Teratogenicity: analysis of European risk management plan summaries.
Teratogenicity risk: content analysis of European risk management plan summaries
Background: A judicious decision is significant in clinical practice when a known teratogenic medicine is prescribed for women considering her ailment or avoiding its exposure due to foetal harm. For this careful balance, European medicine agency (EMA) and marketing authorization holder provides complete pharmacological information regarding each medicinal product for clinicians to take informed decision. Proactively, EMA publishes the safety concerns included in the risk management plan (RMP) and subsequent risk minimisation measures.
Objectives: The objective of present study is to review safety information published in RMP summaries for teratogenic medicines and to explore the proactive approaches considered to improve its benefit-risk balance.
Method: All safety concerns (SC) included in the RMPs of originator centrally authorised products (CAPs), authorised between 1 August 2012 and 31 December 2022, were collected from the European Public Assessment Report. Teratogenicity SCs were categorized by Anatomical Therapeutic Classification code, year of authorisation, category of safety concern and type of risk minimisation measures. Further, Summary of Product Characteristics (SmPC) were reviewed for safety information.
Results: During the study period, 324 CAPs were found to be associated with teratogenicity SC. Antineoplastic and immunomodulating agents had teratogenicity SCs most often. Out of 324 CAPs, 221 product SCs were categorized as missing information. Twenty-nine products had additional risk minimisation measures (aRMMs) which addressed teratogenicity SC. These aRMMs consisted of educational program, controlled distribution system and pregnancy prevention program targeted towards healthcare professionals and/or patients. Further, 155 additional pharmacovigilance activities were identified in these product RMP summaries for teratogenicity risk. Content analysis of SmPC revealed that important information on the use of medicines during pregnancy is missing.
Conclusion: More than half of the RMP summaries described teratogenicity as SC for the medicines approved during the study period. Post-authorization data on teratogenic medication should be actively collected and ensured to reach the clinicians via SmPC and/or aRMMs to keep them updated and enhance evidence-based decision making.
Arguello, B., & Fernandez-Llimos, F. (2007). Clinical pharmacology information in summaries of product characteristics and package inserts. Clinical pharmacology and therapeutics, 82(5), 566–571. https://doi.org/10.1038/sj.clpt.6100198
ConcePTION consortium. www.imi-conception.eu Accessed on 3 April 2023
Dreyer, N. A., Blackburn, S. C., Mt-Isa, S., Richardson, J. L., Thomas, S., Laursen, M., Zetstra-van der Woude, P., Jamry-Dziurla, A., Hliva, V., Bourke, A., & de Jong-van den Berg, L. (2015). Direct-to-Patient Research: Piloting a New Approach to Understanding Drug Safety During Pregnancy. JMIR public health and surveillance, 1(2), e22. https://doi.org/10.2196/publichealth.4939
European Commission. Notice to Applicants. A guideline on Summary of Product Characteristics (SmPC). 2009. Available from https://health.ec.europa.eu/system/files/2016-11/smpc_guideline_rev2_en_0.pdf. Accessed 3 April 2023
European medicines Agency (EMA). Guidelines on good pharmacovigilance practices (GVP) Module V- Risk management systems (Rev 2). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf. Accessed on 03 April 2023
European medicines Agency (EMA). Guidelines on good pharmacovigilance practices (GVP) Product- or Population-Specific Considerations III: Pregnant and 5 breastfeeding women. DRAFT FOR PUBLIC CONSULTATION. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-good-pharmacovigilance-practices-product-population-specific-considerations-iii_en.pdf . Accessed on 3 April 2023
European Medicines Agency (EMA). Public hearing on valproate: first experience and lessons learnt. London: EMA; 2017. Available from: https://www.ema.europa.eu/en/documents/report/public-hearing-valproate-first-experience-lessons-learnt_en.pdf Accessed 3 April 2023.
European Medicines Agency. Better safety for patients through EU-funded research. https://www.ema.europa.eu/en/news/better-safety-patients-through-eu-funded-research
European Medicines Agency. Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling. 2008. Available at http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003307.pdf
European Medicines Agency. ICH S5 (R3) guideline on reproductive toxicology: Detection of Toxicity to Reproduction for Human Pharmaceuticals. 2020. Available at https://www.ema.europa.eu/en/ich-s5-r3-guideline-reproductive-toxicology-detection-toxicity-reproduction-human-pharmaceuticals. Accessed on 3 April 2023
European medicines Agency. Improving patient safety through more proactive risk management. https://www.ema.europa.eu/en/news/improving-patient-safety-through-more-proactive-risk-management. Accessed on 03 April 2023
European medicines Agency. Workshop: safe use of medicines during pregnancy and breastfeeding. https://www.ema.europa.eu/en/news/workshop-safe-use-medicines-during-pregnancy-breastfeeding. Accessed 03 April 2023.
Genetic Alliance & District of Columbia Department of Health. (2010). Understanding Genetics: A District of Columbia Guide for Patients and Health Professionals. Genetic Alliance.
Hapani, K., Parikh, N., Pianka, K., & Patel, H. (2022). Chaos to Clarity: Pragmatic Approaches to Overcome Challenges for Successful Implementation of Additional Risk Minimisation Measures in the European Union and the UK by a Marketing Authorisation Holder. Pharmaceutical medicine, 36(3), 173–188. https://doi.org/10.1007/s40290-022-00426-y
Honein, M. A., Moore, C. A., & Erickson, J. D. (2004). Can we ensure the safe use of known human teratogens? Introduction of generic isotretinoin in the US as an example. Drug safety, 27(14), 1069–1080. https://doi.org/10.2165/00002018-200427140-00001
Lupattelli, A., Spigset, O., Twigg, M. J., Zagorodnikova, K., Mårdby, A. C., Moretti, M. E., Drozd, M., Panchaud, A., Hämeen-Anttila, K., Rieutord, A., Gjergja Juraski, R., Odalovic, M., Kennedy, D., Rudolf, G., Juch, H., Passier, A., Björnsdóttir, I., & Nordeng, H. (2014). Medication use in pregnancy: a cross-sectional, multinational web-based study. BMJ open, 4(2), e004365. https://doi.org/10.1136/bmjopen-2013-004365
Mayall, S. J., & Banerjee, A. K. (2014) Therapeutic risk management of medicines.1st edition. Cambridge, MA: Woodhead Publishing.
Schwarz, E. B., Maselli, J., Norton, M., & Gonzales, R. (2005). Prescription of teratogenic medications in United States ambulatory practices. The American journal of medicine, 118(11), 1240–1249. https://doi.org/10.1016/j.amjmed.2005.02.029
Trønnes, J. N., Lupattelli, A., & Nordeng, H. (2017). Safety profile of medication used during pregnancy: results of a multinational European study. Pharmacoepidemiology and drug safety, 26(7), 802–811. https://doi.org/10.1002/pds.4213.
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