What is the best time to administer Wellbutrin (bupropion) and with how much food to a patient with a history of nausea on it, who is also taking Strattera (atomoxetine) for ADHD, and how long should they wait before deciding Wellbutrin (bupropion) is not tolerated?

Managing Bupropion-Induced Nausea in ADHD Treatment

Take bupropion XL 150-300 mg once daily in the morning with food to minimize nausea, and allow 4-6 weeks before determining if the medication is intolerable. 1

Optimal Administration Strategy

Timing and Food Intake

• Administer bupropion XL as a single morning dose with a substantial meal or snack to reduce gastrointestinal side effects, though the FDA label indicates that food does not significantly affect peak concentration or area under the curve. 1
• Taking the medication with breakfast provides the dual benefit of minimizing nausea while ensuring the activating effects occur during waking hours rather than disrupting sleep. 2
• If using the SR formulation instead of XL, divide the dose into twice-daily administration (morning and early afternoon, before 3 PM) to further reduce peak-related side effects. 2

Dosing Strategy for Nausea-Prone Patients

• Start at 150 mg XL once daily for the first 7-14 days to allow tolerance to develop before increasing to the therapeutic target dose of 300 mg daily for depression and ADHD augmentation. 2
• The gradual titration approach is critical because nausea is typically most prominent during initial treatment and often resolves with continued use. 1
• Maximum dose is 450 mg daily for XL formulation, though 300 mg is usually sufficient for ADHD augmentation when combined with atomoxetine. 2

Timeline for Tolerability Assessment

Expected Nausea Resolution Window

• Common side effects including nausea are typically mild to moderate and often diminish within 1-2 weeks of continued treatment as the body develops tolerance to the medication. 3
• Allow a minimum of 4-6 weeks at the therapeutic dose (300 mg XL) before concluding that bupropion is not tolerable, as this timeframe permits both side effect accommodation and adequate assessment of therapeutic benefit. 4

When to Discontinue Earlier

• Discontinue immediately if severe allergic reactions develop, including urticaria, angioedema, or signs of serious hypersensitivity (though these are rare and typically occur weeks after initiation, not immediately). 3
• Consider discontinuation if nausea is severe enough to cause significant functional impairment, persistent vomiting, or inability to maintain adequate nutrition despite supportive measures. 1

Adjunctive Strategies to Manage Nausea

Symptomatic Management Options

• Consider prophylactic antiemetic therapy if nausea is anticipated based on prior history, using agents such as ondansetron (5-HT3 antagonist) or metoclopramide (dopamine antagonist), though these are typically reserved for more severe cases. 5
• Ensure adequate hydration and avoid taking the medication on an empty stomach, as this exacerbates gastrointestinal side effects. 1
• Ginger supplements or small, frequent meals throughout the day may provide additional symptomatic relief through non-pharmacological mechanisms.

Safety Considerations with Concurrent Atomoxetine

Drug Interaction Profile

• The combination of bupropion and atomoxetine is safe with no contraindications, though both medications can cause gastrointestinal side effects including nausea. 2, 6
• Bupropion inhibits CYP2D6, which could theoretically increase atomoxetine levels in extensive metabolizers, but this interaction is generally not clinically significant at standard doses. 2
• Monitor for additive effects on blood pressure and heart rate, as both medications can cause modest elevations. 2, 6

Critical Monitoring Requirements

• Screen for seizure risk factors including eating disorders, alcohol use, history of head trauma, or concurrent medications that lower seizure threshold, as bupropion carries a 0.1% seizure risk. 2, 6
• Monitor blood pressure regularly, particularly during dose titration, as bupropion can cause mild elevations. 2
• Watch for neuropsychiatric effects including worsening depression or suicidal ideation, though large-scale trials show no significant increase compared to placebo. 2

Formulation Considerations

XL vs SR for Nausea Management

• If nausea persists with XL formulation despite food intake and adequate trial duration, consider switching to SR formulation (150 mg twice daily) as the divided dosing may reduce peak-related gastrointestinal effects. 3
• One case report documented successful tolerance of bupropion SR after severe delayed-onset urticaria and angioedema with XL formulation, suggesting formulation-specific tolerability differences may exist. 3
• The SR formulation requires twice-daily dosing but may provide more stable plasma levels throughout the day, potentially reducing side effects. 1

Evidence Quality and Clinical Context

The recommendations are based on FDA labeling data 1, high-quality guideline summaries 2, 6, and clinical trial evidence 4, 3. The evidence for bupropion in ADHD is rated as low-quality due to small sample sizes and risk of bias, but clinical experience supports its use as a non-stimulant alternative, particularly when combined with atomoxetine. 4