuals under 16 years of age have not yet been
established.
Geriatric population
Clinical studies of TRADENAME include participants 6 5years of age and older and their data
contributes to the overall assessment of safet y and efficacy.7Of the total number of
TRADENAME recipients in Study 2 (N=20,033), 17.1% (n=3434) were 65 through 74 years of
age and 4.3% (n=860) were 75 years of age a nd older ( see Section 5.1).8
Method of administration
Administer TRADENAME intramuscularl y in the deltoid muscle after dilution.
Do not inject the vaccine intravascularl y, subcutaneously ,or intradermally.
After dilution, vials of TRADENAME contain 6doses of 0.3 mL of vaccine. L ow dead-volume
syringes and/or needles can be used to extract 6 doses from a single vial. If standard s yringes and
needles are used, there may not be sufficient volume to extract a sixth dose from a single vial.
Irrespective of the type of sy ringe 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.
For in structions on the handling, dilution ,and dose preparation of the vaccine before
administration, see Section 6.6.
4.3. Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in S ection 6.1.
4.4. Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch
number of the administered product should be clearly recorded.
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4General recommendations
As with all injectable vaccines, appropriate medical treatment and supervision must alway s be
readil y available in case of a rare anaph ylactic event following the administration of the
vaccine.9
The administration of TRADENAME should be postponed in individuals suffering from acute
sever e febrile illness .9
Individuals receiving anticoagulant therap y or those with a bleeding disorder that would
contraindicate intramuscular injection, should not be given the vaccine unless the potential
benefit clearl y outweighs the risk of administration.9
Immunocompromised persons, including individuals receiving immunosuppressant therap y, ma y
have a diminished immune response to the vaccine.
As with any vaccine, vaccination with TRADENAME may not protect all vaccine recipients.
4.5.Interaction with o ther medicinal products and other forms of interaction
No interaction studies have been performed.
Do not mix TRADENAME with other vaccines/products in the same s yringe.
4.6. Fertility, pregnancy and lactation
Pregnancy
There are limited amount of data from the use of TRADENAME in pregnant women. Animal
studies do not indicate direct or indirect harmful effects with respect to pregnancy , embry o/fetal
development, parturition ,or post -natal development (see Section 5.3).10,11Administration of
TRADENAME in pregnancy should be considered when the potential benefits outweigh any
potential risks for the mother and fetus.
Lactation
It is unknown whether TRADENAME is excreted in human milk.
Fertility
It is unknown whether TRAD ENAME has an impact on fertility . Animal studies do not indicate
direct or indirect harmful effects with respect to female fertility or reproductive toxicity (see
Section 5.3).10,11
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54.7. Effects on ability to drive and use machines
TRADENAME has no or negligible influence on the ability to drive and use machines. However,
some of the effects mentioned under Section 4.8 “Undesirable effects” may temporaril y affect
the ability to drive or use machines.
4.8. Undesirable effects
Summar y of safet y profile
The safet y of TRADENAME was evaluated in participants 16 years of age and older in 2 clinical
studies conducted in the United States, Europe, Turkey , South Africa, and South America.12
Study BNT162 -01 (Study 1) enrolled 60 participants , 18through 55 years of age.
Study C4591001 (Study 2) enrolled approximately 44,000 participants, 12 years of age or
older.12
In Stud y2, a total of 21,720 participants 16 years of age or older received at least 1dose of
TRADENAME and a total of 21,728 participants 16 years of age or older received placebo.13
The most frequent adverse reactions in participants 16 years of age and older (in order from
highest to lowest frequenc ies)were pain at the injection site (>80%) ,14fatigue (>60%) ,13
headache (>50%) ,13myalgia andchills (>30%) ,13arthralgia (>20%) ,13pyrexia13and injection
site swelling14(>10%) and were usually mild or moderate in intensit y and resolved within a few
days after vaccination. A lower frequency of reactogenicity events was associated with greater
age.15
Table 1. Adverse Drug Reactions13,14,16
System Organ Class Adverse Drug Reactions
Blood and l ymphatic sy stem
disordersLym phadenopathy
Immune s ystem disorders Anaph ylaxis
Hypersensiti vityreactions ( e.g., rash, pruritus, urticaria,
angioedema)
Nervous s ystem disorders Headache
Gastrointestinal disorders Nausea
Musculoskeletal and connective
tissue disorders Arthralgia
Myalgia
General disorders and
administration site conditions Pyrexia
Chills
Malaise
Fatigue
Injection site pain
Injection site swelling
Injection site redness
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6The safet y profile in 545 participants receiving TRADENAME, that were seropositive for
SARS -CoV -2 at baseline, was similar to that seen in the general population.17,28,31
4.9. O verdose
Participants who received 58 micrograms of TRADENAME in clinical trials did not report an
increase in reactogenicit y or adverse events.18
In the event of overdose, monitoring of vital functions and possible sy mptomatic treatment is
recommended.
