Version July 2025
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Dextromethorphan/bupropion is not approved for use in pediatric patients.
Major depressive disorder, unipolar: Initial: Oral: Dextromethorphan 45 mg/bupropion 105 mg once daily in the morning. After 3 days, increase to dextromethorphan 45 mg/bupropion 105 mg twice daily, administered at least 8 hours apart. Maximum daily dose: dextromethorphan 90 mg/bupropion 210 mg.
CYP2D6 poor metabolizers: Oral: Dextromethorphan 45 mg/bupropion 105 mg once daily in the morning.
Discontinuation of therapy:
Bupropion: Withdrawal symptoms resulting from abrupt discontinuation are unlikely because bupropion has minimal serotonergic activity (Ref).
Dextromethorphan: Little is known about the risk of withdrawal with abrupt discontinuation. When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between 2 selective serotonin reuptake inhibitors), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from a monoamine oxidase inhibitor:
Allow 14 days to elapse between discontinuing an MAOI and initiation of dextromethorphan/bupropion.
Allow 14 days to elapse between discontinuing dextromethorphan/bupropion and initiation of an MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to 59 mL/minute/1.73 m2: Dextromethorphan 45 mg/bupropion 105 mg once daily in the morning.
eGFR <30 mL/minute/1.73 m2: Use is not recommended (has not been studied).
Child-Pugh class A or B: No dosage adjustment necessary.
Child-Pugh class C: Use is not recommended (has not been studied).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. Also see individual agents.
>10%:
Gastrointestinal: Nausea (13%)
Nervous system: Dizziness (14% to 16%)
1% to 10%:
Dermatologic: Hyperhidrosis (5%)
Gastrointestinal: Constipation (4%), decreased appetite (4%), diarrhea (7%), xerostomia (6%)
Genitourinary: Sexual disorder (6%)
Nervous system: Anxiety (4%), drowsiness (7%), fatigue (3%), headache (8%), insomnia (4%), paresthesia (3%)
Neuromuscular & skeletal: Arthralgia (3%)
Ophthalmic: Blurred vision (3%)
Frequency not defined: Nervous system: Suicidal ideation, suicidal tendencies
Hypersensitivity (eg, anaphylaxis, Stevens-Johnson syndrome, delayed hypersensitivity) to dextromethorphan, bupropion, or any component of the formulation; current or prior diagnosis of bulimia or anorexia nervosa; patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiseizure drugs; seizure disorder; use with or within 14 days of stopping monoamine oxidase inhibitors; initiation in a patient receiving linezolid or IV methylene blue.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Dizziness: May cause dizziness; use with cause in patients with motor impairment affecting gait or history of falls. Caution patients about operating machinery and driving.
• Hypertension: May elevate BP and cause hypertension. Events have been observed in patients with or without evidence of preexisting hypertension. The risk is increased when used concomitantly with monoamine oxidase inhibitors, nicotine replacement, or other drugs that increase dopaminergic or noradrenergic activity. Assess BP before treatment and monitor periodically.
• Mania/Hypomania: May precipitate a manic, mixed, or hypomania episode. Risks are increased with bipolar disorder or risk factors for bipolar disorder (family history, suicide, depression); screen patients for history or risk factors. Dextromethorphan/bupropion is not approved for use in treatment of bipolar depression.
• Neuropsychiatric effect: Serious neuropsychiatric events have occurred in patients taking bupropion including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. Dose reduction and/or treatment withdrawal resolved symptoms in some cases. Dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability.
• Ocular effects: May cause mild pupillary dilation, which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
• Seizures: May cause a dose-related risk of seizures. Use is contraindicated in patients with a history of seizures or certain conditions with high seizure risk (eg, history of anorexia/bulimia or patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiseizure drugs). Use caution with concurrent use of antipsychotics, antidepressants, theophylline, systemic corticosteroids, stimulants (including cocaine), anorexiants, or hypoglycemic agents, or with excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opioids. Use with caution in seizure-potentiating metabolic disorders (hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia). Do not coadminister with other bupropion-containing formulations. Permanently discontinue if seizure occurs during therapy.
• Suicidal thinking/behavior (use in treating psychiatric disorders): Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults ≤24 years of age. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); advise families and caregivers of the need for close observation and communication with the prescriber. A medication guide concerning the use of antidepressants should be dispensed with each prescription.
