Valproic acid capsule delayed release nonclinical toxicology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum human dose on a mg/m2 basis) for 2 years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days.The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.[1]
References
Adapted from the FDA Package Insert.