Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 1A2, 2C19, and/or 3A4 may significantly decrease the plasma concentrations of stiripentol, which has been shown in vitro to undergo phase I metabolism via these pathways. Pharmacokinetic studies have not been conducted. In a retrospective analysis of 220 stiripentol serum concentrations derived from 75 patients in three German epilepsy centers, concomitant use of phenobarbital or phenytoin (n=7) was associated with a 63% decrease in stiripentol serum concentrations.

GENERALLY AVOID: Coadministration with stiripentol may increase the plasma concentrations of other anticonvulsants that are metabolized by CYP450 2C19 or 3A4 such as carbamazepine, phenobarbital, phenytoin, and primidone. Stiripentol itself is metabolized by these pathways and has been reported to also inhibit multiple CYP450 isoenzymes in vitro, thus both competitive and noncompetitive inhibition may occur. In a small pharmacokinetics study (n=6), stiripentol 1200 mg/day and 2400 mg/day reduced carbamazepine elimination clearance by 39% and 71%, respectively, in one subject, and phenytoin elimination clearance by 37% and 78%, respectively, in five subjects. Phenytoin toxicity was observed in two subjects. Stiripentol 2400 mg/day reduced phenobarbital elimination clearance by 33% and 39% in two subjects.

MONITOR CLOSELY: Coadministration of stiripentol with other anticonvulsants may increase central nervous system adverse effects such as somnolence, dizziness, confusion, difficulty concentrating, and impairment of psychomotor skills.

MANAGEMENT: Concomitant use of stiripentol with potent CYP450 inducers such as carbamazepine, phenobarbital, phenytoin, and primidone should generally be avoided. If coadministration is required, patients should have plasma anticonvulsant concentrations monitored and dosage adjustments made accordingly. Patients should also be monitored for increased adverse effects such as dizziness, drowsiness, lethargy, confusion, diplopia, nystagmus, ataxia, dysarthria, hypothermia, and hypotension.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

GENERALLY AVOID: Taking stiripentol on an empty stomach may reduce its oral bioavailability. Stiripentol degrades rapidly when exposed to gastric acid in an empty stomach.

GENERALLY AVOID: Alcohol may potentiate the depressant effects of stiripentol on the central nervous system. Concomitant use may result in increased sedation and dizziness as well as impairment of psychomotor skills.

GENERALLY AVOID: It is not known whether stiripentol may reduce theophylline and caffeine metabolism, as data on the potential for inhibition of CYP450 1A2 are limited. Consumption of foods and nutritional products such as cola drinks (which contain significant quantities of caffeine) and chocolate (which contains caffeine and trace amounts of theophylline) may be unsafe during treatment with stiripentol, particularly in children.

MANAGEMENT: Stiripentol should be taken during a meal for optimal absorption; however, it should not be taken with milk, dairy products (e.g., yogurt, soft cream cheese), fruit juice, or carbonated beverages. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them. Food and beverages that may contain caffeine or theophylline such as colas, chocolate, coffee, tea, or energy drinks should also be avoided during treatment with stiripentol.