What is the appropriate dosing schedule for Auvelity (dextromethorphan/84 mg bupropion) in adults, including initiation, maintenance, adjustments for hepatic impairment, contraindications with strong CYP2D6 inhibitors, and missed‑dose instructions?

Auvelity Dosing for Major Depressive Disorder

Auvelity (dextromethorphan 45 mg/bupropion 105 mg) should be initiated at one tablet once daily in the morning for 3 days, then increased to the maintenance dose of one tablet twice daily (separated by at least 8 hours), with dose reductions to once daily required for moderate renal impairment, strong CYP2D6 inhibitor co-administration, or known CYP2D6 poor metabolizers. 1

Standard Dosing Schedule

Initiation Phase

• Days 1-3: One tablet (45 mg/105 mg) once daily in the morning 1
• Day 4 onward: One tablet twice daily, with doses separated by at least 8 hours 1
• Maximum: Do not exceed two doses within the same day 1

Administration Instructions

• Swallow tablets whole—do not crush, divide, or chew 1
• May be taken with or without food 1
• Avoid taking the second dose late in the day to minimize insomnia risk 1

Dose Adjustments for Special Populations

Moderate Renal Impairment (eGFR 30-59 mL/min/1.73 m²)

Reduce to one tablet once daily in the morning only 1. This represents a 50% dose reduction from the standard maintenance regimen and is critical to prevent drug accumulation.

Severe Renal Impairment or End-Stage Renal Disease

Auvelity has not been adequately studied in this population; use with extreme caution or consider alternative treatments 1.

Hepatic Impairment

While the FDA label does not specify hepatic dose adjustments for Auvelity specifically, bupropion-containing products generally require caution in hepatic impairment. Based on related bupropion formulations, consider dose reduction in moderate-to-severe hepatic impairment 2, 3.

Drug Interaction Dosing Modifications

Strong CYP2D6 Inhibitors

Reduce to one tablet once daily in the morning when co-administered with strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine) 1. Bupropion itself inhibits CYP2D6, and the combination increases dextromethorphan exposure significantly, necessitating this dose reduction to prevent excessive drug levels 4, 5.

CYP2D6 Poor Metabolizers

Patients known to be CYP2D6 poor metabolizers should receive one tablet once daily in the morning 1. These individuals lack functional CYP2D6 enzyme activity, resulting in substantially higher dextromethorphan levels even at standard doses.

MAOI Interactions and Washout Periods

Critical Timing Requirements

• Discontinuing MAOIs before Auvelity: Wait at least 14 days after stopping an MAOI antidepressant before initiating Auvelity 1
• Starting MAOIs after Auvelity: Wait at least 14 days after stopping Auvelity before initiating an MAOI 1

Auvelity is absolutely contraindicated with concurrent MAOI use due to risk of hypertensive crisis and serotonin syndrome 1. This includes reversible MAOIs like linezolid or intravenous methylene blue 1.

Missed Dose Instructions

If a dose is missed:

• Take the missed dose as soon as remembered, unless it is close to the time for the next scheduled dose
• Never take two doses at the same time or within 8 hours of each other to make up for a missed dose 1
• If uncertain about timing, skip the missed dose and resume the regular schedule

Contraindications Requiring Dose Avoidance

Do not use Auvelity in patients with:

• Seizure disorders (absolute contraindication) 1
• Current or prior bulimia or anorexia nervosa (higher seizure risk) 1
• Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs (seizure risk) 1
• Known hypersensitivity to dextromethorphan or bupropion 1

Pre-Treatment and Monitoring Requirements

Before Initiating Treatment

• Assess blood pressure (bupropion can elevate BP) 1
• Screen for personal or family history of bipolar disorder, mania, or hypomania 1
• Verify patient is not taking other bupropion-containing products (e.g., Wellbutrin, Zyban, Contrave) or dextromethorphan-containing medications 1
• Assess renal function (eGFR) 1
• Determine CYP2D6 metabolizer status if known, or review medication list for strong CYP2D6 inhibitors 1

During Treatment

• Monitor blood pressure periodically 1
• Assess for emergence of suicidal thoughts, especially in patients under 25 years old 1
• Watch for signs of activation, agitation, or manic symptoms 1

Common Pitfalls to Avoid

1. Combining with other bupropion products: Patients may already be on Wellbutrin, Zyban (smoking cessation), or Contrave (weight loss). The bupropion component in Auvelity adds to total bupropion exposure and increases seizure risk 1.

2. Ignoring CYP2D6 interactions: Failing to reduce the dose when adding strong CYP2D6 inhibitors (like fluoxetine or paroxetine) can lead to excessive dextromethorphan levels and increased side effects 1, 5.

3. Inadequate MAOI washout: The 14-day washout period is mandatory in both directions to prevent potentially fatal drug interactions 1.

4. Crushing or splitting tablets: The extended-release formulation requires intact tablets for proper drug delivery 1.

5. Dosing too late in the day: The second daily dose should be given at least 8 hours after the first but not late in the evening to avoid insomnia 1.