What is the recommended dosing when combining Wellbutrin (bupropion) and Ingrezza (valbenazine)?

Bupropion and Ingrezza Drug Interaction: Dosing Recommendations

When combining Wellbutrin (bupropion) with Ingrezza (valbenazine), reduce the bupropion dose by 50% due to CYP2D6 inhibition by valbenazine, which increases bupropion exposure and seizure risk.

Understanding the Drug Interaction

Valbenazine is a VMAT-2 inhibitor that undergoes hepatic metabolism and can affect the metabolism of other medications through CYP enzyme interactions 1. Bupropion is extensively metabolized by CYP2D6 into active metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion), and any inhibition of this pathway increases parent drug levels 2.

Specific Dosing Algorithm

Starting Scenario: Patient Already on Bupropion

• If patient is on bupropion SR 150 mg twice daily (300 mg total): Reduce to 150 mg once daily when initiating valbenazine 3
• If patient is on bupropion XL 300 mg once daily: Reduce to 150 mg once daily when initiating valbenazine 3
• Maximum bupropion dose when combined: Do not exceed 150 mg daily to minimize seizure risk, which is the most serious adverse effect of bupropion 2, 4

Starting Scenario: Initiating Both Medications Simultaneously

• Begin bupropion at 50% of standard dose: Start with 150 mg once daily (SR or XL formulation) 3
• Initiate valbenazine at standard dose: 40 mg once daily, with option to increase to 80 mg daily after one week based on tolerability and efficacy 1
• Do not titrate bupropion upward while on valbenazine due to cumulative seizure risk 3, 2

Critical Monitoring Parameters

• Seizure risk assessment: Screen for predisposing factors including history of seizures, eating disorders (bulimia/anorexia), abrupt alcohol or benzodiazepine withdrawal, head trauma, or CNS tumor before initiating this combination 3, 2
• Blood pressure monitoring: Check at baseline and every 2-4 weeks, as bupropion can cause hypertension, particularly in combination with other medications 3
• Movement disorder assessment: Monitor for worsening or improvement of tardive dyskinesia using standardized scales (AIMS), as valbenazine is specifically indicated for TD treatment 1
• Neuropsychiatric symptoms: Assess for agitation, insomnia, anxiety, and mood changes within the first 2 weeks, as these are common with bupropion and may be exacerbated by higher drug levels 2, 5

Special Population Adjustments

Hepatic Impairment

• Moderate to severe hepatic dysfunction: Maximum bupropion dose of 75 mg daily (further 50% reduction from the already-reduced dose) when combined with valbenazine 3

Renal Impairment

• GFR <90 mL/min: Reduce bupropion to 75 mg daily (50% of the already-reduced 150 mg dose) due to accumulation of renally-cleared metabolites 3

Older Adults

• Age >65 years: Start bupropion at 37.5 mg daily and increase by 37.5 mg every 3 days to maximum of 75 mg daily when combined with valbenazine 3
• Administer second dose (if using SR formulation) before 3 p.m. to minimize insomnia 3

Common Pitfalls to Avoid

• Do not use standard bupropion dosing (300-450 mg daily) when combined with valbenazine, as this dramatically increases seizure risk beyond the baseline 0.1% seen in clinical trials 2, 5
• Avoid in patients with eating disorders: Bupropion is contraindicated in bulimia or anorexia nervosa due to increased seizure risk, and this risk is further elevated with reduced clearance 3
• Do not combine with MAOIs: Maintain 14-day washout period before or after MAOI use 3
• Watch for additive side effects: Both medications can cause nausea, insomnia, and anxiety; consider symptomatic management or further dose reduction if these become intolerable 2, 5, 1

Timeline for Efficacy Assessment

• Bupropion antidepressant effect: Initial response at 2 weeks, full efficacy at 4 weeks 2
• Valbenazine for tardive dyskinesia: Assess improvement in abnormal movements at 4-6 weeks using standardized rating scales 1
• Schedule follow-up at 2 weeks after initiating combination to assess tolerability and side effects 6

Alternative Considerations

If seizure risk factors are present or side effects are intolerable with this combination, consider switching bupropion to an alternative antidepressant class (SSRI or SNRI) that does not have seizure risk and has less problematic drug interactions with valbenazine 6, 4.