Effect of oral contraceptives on lamotrigine levels depends on comedication

Objectives To evaluate prospectively the influence of cyclic oral contraceptive ( OC ) use on lamotrigine ( LTG ) serum levels when used in combination therapy. Methods Women with epilepsy using LTG in combination with valproate ( VPA ; n  = 7), carbamazepine ( CBZ ; n  = 3) or oxcarbazepine ( OXC ; n  = 1) were evaluated during two periods of 28 days cyclic OC use, monitoring antiepileptic drug ( AED ) levels every other day with the dried blood spot sampling method. Results were compared with women on LTG monotherapy and OC s ( n  = 12). Pharmacokinetic analysis was performed using NONMEM software. Results Mean study population value of LTG clearance estimated by the final model was 3.17 l/h. Introduction of covariates for comedication ( VPA , CBZ , OXC and OC ) significantly reduced the between‐subject variability. A significant influence of OC comedication on LTG clearance was seen in both LTG monotherapy (clearance with OC 4.02 ± 0.38 l/h, OC ‐free week 3.03 ± 0.39 l/h) and in LTG ‐ CBZ combination (clearance with OC 4.95 ± 0.15 l/h, OC ‐free week 4.15 ± 0.26 l/h). No influence of OC was found in LTG ‐ VPA combination (clearance with OC 0.99 ± 0.16 l/h, OC ‐free week 0.90 ± 0.15 l/h). Conclusions Adding OC s to LTG monotherapy or the combination LTG ‐ CBZ significantly increased the LTG clearance and thus reduced LTG serum levels. In the combination LTG ‐ CBZ , OC s had a non‐significant effect on CBZ clearance. No significant influence of cyclic OC use on LTG or VPA clearance was found when these AED s were used in combination.