Drug Interactions between bupropion / dextromethorphan and ticlopidine

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 Clinical and laboratory monitoring may be appropriate for some drugs whenever bupropion is added to or withdrawn from therapy.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 ticlopidine may increase the plasma concentrations of bupropion. The proposed mechanism is ticlopidine inhibition of bupropion hydroxylation via CYP450 2B6. In 12 healthy male volunteers, administration of a single 150 mg dose of bupropion in combination with ticlopidine (250 mg orally twice daily for 4 days) resulted in a 38% increase in bupropion peak plasma concentration (Cmax) and 85% increase in systemic exposure (AUC) compared to administration of bupropion alone. Additionally, the AUC of the hydroxybupropion metabolite decreased by 84% and the AUC ratio of hydroxybupropion to bupropion decreased by 90% with ticlopidine, while oral clearance decreased by 36%. The clinical consequence of increased bupropion plasma levels and changes in the bupropion to hydroxybupropion ratio are currently unknown.

MANAGEMENT: Caution is advised if bupropion is prescribed with ticlopidine. Pharmacologic response to bupropion should be monitored closely whenever ticlopidine is added to or withdrawn from therapy. Based on clinical response, dose adjustments of bupropion may be necessary. Concomitant use with once-daily bupropion hydrochloride 450 mg extended release tablets is not recommended. When bupropion/naltrexone is used for weight loss, some authorities recommend a maximum bupropion dosage of 180 mg per day provided as 1 tablet (bupropion 90 mg/naltrexone 8 mg) twice a day (AU, CA, US). Patients should be advised to contact their physician if they experience symptoms of bupropion toxicity such as agitation, anxiety, tremor, insomnia and seizures, or neuropsychiatric symptoms such as delusions, hallucinations, psychosis, impaired concentration, paranoia and confusion.

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.