Levetiracetam

Additional information

Pharmacokinetics and dosing

There is no evidence for relevant sex differences in levetiracetam pharmacokinetics [1]. Studies have shown 20% higher Cmax and AUC in women [2-4] and 15% higher clearance in men [5]. However, differences in clearance disappeared when adjusted for body weight [2, 5]. A study in children aged 2.3-46.2 months (7 boys, 6 girls) found no significant sex differences in pharmacokinetic parameters of levetiracetam [6].

Effects

Efficacy of levetiracetam in adults with partial seizures has been evaluated in randomized, placebo-controlled, double-blind trials conducted by the pharmaceutical company. Levetiracetam reduced the frequency of partial seizures for both men and women, for both add-on therapy (1000 and 3000 mg/day) and monotherapy (3000 mg/day) [3, 4].

Adverse effects

The pharmaceutical company reports that the overall adverse reaction profile of levetiracetam was similar in men and women in their clinical studies [2]. No sex differences in the effect of levetiracetam monotherapy on bone mineral density were shown in a retrospective cohort study (18 men, 28 women) [7].

Reproductive health issues

A clinical trial (30 men, 27 women) found no apparent sexual or endocrine side effects of levetiracetam treatment in men and women (age 18-45 years). Men treated with levetiracetam had lower free testosterone and androstenedione levels than healthy controls, but this was also seen in men treated with either carbamazepine or lamotrigine. This could thus be a difference between persons with and without epilepsy, and not a specific drug effect. Menstrual disturbances were more commonly reported in the epilepsy group than in the control group, but there was no difference in menstrual disturbances between treated women and controls. According to ASEX scores (Arizona Sexual Experience Scale), women using levetiracetam were more satisfied with their sexual lives than healthy controls without epilepsy while no differences were found in men.  The etiology of this improvement in women is unclear [8]. A cross-sectional cohort study found no impact of levetiracetam monotherapy for 6 months on serum concentrations of sex-steroid hormones in pre-pubertal children. However, this study had a small sample size (7 boys and 3 girls on levetiracetam). There is reason to assume that levetiracetam monotherapy for 6 months does not result in clinically relevant endocrine side effects in prepubertal children [9].

Semen quality, sexual function and sex hormones in men with epilepsy are not affected by treatment with lamotrigine, levetiracetam, or oxcarbazepine, according to a randomized controlled trial including 38 adult men with newly diagnosed epilepsy [10]. Reports of sexual dysfunction caused by levetiracetam or oxcarbazepine are limited to case reports. Larger studies suggest that lamotrigine, levetiracetam and oxcarbazepine can improve sexual function [10, 11]. However, one study showed that levetiracetam treatment decreased sperm parameters but not sex hormone levels [12].

In pregnant women, increased renal elimination or enzymatic hydrolysis lead to faster elimination of levetiracetam from the first trimester and up to 40-60% in the third trimester. The inter-individual variation is large, and a fast normalization is seen after delivery [13]. Dose adjustments and monitoring of plasma concentration may thus be necessary. Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

In a post-hoc analysis of serologic data from a randomized double-blind study (125 men, 69 women), women treated with levetiracetam had higher LDL concentrations, compared to women treated with carbamazepine or lamotrigine. Men treated with carbamazepine had higher LDL concentrations and higher non-HDL concentrations than men treated with levetiracetam or lamotrigine. However, the population included both those taking and not taking hyperlipidemic agents [14].