General Description

Auvelity is an extended-release tablet formulation of dextromethorphan hydrobromide, an uncompetitive N-methyl D-aspartate (NDMA) receptor antagonist and sigma-1 receptor agonist and bupropion hydrochloride, an aminoketone and CYP450 2D6 inhibitor.

Auvelity is specifically indicated for the treatment of major depressive disorder (MDD) in adults.

Auvelity is supplied as a tablet for oral administration. The recommended starting dosage of Auvelity (45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) is one tablet once daily in the morning. After 3 days, increase to the maximum recommended dosage of one tablet twice daily, given at least 8 hours apart. Do not exceed two doses within the same day. Administer Auvelity orally with or without food. Swallow tablets whole, do not crush, divide, or chew.

Mechanism of Action

Dextromethorphan is an uncompetitive antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. The mechanism of dextromethorphan in the treatment of MDD is unclear. The mechanism of action of bupropion in the treatment of MDD is unclear; however, it may be related to noradrenergic and/or dopaminergic mechanisms.

Bupropion increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

Side Effects

Adverse effects associated with the use of Auvelity may include, but are not limited to, the following:

• dizziness
• headache
• diarrhea
• somnolence
• dry mouth
• sexual dysfunction
• hyperhidrosis

Auvelity comes with a Black Box Warning for increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. AUVELITY is not approved for use in pediatric patients.

Clinical Trial Results

FDA approval was based on a comprehensive clinical program which included more than 1,100 patients with depression. This included the GEMINI placebo-controlled study, and confirmatory evidence which included the ASCEND study comparing Auvelity to bupropion sustained-release tablets. In the GEMENI study, Auvelity was statistically significantly superior to placebo in improvement of depressive symptoms as measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6, 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. The difference between Auvelity and placebo in change from baseline in MADRS total score was statistically significant at Week 1 and at Week 2. In the ASCEND study, Auvelity was statistically significantly superior to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure. The primary outcome measure of the ASCEND study was calculated by assessing the change from baseline in MADRS total scores from Week 1 to Week 6 and then taking the average of those scores.