Disease-related concerns:
• Hepatic impairment: Use caution in patients with hepatic impairment; plasma concentrations are increased. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mauri 2014; Mullish 2014).
• Renal impairment: Use with caution in patients with renal impairment; reduce dose for moderate impairment and avoid in cases of severe impairment.
Other warnings/precautions:
• Abuse/Misuse: Using bupropion doses higher than prescribed may result in increased motor activity, agitation/excitement, and euphoria.
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy (ECT); consider discontinuing, when possible, prior to ECT treatment (APA 2010).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release, Oral:
Auvelity: Dextromethorphan hydrobromide 45 mg and bupropion hydrochloride 105 mg
No
Tablet, controlled release (Auvelity Oral)
45-105 mg (per each): $23.55
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Oral: Administer with or without food. Swallow whole; do not crush, divide, or chew.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215430s000lblCorrect3.pdf#page=25, must be dispensed with this medication.
Major depressive disorder, unipolar: Treatment of unipolar major depressive disorder in adults.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents With Seizure Threshold Lowering Potential: BuPROPion may increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor
Ajmaline: CYP2D6 Inhibitors (Strong) may increase serum concentration of Ajmaline. Risk C: Monitor
Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Alcohol (Ethyl): May increase adverse/toxic effects of BuPROPion. Specifically, seizure threshold may be lowered. BuPROPion may increase adverse/toxic effects of Alcohol (Ethyl). Specifically, alcohol tolerance may decrease during treatment. Management: Patients receiving bupropion should be advised to minimize or avoid alcohol consumption due to possible lower alcohol tolerance, and lower seizure threshold associated with heavy alcohol consumption/abrupt discontinuation of heavy consumption. Risk D: Consider Therapy Modification
Aldesleukin: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor
Anti-Parkinson Agents (Dopamine Agonist): May increase adverse/toxic effects of BuPROPion. Risk C: Monitor
Antihepaciviral Combination Products: May decrease serum concentration of BuPROPion. Risk C: Monitor
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase active metabolite exposure of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Risk D: Consider Therapy Modification
ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions or avoidance are required for indications other than major depressive disorder. Dose adjustments vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See interact monograph for details Risk D: Consider Therapy Modification
Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Atomoxetine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Atomoxetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. Risk D: Consider Therapy Modification
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Benzhydrocodone: CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of Benzhydrocodone. Risk C: Monitor
Blonanserin: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Blonanserin. Specifically, the risk of seizures may be increased. Risk C: Monitor
Brexanolone: BuPROPion may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brexpiprazole: May increase adverse/toxic effects of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual dose with bupropion; reduce to 25% of usual if used with both bupropion and a strong or moderate CYP3A4 inhibitor. These recommendations do not apply if treating major depressive disorder. Monitor for seizures. Risk D: Consider Therapy Modification
Bromperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Bromperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Broom: CYP2D6 Inhibitors (Strong) may increase serum concentration of Broom. Specifically, the concentrations of sparteine, a constituent of broom, may be increased. Risk C: Monitor
Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Carvedilol: CYP2D6 Inhibitors (Strong) may increase serum concentration of Carvedilol. Risk C: Monitor
Chlorpheniramine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Chlorpheniramine. Risk C: Monitor
ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor
Citalopram: BuPROPion may increase adverse/toxic effects of Citalopram. BuPROPion may increase serum concentration of Citalopram. Management: Initiate citalopram at the lower end of the normal dose range in patients receiving bupropion and consider limiting the maximum citalopram adult dose to 20 mg/day during concomitant bupropion treatment. Monitor for citalopram toxicities. Risk D: Consider Therapy Modification
Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of CloZAPine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: CYP2D6 Inhibitors (Strong) may increase serum concentration of CloZAPine. Risk C: Monitor
Codeine: CYP2D6 Inhibitors (Strong) may decrease therapeutic effects of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor
CYP2B6 Inducers (Moderate): May decrease serum concentration of BuPROPion. Risk C: Monitor
CYP2B6 Inducers (Weak): May decrease serum concentration of BuPROPion. Risk C: Monitor
