EUROPEAN UNION RISK MANAGEMENT PLAN (EU RMP) …

1 EUROPEAN UNION Risk MANAGEMENT PlanAstraZenecaChAdOx1-S (recombinant) (AZD1222)Version: 4, Succession number: 2 CONFIDENTIAL AND PROPRIETARY 1 (111) EUROPEAN UNION Risk MANAGEMENT PlanDrug SubstanceChAdOx1-S (recombinant) (AZD1222)Version Number4 Succession number2 Data lock point25 June 2021 Date of final sign-offSee e-signature pageEUROPEAN UNION RISK MANAGEMENT plan (EU RMP)FOR VA XZEVRIA (ChAdOx1-S [RECOMBINANT])The content of this RMP has been reviewed and approved by the EU QPPVE uropean UNION Risk MANAGEMENT PlanAstraZenecaChAdOx1-S (recombinant) (AZD1222)Version: 4, Succession number: 2 CONFIDENTIAL AND PROPRIETARY 2 (111)ADMINISTRATIVE INFORMATIONR ationale for submitting an updated RMPThis EU RMP (Version 4) has been updated to include additional safety concerns of Thrombocytopenia, including immune thrombocytopenia and Guillain-Barr syndrome (GBS) which are categorised as important identified risks(IIR).

2 This EU RMP (Version 4) has also been updated to include Acute macular neuroretinopathy (AMN)/ Acute macular outer retinopathy (AMOR), Paracentral acute middle maculopathy (PAMM), Paraesthesia and Dysaesthesia in the list of adverse event of special interest (AESI). The AESI concept of "Thrombocytopenia with associated bleeding" has been renamed to "Thrombocytopenia including immune thrombocytopenia"The Enhanced active surveillance (EAS) studies (EAS (D8111R00003 [EU], D8110R00001 [US], D8111C00004 [UK]) have been removed as post authorisation safety studies(PASS). The reason for this being recruitment challenges for study D8111R00003, due to National Immunization Technical Advisory Groups (NITAGs) recommendations restricting Vaxzevria use to elderly age post authorisation safety studies have been added.)

3 One voluntary PASS study (D8111R00010) was added for transparency and the other category 3 UK vaccine effectiveness study (D8111R00007) was added at the request of CHMP as part of post authorisation measure status of PASS studies has been updated. References to the SmPC are to the version approved on 15 Oct of significant changes in this RMPPart I:No changesPart II SI:Section updated to reflect the latest II SII:No changes. Part II SIII:No changes Part II SIV:No changesPart II SV:Latest cumulative post-marketing exposure data added (data cut-off date of 25 June 2021). Part II SVI:No II SVII: Section was updated to add new IIRs of Thrombocytopenia, including immune thrombocytopenia and Guillain-Barr syndrome (GBS) The AESI list has been updatedto addAcute Macular neuroretinopathy/ Acute Macular outer retinopathy, Paracentral acute middle maculopathy, Paraesthesia,andDysaesthesia.

4 EUROPEAN UNION Risk MANAGEMENT PlanAstraZenecaChAdOx1-S (recombinant) (AZD1222)Version: 4, Succession number: 2 CONFIDENTIAL AND PROPRIETARY 3 (111)The AESI concept of " Thrombocytopenia with associated bleeding" has been renamed to "Thrombocytopenia including immune thrombocytopeniaPart II SVIII:Section has been updated to add new IIRs of Thrombocytopenia, including immune thrombocytopenia and Guillain-Barr syndrome .Part III: Updated ICSR reporting language Updated information on summary safety reports. Details and milestones relating to the, Pregnancy Registry, Post-marketing observational study using existing secondary health data sources, Post-marketing effectiveness study, Metanalytic post-marketing safety study in patients receiving immunosuppressant medication or with primary immunodeficiency using existing secondary health data sourcesand ongoing clinical trials updated to reflect latest available information.

5 Details and milestones of two PASS added:o Voluntary PASS -Thrombotic thrombocytopenia syndrome (D8111R00010) o Category 3 PASS - UK vaccine effectiveness study (D8111R00007) Updated status of PASS studies (1169DM, MS 1222-0002,MS1222-0001,MS1222-0003, D8111C00002 as completed and D8110C00003as ongoing). Removed Enhanced active surveillance (EAS) studies (D8111R00003 [EU], D8110R00001 [US], D8111C00004 [UK]) throughout the IV:No V:Routine risk minimisation measures added for the IIRs of Thrombocytopenia including immune thrombocytopenia and GBS. Part VI:Updated to reflect changes throughout the EU RMP.

