Effectiveness of risk minimization measures for valproate: a drug utilization study based on implementation of a risk minimization programme in Europe, analysis of data from the UK

Ehlken, B; Nishikawa, Chihiro; Kaplan, Sigal; Dresco, I.; Granados, Denis; Toussi, Massoud

doi:10.1080/03007995.2021.1997286

Cited by 4 publications

(5 citation statements)

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“…However, the value of these findings remains limited due to the descriptive nature of the study and reliance on absolute counts instead of standardised rates. Running an ITS model on the UK data from the same group showed that there was no statistically significant change in period (level) or trend in the proportion of valproate initiation as second-line therapy before versus after the 2014 RMMs [ 27 ]. Another study in France reported an overall decrease in valproate use among females of childbearing potential with epilepsy after the 2014 RMMs, in an ITS study with a control group (males with epilepsy) [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-023-01314-3.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…Several published studies evaluated the impact or effectiveness of RMM in 2014 on VPA use in the EU [ 14 , 15 , 17 , 24 – 26 , 29 – 31 ]. The methods differ between the studies, making direct comparison difficult; however, the 2014 RMMs have had a positive impact on incident prescriptions, VPA prescribing rates, VPA initiations as second-line therapy, incidence of VPA-exposed pregnancies and the use of effective contraception by patients in many countries [ 14 , 17 , 26 , 29 , 31 ]. Only a few studies identified a limited impact on the proportion of initiations of VPA, suggesting that the national context could play a role in the effectiveness of RMMs [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Risk Minimisation Measures on Valproate Use among Women of Reproductive Age in Latvia Between 2013 and 2020: A 7-Year Nationwide Prescription Database Study

Rutkovska,

Seilis,

Neikena

et al. 2023

Drugs - Real World Outcomes

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Background A relevant safety concern for the use of valproate (VPA) in women of reproductive age is its teratogenicity. In 2014 European Medicines Agency (EMA) introduced risk minimisation measures (RMMs) to reduce the VPA use by women of reproductive age, where the impact on VPA use was not as large as expected. In 2018, the EMA introduced additional RMMs, and it is essential to assess impact of these interventions. Objective The objective of this study was to evaluate the impact of the EMA-published RMMs in 2014 and 2018 on the prevalence of VPA use and to describe trends in the prevalence rate and incidence proportion of VPA use in epilepsy, bipolar disorder and off-label indications in Latvia. Methods This was a nationwide population-based study using a primary care prescription database. The study included women in age groups < 15, 15–49 and > 49 years and men in age group 15–49 years who have received VPA. This study assessed the prevalence rate and the incidence proportion of VPA use. The impact of RMMs on the two study intervention periods [fourth quarter (Q4) 2014 and Q4 2018] in men and women was evaluated using causal impact analysis. Results In the study cohort, VPA use in women in the age group 15–49 years decreased after the first and second intervention periods, where after the first intervention period the relative reduction in prevalence of VPA consumption was −7.7 [95% confidence interval (CI) −10%, −5.1%] and after both study periods −6.4% (95% CI −11%, −1.5%). In girls < 15 years of age, valproate use decreased after both intervention periods, while in women > 49 years old VPA use increased. In men aged 15–49 years, an increase after the first period and a non-significant decrease after both intervention periods was observed. The prevalence of valproate use in girls < 15 years and women 15–49 years of age with bipolar disorder, epilepsy and off-label indications decreased per 1000 people during the study period. The incidence proportion of VPA use in women aged 15–49 years decreased each year since the beginning of the study period. Conclusions A statistically significant decrease in the prevalence of VPA use was identified among girls < 15 years and women 15–49 years of age. In Latvia, an overall good reaction to the EMA RMMs was observed. The effects go beyond the target population and affect the use of VPA in young girls as well. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-023-00394-y.

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“…It is no longer listed as the first-choice treatment for women with genetic generalised epilepsies, despite its superior efficacy to all other ASMs [4]. Risk minimisation measures (RMMs) to reduce teratogenicity and/or developmental disorders mandated the Pregnancy Prevention Programme (PPP): that is "user independent" contraception (intrauterine devices or subdermal progesterone only implant) for women taking valproate [5]. This created a gender divide in prescribing practice based on guidelines and increasing statutory restrictions [6].…”

Section: History Of Regulationmentioning

confidence: 99%

New valproate regulations, informed choice and seizure risk

Angus-Leppan,

Arkell,

Watkins

et al. 2024

J Neurol

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Valproate is the most effective medication for generalised epilepsies, and several specific epilepsy syndromes. For some people, it will be the only medication to establish seizure remission, and withdrawing it carries risks of seizure recurrence and Sudden Unexpected Death in Epilepsy (SUDEP). It is also of proven efficacy for bipolar disorder and migraine prevention. Guidelines based on observational and epidemiological studies stress that maternal valproate related teratogenicity and neurodevelopmental effects are significantly higher than for other antiseizure medications (ASMs). It should, therefore, only be used if other medications are ineffective and after balancing the teratogenicity risk. Regulatory restrictions have changed prescribing practices and reduced valproate use. The number of other medications that must be trialled in the different conditions for which valproate has effectiveness and the consequences of the lack of efficacy of those drugs leading to significant harm including death remains unexplored. Risk minimisation measures (RMMs) for valproate, chiefly Pregnancy Prevention practices (PPP), consider foetal risk and not risk to people living with epilepsy. In the United Kingdom (UK), limitations relating to valproate use in all people < 55 years commenced in January 2024. While the evidence in child-bearing women is not disputed, the data in males are based on animal models, case reports, and one commissioned, unpublished, non-peer reviewed report unavailable to the UK public, stakeholder charities or professionals. Evidence suggests that 30–40% of people switching from valproate have breakthrough seizures. Thus, an estimated 21,000–28000 people in the UK will imminently be exposed to the potential hazards of breakthrough seizures, including death. There is little government investment in monitoring the effects of these changes to valproate prescribing on patient health and quality of life. This review summarises the history of valproate regulation, evidence underpinning it and argues how the latest regulations in the UK do not align with the country’s medical regulatory bodies ethical principles nor with the Montgomery principles of informed patient choice and autonomy. It dissects how such regulations infringe Common Law principles, nor give due regard for patient outcomes beyond reproduction. The paper looks to provide recommendations to redress these concerns while appreciating the core need for such governance to emerge in the first place.

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Effectiveness of risk minimization measures for valproate: a drug utilization study based on implementation of a risk minimization programme in Europe, analysis of data from the UK

Cited by 4 publications

References 10 publications

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

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

Impact of Risk Minimisation Measures on Valproate Use among Women of Reproductive Age in Latvia Between 2013 and 2020: A 7-Year Nationwide Prescription Database Study

New valproate regulations, informed choice and seizure risk

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