U.S. FDA grants approval for dextromethorphan–bupropion combo for depression

New York-based Axsome Therapeutics has received US Food and Drug Administration approval for Auvelity (dextromethorphan HBr 45 mg/bupropion HCl 105 mg) extended-release tablets for the treatment of major depressive disorder in adults.1-3 The product was developed with FDA Breakthrough Therapy designation and evaluated by the FDA under Priority Review.4 The manufacturer states that the antidepressant combination is the “first and only rapid-acting oral treatment approved with labeling of statistically significant improvement in depressive symptoms compared to placebo starting at one week.”4 US approval was based on two trials. In the GEMENI study, dextromethorphan–bupropion was statistically significantly superior to placebo in improving depressive symptoms as measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week six, the study’s primary endpoint. To evaluate speed of onset of action, the change in MADRS total score from baseline to Week 1 and from baseline to Week 2 were pre-specified secondary efficacy endpoints.4,5 The difference between dextromethorphan–bupropion and placebo in change from baseline in MADRS total score was statistically significant at Week 1 and at Week 2.4 At week 6, remission was achieved by 39.5% of patients with dextromethorphan–bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response was achieved by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001).6 Read: Bad mix: hot summer days and anti-platelet medications, beta-blockers In the ASCEND study, dextromethorphan–bupropion was statistically significantly superior to bupropion sustained-release tablets (105 mg twice daily) on the primary outcome measure (the change from baseline in MADRS total scores from Week 1 to Week 6). Remission rates were significantly higher with dextromethorphan–bupropion at Week 2 and every time point thereafter (Week 6: 46.5% vs. 16.2%; mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥ 50% decrease in MADRS score from baseline) at Week 6 were 60.5% with dextromethorphan–bupropion and 40.5% with bupropion (mean difference=19.9%, 95% CI=-1.6, 41). The most commonly reported adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction and hyperhidrosis.4,7 The exact mechanism of action of dextromethorphan–bupropion in the treatment of depression is unclear. Dextromethorphan is an uncompetitive antagonist of the N-methyl D-aspartate (NMDA) receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine; it does not inhibit monoamine oxidase or the reuptake of serotonin. Bupropion also increases plasma levels of dextromethorphan by competitively inhibiting CPY2D6, which catalyzes a major biotransformation pathway for dextromethorphan.3 The recommended starting dosage of Auvelity (dextromethorphan HBr 45 mg/bupropion HCl 105 mg) is one tablet once daily in the morning, with or without food. After three days, the dose is increased to the maximum recommended dosage of one tablet twice daily, given at least eight hours apart.3 The dextromethorphan–bupropion combination product is not currently under review by Health Canada.8 At the time this article was posted, the US manufacturer had not yet responded to a request for further details about possible future marketing in Canada. Read: 'Magic mushroom' psychedelic may help heavy drinkers quit References 1. FDA News. FDA grants approval to Axsome’s Auvelity for major depressive disorder. August 22, 2022. (accessed August 25, 2022). 2. Brooks M. FDA approves 'rapid-acting' oral drug for major depression. Medscape Pharmacists, August 22, 2022. https://www.medscape.com/viewarticle/979568 (accessed August 25, 2022). 3. Axsome Therapeutics Inc. Auvelity (dextromethorphan HBr/bupropion HCl) extended-release tablets prescribing information. (accessed August 25, 2022). 4. Axsome Therapeutics Inc. Axsome Therapeutics announces FDA approval of Auvelity, the first and only oral NMDA receptor antagonist for the treatment of major depressive disorder in adults. August 19, 2022. (accessed August 25, 2022). 5. FDA approves rapid-acting Auvelity for major depression. Formulary Watch, August 22, 2022. (accessed August 25, 2022). 6. Iosifescu DV, Jones A, O'Gorman C, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry 2022;83(4):21m14345. doi: 10.4088/JCP.21m14345. 7. Tabuteau H, Jones A, Anderson A, et al. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry 2022;179(7):490-9. doi: 10.1176/appi.ajp.21080800. 8. Government of Canada. Drug and health product submissions under review (SUR): new drug submissions under review. (accessed August 25, 2022)

U.S. FDA grants approval for dextromethorphan–bupropion combo for depression

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