Long-Term
Data

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Clinical study overview

COMET was a 12-month, Phase 3, multicenter, long-term, open-label safety study assessing AUVELITY (twice daily) in 876 patients (rollover from prior AUVELITY studies and newly enrolled) with MDD. Efficacy measures were secondary endpoints based on newly enrolled patients (n=609).1-4 See full study design.

Long-term safety of AUVELITY from a study lasting up to 12 months1,3*

Long-term safety in the open-label COMET study was consistent with controlled clinical studies.3,5,6

Common adverse events
(≥5% of AUVELITY-treated patients)3

Adverse eventAUVELITY (N=876)
Dizziness12.7%
Nausea11.9%
Headache8.8%
Dry mouth7.1%
Decreased appetite6.1%

*The overall safety population includes all patients who received study medication.3,7

8.4%Discontinuation
rate

8.4% (74/876) of patients on AUVELITY discontinued study participation due to adverse events.3

The most common adverse events resulting in discontinuation were dizziness (1.5%), nausea (1.1%), headache (1.0%), anxiety (0.8%), and decreased appetite (0.6%).3

Long-term safety and effectiveness were measured for
AUVELITY in an open-label study1

AUVELITY had a demonstrated safety profile in a study lasting up to 12 months. The most common adverse events experienced in ≥5% of AUVELITY-treated patients were dizziness (12.7%), nausea (11.9%), headache (8.8%), dry mouth (7.1%), and decreased appetite (6.1%). Long-term safety data up to 12 months were consistent with the controlled clinical studies.3,5,6

Protocol-defined remission2,4*†

MADRS total score ≤10

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Bar graph with percentage of patients achieving protocol-defined response in the long-term COMET study.

Protocol-defined response2,4*†

≥50% improvement in MADRS
total score from baseline

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Bar graph with percentage of patients achieving protocol-defined response in the long-term COMET study.

Data from open-label studies have limitations. As the study was not blinded or placebo-controlled, results should be interpreted with these factors in mind. Endpoints were analyzed descriptively, and statistical significance cannot be attributed.

All newly enrolled patients were assessed for efficacy through Week 6. Only patients whose MADRS scores improved by ≥25% were eligible to continue in the study. 6% of subjects met discontinuation criteria at Week 6.1,7

The decrease in patient number over time is primarily due to staggered entry into the study and the closing of the study once enrollment goals were met.1

COMET Study Design

*AUVELITY-naïve ITT population.2

†Missing data were not imputed. Efficacy data from early termination visits were included in the summary of the next scheduled efficacy assessment visit.1

BID=twice a day; ITT=intention-to-treat; MADRS=Montgomery-Åsberg Depression Rating Scale.

COMET Phase 3 Study

COMET was a Phase 3, multicenter, open-label US study. Patients with MDD were treated with AUVELITY twice daily in a 12-month study. The study enrolled both patients completing a prior AUVELITY study and newly enrolled patients. The trial was concluded once at least 300 patients had been treated for 6 months and at least 100 patients had been treated for 12 months, as prespecified. At the time of study conclusion, 597 patients had reached at least 6 months, and 110 patients had reached at least 12 months of treatment.1,4,8

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Diagram of COMET phase 3 study design.
Total population included 876 patients. 265 patients rolled over from prior Auvelity controlled studies and 611 were newly enrolled. Patients received Auvelity once daily for the first 3 days and twice daily thereafter.

Secondary endpoint results were based on the newly enrolled patients (n=609) and the safety results from the full population (n=876).2,3

All newly enrolled patients were assessed for efficacy through Week 6. Only patients whose MADRS scores improved by ≥25% were eligible to continue in the study. 6% of subjects met discontinuation criteria at Week 6.1,7

Select secondary endpoints include: clinical remission (MADRS total score ≤10), clinical response (≥50% improvement in MADRS total score from baseline), CGI-I, and SDS.1

Clinical response and clinical remission were assessed on the MADRS scale. The MADRS is a clinician-rated scale used to assess depressive symptom severity. Patients are rated on 10 items to assess feelings of sadness, inner tension, reduced sleep or appetite, difficulty concentrating, lassitude, lack of interest, pessimism, and suicidality. Scores range from 0 to 60, with higher scores indicating more severe depression.1,5

BID=twice a day; CGI-I=Clinical Global Impression-Improvement; MADRS=Montgomery-Åsberg Depression Rating Scale; MDD=major depressive disorder; SDS=Sheehan Disability Scale.

GEMINI Study—Safety Profile

Dosing and Administration

Indication

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

Important Safety Information

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

  • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies.
  • 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.

CONTRAINDICATIONS

Seizure: Do not use AUVELITY in patients with a seizure disorder.

Current or prior diagnosis of bulimia or anorexia nervosa: A higher incidence of seizure was observed in such patients treated with bupropion.

Undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs: Due to risk of seizure.

Monoamine Oxidase Inhibitors (MAOIs): Do not use AUVELITY concomitantly with, or within 14 days of stopping, an MAOI due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome. Conversely, at least 14 days must be allowed after stopping AUVELITY before starting an MAOI antidepressant. Do not use AUVELITY with reversible MAOIs such as linezolid or intravenous methylene blue.

Hypersensitivity: Do not use in patients with known hypersensitivity to dextromethorphan, bupropion, or any component of AUVELITY. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion. Arthralgia, myalgia, fever with rash, and other serum sickness-like symptoms suggestive of delayed hypersensitivity have also been reported with bupropion.

