Valproic acid

Additional information

Pharmacokinetics and dosing

A small single dose pharmacokinetic study showed women, particularly women without contraceptive treatment, to have higher valproic acid exposure than men. The reason being that hepatic reabsorption was twice that in men (46% vs. 22%) [1]. Another study showed men to have a larger distribution volume than women even though the differences were mainly attributed to weight [2]. A study based on therapeutic drug monitoring data showed that women and patients over 65 years had lower daily dose and higher mean dose-adjusted serum concentrations of valproic acid, compared to men and younger patients. The authors suggest that women over 65 years would require 30-50% lower daily dose to achieve therapeutic serum concentrations comparable to younger men [3].

No studies with a clinically relevant sex analysis regarding the dosing of valproic acid have been found. The producer does not recommend different dosing in men and women [4, 5].

During pregnancy, total concentrations of valproic acid have been reported to fall in late pregnancy by up to 40% compared with before pregnancy [6].

Effects

No studies with a clinically relevant sex analysis regarding the effects of valproic acid have been found.

Adverse effects

Women seem to be more prone to weight gain during valproic acid monotherapy than men. Several studies report that the increase in body weight appears to occur most frequently in post-pubertal girls. The underlying mechanism of induced weight gain by valproic acid is still unclear and various hypotheses have been suggested: dysregulation of the hypothalamic system, effect on adipokine levels, insulin and leptin resistances. It is most likely to be multifactorial [7]. A retrospective Japanese study in children with epilepsy (51 boys, 34 girls) showed that girls with loss-of-function CYP2C19 polymorphism were at risk for becoming overweight during valproic acid treatment, while no such association was observed in boys [8].

A review confirms that valproic acid in women is associated with reproductive endocrine disorders, such as PCO (Polycystic Ovarian Syndrome), high serum concentrations of testosterone and androstenedione, increased LH levels and LH/FSH ratio, and amenorrhea. These abnormalities were especially common among women who had gained weight during valproic acid therapy. PCO and hyperandrogenism seemed to be common if valproic acid was initiated before the age of 20 years. The mechanism behind this is unclear. The endocrine effects of valproic acid may be reversible after the medication is discontinued [9].

There are studies indicating that treatment with valproic acid (as well as carbamazepine and oxcarbazepine) is associated with sperm abnormalities in men with epilepsy. The clinical relevance of this finding is unclear [10, 11].

Patient’s sex can be a risk factor for hyperammonemia from valproic acid treatment. Some studies report that female sex is a risk factor [12, 13], while other studies report that male sex is a risk factor [14]. However, the number of included men and women varied between studies and other factors could explain the findings, such as differences in body weight [14].

Drug interactions

Swedish users, please consult Janusmed Interactions (Janusmed interaktioner).

Birth defects

Valproic acid can cause fetal harm and long-term development disorders in children when administered to a pregnant woman. Swedish users, please consult Janusmed Drugs and Birth Defects (Janusmed fosterpåverkan). Valproic acid is contraindicated during pregnancy in epilepsy unless no other treatment alternatives are insufficient, and contraindicated during pregnancy in bipolar disorder.  Valproic acid is contraindicated in girls and women of childbearing potential unless the terms of a special pregnancy prevention program are followed. For more information see product information for valproic acid containing products [4, 5, 15].