3.1 Estimated Cumulative Exposure to Sandoz Biosimilars

Combined post-approval cumulative exposure to seven of the eight marketed Sandoz biosimilars (adalimumab, epoetin alfa, etanercept, filgrastim, infliximab, pegfilgrastim, and somatropin) was more than 1.3 billion PTD. Post-approval cumulative exposure to Sandoz rituximab, was more than 1.8 million patient doses (Table 1).

Table 1 Cumulative post-approval exposure to Sandoz biosimilars3.2 Safety Experience for Sandoz Biosimilars

An overview of all important identified risks, potential risks, and missing information as listed in the most recent PSURs for Sandoz biosimilars are provided in Tables 2, 3, 4, 5, 6, 7, 8 and 9. Overall, no new or changing safety findings or risks were detected, no new actions were taken due to safety concerns, and there were no changes to the safety information during the last reporting interval that were unique to Sandoz biosimilars. This is consistent with previous PSURs where safety and risk information was aligned with the respective reference biologic. Ongoing pharmacovigilance activities are considered adequate to monitor any potential safety issues or potential risks. The summary of safety concerns for Sandoz biosimilars match the summary of safety concerns of the reference biologic (Tables 2, 3, 4, 5, 6, 7, 8 and 9). A critical analysis of the cumulative safety data and benefit–risk of all Sandoz biosimilar PSURs by Sandoz and the PRAC, where assessment reports were available, concluded that the overall benefit–risk profile of Sandoz biosimilars remains favorable. Relevant new safety information from respective PSURs for each Sandoz biosimilar is presented in next sections. Unless otherwise specified, changes to the RMP did not impact the Core Data Sheet (CDS) and associated product labels. The CDS is an internal, nonpublic document prepared by the MAH that summarizes the efficacy and safety information for a given product, and other information including indications, pharmacology, dosing recommendations, and storage details. The CDS serves as the basis for local product information for HCPs and patients once approved by HA. The purpose of a CDS is to align the labelling (including core safety information) of any product across the globe and provide the “reference safety information” for the assessment of aggregate reports for the product.

Table 2 Overview of risks and missing information for the INN adalimumab as listed in the Sandoz adalimumab PSUR and conclusions/actions from the reporting interval 01 January 2021–31 December 2021.Table 3 Overview of risks and missing information for the INN epoetin alfa as listed in the Sandoz epoetin alfa PSUR and conclusions/actions from the reporting interval 01 September 2018–31 August 2021.Table 4 Overview of risks and missing information for the INN etanercept as listed in the Sandoz etanercept PSUR and conclusions/actions from the reporting interval 03 February 2021–02 February 2022.Table 5 Overview of all important identified risks and important potential risks as well as missing information for Sandoz filgrastim.Table 6 Overview of risks and missing information for the INN infliximab as listed in the Sandoz infliximab PSUR and conclusions/actions from the reporting interval 24 August 2019–23 August 2022.Table 7 Overview of risks and missing information for the INN pegfilgrastim as listed in the Sandoz pegfilgrastim PSUR and conclusions/actions from the reporting interval 01 February 2019–31 January 2022.Table 8 Overview of risks and missing information for the INN rituximab as listed in the Sandoz rituximab PSUR and conclusions/actions from the reporting interval 18 November 2020–17 November 2021.Table 9 Overview of risks and missing information for the INN somatropin as listed in the Sandoz somatropin PSUR and conclusions/actions from the reporting interval 01 April 2020–31 January 2022.3.2.1 Worldwide Marketing Authorization Status and Safety Review of Sandoz Adalimumab

Sandoz is the MAH for a biosimilar adalimumab marketed in 76 countries/regions worldwide. Sandoz adalimumab was first registered in the European Economic Area (EEA) on 26 July 2018 [international birth date (IBD) and European birth date (EBD)] via the EMA centralized procedure. Since first registration in the EEA, six PSURs have been published (see Supplementary Table 1 for all PSUR reporting intervals). The data included here (Table 2) are from the most recent Sandoz adalimumab PSUR, reporting interval 01 January 2021–31 December 2021.

During the reporting interval, Sandoz participated in three European disease-based registries to collect long-term post-approval data on Sandoz adalimumab in a real-world setting: British Association of Dermatologists Biologic Interventions Register (BADBIR), German Registry for Observation of Biologic Therapy in Rheumatoid Arthritis (RABBIT), and UK Inflammatory Bowel Disease Registry (IBDR). No change in the benefit–risk profile of Sandoz adalimumab was identified from these registries during the last PSUR reporting interval.

