What are the dosing guidelines, contraindications, monitoring requirements, and common adverse effects for Auvelity (dextromethorphan/bupropion extended-release) in adults with major depressive disorder?

Auvelity (Dextromethorphan/Bupropion Extended-Release) for Major Depressive Disorder

Auvelity is FDA-approved for treating major depressive disorder in adults, with a starting dose of one 45mg/105mg tablet once daily in the morning for 3 days, then increasing to one tablet twice daily (separated by at least 8 hours) as the standard therapeutic dose. 1

Dosing Guidelines

Standard Dosing

• Days 1-3: One tablet (45mg dextromethorphan/105mg bupropion) once daily in the morning
• Day 4 onward: One tablet twice daily, separated by at least 8 hours
• Maximum: Two tablets per day (do not exceed two doses within the same day)
• Administration: Swallow tablets whole—do not crush, divide, or chew 1

Modified Dosing for Special Populations

Moderate renal impairment (eGFR 30-59 mL/min/1.73 m²): One tablet once daily in the morning only 1

CYP2D6 poor metabolizers: One tablet once daily in the morning only 1

Concomitant strong CYP2D6 inhibitors: One tablet once daily in the morning only 1

Severe renal or hepatic impairment: Avoid use entirely 1

Contraindications

Auvelity is absolutely contraindicated in the following situations 1:

• Seizure disorder (any history)
• Current or prior bulimia or anorexia nervosa (higher seizure risk with bupropion)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs (precipitates seizures)
• MAOI use: Do not use within 14 days of stopping an MAOI; wait 14 days after stopping Auvelity before starting an MAOI
• Known hypersensitivity to dextromethorphan, bupropion, or any component

Pre-Treatment and Monitoring Requirements

Before Initiating Treatment 1

1. Assess blood pressure (baseline measurement required)
2. Screen for bipolar disorder, mania, or hypomania (personal or family history)
3. Verify no other bupropion or dextromethorphan-containing medications are being taken
4. Screen for seizure risk factors and eating disorders

Ongoing Monitoring 2

Weeks 1-2: Monitor closely for suicidal ideation, agitation, irritability, or unusual behavioral changes (highest risk period for suicide attempts) 2

Throughout treatment:

• Monitor blood pressure periodically 1
• Assess therapeutic response and adverse effects regularly
• Evaluate treatment response by 6-8 weeks—if inadequate response, modify treatment 2

The evidence shows that Auvelity demonstrates rapid antidepressant effects, with significant improvement as early as week 1-2 compared to bupropion alone 3, 4. However, consistent with general antidepressant guidelines, formal assessment of adequate response should occur at 6-8 weeks 2.

Common Adverse Effects

The most frequently reported adverse effects (≥5% and more than twice placebo rates) include 1, 5:

• Dizziness (most common)
• Headache
• Diarrhea
• Somnolence
• Dry mouth
• Sexual dysfunction
• Hyperhidrosis (excessive sweating)

Additional common effects include nausea, anxiety, constipation, decreased appetite, and insomnia 1, 5. Most adverse effects are transient and tend to improve over time 6.

Notably, Auvelity is NOT associated with significant weight gain or sexual dysfunction compared to SSRIs, which is an important advantage given that bupropion has historically shown lower rates of sexual adverse events than other antidepressants 2.

Serious Warnings and Precautions

Boxed Warning: Suicidality 1

All antidepressants carry increased risk of suicidal thoughts and behaviors in patients under age 25. Close monitoring is mandatory, especially during the first 1-2 months of treatment. Auvelity is not approved for pediatric use.

Seizure Risk 1

Seizure risk is dose-related with bupropion. The risk increases with:

• Doses exceeding recommendations
• History of seizures or eating disorders
• Abrupt alcohol/benzodiazepine discontinuation
• Concomitant medications that lower seizure threshold

Discontinue immediately if seizure occurs.

Hypertension 1

Auvelity can increase blood pressure and cause hypertension. This is particularly important given that bupropion has been associated with cardiovascular risks 2.

Activation of Mania/Hypomania 1

Screen all patients for bipolar disorder before initiating treatment, as antidepressants can precipitate manic episodes.

Serotonin Syndrome 1

Risk increases when combined with SSRIs, SNRIs, or tricyclic antidepressants. Discontinue if serotonin syndrome develops.

Angle-Closure Glaucoma 1

Can occur in patients with untreated anatomically narrow angles.

Drug Interactions

Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine): Reduce dose to once daily 1

Strong CYP2B6 inducers: Avoid concomitant use 1

CYP2D6 substrates: Auvelity increases exposure of drugs metabolized by CYP2D6 1

Digoxin: May decrease plasma digoxin levels—monitor levels 1

Drugs that lower seizure threshold: Increased seizure risk with coadministration 1

Dopaminergic drugs: CNS toxicity can occur 1

MAOIs: Absolute contraindication (see above) 1

Important Note on Drug Testing

Auvelity can cause false-positive urine test results for amphetamines 1

Clinical Context and Positioning

While the provided guidelines [2-7] focus on second-generation antidepressants broadly and do not specifically address Auvelity (approved in 2022), they establish that antidepressant selection should be based on adverse effect profiles, cost, and patient preferences rather than efficacy differences 2.

Auvelity represents a novel mechanism combining NMDA receptor antagonism (dextromethorphan) with monoamine reuptake inhibition (bupropion) 6, 3. Clinical trial data suggest faster onset of action compared to bupropion alone, with significant improvement by week 2 and remission rates of 46.5% at week 6 versus 16.2% with bupropion alone 3, 4.

Key advantages: Lower sexual dysfunction risk, no significant weight gain, rapid onset of action, and efficacy in treatment-resistant depression 6, 8, 4

Key disadvantages: Dizziness (most common side effect), seizure contraindications, twice-daily dosing, and higher cost compared to generic antidepressants 6, 5

Special Considerations

Pregnancy: May cause fetal harm. Discontinue in pregnant females and use alternative treatment for those planning pregnancy 1

Lactation: Breastfeeding not recommended 1

Switching from ketamine/esketamine: Exercise caution and be aware of short-to-intermediate elimination half-lives 8

Expert consensus supports Auvelity as a first-line treatment option for MDD, including in patients with co-occurring anxiety symptoms, inadequate response to prior treatments, or intolerable side effects from other antidepressants 8.