Valproate is a drug used to treat epilepsy and bipolar disorder in Europe. In 2014, the Pharmacovigilance Risk Assessment Committee reviewed the safety of treating pregnant women, female children, and fertile women with valproate due to reports from both literature and clinics about the risk of unborn babies developing birth defects and developmental disorders when their mothers were treated with valproate. This prompted the implementation of risk minimisation measures such as education materials and applying restrictions on valproate use to the label. However, various studies showed that the use of valproate by fertile women had not changed significantly over the period 2014-2016. In 2017-2018 the Pharmacovigilance Risk Assessment Committee further assessed the implemented regulations and new risk minimisation measures were adopted by the European Commission on 31 May 2018. Changes included revised prescribing conditions in the product information, revised educational measures and the launch of the Pregnancy Prevention Programme. The Pharmacovigilance Risk Assessment Committee requested a new study to understand the effect of implementing the new risk minimisation measures in the UK on how valproate is prescribed to women that are of child-bearing age, which is the goal of this study. This will be achieved by comparing differences in valproate prescribing practices before and after the new measures are put in effect. The importance of this study lies in understanding if the new risk minimisation measures are effective and whether there is a reduction in the use of valproate by pregnant and fertile women.
Valproate and related substances are licensed to treat epilepsy and bipolar disorder in Europe. In 2014 PRAC concluded a review on the safety and efficacy of these in female children, women of child bearing potential (WCBP) and pregnant women. Consequently, restrictions on valproate use were applied and risk minimisation measures (RMM) were implemented. In February 2018 PRAC issued a recommendation including revised prescribing conditions in the product information, a Pregnancy Prevention Programme (PPP) and revised educational measures.
PRAC requested continuation of the ongoing drug utilisation study conducted in the UK, France, Germany, Spain, Sweden. The study primary objectives are to describe and compare the valproate prescribing practices in WCBP, proportion of patients where all PPP measurable elements are fulfilled, the count of incidence and characteristics of valproate exposed pregnancies, during the 3-year pre and post-implementation period of the new RMM. This is a non-interventional longitudinal retrospective cohort study. A cohort of patients initiating valproate will be defined with a pre- and post-study design. Prescription, demographic and diagnosis data will be used. The study population will include women 13-49 years with at least one prescription of valproate during the pre-defined periods. Exposure is defined as one or more valproate prescriptions during a study period. The following variables will be considered: patient age, use of medications related to valproate indication ever recorded before valproate initiation, prescriber specialty, as well as PPP-specific variables such as contraceptive use and pregnancy testing. In addition, information on exposed pregnancies and outcome will be provided. The analyses will be mainly descriptive where the quantitative variables described above will be statistically compared via StudentÂ’s t-test or Wilcoxon signed-rank sum test, whereas categorical variables - via Pearson Chi2 or FisherÂ’s exact test. No adjustment for multiple comparisons will be made. As appropriate, 95% confidence intervals will also be calculated.
Pregnancies exposed to valproate; Effectiveness of the risk minimisation measures (RMMs); Compliance to elements of the Pregnancy Prevention Programme (PPP); outcomes of birth
Anne Broe - Chief Investigator - IQVIA Ltd ( UK )
Christopher Lee - Corresponding Applicant - IQVIA Ltd ( UK )
Christopher Lee - Collaborator - IQVIA Ltd ( UK )
Eleanor Ralphs - Collaborator - IQVIA Ltd ( UK )
Ninoa Malki - Collaborator - IQVIA Solutions Sweden AB
Peter McMahon - Corresponding Applicant - IQVIA Ltd ( UK )
CPRD Mother-Baby Link;Pregnancy Register