CYP2B6 Inhibitors (Weak): May increase serum concentration of BuPROPion. Risk C: Monitor
CYP2D6 Inhibitors (Moderate): May increase serum concentration of Dextromethorphan. Risk C: Monitor
Dapoxetine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Dapoxetine. Risk C: Monitor
Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase active metabolite exposure of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg with concurrent use of a strong CYP2D6 inhibitor. Risk D: Consider Therapy Modification
Digoxin: BuPROPion may decrease serum concentration of Digoxin. Risk C: Monitor
Dinutuximab Beta: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Direct Oral Anticoagulants (DOACs): BuPROPion may increase anticoagulant effects of Direct Oral Anticoagulants (DOACs). Risk C: Monitor
Disulfiram: May increase adverse/toxic effects of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Risk X: Avoid
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase serum concentration of DOXOrubicin (Conventional). Risk X: Avoid
DroPERidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of DroPERidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
DULoxetine: CYP2D6 Inhibitors (Strong) may increase serum concentration of DULoxetine. Risk C: Monitor
Eliglustat: CYP2D6 Inhibitors (Strong) may increase serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Risk D: Consider Therapy Modification
Elranatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Epcoritamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Escitalopram: BuPROPion may increase adverse/toxic effects of Escitalopram. Risk C: Monitor
Fenfluramine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Fenfluramine. Management: Limit fenfluramine dose to 20 mg/day without concurrent stiripentol or to 17 mg/day with concomitant stiripentol and clobazam when used with a strong CYP2D6 inhibitor. Risk D: Consider Therapy Modification
Fesoterodine: CYP2D6 Inhibitors (Strong) may increase active metabolite exposure of Fesoterodine. Risk C: Monitor
Fexinidazole: May decrease serum concentration of CYP2B6 Substrates (High risk with Inducers). Management: Avoid concomitant use of fexinidazole and CYP2B6 substrates when possible. If combined, monitor for reduced efficacy of the CYP2B6 substrate. Risk D: Consider Therapy Modification
Flecainide: CYP2D6 Inhibitors (Strong) may increase serum concentration of Flecainide. Risk C: Monitor
Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor
FluPHENAZine: CYP2D6 Inhibitors (Strong) may increase serum concentration of FluPHENAZine. Risk C: Monitor
FluvoxaMINE: BuPROPion may increase adverse/toxic effects of FluvoxaMINE. Risk C: Monitor
Gefitinib: CYP2D6 Inhibitors (Strong) may increase serum concentration of Gefitinib. Risk C: Monitor
Glofitamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Haloperidol: CYP2D6 Inhibitors (Strong) may increase serum concentration of Haloperidol. Risk C: Monitor
HYDROcodone: CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Risk C: Monitor
Iboga: CYP2D6 Inhibitors (Strong) may increase serum concentration of Iboga. Risk C: Monitor
Iloperidone: May increase adverse/toxic effects of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may decrease active metabolite exposure of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. BuPROPion may increase active metabolite exposure of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. BuPROPion may increase serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with bupropion. Monitor for increased iloperidone toxicities, including QTc prolongation and arrhythmias. Additionally, monitor for increased risk of seizures when these agents are combined. Risk D: Consider Therapy Modification
Indoramin: CYP2D6 Inhibitors (Strong) may increase serum concentration of Indoramin. Risk C: Monitor
Iobenguane Radiopharmaceutical Products: BuPROPion may decrease therapeutic effects of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer bupropion until at least 7 days after each iobenguane dose. Risk X: Avoid
Ioflupane I 123: Coadministration of BuPROPion and Ioflupane I 123 may alter diagnostic results. Risk C: Monitor
Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Lofexidine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Lofexidine. Risk C: Monitor
Loxapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lumacaftor and Ivacaftor: May decrease serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor
Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Maprotiline: CYP2D6 Inhibitors (Strong) may increase serum concentration of Maprotiline. Risk C: Monitor
Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid
Memantine: NMDA Receptor Antagonists may increase adverse/toxic effects of Memantine. Risk C: Monitor
Mequitazine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Mequitazine. Risk X: Avoid
Methadone: CYP2D6 Inhibitors (Strong) may increase serum concentration of Methadone. Risk C: Monitor
Methotrimeprazine: May increase CNS depressant effects of Products Containing Ethanol. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Risk X: Avoid
Metoclopramide: CYP2D6 Inhibitors (Strong) may increase serum concentration of Metoclopramide. Management: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for toxicity when combined. Risk D: Consider Therapy Modification