Before the reporting interval of the last PSUR, the PRAC Rapporteur requested that vitiligo, amicrobial pustulosis of the folds (APF), and human papillomavirus (HPV) infection/cervical dysplasia/cervical cancer be addressed by the MAHs of all adalimumab products (reference biologic and biosimilars) for the next PSUR to discuss whether a potential causal relationship exists between adalimumab and vitiligo or APF and whether events of cervical dysplasia/cervical cancer were reported in the context of HPV infection/reactivation during therapy with adalimumab. An analysis of data received in the PSUR reporting interval did not identify any new relevant safety findings for Sandoz adalimumab for these conditions, and they will continue to be monitored in the subsequent PSUR.

For the adalimumab reference biologic, “weight increased” was added to the label as an “undesirable effect”, which in consequence resulted in a change to the Sandoz adalimumab CDS and corresponding labels to align with this change. This is consistent with previous PSURs where safety and risk information related to Sandoz adalimumab was aligned with the reference biologic label. “Long-term safety information in the treatment of children aged from 6 years to less than 18 years with ulcerative colitis” was also added as a missing information topic during the reporting interval to align with an update to the reference biologic RMP.

3.2.2 Worldwide Marketing Authorization Status and Safety Review of Sandoz Epoetin Alfa

Sandoz and the license partner Medice Arzneimittel Putter GmbH and Co. KG are the MAHs for a biosimilar epoetin alfa marketed in 70 countries/regions worldwide. Sandoz epoetin alfa was first registered in the EEA on 28 August 2007 (IBD and EBD). Since first registration, 25 PSURs have been published (Supplementary Table 1). The data included here (Table 3) are from the most recent Sandoz epoetin alfa PSUR, reporting interval 01 September 2018–31 August 2021, and from the corresponding EMA PRAC assessment report, publication date 7 April 2022 (procedure number: EMEA/H/C/PSUSA/00001237/202108).

One signal “bone fractures,” detected by Sandoz during clinical and nonclinical literature review, was evaluated. Following a cumulative review of all sources, the signal was assessed as “undetermined/inconclusive” due to insufficient information to confirm or refute the signal. The PRAC rapporteur proposed to keep this signal open for all MAHs and that a thorough cumulative review for this risk be conducted during the next PSUR period.

For the epoetin alfa reference biologic, the RMP was updated to redefine “premature death” and replace it with “survival impact,” “tumor growth potential” was renamed as “disease progression,” and nine safety concerns [“hyperkalemia,” “hypersensitivity reactions (including anaphylactic reactions),” “hypertension/hypertensive crisis,” “seizure,” “thromboembolic events,” “congestive heart failure,” “misuse,” “safety in lactation,” and “safety in children“] were removed. This resulted in a change of the Sandoz epoetin alfa RMP during the reporting interval to align with the reference biologic. This is consistent with previous PSURs where safety and risk information related to Sandoz epoetin alfa was aligned with the reference biologic RMP.

3.2.3 Worldwide Marketing Authorization Status and Safety Review of Sandoz Etanercept

Sandoz is the MAH for a biosimilar etanercept marketed in 59 countries/regions worldwide. Sandoz etanercept was first registered in the USA on 30 August 2016 (IBD) and in the EEA on 23 June 2017 (EBD). Since first registration, six PSURs have been published (Supplementary Table 1). The data included here (Table 4) are from the most recent Sandoz etanercept PSUR, reporting interval 03 February 2021–02 February 2022.

During the reporting interval, Sandoz participated in three European disease-based registries to collect long-term post-approval data on Sandoz etanercept: BADBIR, RABBIT, and the British Society for Rheumatology Biologics Register in Rheumatoid Arthritis (BSRBR). No change in the benefit–risk profile of Sandoz etanercept was identified from these registries during the last reporting interval.

During the last reporting interval, the CDS and associated labels for Sandoz etanercept was amended in line with the changes to the reference biologic EU Summary of Product Characteristics (SmPC) to include headache as a new AE and remove inflammatory bowel disease and uveitis as ADRs specific for the pediatric population.

3.2.4 Worldwide Marketing Authorization Status and Safety Review of Sandoz Filgrastim

Sandoz is the MAH for a biosimilar filgrastim marketed in 83 countries/regions worldwide. Sandoz filgrastim was first registered in the EEA on 06 February 2009 (IBD and EBD). Since first registration, 19 PSURs have been published (Supplementary Table 1). The data included here (Table 5) are from the Sandoz filgrastim PSUR, reporting interval 16 September 2018–15 September 2021.

During the most recent reporting interval, the Sandoz filgrastim RMP was updated, in line with other filgrastim product labels, to include “glomerulonephritis” as a new important potential risk. One signal “Immune Reconstitution Inflammatory Syndrome” was initiated by the PRAC for all MAHs of filgrastim products; however, having assessed the responses submitted by the MAHs, the PRAC agreed that the likelihood of a causal relationship was not sufficiently strong and no further actions were required aside from routine pharmacovigilance activities.

