Drug products: Epanutin®, Fenantoin Meda, Lehydan®
ATC code: N03AB02
Substances: phenytoin, phenytoin sodium
Randomized controlled studies on differences between men and women in efficacy, safety, or pharmacokinetics of phenytoin are lacking except for studies in pregnant women.
Physiological changes during pregnancy may alter plasma concentrations of phenytoin and thus the seizure frequency can increase.
Phenytoin can affect the metabolism of oral contraceptives and additional contraception should be used.
A randomized controlled trial in healthy subjects (12 men, 12 women) showed that the mean AUC, normalized for the mg/kg phenytoin dose, was about 30% lower in women than men. This might be explained by a more rapid elimination in women. This counterbalance the generally lower weight in women that result in higher phenytoin concentration levels . Another study (39 men, 24 women) found no difference between men and women in phenytoin clearance, distribution volume or half-life. Men and women received the same daily dose (4.8 mg/kg/day) and trough phenytoin concentrations were similar between men and women . Dose regimens for phenytoin do not need to be adjusted based on sex, since the more rapid elimination in women counterbalance the generally lower weight that result in higher phenytoin concentration levels .
A study examining binding characteristics of phenytoin to serum proteins in healthy adults (40 men, 40 women) on monotherapy found no sex differences. The affinity of phenytoin to serum proteins was similar in men and women, and sex does not have a significant effect on binding characteristics of phenytoin to serum proteins in adult patients .
Phenytoin pharmacokinetics is altered during pregnancy. For appropriate dose adjustment in pregnant women, periodic measurement of plasma phenytoin concentrations may be valuable .
No studies with a clinically relevant sex analysis regarding effects of phenytoin have been found.
Enzyme-inducing antiepileptic drugs, such as carbamazepine, phenytoin and lamotrigine, can contribute to reproductive disorders among men with epilepsy. These antiepileptic drugs (AEDs) increase SHBG (sex hormone-binding globulin) and thereby decreasing free androgens. This may result in sexual dysfunction, as demonstrated by lower scores on a standardized sexual function questionnaire. A study in 85 men with epilepsy treated with carbamazepine, phenytoin, lamotrigine or no AEDs, showed that 32% had scores below the control group and 24% of men treated with phenytoin had scores below the control group. SHBG was significantly higher in carbamazepine and phenytoin groups than in all other groups. However, most studies evaluating sex steroid hormone profiles in men and women treated with enzyme-inducing AEDs were cross-sectional with limited controls groups . A retrospective analysis analysis (320 men, 343 women) of patients on AED treatment showed fertile women to have a higher risk for skin reactions than men when treated with phenytoin .
Phenytoin may affect the metabolism of estrogens and progestogens. Thus, the effect of these can be reduced. Additional contraceptive method should be used . Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2013-02-06
Reviewed by: Expertrådet för neurologiska sjukdomar, Ellen Vinge
Approved by: Mia von Euler