5. PHARMACOLOGICAL P ROPERTIES
5.1. Pharmacodynamic properties
Pharmacological class, therapeutic class
Vaccines
Refer to the current ATC code index for the appropriate code assignment for the pharmacologic
and/or therapeutic class.
Mechanism of actio n
The nucleoside -modified messenger RNA in TRADENAME is formulated in lipid nanoparticles,
which enable delivery of the RNA into host cells to allow expression of the SARS -CoV -2
Santigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the
spike (S) antigen, which may contribute to protection against COVID -19 disease.19,20
Efficacy in participants 16 years of age and older
Study 2 is a multicent er, placebo -controlled efficacy study in participants 12 years of age and
older. Randomi zation 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 .12The study excluded participants who were immunocompromised an d those who had
previous clinical or microbiological diagnosis of COVID -19 disease .12Participants with
pre-existing stable disease, defined as disease not requiring significant change in therapy or
hospitalization for worsening disease during the 6 weeks before enroll ment ,21were included as
were participants with known stable infection with human immunodeficiency virus (HIV),
hepatitis C virus (HCV), or hepatitis B virus (HBV) .12
In the Phase 2/3 portion approximately 44,000 participants 12 years of age and older were
randomi zed equally and received 2 doses of COVID -19 mRNA Vaccine or placebo separated b y
21days. The efficacy analy ses included participants that received their second vaccination
within 19 to 42 days after their first vaccination. Participants are planned to be followed for up to
24months, for assessments of safet y and efficacy against COVID -19 disease.12,27
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7The population for the analy sis of the primary efficacy endpoint included, 36,621 participants
12years 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 .22Table 2 presents the specific demographic characteristics in the studied
population.
Table2.Demographics ( Population for the Primary Efficacy Endpoint)a,22
TRADENAME
(N=18,242)
n (%)Placebo
(N=18,379)
n (%)
Sex
Male 9318 (51.1) 9225 (50.2)
Female 8924 (48.9) 9154 (49.8)
Age (y ears)
Mean (SD) 50.6 (15.70) 50.4 (15.81)
Median 52.0 52.0
Min, max (12, 89) (12, 91)
Age group
12 to15 years 46 (0.3) 42 (0.2)
16 to 17 years 66 (0.4) 68 (0.4)
16 to 64 years 14,216 (77.9) 14,299 (77.8)
65 to 74 years 3176 (17.4) 3226 (17.6)
≥75 y ears 804 (4.4) 812 (4.4)
Race
White 15,110 (82.8) 15,301 (83.3)
Black or African American 1617 (8.9) 1617 (8.8)
American Indian or Alaska Native 118 (0.6) 106 (0.6)
Asian 815 (4.5) 810 (4.4)
Native Hawaiian or other Pacific
Islander 48 (0.3) 29 (0.2)
Otherb534 (2.9) 516 (2.8)
Ethnicity
Hispanic or Latino 4886 (26.8) 4857 (26.4)
Not Hispanic or Latino 13,253 (72.7) 13,412 (73.0)
Not reported 103 (0.6) 110 (0.6)
Comorbiditiesc
Yes 8432 (46.2) 8450 (46.0)
No 9810 (53.8) 9929 (54.0)
a.All eligible randomized participants who receive all vaccination(s) as randomized within the predefined
windo
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