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Fingolimod, teriflunomide and cladribine for the treatment of multiple sclerosis in women of childbearing age: description of drug utilization and exposed pregnancies in Germany

  • Katharina Platzbecker
    Correspondence
    Corresponding author: Katharina Platzbecker, Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Achterstraße 30, 28359 Bremen, Germany.
    Affiliations
    Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
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  • Nadine Wentzell
    Affiliations
    Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
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  • Bianca Kollhorst
    Affiliations
    Department of Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
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  • Ulrike Haug
    Affiliations
    Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany

    Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany
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Published:September 26, 2022DOI:https://doi.org/10.1016/j.msard.2022.104184

      Highlights

      • Fingolimod, teriflunomide and cladribine use increased in women aged 13–49 years.
      • A high proportion of users was in age groups in which pregnancies typically occur.
      • Despite risk minimization measures, we observed exposed pregnancies.
      • About 9–10% of children born from exposed pregnancies had relevant malformations.

      Abstract

      Background

      Authorizations of fingolimod, teriflunomide and cladribine were accompanied by risk minimization measures concerning their teratogenic potential. Real-world data on their use are scarce. We aimed to assess trends in the use of fingolimod, teriflunomide and cladribine among women of childbearing age, estimate the number of pregnancies occurring under treatment and explore the occurrence of malformations in newborns exposed during early pregnancy in Germany.

      Methods

      Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from ∼20% of the German population), we determined annual age-standardized prevalences of fingolimod, teriflunomide and cladribine use from their authorization until 2019 among women aged 13–49 years (cross-sectional analyses). In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether there was an overlap between the exposure windows assigned to dispensations and the onset of pregnancy or a dispensation in the first eight weeks of pregnancy. For live births, a mother-baby linkage was performed. All available data of children with in-utero exposure and malformation codes in the first year of life were reviewed to verify the occurrence of congenital malformations.

      Results

      For fingolimod, the age-standardized prevalence of use per 1,000 females increased from 0.14 in 2011 to 0.46 in 2019; for teriflunomide, from 0.06 in 2013 to 0.28 in 2019; for cladribine, from 0.01 in 2017 to 0.07 in 2019. The proportion of users aged ≤40 years was 60% for fingolimod, 45% for teriflunomide and 65% for cladribine. We identified 136 pregnancies exposed to fingolimod, 50 to teriflunomide and one to cladribine. For fingolimod and teriflunomide, respectively, 72% and 62% of exposed pregnancies ended in a live birth. Mother-newborn linkage was successful in 64 (fingolimod) and 20 (teriflunomide) live-born children. Among these, there were six with relevant malformations (mainly heart defects) for fingolimod and two for teriflunomide.

      Conclusion

      Use of fingolimod, teriflunomide and cladribine among women of childbearing age has substantially increased in Germany. A high proportion of users was in age groups in which pregnancies typically occur. Despite risk minimization measures, early pregnancy exposure to these drugs was observed.

      Keywords

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      References

        • Blotière P.O.
        • Damase-Michel C.
        • Weill A.
        • Maura G.
        Dispensing of potentially harmful prescription drugs in 1.8 million pregnant women in France: a nationwide study based on two risk classification systems.
        Drug Saf. 2021; 44: 1323-1339https://doi.org/10.1007/s40264-021-01117-4
      1. Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), 2019. Rote-Hand-Brief zu Fingolimod (Gilenya): Neue Kontraindikation bei Anwendung während der Schwangerschaft und bei Frauen im gebärfähigen Alter. https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2019/rhb-gilenya.html (Accessed June 16, 2022).

        • Duchesneau E.D.
        • Kinlaw A.C.
        • Jonsson Funk M.
        • Pate V.
        • Lund J.L.
        Trends in the use of disease-modifying therapies among reproductive-aged women with multiple sclerosis in the United States from 2010 to 2019.
        Pharmacoepidemiol Drug Saf. 2022; 31: 481-487https://doi.org/10.1002/pds.5411
      2. European Medicines Agency (EMA), 2012. Assessment Report for Gilenya. https://www.ema.europa.eu/en/documents/variation-report/gilenya-h-c-2202-a20-0008-epar-assessment-report-article-20_en.pdf (Accessed December 14, 2021).

      3. European Medicines Agency (EMA), 2013. Assessment Report Aubagio. https://www.ema.europa.eu/en/documents/assessment-report/aubagio-epar-public-assessment-report_en.pdf (Accessed December 14, 2021).

      4. European Medicines Agency (EMA), 2017. Assessment Report Mavenclad. https://www.ema.europa.eu/en/documents/assessment-report/mavenclad-epar-public-assessment-report_en.pdf (Accessed December 14, 2021).

      5. European Medicines Agency (EMA), 2019. Updated restrictions for gilenya: multiple sclerosis medicine not to be used in pregnancy. https://www.ema.europa.eu/en/documents/press-release/updated-restrictions-gilenya-multiple-sclerosis-medicine-not-be-used-pregnancy_en.pdf (Accessed December 14, 2021).