6 Part VII:Annexes updatedto reflect changes throughout the EU RMP, including Annex 2 (Tabulated summary of planned, ongoing, and completed pharmacovigilance study programme), Annex 3 (Protocols for proposed, ongoing and completed studies in the pharmacovigilance plan ), Annex 4 (Specific adverse drug reaction follow-up forms), Annex 7 (Other supporting data (including referenced material) and Annex 8 (Summary of changes to the risk MANAGEMENT plan over time).Other RMP versions under evaluationVersion number:Not applicableSubmitted:Not applicableProcedure number:Not applicableDetails of currently approved RMPV ersion number:Version 3, Succession 4 Approved with procedure:EMEA/H/C/005675/II/0026 Date of approval:15 Oct 2021 EUROPEAN UNION Risk MANAGEMENT PlanAstraZenecaChAdOx1-S (recombinant) (AZD1222)Version: 4, Succession number: 2 CONFIDENTIAL AND PROPRIETARY 4 (111)TABLE OF CONTENTSTABLE OF OF OF ABBREVIATIONS AND DEFINITION OF I: PRODUCT II: SAFETY SI: EPIDEMIOLOGY OF THE INDICATION AND TARGET of COVID-19.)

7 SII: NON-CLINICAL PART OF THE SAFETY of Key Findings from Nonclinical SIII: CLINICAL TRIAL SIV: POPULATIONS NOT STUDIED IN CLINICAL Criteria in Pivotal Clinical Studies within the Development to Detect Adverse Reactions in Clinical Trial Development in Respect to Populations Typically Under-represented in Clinical Trial Development SV: POST-AUTHORISATION used to calculate SVI: ADDITIONAL EU REQUIREMENTS FOR THE SVII: IDENTIFIED AND POTENTIAL of Safety Concerns in the Initial RMP Submission .. Not Considered Important for Inclusion in the List of Safety Concerns in the Considered Important for Inclusion in the List of Safety Concerns in the Events of Special Considerations for COVID-19 Safety Concerns and Reclassification with a Submission of an Updated of Important Identified Risks, Important Potential Risks, and Missing of Important Identified Risks and Important Potential of Missing Information.

8 SVIII: SUMMARY OF THE SAFETY III: PHARMACOVIGILANCE PHARMACOVIGILANCE UNION Risk MANAGEMENT PlanAstraZenecaChAdOx1-S (recombinant) (AZD1222)Version: 4, Succession number: 2 CONFIDENTIAL AND PROPRIETARY 5 (111) Detection .. Adverse Reaction Follow-Up Safety Passive PHARMACOVIGILANCE Marketing safety Clinical TABLE OF ADDITIONAL PHARMACOVIGILANCE IV: PLANS FOR POST-AUTHORISATION EFFICACY V: RISK MINIMISATION RISK MINIMISATION RISK MINIMISATION OF RISK MINIMISATION VI: SUMMARY OF THE RISK MANAGEMENT plan FOR MEDICINE AND WHAT IT IS USED ASSOCIATED WITH THE MEDICINE AND ACTIVITIES TO MINIMISE OR FURTHER CHARACTERISE THE of important risks and missing information.

9 Of important development which are conditions of the marketing authorisation .. studies in post-authorisation development OF 103 LIST OF TABLEST ableI-1 Product Trial Exposure to AZD1222 (US Study D8110C00001 and Pooled Oxford Studies - Safety Analysis Set)..20 TableII-2 Clinical Trial Exposure to AZD1222 by Age Group and Sex (US Study D8110C00001 Pooled Oxford Studies - Safety Analysis Set)..20 TableII-3 Clinical Trial Exposure to AZD1222 by Race (US Study D8110C00001 and Pooled Oxford Studies Safety Analysis Set)..21 TableII-4 Exposure of Special Populations Included or not Included in the Clinical Development cumulative exposure (based on doses distributed) from IBD to 25 June 2021, by Region/ UNION Risk MANAGEMENT PlanAstraZenecaChAdOx1-S (recombinant) (AZD1222)Version: 4, Succession number.

10 2 CONFIDENTIAL AND PROPRIETARY 6 (111)TableII-6 VAXZEVRIA cumulative exposure (by doses administered), by 26 TableII-7 List of AZD1222 of Safety sources for signal detection and frequency of 50 TableIII-2 Ongoing and planned additional pharmacovigilance of routine risk minimisation measures by safety table of pharmacovigilance activities and risk minimisation activities by safety of important risks and missing identified risk: Thrombosis with thrombocytopenia identified risk: Thrombocytopenia, including immune identified risk: Guillain-Barr VI-5 Important identified risk: potential risk: 95 Table VI-7 Important potential risk: Nervous system disorders, including immune-mediated neurological VI-8 Important potential risk: Vaccine-associated enhanced disease (VAED), including vaccine-associated enhanced respiratorydisease (VAERD).