Drug Interactions between bupropion / dextromethorphan and ritonavir

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6 (e.g., selective serotonin reuptake inhibitors; tricyclic antidepressants; some beta blockers, antiarrhythmics, and antipsychotics). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, administration of a single 50 mg dose of desipramine following treatment with bupropion 150 mg twice daily increased the desipramine peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. A case report describes a 4-fold increase in plasma levels of imipramine and its metabolite, desipramine, in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. In another report, an 83-year-old woman became unsteady, confused, and lethargic following the addition of bupropion SR 300 mg/day. Her nortriptyline level was found to have increased by 185%. A later rechallenge prompted recurrence of the interaction. Likewise, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion 300 mg/day. No further seizures occurred following dosage reductions of both drugs.

MANAGEMENT: Caution is advised if bupropion must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Concomitant medications should be initiated at the lower end of the dose range. Clinical and laboratory monitoring may be appropriate for some drugs whenever bupropion is added to or withdrawn from therapy.

MONITOR: Coadministration with ritonavir may decrease the plasma concentrations of bupropion and its pharmacologically active metabolites. The proposed mechanism is ritonavir induction of the CYP450 2B6-mediated metabolism of bupropion to hydroxybupropion and the further metabolism of the latter via glucuronidation. Additionally, ritonavir may inhibit the carbonyl reductase enzyme responsible for formation of two other metabolites. In healthy volunteers, administration of bupropion in combination with ritonavir 100 mg twice daily decreased bupropion peak plasma concentration (Cmax) by 21% and systemic exposure (AUC) by 22%. Likewise, the AUC of the metabolites hydroxybupropion, threohydrobupropion, and erythrohydrobupropion decreased by 23%, 38%, and 48%, respectively. When ritonavir was administered at a dose of 600 mg twice daily in healthy volunteers, the Cmax and AUC of bupropion decreased by 62% and 66%, respectively, while the AUC of hydroxybupropion, threohydrobupropion and erythrohydrobupropion decreased by 78%, 50% and 68%, respectively. The interaction has also been studied with lopinavir-ritonavir. When a single 100 mg dose of sustained-release bupropion was administered following lopinavir-ritonavir 400 mg-100 mg twice daily for two weeks in 12 healthy volunteers, bupropion Cmax and AUC decreased by 57% each, and hydroxybupropion Cmax and AUC decreased by 31% and 50%, respectively. The onset of interaction may be about three days after ritonavir initiation, as ritonavir does not appear to have significant acute effects on bupropion. A study in 7 healthy volunteers found that ritonavir 200 mg given for 2 days had minimal impact (less than 20% mean change) on the pharmacokinetics of a single 75 mg dose of bupropion.

MANAGEMENT: Patients should be monitored for altered efficacy of bupropion following the initiation or discontinuation of ritonavir. Dosage adjustments for bupropion may be required; however, the maximum recommended dosage should not be exceeded. When bupropion/naltrexone is used for weight loss, some authorities advise against concomitant use of ritonavir. (AU, CA, US).

MONITOR: Coadministration with CYP450 2D6 inhibitors may increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. Coadministration of dextromethorphan (60 mg orally, once) with the CYP450 2D6 inhibitor panobinostat (20 mg orally once a day on days 3, 5, and 8) in 14 patients with advanced cancer had a highly variable effect on dextromethorphan levels, increasing the peak plasma concentration (Cmax) of dextromethorphan by 20% to 200%, and total systemic exposure (AUC 0 to infinity) by 20% to 130%, compared to dextromethorphan given alone. The moderate CYP450 2D6 inhibitor asunaprevir, given at 200 mg twice daily, also increased Cmax and AUC of a single 30 mg dose of dextromethorphan by 2.7- and 3.9-fold, respectively, in 17 study subjects.

MANAGEMENT: Caution should be exercised if these drugs must be used together. Patients should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.