Depakote ER Use In Pregnancy & Lactation

Treatment of epilepsy: Divalproex sodium/Valproate/Valproic Acid is contraindicated during pregnancy, unless there is no suitable alternative treatment.
Divalproex sodium/Valproate/Valproic Acid is contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see Contraindications and Warnings).
Treatment of mania and prophylaxis of migraine attacks: Divalproex sodium/Valproate/Valproic Acid is contraindicated during pregnancy.
Divalproex sodium/Valproate/Valproic Acid is contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see Contraindications and Warnings).
Teratogenicity and Developmental Effects from female and male exposure: Pregnancy Exposure Risk related to valproate: Valproate was shown to cross the placental barrier both in animal species and in humans (see Pharmacology: Pharmacokinetics under Actions).
Pregnancy Exposure Risk related to Divalproex sodium/valproate sodium/valproic acid: In females, both Divalproex sodium/Valproate/Valproic Acid monotherapy and Divalproex sodium/valproate/valproic acid polytherapy are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neurodevelopmental disorders in both Divalproex sodium/Valproate/Valproic Acid monotherapy and polytherapy (concomitantly with other antiepileptic drugs) compared to the population not exposed to Divalproex sodium/Valproate/Valproic Acid.
Risk to children of fathers treated with valproate/Divalproex sodium/Valproate/Valproic Acid: A retrospective observational study on electronic medical records in 3 European Nordic countries indicates an increased risk of neuro-developmental disorders (NDDs) in children (from 0 to 11 years old) born to men treated with valproate at time of conception compared to those treated with lamotrigine or levetiracetam. The adjusted cumulative risk of NDDs ranged between 4.0% to 5.6% in the valproate group versus between 2.3% to 3.2% in the composite lamotrigine/levetiracetam monotherapy group. The pooled adjusted hazard ratio (HR) for NDDs overall obtained from the meta-analysis of the datasets was 1.50 (95% CI: 1.09, 2.07).
Due to study limitations, it is not possible to determine which of the studied NDD subtypes (autism spectrum disorder, intellectual disability, communication disorder, attention deficit/hyperactivity disorder, movement disorders) contributes to the overall increased risk of NDDs.
The study data on male patients had limitations, including differences between the groups in the conditions for which the medicines were used and in follow-up times.
The data showed that around 5 out of 100 children had a neurodevelopmental disorder when born to fathers treated with valproate compared with around 3 out of 100 when born to fathers treated with lamotrigine or levetiracetam. The study did not investigate the risk in children born to men who stopped using valproate more than 3 months before conception.
The possible risk in children born to men treated with valproate in the 3 months before conception is lower than the previously confirmed risk in children born to women treated with valproate during pregnancy. Alternative therapeutic options and the need for effective contraception while using valproate and for 3 months after stopping the treatment should be discussed with male patients of reproductive potential regularly (see Precautions).
Congenital malformations from in utero exposure: A meta-analysis (including registries and cohort studies) showed that about 11% of children of epileptic women exposed to Divalproex sodium/valproate/valproic acid monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations in the general population (about 2-3%). The risk of major congenital malformations in children after in utero exposure to antiepileptic polytherapy including Divalproex sodium/Valproate/Valproic Acid is higher than that of antiepileptic drugs polytherapy not including Divalproex sodium/Valproate/Valproic Acid. This risk is dose-dependent in Divalproex sodium/Valproate/Valproic Acid monotherapy, and available data suggest it is dose-dependent in Divalproex sodium/Valproate/Valproic Acid polytherapy. However, a threshold dose below which no risk exists cannot be established based on available data.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include 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.
In utero exposure to Divalproex sodium/Valproate/Valproic Acid may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
In utero exposure to Divalproex sodium/Valproate/Valproic Acid may also result in hearing impairment/loss due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Monitoring of signs and symptoms of ototoxicity is recommended.
Neurodevelopmental disorders from in utero exposure: Data have shown that exposure to Divalproex sodium/valproate/valproic acid in utero can have adverse effects on mental and physical development of the exposed children. The risk of neurodevelopmental disorders (including that of autism) seems to be dose-dependent when Divalproex sodium/Valproate/Valproic Acid is used in monotherapy but a threshold dose below which no risk exists, cannot be established based on available data. When Divalproex sodium/Valproate/Valproic Acid is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neurodevelopment disorders in the offspring were also significantly increased as compared with those in children from general population or born to untreated epileptic mothers. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded. When Divalproex sodium/Valproate/Valproic Acid is administered in monotherapy, studies in preschool children exposed in utero to Divalproex sodium/valproate/valproic acid show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems, possibly indicating neurodevelopmental disorders.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of Divalproex sodium/Valproate/Valproic Acid exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.