3.2.5 Worldwide Marketing Authorization Status and Safety Review of Sandoz Infliximab

Sandoz and Pfizer are the MAHs for a biosimilar infliximab marketed in 59 countries/regions worldwide. Sandoz infliximab was first registered in the EEA on 18 May 2018 (IBD and EBD). Since first registration, two PSURs have been published (Supplementary Table 1). The data included here (Table 6) are from the Sandoz infliximab PSUR, reporting interval 24 August 2019–23 August 2022, which includes data from Sandoz and Pfizer, and from the corresponding EMA PRAC assessment report, publication date 14 April 2023 (procedure number: EMEA/H/C/PSUSA/00010759/202208).

During the reporting interval, Sandoz participated in three European disease-based registries to collect long-term post-approval data on infliximab: BADBIR, RABBIT, and UK-IBDR. No information relevant to the benefit–risk assessment for Sandoz infliximab was identified from these registries during the last PSUR reporting interval.

In a previous PRAC assessment report, all infliximab MAHs were requested to assess “acquired perforating dermatosis” and “antimicrobial pustulosis of the folds;” however, a cumulative analysis of data from all available sources did not reveal any evidence of a causal association. One signal of “Kaposi’s sarcoma” was validated for the entire infliximab drug class and closed by the PRAC with a recommendation to update the EU SmPC for all infliximabs.

Updates to the Sandoz CDS and associated labels during the reporting interval to align with the reference biologic label were the addition of Kaposi’s sarcoma, cerebrovascular accident, and dyslipidaemia under “undesirable effects”. During the reporting interval, a direct HCP communication letter was mandated by the PRAC for all infliximab-containing products in the EU to inform HCPs on the need to postpone the use of live vaccines in infants that were exposed to infliximab during pregnancy or breastfeeding; the SmPCs were updated accordingly.

3.2.6 Worldwide Marketing Authorization Status and Safety Review of Sandoz Pegfilgrastim

Sandoz is the MAH for a biosimilar pegfilgrastim marketed in 51 countries worldwide. Sandoz pegfilgrastim was first registered in the EEA on 22 November 2018 (IBD and EBD). Since first registration, four PSURs have been published (Supplementary Table 1). The data included here (Table 7) are from the most recent Sandoz pegfilgrastim PSUR, reporting interval 01 February 2019–31 January 2022, and from the corresponding EMA PRAC assessment report, publication date 29 September 2022 (procedure number: EMEA/H/C/PSUSA/00002326/202201).

The safety information for all pegfilgrastim products was updated during the most recent reporting interval to include Stevens–Johnson syndrome as an adverse drug reaction and to include warnings on thrombocytopenia, myelodysplastic syndrome, and acute myeloid leukemia. The Sandoz CDS and associated labels were updated accordingly.

3.2.7 Worldwide Marketing Authorization Status and Safety Review of Sandoz Rituximab

Sandoz is the MAH for a biosimilar rituximab marketed in 75 countries/regions worldwide. Sandoz rituximab was first registered in the EEA on 15 June 2017 (IBD and EBD). Since first registration, seven PSURs have been published (Supplementary Table 1). The data included here (Table 8) are from the Sandoz rituximab PSUR, reporting interval 18 November 2020–17 November 2021, and from the corresponding EMA PRAC assessment report, publication date 10 June 2022 (procedure number: EMEA/H/C/PSUSA/00002652/202111).

During the most recent reporting interval, the RMP was updated to align with changes to the reference biologic RMP. The important potential risks “malignant events” and “worsening of preexisting cardiovascular disorders” were removed for nononcology indications and “use in pregnancy and lactation” was removed from the category “missing information.” The PRAC also recommended that the SmPC for all rituximab products be amended to add the risk of serious viral infections. The Sandoz CDS and associated labels were updated accordingly.

During the reporting interval, Sandoz participated in the RABBIT and BSRBR registries. No information relevant to the benefit–risk profile of Sandoz rituximab was identified from these registries during the last reporting interval.

3.2.8 Worldwide Marketing Authorization Status and Safety Review of Sandoz Somatropin

Sandoz is the MAH for a biosimilar somatropin marketed in 80 countries/regions worldwide. Sandoz somatropin was first registered in Australia on 29 Sep 2004 (IBD) and in the EEA on 12 April 2006 (EBD). Since first registration, 28 PSURs have been published (Supplementary Table 1). The data included here (Table 9) are from the most recent Sandoz somatropin PSUR, reporting interval 01 April 2020–31 January 2022.

During the most recent reporting interval, the safety information of all somatropin containing products was updated to add a warning on “pancreatitis” and to add the adverse reactions “face edema,” “headache,” “hypothyroidism,” “rash,” “pruritus,” “urticaria,” and “gynecomastia.” The Sandoz CDS and associated labels were updated accordingly.