Abstracts

Enzyme inducing antiepileptic drugs affect the metabolism of combined oral contraceptives (COC) that may result in contraceptive failure. Lamotrigine (LTG) is increaslingly used as a AED of choice in woman, because it does not seem to influence the pharmacokinetics of COCs, and because it seems to be a comparatively safe drug during pregnancy. Retrospective data showed that desogestrel or levonorgestrel containing COCs may reduce LTG plasma levels(Sabers A et al. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res 2001 47:151-4.). We wanted to further clarify time-course and magnitude of this clinically relevant interaction in a prospective evaluation. 26 women on a stable LTG monotherapy (22) or a combination with one other AED (4) received a COC (ethinylestradiol in combination with either desogestrel or levonorgestrel or cyproterone acetate or dienogest or chlormadinon acetate) or a vaginal ring releasing ethinylestradiol and etonogestrel (Nuvaring[reg]) for up to 3 consecutive treatment cycles (1 treatment cycle: 3 consecutive weeks on COC or Nuvaring[reg], 1 week off). Serial blood samples were drawn at baseline, week 1 ,3 and in the contraceptive free week of each cycle and analyzed for lamotrigine trough and peak levels. In some patients a diurnal profile with calculation of AUC was performed. In all patients LTG trough levels decreased between 25-70 % (median [gt]50%) during COC and 15-50% during Nuvaring treatment. Surprisingly, a marked reduction ([gt]20%) of the LTG level was observed after only 1-3 days of COC treatment in most patients. Lowest LTG levels were observed at the end of the 3 weeks on contraceptives. In all women there was an increase of LTG levels in the contraceptive-free week up to 80-100% of baseline level. These fluctuations of LTG levels were reproducible within subsequent treatment cycles. The degree and time course of LTG level changes varied considerably between patients. Our data confirm previous reports of a remarkable decrease of LTG levels when combined with hormonal contraceptives for all COCs studied. Local vaginal application (Nuvaring[reg]) had a somewhat smaller but still relevant influence and therefore seems to be only a minor improvement. The newly demonstrated rapid fluctuation of LTG levels depending on wether the patient was in the 3 weeks on or 1 week off contraceptives was of clincal relevance in about 1/4 of our patients. Since the LTG-level changes occur so rapidly, other mechanism than the induction of uridine 5[rsquo]-diphosphate-glucuronosyl transferase (UGT1A4), the enzyme primarily responsible for LTG-elimination, might also be important.
Clinicians must be aware of these interactions in order to avoid seizure recurrence on contraceptives or dose-dependant adverse effects during the contraceptive-free week.