Drug Interactions between Estratest and Lamictal

MONITOR: Coadministration with estrogens or progestins may decrease the plasma concentrations and pharmacologic effects of lamotrigine due to induction of lamotrigine glucuronidation. One group of investigators cited seven suspected cases of this interaction in women treated with oral contraceptives that contained either ethinyl estradiol in combination with desogestrel or norethindrone or norethindrone alone. The contraceptives reduced plasma levels of lamotrigine by 41% to 64%, and a deterioration in seizure control was observed several days to two months after initiation of contraceptive use, necessitating an increase in lamotrigine dosage or discontinuation of the contraceptive. In some cases, contraceptive discontinuation led to lamotrigine toxicity that required dosage reduction. A pharmacokinetic study also reported similar reductions in lamotrigine plasma levels in patients on combination oral contraceptives, with lamotrigine clearance 2.5 times greater than in controls. The interaction is further supported by the fact that changes in hormone levels are known to influence the pharmacokinetics of glucuronidated drugs in humans, and elimination of lamotrigine is significantly increased during pregnancy. However, a population pharmacokinetics study in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks found no significant effect of oral contraceptive use or dose on the oral clearance of lamotrigine. Lamotrigine also has been shown to have little or no effect on the pharmacokinetics of contraceptive hormones, although measurement of serum FSH, LH, and estradiol has indicated some loss of suppression of the hypothalamic-pituitary-ovarian axis. The clinical significance is unknown. Measurement of serum progesterone indicated no hormonal evidence of ovulation.

MANAGEMENT: Pharmacologic response and plasma lamotrigine levels should be monitored more closely whenever estrogen- and/or progestin-containing drugs are added to or withdrawn from therapy, and the lamotrigine dosage adjusted as necessary. The manufacturer's labeling should be consulted for detailed dosage recommendations. Patients should be advised to contact their physician if they experience loss of seizure control or symptoms of lamotrigine toxicity such as ataxia, nystagmus, increased seizures, irregular heartbeat, and changes in mental status. In patients receiving oral contraceptives, gradual transient increases in lamotrigine levels will occur during the pill-free week for women not also taking an enzyme-inducing drug (e.g., carbamazepine, phenytoin, phenobarbital, primidone, rifampin). The increase in lamotrigine levels will be greater if the dose of lamotrigine is increased in the few days before or during the pill-free week. Although diminished contraceptive efficacy has not been reported, the possibility should be considered. Patients should be instructed to promptly report changes in their menstrual pattern.

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