Drug Interactions between bortezomib and Mudrane GG

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of bortezomib, which is primarily metabolized by the isoenzyme with secondary contribution from CYP450 2C19. In a study of patients with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma treated with intravenous bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11 of each 21-day cycle) for 3 cycles, six patients who were coadministered the potent CYP450 3A4 inducer rifampin (600 mg once daily on days 4 to 10 of cycle 3) had an approximately 23% decrease in bortezomib peak plasma concentration (Cmax) and 45% decrease in systemic exposure (AUC) compared to 12 patients treated with bortezomib alone. Because the study was not designed to exert the maximum effect of rifampin on bortezomib pharmacokinetics, greater decreases may be possible. In the same study, seven patients who were coadministered the weaker CYP450 3A4 inducer dexamethasone (40 mg once daily on days 1 to 4 and 9 to 12 of cycle 3) did not demonstrate significant changes in the pharmacokinetics of bortezomib compared to patients administered bortezomib alone. In a phase I trial to determine the dose-limiting toxicities and maximum tolerated dose (MTD) of bortezomib in patients with recurrent high-grade gliomas, patients who received concomitant enzyme-inducing antiepileptic drugs (primarily phenytoin, but also carbamazepine, oxcarbazepine, phenobarbital, and primidone) were found to tolerate a higher dosage of bortezomib compared to those who either did not receive antiepileptic medications or received ones that did not significantly induce hepatic microsomal enzymes. Bortezomib doses were escalated to 2.5 mg/m2 without reaching the MTD in the former group, whereas MTD was found to be 1.7 mg/m2 in the latter group. Moreover, maximum proteasome inhibition was reached at a higher dosage of bortezomib in the former group relative to the latter group. Although pharmacokinetics of bortezomib were not examined in the trial, these results suggest enhanced clearance of bortezomib in the presence of enzyme-inducing antiepileptic drugs.

MANAGEMENT: Given the potential for diminished pharmacologic effects of bortezomib in the presence of potent CYP450 3A4 inducers, concomitant use is not recommended.

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MONITOR: Barbiturates may decrease serum levels and therapeutic effects of the methylxanthines. The mechanism is barbiturate induction of CYP450 3A4 and 1A2 hepatic metabolism of methylxanthines.

MANAGEMENT: Close observation for clinical and laboratory evidence of decreased methylxanthine effect is indicated if these drugs must be used together. Patients should be advised to notify their physician if they experience a worsening of their respiratory symptoms.

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Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

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