Can coadministration of Auvelity (dextromethorphan‑bupropion) and Spravato (esketamine) increase the risk of nausea?

Can Combining Auvelity with Spravato Cause Nausea?

Yes, combining Auvelity (dextromethorphan-bupropion) with Spravato (esketamine) can increase the risk of nausea, as both medications independently cause nausea as a common side effect, and their combination may have additive gastrointestinal effects.

Individual Nausea Risk Profiles

Auvelity (Dextromethorphan-Bupropion)

• Nausea is one of the most common adverse effects of Auvelity, occurring frequently in clinical trials alongside dizziness, headache, diarrhea, and dry mouth 1.
• In the pivotal phase 2 trial, nausea was specifically identified as a common adverse event, though most side effects were rated as mild-to-moderate in severity 2.
• The dextromethorphan component appears to contribute significantly to gastrointestinal side effects, while bupropion also independently causes nausea in many patients 3.

Spravato (Esketamine)

• Esketamine nasal spray commonly causes nausea and vomiting as part of its side effect profile, particularly during and immediately after administration.
• The dissociative and NMDA receptor antagonist properties of esketamine contribute to gastrointestinal disturbances in a substantial proportion of patients.

Mechanism of Additive Nausea Risk

Overlapping Pharmacologic Pathways

• Both medications modulate glutamatergic neurotransmission through NMDA receptor antagonism (dextromethorphan in Auvelity and esketamine in Spravato), which can trigger nausea through central mechanisms 4, 2.
• The sigma-1 receptor agonism of dextromethorphan and the dopaminergic effects of bupropion may further contribute to gastrointestinal side effects 5.
• When combined, these overlapping mechanisms create a higher likelihood of experiencing nausea compared to either medication alone.

Clinical Management Strategies

Timing and Administration Considerations

• Administer Auvelity with food to minimize gastrointestinal upset, as this can reduce the severity of nausea without significantly affecting absorption 3.
• Schedule Spravato administration at times when the patient can rest afterward, as nausea typically peaks within the first 1-2 hours post-administration.
• Consider separating the timing of Auvelity doses from Spravato administration by several hours if possible to avoid peak plasma concentrations occurring simultaneously.

Prophylactic Antiemetic Strategies

• Prescribe ondansetron 4-8 mg orally 30 minutes before Spravato administration to prevent acute nausea, as 5-HT3 antagonists are highly effective for NMDA antagonist-induced nausea 6.
• For persistent nausea with Auvelity, consider dose reduction or slower titration, starting at the lower end of the dosing range and increasing gradually over 1-2 weeks 2.
• Avoid using metoclopramide chronically due to risk of tardive dyskinesia, but it can be used for breakthrough nausea on an as-needed basis 6.

Monitoring Protocol

• Assess nausea severity at each visit using a standardized scale (such as a 0-10 numeric rating scale or visual analog scale) to track trends and guide management 6.
• Schedule follow-up within 2-3 weeks of initiating the combination to evaluate tolerability and adjust management strategies as needed 6.
• Document whether nausea occurs primarily with Spravato administration, throughout the day with Auvelity, or both, as this guides targeted interventions.

Important Caveats and Contraindications

When to Avoid This Combination

• Patients with active eating disorders should not receive Auvelity due to increased seizure risk with bupropion, and the nausea from this combination could exacerbate disordered eating behaviors 6, 7.
• Those with severe baseline nausea or gastroparesis may not tolerate this combination well and may require alternative treatment approaches.
• Patients receiving chemotherapy or with other causes of chronic nausea should have aggressive antiemetic prophylaxis before attempting this combination 6.

Drug Interaction Considerations

• Never combine Auvelity with MAOIs or within 14 days of stopping MAOIs due to hypertensive crisis risk, which could be masked by severe nausea and vomiting 8, 7.
• The bupropion component inhibits CYP2D6, which may affect metabolism of other medications the patient is taking, potentially altering their side effect profiles 4, 2.

Special Population Warnings

• In patients with hepatic impairment, reduce Auvelity dosing as exposure increases significantly, which may worsen nausea 7.
• Renal impairment requires dose reduction of Auvelity by 50% in moderate to severe cases, as accumulation can increase side effects including nausea 7.

Quality of Life Considerations

• While nausea is common with this combination, most patients in clinical trials found the side effects tolerable and did not discontinue treatment, suggesting that with appropriate management, the therapeutic benefits can outweigh the gastrointestinal side effects 3, 2.
• The rapid antidepressant effect of both medications (improvements seen within 1-2 weeks) may justify tolerating initial nausea, as symptoms often improve with continued treatment 3, 2.
• Proactive nausea management from treatment initiation is preferable to reactive treatment after symptoms become severe, as this improves adherence and treatment outcomes 6.