New Drug
Lauren Walters, PharmD
In August of 2022, FDA announced the approval of Auvelity, the first oral NMDA receptor antagonist approved for the treatment of major depressive disorder (MDD) in adults. Along with this novel mechanism comes a surprisingly fast onset of action. Whereas most antidepressants take up to 8 weeks before patients experience any resolution of depressive symptoms, there are data to show that Auvelity improves symptoms in just one week.
Recommended dosage and how it works
The recommended starting dosage of Auvelity is 1 tablet (45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) daily in the morning. After 3 days, this can be increased to the maximum recommended dosage of 1 tablet twice daily.
The 2 doses should be separated by at least 8 hours and patients should not take more than 2 doses within the same day. In moderate renal impairment, this recommended dosage is decreased to 1 tablet by mouth once daily in the morning. Auvelity is formulated as extended-release tablets, so it is important that the medication is swallowed whole and not crushed, chewed, or divided.
Auvelity is the first drug indicated for major depressive disorder in over 60 years that has a novel approach to treatment. Data from neuroimaging, cellular, and clinical studies suggest a role for the glutamatergic system in the treatment course of depression, which is the role of the dextromethorphan.
The rationale behind the combination product is that bupropion decreases the metabolism of and increases the bioavailability of the dextromethorphan.
Drug interactions and pharmacogenomics
Dextromethorphan is a substrate of CYP2D6. Bupropion is a CYP2D6 inhibitor. If a patient takes both Auvelity and a strong CYP2D6 inhibitor, the recommended dosage is 1 tablet by mouth daily. Auvelity should be avoided in those taking strong CYP2B6 inducers. Additionally, taking Auvelity increases the exposures of drugs that are substrates of CYP2D6.
Auvelity may lower plasma digoxin levels and if a patient is taking Auvelity and digoxin together, digoxin levels should be monitored. If taken with drugs that lower seizure threshold, Auvelity may increase the risk for seizure. Central nervous system toxicity can occur if used concomitantly with dopaminergic drugs. Additionally, Auvelity can cause false-positive urine test results for amphetamines.
Clinical trial highlights
The efficacy of Auvelity for the treatment of MDD in adults was demonstrated in a placebo-controlled clinical study. A second study comparing Auvelity to buproprion hydrochloride sustained-release tablets was used as confirmatory evidence.
In the first study, adult patients who met the DSM-5 criteria for MDD were randomized to receive either Auvelity or placebo twice daily for 6 weeks. The primary outcome measure was the change from baseline to week 6 in total MADRS score. Auvelity was found to be statistically significantly superior to placebo in improvement of depressive symptoms as measured by decrease in MADRS score at week 6. The results from the second study demonstrated that dextromethorphan contributes to the antidepressant properties of Auvelity.
Adverse effects and contraindications
The most common adverse reactions in those taking Auvelity are dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis. There is also a dose-related seizure risk associated with Auvelity; treatment should be discontinued if a seizure occurs.
Auvelity can increase blood pressure so an assessment for hypertension should occur before initiating treatment and periodically during treatment. Patients should be screened for bipolar disorder. Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants, and the risk of serotonin syndrome increases if Auvelity is used with SSRIs or tricyclic antidepressants. Auvelity may cause fetal harm and pregnant patients should be advised of this potential risk.
Auvelity is contraindicated in patients with seizure disorder, a current or prior diagnosis of bulimia or anorexia nervosa, use of an MAOI or within 14 days of stopping use, known hypersensitivity to dextromethorphan, bupropion, or any component of Auvelity. Auvelity is also contraindicated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Use should be avoided in those with severe renal or hepatic impairment.
Patient counseling
Patients should be educated on the risk of suicidal thoughts and who to contact in the case of them occurring. Additionally, patients should be advised to make their physician aware of any and all medications that they take to prevent drug interactions and adverse reactions. ■