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In women taking oral contraceptives, serum levels of valproate decrease during active pill use, findings suggest

Thursday, March 19 2009 | Comments

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What's This? Existing research suggests that the use of combined oral contraceptives (COCs) in women with epilepsy affects serum levels of lamotrigine, and new findings indicate that a similar interaction is present between COCs and divalproex sodium, or valproate.

The authors of the prospective study evaluated the effects of COCs on serum levels of valproate and lamotrigine, as well as the potential effects of the naturally occurring phases of the menstrual cycle (and the corresponding fluctuations in reproductive steroid levels) in women who did not use COCs.

The study included 24 women who took valproate (including 12 COC users) and 24 women who took lamotrigine (including 12 COC users). For the COC users, AED levels were measured during the third week of active pill use and at the end of the week of inactive pill use. For the COC nonusers, AED levels were measured during the mid-luteal phase and again during the early mid-follicular phase.

Among the COC users, serum levels of both drugs were significantly lower during the use of active COC pills than during inactive pill use (P<.01). Specifically, valproate levels showed a median decrease of 23.4% and lamotrigine levels a median decrease of 32.6%.

Among the women who did not use COCs, lamotrigine levels decreased 31.3% during the mid-luteal phase compared with the early mid-follicular phase. This change was not significant, perhaps because of the small sample size, according to the investigators. By contrast, valproate levels decreased only 8.3% between these 2 time points.

In an analysis of the women who did not use COCs, there were no significant correlations between the changes in AED levels and serum estradiol levels, changes in estradiol levels, proportional changes in estradiol levels, or progesterone levels.

Changes in serum AED levels did not correlate with age, basal metabolic index, epilepsy type, epilepsy duration, or prior use of enzyme-inducing AEDs. Among the women taking valproate, changes in serum levels did not vary with formulation (original vs extended-release) or between the subjects with idiopathic generalized epilepsy and those with localization-related epilepsy, although the authors acknowledged that these sample sizes were small.

"The finding that valproate levels may drop substantially during active COC use in this investigation as well as in a previously published case report raises the possibility that the COC-related drop might be of some clinical significance in the form of seizure exacerbation, not unlike that found in reports for lamotrigine," the authors commented.

They added that larger studies should be undertaken in naturally cycling women to determine whether lamotrigine levels decrease significantly during the high-steroid phase of the menstrual cycle, and whether valproate levels show greater stability throughout the menstrual cycle in these patients. (Herzog AG, et al. Neurology 2009;72:911-914.)

This research was funded by Abbott.

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