Fenytoin

Additional information

Pharmacokinetics and dosing

A 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) of phenytoin or fosphenytoin and trough phenytoin concentrations were similar between men and women [4]. Also, 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 body weight in women that results in higher phenytoin concentration levels [5]. Dose regimens for phenytoin do not need to be adjusted based on patient’s sex, since the more rapid elimination in women counterbalance the generally lower weight that result in higher phenytoin concentration levels [5].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 patient’s sex does not have a significant effect on binding characteristics of phenytoin to serum proteins in adult patients [6].

Effects

No studies with a clinically relevant sex analysis regarding effects of phenytoin have been found.

Adverse effects

A retrospective analysis (320 men, 343 women) of patients on antiepileptic drug treatment showed fertile women to have a higher risk for skin reactions than men when treated with phenytoin [7].

Reproductive health issues

Enzyme-inducing antiepileptic drugs, such as carbamazepine, phenytoin and phenobarbital, may have potentially negative effects on reproductive endocrine function in men and women. These antiepileptic drugs increase concentrations of sex hormone-binding globulin (SHBG) and thereby reducing the concentrations of unbound biologically active androgens [1-3]. This may result in sexual dysfunction. 

Phenytoin pharmacokinetics is altered during pregnancy resulting in lower plasma concentrations and thus, an increased risk of seizures. For appropriate dose adjustment in pregnant women, monitoring of plasma phenytoin concentrations is recommended [8]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Phenytoin may affect the metabolism of estrogens and progestogens. Thus, the effect of these can be reduced. Additional contraceptive method should be used [9]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).