Drug Interactions between ethinyl estradiol and Valproate Sodium

MONITOR: A case report suggests that estrogens or progestins may decrease the serum concentrations and pharmacologic effects of valproic acid (VPA). The proposed mechanism is induction of hepatic glucuronidation by sex hormones. The case report involves a 26-year-old woman with a history of epilepsy since childhood. Petite mal seizures developed at age seven, which were treated with ethosuximide for approximately 2 years. She was seizure-free from age nine and did not require medication until age 13, when she had her first generalized convulsive seizure that corresponded with her first menstrual cycle. She continued to have one or two episodes each year under treatment with a variety of anticonvulsants, but had her last generalized convulsion at age 23 while taking VPA. Subsequently, she developed partial seizures that began around the time she was started on an oral contraceptive containing ethynodiol 1 mg and ethinyl estradiol 35 mcg. The patient's seizure charting indicated that her partial seizures occurred more frequently during the weeks she was taking active contraceptive pills than the weeks when she took the inactive pills. Specifically, over a 5-month period, she had 12 seizures during 105 days of active pill use and none during 35 days of inactive pill use. In two separate cycles, morning trough serum VPA level during the third week of active pill use was 39% and 64% of that between days 5 and 7 of inactive pill use. Conversely, VPA reportedly has no effects on the pharmacokinetics of contraceptive steroids. In one study, VPA given at a dosage of 200 mg twice daily for 2 months did not significantly affect the systemic exposure (AUC) of ethinyl estradiol or levonorgestrel in six women.

MANAGEMENT: Pharmacologic response and serum valproic levels should be monitored more closely whenever estrogen- and/or progestin-containing drugs are added to or withdrawn from therapy, and the valproic acid dosage adjusted as necessary. Patients should be advised to contact their physician if they experience loss of seizure control or symptoms of valproic acid toxicity such as tremors, ataxia, nystagmus, increased seizures, and changes in mental status. In patients receiving oral contraceptives, gradual transient increases in valproic acid levels will likely 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 valproic acid levels will be greater if the dose of valproic acid is increased in the few days before or during the pill-free week.

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