      6. European Medicines Agency (EMA), 2021a. Aubagio: EPAR - product information. https://www.ema.europa.eu/en/documents/product-information/aubagio-epar-product-information_en.pdf (Accessed December 1, 2021).

      7. European Medicines Agency (EMA), 2021b. Gilenya: EPAR - product information. https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf (Accessed December 14, 2021).

      8. European Medicines Agency (EMA), 2022. Mavenclad: EPAR - product information. https://www.ema.europa.eu/en/documents/product-information/mavenclad-epar-product-information_en.pdf (Accessed May 02, 2022).

      9. European Registry of Congenital Anomalies and Twins (EUROCAT), 2018. EUROCAT Guide 1.4 and reference documents. https://eu-rd-platform.jrc.ec.europa.eu/sites/default/files/Full_Guide_1_4_version_28_DEC2018.pdf (Accessed May 25, 2022).

      10. European Registry of Congenital Anomalies and Twins (EUROCAT), 2022. Prevalence charts and tables. https://eu-rd-platform.jrc.ec.europa.eu/eurocat/eurocat-data/prevalence_en (Accessed June 16, 2022).

        • Garbe E.
        • Suling M.
        • Kloss S.
        • Lindemann C.
        • Schmid U.
        Linkage of mother–baby pairs in the German Pharmacoepidemiological Research Database.
        Pharmacoepidemiol Drug Saf. 2011; 20: 258-264https://doi.org/10.1002/pds.2038
        • Giovannoni G.
        • Galazka A.
        • Schick R.
        • Leist T.
        • Comi G.
        • Montalban X.
        • Damian D.
        • Dangond F.
        • Cook S.
        Pregnancy outcomes during the clinical development program of cladribine in multiple sclerosis: an integrated analysis of safety.
        Drug Saf. 2020; 43: 635-643https://doi.org/10.1007/s40264-020-00948-x
      11. Grandt, D., Lappe, V., Schubert, I., 2021. BARMER Arzneimittelreport 2021 Arzneimitteltherapie in der Schwangerschaft und bei Frauen im gebärfähigen Alter, Schriftenreihe zur Gesundheitsanalyse BARMER.

        • Haug U.
        • Schink T.
        German Pharmacoepidemiological Research Database (GePaRD).
        in: Sturkenboom M. Schink T. Databases For Pharmacoepidemiological Research. Springer International Publishing, Cham2021: 119-124
      12. Hemmer, B., 2021. Diagnose und Therapie der Multiplen Sklerose, Neuromyelitis-optica-Spektrum-Erkrankungen und MOG-IgG-assoziierten Erkrankungen, S2k-Leitlinie, 2021. https://dgn.org/wp-content/uploads/2021/04/030050_LL_Multiple_Sklerose_2021.pdf (Accessed June 16, 2022).

        • Illoh O.A.
        • Toh S.
        • Andrade S.E.
        • Hampp C.
        • Sahin L.
        • Gelperin K.
        • Taylor L.
        • Bird S.T.
        Utilization of drugs with pregnancy exposure registries during pregnancy.
        Pharmacoepidemiol Drug Saf. 2018; 27: 604-611https://doi.org/10.1002/pds.4409
      13. Leibniz Institute for Prevention Research and Epidemiology - BIPS (BIPS), 2020. The German Pharmacoepidemiological Research Database (GePaRD). https://www.bips-institut.de/en/research/research-infrastructures/gepard.html (Accessed April 12, 2022).

        • MacDonald S.C.
        • McElrath T.F.
        • Hernández-Díaz S.
        Use and safety of disease-modifying therapy in pregnant women with multiple sclerosis.
        Pharmacoepidemiol Drug Saf. 2019; 28: 556-560https://doi.org/10.1002/pds.4735
        • Mikolajczyk R.T.
        • Kraut A.A.
        • Garbe E.
        Evaluation of pregnancy outcome records in the German Pharmacoepidemiological Research Database (GePaRD).
        Pharmacoepidemiol Drug Saf. 2013; 22: 873-880https://doi.org/10.1002/pds.3467
        • Schink T.
        • Princk C.
        • Haug U.
        Risiko Venöser Thromboembolien bei Einnahme von Kombinierten Hormonalen Kontrazeptiva.
        Bulletin zur Arzneimittelsicherheit. 2021; : 13-17
        • Schink T.
        • Wentzell N.
        • Dathe K.
        • Onken M.
        • Haug U.
        Estimating the beginning of pregnancy in German claims data: development of an algorithm with a focus on the expected delivery date.
        Front Public Health. 2020; 8https://doi.org/10.3389/fpubh.2020.00350
        • Wentzell N.
        • Schink T.
        • Haug U.
        • Ulrich S.
        • Niemeyer M.
        • Mikolajczyk R.
        Optimizing an algorithm for the identification and classification of pregnancy outcomes in German claims data.
        Pharmacoepidemiol Drug Saf. 2018; 27: 1005-1010https://doi.org/10.1002/pds.4588