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Keywords:

  • combined oral contraceptive;
  • interaction;
  • lamotrigine;
  • pharmacodynamics;
  • pharmacokinetics

Aims

To assess the pharmacokinetic and pharmacodynamic effects of co-administration of a combined oral contraceptive (ethinyloestradiol plus levonorgestrel) and lamotrigine.

Methods

Over 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 co-therapy. 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.

Results

Of 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 (Cmax) 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 Cmax 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.

Conclusions

A 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.