Although the role of confounding factors cannot be excluded, there is evidence in children exposed to Divalproex sodium/valproate sodium/valproic acid that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long term outcomes.
Available data show that children exposed to Divalproex sodium/Valproate/Valproic acid in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Available data suggest that children exposed to Divalproex sodium/Valproate/Valproic Acid in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the general population.
Female children, female adolescents and woman of childbearing potential (see previously mentioned and Warnings): If a woman wants to plan a Pregnancy: For epilepsy indication: During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
For epilepsy and/or mania/bipolar disorder/prophylaxis of migraine indication: In women planning to become pregnant or who are pregnant, Divalproex sodium/Valproate/Valproic Acid therapy should be reassessed.
For epilepsy and/or mania/bipolar disorder/prophylaxis of migraine indication: If a woman plans a pregnancy or becomes pregnant, Divalproex sodium/Valproate/Valproic Acid therapy should be stopped.
For epilepsy and/or mania/bipolar disorder/prophylaxis of migraine indication: In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.
If a woman plans a pregnancy: For the indication epilepsy, if a woman is planning to become pregnant, a specialist (preferably) experienced in the management of epilepsy, must reassess Divalproex sodium/Valproate/Valproic Acid therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see Warnings). If switching is not possible, the woman should receive further counselling regarding the Divalproex sodium/Valproate/Valproic Acid risks for the unborn child to support her informed decision making regarding family planning.
For the indication(s) mania and prophylaxis of migraine, if a woman is planning to become pregnant, preferably a specialist experienced in the management of mania or prophylaxis of migraine must be consulted and treatment with Divalproex sodium/Valproate/Valproic Acid should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.
Pregnant women: Divalproex sodium/Valproate sodium/Valproic Acid as treatment for mania and prophylaxis of migraine attacks is contraindicated for use during pregnancy. Divalproex sodium/Valproate/Valproic Acid as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see Contraindications and Warnings), as evaluated and decided by the treating physician.
If a woman using Divalproex sodium/Valproate/Valproic Acid becomes pregnant, she must be immediately referred to a specialist (preferably) to consider alternative treatment options. During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
If, despite the known risks of Divalproex sodium/Valproate/Valproic Acid in pregnancy and after careful consideration of alternative treatment preferably by the specialist, in exceptional circumstances a pregnant woman must receive Divalproex sodium/Valproate/Valproic Acid for epilepsy, it is recommended to: Use the lowest effective dose and divide the daily dose of Divalproex sodium/Valproate/Valproic Acid into several small doses to be taken throughout the day. The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations (see Dosage & Administration).
All patients with a Divalproex sodium/Valproate/Valproic Acid exposed pregnancy and their partners should consider specialized prenatal monitoring to detect the possible occurrence of neural tube defects or other malformations.
The available evidence does not suggest that folate supplementation before the pregnancy may prevent the risk of neural tube defects which may occur in all pregnancies.
Risk in the neonate: Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken Divalproex sodium/Valproate sodium/Valproic Acid during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycemia have been reported in neonates whose mothers have taken Divalproex sodium/Valproate sodium/Valproic Acid during the third trimester of their pregnancy.
Cases of hypothyroidism have been reported in neonates whose mothers have taken Divalproex sodium/Valproate/Valproic Acid during pregnancy.
Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken Divalproex sodium/Valproate/Valproic Acid during the last trimester of their pregnancy.
Breastfeeding: Divalproex sodium/Valproate/Valproic Acid is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women (see Adverse Reactions).
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from divalproex sodium therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: Amenorrhea, polycystic ovaries and increased testosterone levels have been reported in women using Divalproex sodium/Valproate/Valproic Acid (see Adverse Reactions). Divalproex sodium/Valproate/Valproic Acid administration may also impair fertility in men (see Adverse Reactions).
In the few cases in which valproate was switched/discontinued or the daily dose reduced, the decrease in male fertility potential was reported as reversible in most but not all cases, and successful conceptions have also been observed.