Drug Interaction Report

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valproic levels should be monitored more closely whenever estrogen- and/or progestin-containing drugs are added to or withdrawn from therapy, and the valproic acid dosage adjusted as necessary.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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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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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

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Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

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The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.

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The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.

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