WARNINGS AND PRECAUTIONS

Suicidal Thoughts and Behaviors in Pediatrics and Young Adults: Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing AUVELITY, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Seizure: Bupropion, a component of AUVELITY, can cause seizure and the risk is dose related. Because the risk of seizure with bupropion is dose-related, screen patients for use of other bupropion-containing products prior to initiating AUVELITY. If concomitant use of AUVELITY with other bupropion-containing products is clinically warranted, inform patients of the risk. Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure.

Increased Blood Pressure and Hypertension: Treatment with bupropion, a component of AUVELITY, can cause elevated blood pressure and hypertension. The risk of hypertension is increased if AUVELITY is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity. Assess blood pressure before initiating treatment with AUVELITY and monitor periodically during treatment. Monitor blood pressure, particularly in patients who receive the combination of bupropion and nicotine replacement.

Activation of Mania/Hypomania: Antidepressant treatment can precipitate a manic, mixed, or hypomanic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating AUVELITY, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). AUVELITY is not approved for use in treating bipolar depression.

Psychosis and Other Neuropsychiatric Reactions: AUVELITY contains bupropion and dextromethorphan. Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability.

Because the risks of neuropsychiatric reactions are dose-related, screen patients for use of other bupropion- or dextromethorphan-containing products prior to initiating AUVELITY. If concomitant use of AUVELITY with other bupropion- or dextromethorphan-containing products is clinically warranted, monitor patients for neuropsychiatric reactions and instruct patients to contact a healthcare provider if such reactions occur.

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressants, including AUVELITY, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including AUVELITY, in patients with untreated anatomically narrow angles.

Dizziness: AUVELITY may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that AUVELITY therapy does not affect them adversely.

Serotonin Syndrome: AUVELITY contains dextromethorphan. Concomitant use with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants increases the risk of serotonin syndrome, a potentially life-threatening condition. Prior to initiating therapy with AUVELITY, screen patients for use of other dextromethorphan-containing products. If concomitant use of AUVELITY with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome, and monitor for symptoms. Discontinue AUVELITY and/or concomitant serotonergic drug(s) immediately if symptoms of serotonin syndrome occur and initiate supportive symptomatic treatment.

Embryo-fetal Toxicity: Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy. Discontinue treatment in pregnant females and advise the patient about the potential risk to a fetus. Use alternative treatment for females who are planning to become pregnant.

DRUG INTERACTIONS

Strong Inhibitors of CYP2D6: Concomitant use with AUVELITY increases plasma concentrations of dextromethorphan. Dosage adjustment is necessary. Monitor patients for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness.

Strong CYP2B6 Inducers: Concomitant use with AUVELITY decreases plasma concentrations of dextromethorphan and bupropion and may decrease efficacy of AUVELITY. Avoid co-administration of AUVELITY.

CYP2D6 Substrates: Concomitant use with AUVELITY can increase the exposures of drugs that are substrates of CYP2D6. It may be necessary to decrease the dose of CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Digoxin: Concomitant use with AUVELITY may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with AUVELITY.

Drugs that Lower Seizure Threshold: Concomitant use with AUVELITY may increase risk of seizure. Use AUVELITY with caution. Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure.

Dopaminergic Drugs: Concomitant use with AUVELITY can result in central nervous system toxicity. Use AUVELITY with caution.

USE IN SPECIFIC POPULATIONS

Lactation: Because of the potential for neurotoxicity, advise patients that breast-feeding is not recommended during treatment with AUVELITY and for 5 days following final dose.

Renal Impairment: Dosage adjustment is recommended in patients with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2). AUVELITY is not recommended in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2).

Hepatic Impairment: AUVELITY is not recommended in patients with severe hepatic impairment.

ADVERSE REACTIONS

Most common adverse reactions (≥5% and twice the rate of placebo): dizziness (16%), headache (8%), diarrhea (7%), somnolence (7%), dry mouth (6%), sexual dysfunction (6%), and hyperhidrosis (5%).

Please see full Prescribing Information, including Boxed Warning for suicidal thoughts and behaviors.

AUV HCP ISI 10/2022

REFERENCES

  1. 1. Data on File. Axsome Therapeutics, Inc. DOF-AUV-00443.
  2. 2. Data on File. Axsome Therapeutics, Inc. DOF-AUV-00442.
  3. 3. Data on File. Axsome Therapeutics, Inc. DOF-AUV-00441.
  4. 4. Jones A, O'Gorman C, Tabuteau H. Sustained efficacy and long-term safety of AXS-05, an oral NMDA receptor antagonist, in major depressive disorder: COMET study results. Poster presented at American Psychiatric Association Annual Meeting: May 1-3, 2021.
  5. 5. AUVELITY [Prescribing Information]. Axsome Therapeutics, Inc.: New York, NY.
  6. 6. Tabuteau H, Jones A, Anderson A, Jacobson M, losifescu DV. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder, a randomized double-blind controlled trial. Am J Psychiatry. 2022;179(7):490-499.
  7. 7. Data on File. Axsome Therapeutics, Inc. DOF-AUV-02003.
  8. 8. Guidance for Industry. Premarketing Risk Assessment. U.S. Department of Health and Human Services Food and Drug Administration; March 2005. Accessed March 31, 2025. https://www.fda.gov/media/71650/download