TY - JOUR

T1 - Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate

T2 - An Interrupted Time Series Study

AU - Abtahi, Shahab

AU - Pajouheshnia, Romin

AU - Durán, Carlos E.

AU - Riera-Arnau, Judit

AU - Gamba, Magdalena

AU - Alsina, Ema

AU - Hoxhaj, Vjola

AU - Andersen, Morten

AU - Bartolini, Claudia

AU - Kristiansen, Sarah Brøgger

AU - Brown, Jeremy

AU - Hallgreen, Christine Erikstrup

AU - Garcia-Poza, Patricia

AU - Gardarsdottir, Helga

AU - Gini, Rosa

AU - Girardi, Anna

AU - Holthuis, Emily

AU - Huerta, Consuelo

AU - Ibánez, Luisa

AU - Limoncella, Giorgio

AU - Martín-Pérez, Mar

AU - Paoletti, Olga

AU - Roberto, Giuseppe

AU - Souverein, Patrick

AU - Swart, Karin M.A.

AU - Wing, Kevin

AU - Sturkenboom, Miriam

AU - Klungel, Olaf

N1 - Funding Information: The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network, which is a public academic partnership coordinated by the Utrecht University, the Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE. The content of this paper expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

PY - 2023

Y1 - 2023

N2 - Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. Methods: A multi-database, times series study of females of childbearing potential (12–55 years) was conducted using electronic medical records from five countries/regions (01.01.2010–31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention −7.7%), Spain (−11.3%), and UK (−5.9%) and a non-significant decline in the Netherlands (−3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future.

AB - Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. Methods: A multi-database, times series study of females of childbearing potential (12–55 years) was conducted using electronic medical records from five countries/regions (01.01.2010–31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention −7.7%), Spain (−11.3%), and UK (−5.9%) and a non-significant decline in the Netherlands (−3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future.

U2 - 10.1007/s40264-023-01314-3

DO - 10.1007/s40264-023-01314-3

M3 - Journal article

C2 - 37294532

AN - SCOPUS:85161416615

VL - 46

SP - 689

EP - 702

JO - Drug Safety

JF - Drug Safety

SN - 0114-5916

IS - 7

ER -