Drug Interaction Report

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring 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.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of imatinib, which is primarily metabolized by the isoenzyme. When a single 400 mg oral dose of imatinib was administered to 14 healthy adult volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 8 days), mean imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 54% and 74%, respectively, compared to administration alone. The oral clearance of imatinib was increased by 3.8-fold during rifampin coadministration. Similar results were observed in patients with malignant gliomas receiving imatinib 400 to 1200 mg/day concomitantly with enzyme-inducing antiepileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The mean dose-normalized AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib and a product containing St. John's wort led to a 30% to 32% reduction in the AUC of imatinib. The extent to which other, less potent CYP450 3A4 inducers may interact with imatinib is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of imatinib should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of imatinib, which is primarily metabolized by the isoenzyme. When a single 400 mg oral dose of imatinib was administered to 14 healthy adult volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 8 days), mean imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 54% and 74%, respectively, compared to administration alone. The oral clearance of imatinib was increased by 3.8-fold during rifampin coadministration. Similar results were observed in patients with malignant gliomas receiving imatinib 400 to 1200 mg/day concomitantly with enzyme-inducing antiepileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The mean dose-normalized AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib and a product containing St. John's wort led to a 30% to 32% reduction in the AUC of imatinib. The extent to which other, less potent CYP450 3A4 inducers may interact with imatinib is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of imatinib should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. 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. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.