Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Shahab Abtahi, Romin Pajouheshnia, Carlos E. Durán, Judit Riera-Arnau, Magdalena Gamba, Ema Alsina, Vjola Hoxhaj, Morten Andersen, Claudia Bartolini, Sarah Brøgger Kristiansen, Jeremy Brown, Christine Erikstrup Hallgreen, Patricia Garcia-Poza, Helga Gardarsdottir, Rosa Gini, Anna Girardi, Emily Holthuis, Consuelo Huerta, Luisa Ibánez, Giorgio Limoncella, Mar Martín-Pérez, Olga Paoletti, Giuseppe Roberto, Patrick Souverein, Karin M. A. Swart, Kevin Wing, Miriam Sturkenboom and Olaf Klungel ()
Additional contact information
Shahab Abtahi: Utrecht Institute for Pharmaceutical Sciences, Utrecht University (UU)
Romin Pajouheshnia: Utrecht Institute for Pharmaceutical Sciences, Utrecht University (UU)
Carlos E. Durán: University Medical Center Utrecht (UMCU)
Judit Riera-Arnau: University Medical Center Utrecht (UMCU)
Magdalena Gamba: Utrecht Institute for Pharmaceutical Sciences, Utrecht University (UU)
Ema Alsina: University Medical Center Utrecht (UMCU)
Vjola Hoxhaj: University Medical Center Utrecht (UMCU)
Morten Andersen: Faculty of Health and Medical Sciences, University of Copenhagen
Claudia Bartolini: Agenzia Regionale di Sanità della Toscana (ARS)
Sarah Brøgger Kristiansen: Faculty of Health and Medical Sciences, University of Copenhagen
Jeremy Brown: London School of Hygiene & Tropical Medicine (LSHTM)
Christine Erikstrup Hallgreen: Faculty of Health and Medical Sciences, University of Copenhagen
Patricia Garcia-Poza: Agencia Espanola de Medicamentos y Productos Sanitarios (AEMPS)
Helga Gardarsdottir: Utrecht Institute for Pharmaceutical Sciences, Utrecht University (UU)
Rosa Gini: Agenzia Regionale di Sanità della Toscana (ARS)
Anna Girardi: Agenzia Regionale di Sanità della Toscana (ARS)
Emily Holthuis: PHARMO Institute for Drug Outcomes Research
Consuelo Huerta: Universidad Complutense de Madrid
Luisa Ibánez: Hospital Universitari de la Vall d’Hebron, Universitat Autònoma de Barcelona (UAB)
Giorgio Limoncella: Agenzia Regionale di Sanità della Toscana (ARS)
Mar Martín-Pérez: Agencia Espanola de Medicamentos y Productos Sanitarios (AEMPS)
Olga Paoletti: Agenzia Regionale di Sanità della Toscana (ARS)
Giuseppe Roberto: Agenzia Regionale di Sanità della Toscana (ARS)
Patrick Souverein: Utrecht Institute for Pharmaceutical Sciences, Utrecht University (UU)
Karin M. A. Swart: PHARMO Institute for Drug Outcomes Research
Kevin Wing: London School of Hygiene & Tropical Medicine (LSHTM)
Miriam Sturkenboom: University Medical Center Utrecht (UMCU)
Olaf Klungel: Utrecht Institute for Pharmaceutical Sciences, Utrecht University (UU)

Drug Safety, 2023, vol. 46, issue 7, No 7, 689-702

Abstract: Abstract 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 (

Date: 2023
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DOI: 10.1007/s40264-023-01314-3

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