Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [see Data (Human)].
There are no data to assess the effects of valproate sodium on milk production or excretion.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for valproate sodium and any potential adverse effects on the breastfed infant from valproate sodium or from the underlying maternal condition.
Monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. There have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see Use in Specific Populations (8.1)].
In a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. In 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/mL (range: 1.1 mcg/mL to 2.2 mcg/mL), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). Across all patients (7 of whom were taking other AEDs concomitantly), similar results were obtained for breast milk concentration (1.8 mcg/mL, range: 0.4 mcg/mL to 3.9 mcg/mL) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%).
A published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). None of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. Infant serum levels ranged from 0.7 mcg/mL to 1.5 mcg/mL. With maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. Similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively.
A prospective observational multicenter study evaluated the long-term neurodevelopmental effects of AED use on children. Pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. Mothers continued AED therapy during the breastfeeding period. Adjusted IQs measured at 3 years for breastfed and non-breastfed children were 93 (n=11) and 90 (n=24), respectively. At 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). For other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an AED (including valproate) via breast milk were observed.
Women of childbearing potential should use effective contraception while taking valproate [see Boxed Warning, Warnings and Precautions (5.4), Drug Interactions (7), and Use in Specific Populations (8.1)]. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see Contraindications (4)].
There have been reports of male infertility coincident with valproate therapy [see Adverse Reactions (6.4)].
In animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see Nonclinical Toxicology (13.1)].
Experience with oral valproate has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning]. The safety of valproate sodium has not been studied in individuals below the age of 2 years. If a decision is made to use valproate sodium in this age group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
No unique safety concerns were identified in the 35 patients age 2 to 17 years who received valproate sodium in clinical trials.
One twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis.
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2)].
No unique safety concerns were identified in the 21 patients > 65 years of age receiving valproate sodium in clinical trials.
Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported; however patients have recovered from valproate serum concentrations as high as 2,120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.
Valproate sodium is the sodium salt of valproic acid designated as sodium 2-propylpentanoate. Valproate sodium has the following structure:
|C 8 H 15 NaO 2||M.W. 166.2|
Valproate sodium occurs as an essentially white and odorless, crystalline, deliquescent powder.
Valproate sodium injection, USP is available in 5 mL single-dose vials for intravenous injection. Each mL contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and water for injection to volume. The pH is adjusted to 7.6 with sodium hydroxide and/or hydrochloric acid. The solution is clear and colorless.
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