Summary of presentation

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1 Valproat och graviditet Seminarium för hälso och sjukvårdspersonal om läkemedelssäkerhetsarbete Ulla Wändel Liminga, PhD Ämnesområdesansvarig farmakologi/toxikologi; PRAC delegat Summary of presentation Pharmacovigilance Risk Assessment Committee (PRAC) Structure, responsibilities & tasks Valproate & pregnancy Referrals ; Situation in Sweden

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4 October 2013 Valproate PRAC referral 1 Start EMA started review of valproate & use in pregnancy Delayed development in children born to women treated with valproate during pregnancy; e.g. autism; may be long lasting Need for updates of product information & risk minimisation measures Valproate PRAC referral 1 Conclusion October 2014 Review of relevant data on efficacy & safety re. in utero exposure to valproate; views of patients/carers, healthcare professionals re. understanding / awareness of risks Confirms teratogenic risks Meta analysis*: Congenital malformations in 10.7% (95% CI: ) of children of epileptic women exposed to valproate monotherapy during pregnancy. Greater than general population (2 3%.) * Meador K, Reynolds MW, Crean S et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81(1):1 13.

5 Valproate PRAC referral 1 Conclusion October 2014 Adverse effects on mental & physical development. Dose dependent, no threshold. Limited data on long term outcomes Exact gestational risk period uncertain Preschool children: up to 30 40% experience early development delay (e.g. talk, walk later, lower intellectual abilities, poor language skills, memory problems) IQ in children (age 6 y) average 7 10 points lower vs children exposed to other antiepileptics. Support risk independent from maternal IQ Increased risk of autistic spectrum disorder (~ 3 fold); childhood autism (~5 fold) vs general study population; some data support increasing development of ADHD symptoms Valproate PRAC referral 1 Recommendation October 2014 cont' Valproate effective treatment of epilepsy & manic episode in bipolar disorder; serious conditions remain option for females when other treatment alternatives tried & failed /not tolerated Migraine prophylaxis contraindicated in pregnancy; fertile women not using effective contraception Communication activities Direct healthcare professional communication (letter) Education materials for healthcare professionals & patients on risks and measures to minimise risks Further studies on ADHD Drug utilisation to assess effectiveness of risk minimisation measures; characterise prescribing patterns 77

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7 View of risks of using valproate during pregnancy, incl. child? Agreement risks undeniable, well characterised. Seriousness & impact on those affected powerfully & movingly conveyed Views on current risk minimisation measures? Improved information resources developed after PRAC review 2014; BUT not reaching right people at right time Hoped for strengthening of risk minimisation not seen Other measures to reduce valproate risks during pregnancy? Many proposals e.g. Visual reminder on package Always dispensed in appropriate package + adequate risk info Alert in prescribing / dispensing software Regular reviews for all women on long term valproate Record women appropriately counselled Development of professional education More coordinated care services at national level Public awareness (tools for campaigns) Valproate referral 2 : Outcome Mar 2018 Contraindicated in girls / women of child bearing potential unless pregnancy prevention programme followed assessment of each patient s potential for becoming pregnant pregnancy tests before starting & during treatment as needed, counselling risks & need for effective contraception whole treatment at least annual review of ongoing treatment by specialist new risk acknowledgement form Not used unless alternative treatments not suitable Visual warning on package (boxed text / pictogram) Educational materials for patients & prescribers MAHs undertake further studies drug utilisation study, surveys (HCP, patients) safety study (existing registries) on foetal anticonvulsant syndrome paternal exposure congenital anomalies/ neurodevelopmental disorders best practice for discontinuation & switching of valproate treatment

8 In practice..

9 Practical implications Reviews on how risk minimisation works ongoing In several EU member states via companies Evaluate communication activities from 2014 in SE by MPA Several questions on strong language in educational material e.g. Årlig riskbekräftelsesblankett måste användas av specialistläkarna vid den inledande behandlingen och under varje årlig utvärdering av behandlingen med valproat som görs av specialistläkaren EU obligations on companies But seen as recommendations /support to health care professionals (national law) Frågor.. Hur få fram budskapen i viktiga säkerhetsfrågor? Syn på utbildningsmaterial? Skicka förskrivarbrev (DHPC) till vem (tex. verksamhetschefer /alla förskrivare)?