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Valproate use and safety issues

I received a mail from the safety-monitoring outfit of an ethical pharmaceutical concern (EPC)-SANOFI. It is a regulatory requirement in the country (and global pharma) to have a section for safety monitoring of medicines. I noticed that the circulation list for the mail had about 300 recipients. The email provided information on the recent and continued risk minimisation measures surrounding the use of valproate (and valproate containing compounds) in female children and women of child-bearing potential.

The information was in agreement with the European Medicines Agency (EMA) and Ghana Food & Drug Authority (FDA). It was informing health care workers about new important new contraindications, strengthened warnings and measures to prevent valproate exposure during pregnancy. A check on aspects showed what was required of health care providers in the use of valproate by patients. It was important for health care providers to note the teratogenic risks associated with the use of valproate during pregnancy, the actions necessary to minimise the risks to the patient, and to ensure that the patient had an adequate level of understanding of the risk.

It recommended among others, the issuance of a Patient Guide to all female patients treated with valproate. There should also be annual risk assessment with good documentation of such interventions. There was a Patient Card to be given to every person put on valproate. The EPC had prepared customised materials for such interventions. I find it equally important for health care providers to improvise in documentation since they may be using valproic-based products, which may not necessarily come from the afore-mentioned EPC. The need for effective methods for contraception should be stressed to patients put on valproate. Valproate contained valproic acid which, when administered during pregnancy, was associated with an increased risk of congenital malformations and increased risk of developmental disorders. There were clear steps for each category of health care provider. The essentials were to critically assess the female patient one intended to put on valproate- child, adolescent, or woman of childbearing potential. It was important to decide whether there was no other effective treatment for the female patient. If there was, then it was better to consider the available option over valproate. If there was no other option available to the female patient, then one needed to understand the implications of the treatment with valproate- detailed counselling, regular reviews, effective contraception where applicable, and careful withdrawal where applicable.

Valproate contains valproic acid, an active ingredient with known teratogenic effects, which may result incongenital malformations.

Available data showed that in utero exposure to valproate could be associatedwith an increased risk of developmental disorders. Data derived from two meta-analysis (including registries and cohort studies) showed that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffered from congenital malformations). This represented a greater risk of major malformations than for the general population, for whom the risk was about 2-3%. Available data showed that the risk was dose-dependent. A threshold dose below which no risk existed could not be established based on available data.

The most common types of malformations included neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.

Exposure to valproate in utero could have adverse effects on mental and physical development of the exposed children. The risk seemed to be dose-dependent, but a threshold dose below which no risk existed could not be established based on available data. The exact gestational period of risk for these effects was uncertain.

Studies in preschool children showed that up to 30-40% of children with a history of valproate exposure in utero experienced delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems. Intelligence quotient (IQ) measured in school-aged children (age 6 years old) with a history of valproate exposure in utero was on average 7-10 points lower than children exposed to other antiepileptic drugs.

Available data showed that children with a history of valproate exposure in utero were at increased risk of autistic spectrum disorder (about three-fold) and childhood autism (about five-fold) compared with the general study populations.

General considerations for epileptic patients as issued by Task Force of Commission of European Affairs of International League Against Epilepsy (CEA-ILAE) and European Academy of Neurology (EAN): “Drug withdrawal is usually undertaken gradually over weeks to months, which allows an opportunity to identify the likely minimum required dose, should a seizure occur during drug withdrawal.” “The switch of valproate to an alternative treatment will commonly occur over at least 2–3 months. The new medication is usually first gradually introduced as add on to valproate. This can take up to six weeks to reach a potentially effective dose of the new treatment; thereafter an attempt can be made to gradually withdraw valproate.”

I came across an alert of the USA F.D.A (5thJune, 2013) advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, were contraindicated and should not be taken by pregnant women for the prevention of migraine headaches. There was evidence that these medications could cause decreased IQ scores in children whose mothers took them while pregnant.With regard to women of childbearing age who were not pregnant, valproate should not be taken for any condition unless the drug is essential to the management of the woman’s medical condition. All non-pregnant women of childbearing age taking valproate products should use effective birth control.Valproate products included valproate sodium, divalproex sodium, valproic acid, and their generics.

DR EDWARD O. AMPORFUL

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