The pharmacokinetic and pharmacodynamic consequences of the co‐administration of lamotrigine and a combined oral contraceptive in healthy female subjects

Abstract

AimsTo assess the pharmacokinetic and pharmacodynamic effects of co-administration of a combined oral contraceptive (ethinyloestradiol plus levonorgestrel) and lamotrig ine. MethodsOver a period of 130 days, healthy female subjects took lamotrigine (titrated up to 300 mg day − 1 ) and the combined oral contraceptive, either individually or as cotherapy. Plasma ethinyloestradiol and levonorgestrel concentrations were measured in the presence and absence of lamotrigine, and serum lamotrigine concentrations were measured in the presence and absence of the combined oral contraceptive. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone, oestradiol and sex hormone binding globulin were also determined. ResultsOf the 22 enrolled subjects, 16 had evaluable pharmacokinetic data. The mean (90% CI) ratios of lamotrigine area under the concentration-time curve from 0 to 24 h (AUC(0,24 h)) and maximum observed concentration ( C max ) of lamotrigine when it was given with the combined oral contraceptive and during monotherapy were 0.48 (0.44, 0.53) and 0.61 (0.57, 0.66), respectively. Ethinyloestradiol pharmacokinetics were unchanged by lamotrigine, the mean combined oral contraceptive + lamotrigine : combined oral contraceptive alone ratios (90% CI) of the AUC(0,24 h) and C max of levonorgestrel were 0.81 (0.76, 0.86) and 0.88 (0.82, 0.93), respectively. FSH and LH concentrations were increased (by 4.7-fold and 3.4-fold, respectively) in the presence of lamotrigine, but the low serum progesterone concentrations suggested that suppression of ovulation was maintained. Intermenstrual bleeding was reported by 7/22 (32%) of subjects during co-administration of lamotrigine and combined oral contraceptive. ConclusionsA clinically relevant pharmacokinetic interaction was observed during co-administration of a combined oral contraceptive and lamotrigine. A dosage adjustment for lamotrigine may need to be considered when these agents are co-administered. A modest decrease in the plasma concentration of levonorgestrel was also observed but there was no corresponding hormonal evidence of ovulation. Jagdev Sidhu et al. 19261 :2 Br J Clin Pharmacol

Drug interactions and hormonal contraception

“…8 This is also a good example of a study where the findings were borderline, leading to differences in interpretation. Lamotrigine had no effect on ethinyloestradiol levels, but caused a 19 per cent decrease in the AUC of levonorgestrel (which is just inside the predefined criteria, 20 per cent change, usually used for clinical relevance).…”

Co-prescription of antiepileptic drugs and contraceptives

“…AEDs were grouped into enzyme-inducing AEDs and non-enzyme-inducing AEDs as shown in Table 1. Lamotrigine has no significant effect on ethinylestradiol concentrations, but we labeled it as enzyme-inducing AED because it reduces the levonorgestrel level [7]. We also selected women from the IADB who had at least one prescription of a contraceptive (ATC G02B ⁎ , G03A ⁎ , G03HB01) in 2006.…”

Epilepsy and Oral Hormonal Contraception-Indian Perspective

“…At the same, a modest decrease in serum levenorgestrel levels was also noticed, but there was no change in serum ethinylestradiol concentrations. However, the suppression of HPO axis was adequate and there was no need to switch over to high dose OC pills [21].…”