Metoprolol: CYP2D6 Inhibitors (Strong) may increase serum concentration of Metoprolol. Risk C: Monitor
MetroNIDAZOLE (Systemic): May increase adverse/toxic effects of Products Containing Ethanol. A disulfiram-like reaction may occur. Risk X: Avoid
MetroNIDAZOLE (Topical): May increase adverse/toxic effects of Products Containing Ethanol. A disulfiram-like reaction may occur. Risk C: Monitor
Mexiletine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Mexiletine. Risk C: Monitor
MiFEPRIStone: May increase serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor
Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Monoamine Oxidase Inhibitors: Dextromethorphan may increase serotonergic effects of Monoamine Oxidase Inhibitors. This may cause serotonin syndrome. Risk X: Avoid
Monoamine Oxidase Inhibitors: May increase hypertensive effects of BuPROPion. Risk X: Avoid
Mosunetuzumab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Nebivolol: CYP2D6 Inhibitors (Strong) may increase serum concentration of Nebivolol. Risk C: Monitor
Nicergoline: CYP2D6 Inhibitors (Strong) may increase active metabolite exposure of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Risk C: Monitor
Nirmatrelvir and Ritonavir: May decrease serum concentration of BuPROPion. Risk C: Monitor
OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Oliceridine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Oliceridine. Risk C: Monitor
Olmutinib: CYP2D6 Inhibitors (Strong) may increase serum concentration of Olmutinib. Risk C: Monitor
Opipramol: CYP2D6 Inhibitors (Strong) may increase serum concentration of Opipramol. Risk C: Monitor
OxyCODONE: CYP2D6 Inhibitors (Strong) may increase serum concentration of OxyCODONE. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of OxyCODONE. Specifically, oxymorphone concentrations may be reduced. Risk C: Monitor
Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Parecoxib: May increase serum concentration of Dextromethorphan. Risk C: Monitor
Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Perhexiline: CYP2D6 Inhibitors (Strong) may increase serum concentration of Perhexiline. Risk C: Monitor
Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Perphenazine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Perphenazine. Risk C: Monitor
Pimozide: CYP2D6 Inhibitors (Strong) may increase serum concentration of Pimozide. Risk X: Avoid
Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid
Pitolisant: CYP2D6 Inhibitors (Strong) may increase serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients already receiving strong CYP2D6 inhibitors, initial doses of pitolisant should be reduced and depends on age and patient weight. See full monograph for details. Risk D: Consider Therapy Modification
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor
Primaquine: CYP2D6 Inhibitors (Strong) may decrease therapeutic effects of Primaquine. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of Primaquine. Management: Consider alternatives to the combination of primaquine and strong CYP2D6 inhibitors. If concomitant use is necessary, monitor for signs and symptoms of possible primaquine treatment failure. Risk D: Consider Therapy Modification
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Propafenone: CYP2D6 Inhibitors (Strong) may increase serum concentration of Propafenone. Risk C: Monitor
Propranolol: CYP2D6 Inhibitors (Strong) may increase serum concentration of Propranolol. Risk C: Monitor
Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor
QUEtiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
RisperiDONE: CYP2D6 Inhibitors (Strong) may increase serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider Therapy Modification
Secnidazole: Products Containing Ethanol may increase adverse/toxic effects of Secnidazole. Risk X: Avoid
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Dextromethorphan may increase serotonergic effects of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase serum concentration of Dextromethorphan. Management: Consider alternatives to this drug combination. The dose of dextromethorphan/bupropion product should not exceed 1 tablet once daily. Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity. Risk D: Consider Therapy Modification
Serotonergic Agents (High Risk): Dextromethorphan may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Sertindole: CYP2D6 Inhibitors (Strong) may increase serum concentration of Sertindole. Management: Consider alternatives to this combination when possible. If combined, consider using lower doses of sertindole and monitor the ECG closely for evidence of QTc interval prolongation. Risk D: Consider Therapy Modification
Sertraline: BuPROPion may increase adverse/toxic effects of Sertraline. Risk C: Monitor
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor
Sofpironium: CYP2D6 Inhibitors (Strong) may increase serum concentration of Sofpironium. Risk X: Avoid
Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor
Talquetamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Risk D: Consider Therapy Modification
Tamsulosin: CYP2D6 Inhibitors (Strong) may increase serum concentration of Tamsulosin. Risk C: Monitor
Tarlatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Taurursodiol: May increase serum concentration of CYP2B6 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid
Teclistamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase active metabolite exposure of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Risk D: Consider Therapy Modification
Thioridazine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Thioridazine. Risk X: Avoid
Thiotepa: May increase serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor
Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor
Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase serum concentration of Timolol (Ophthalmic). Risk C: Monitor
Timolol (Systemic): CYP2D6 Inhibitors (Strong) may increase serum concentration of Timolol (Systemic). Risk C: Monitor
Tolterodine: CYP2D6 Inhibitors (Strong) may increase serum concentration of Tolterodine. Risk C: Monitor
TraMADol: CYP2D6 Inhibitors (Strong) may increase serum concentration of TraMADol. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of TraMADol. Risk C: Monitor
Tricyclic Antidepressants: May increase neuroexcitatory and/or seizure-potentiating effects of BuPROPion. BuPROPion may increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Valbenazine: CYP2D6 Inhibitors (Strong) may increase active metabolite exposure of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Risk D: Consider Therapy Modification
Vilazodone: BuPROPion may increase adverse/toxic effects of Vilazodone. Risk C: Monitor
Vortioxetine: BuPROPion may increase adverse/toxic effects of Vortioxetine. BuPROPion may increase serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with bupropion. Following cessation of bupropion, the vortioxetine dose should be returned to the normal level. Risk D: Consider Therapy Modification
Xanomeline: CYP2D6 Inhibitors (Strong) may increase serum concentration of Xanomeline. Risk C: Monitor
Ziprasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Zuclopenthixol: May increase adverse/toxic effects of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase serum concentration of Zuclopenthixol. Risk C: Monitor
Patients planning to become pregnant were not included in the original clinical studies, and participants were required to use contraception (Iosifescu 2022; Tabuteau 2022). Alternative treatments are recommended in patients planning to become pregnant.
Bupropion and its metabolites cross the placenta (Fokina 2016).
Plasma concentrations of dextromethorphan are increased using this combination compared to the use of dextromethorphan alone (Stahl 2020). Adverse events were observed in animal reproduction studies when dextromethorphan was used in combination with another agent that also increased its plasma concentrations.
Pregnant patients were not included in the original clinical studies (Iosifescu 2022; Tabuteau 2022). Use during pregnancy is not recommended. Refer to individual monographs for additional information.
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressants is ongoing. Pregnant patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Patients or their health care providers may contact the registry (1-866-961-2388).
Bupropion and its active metabolites are present in breast milk; excretion of dextromethorphan is not known.
Plasma concentrations of dextromethorphan are increased using this combination compared to the use of dextromethorphan alone (Stahl 2020). Adverse events were observed in animal reproduction studies when dextromethorphan was used in combination with another agent that also increased its plasma concentrations.
Breastfeeding patients or patients planning to breastfeed were not included in the original clinical studies (Iosifescu 2022; Tabuteau 2022). Due to the potential for neurotoxicity in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 5 days after the last dextromethorphan/bupropion dose.
Refer to individual monographs for additional information.
BP (baseline and periodically); personal or family history of bipolar disorder, mania, or hypomania (baseline); renal and hepatic function (baseline and as clinically indicated).
Dextromethorphan acts as an uncompetitive antagonist of the NMDA receptor increasing glutamate, a sigma-1 receptor agonist increasing serotonin, and serotonin reuptake inhibitor. Its mechanism in the treatment of depression is unknown (Stahl 2020).
Like other antidepressants, the mechanism of bupropion's activity is not fully understood. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin. Metabolite inhibits the reuptake of norepinephrine. The primary mechanism of action is thought to be dopaminergic and/or noradrenergic.
As a competitive inhibitor of CYP450 2D6, bupropion increases plasma concentrations of dextromethorphan.
Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvement through 4 to 6 weeks (Iosifescu 2022; Tabuteau 2022).
Protein binding:
Bupropion: 84%. Hydroxybupropion (active metabolite) protein binding is similar to bupropion, and the protein binding of erythrohydroxybupropion and threohydroxybupropion (active metabolites) are approximately half that of bupropion.
Dextromethorphan: 60% to 70%.
Metabolism:
Bupropion: Extensively metabolized to 3 active metabolites: hydroxybupropion (formed via hydroxylation of the tert-butyl group of bupropion), threohydroxybupropion, and erythrohydroxybupropion (both formed via reduction of the carbonyl group).
Dextromethorphan: Via CYP 2D6 to dextrorphan.
Half-life elimination:
Bupropion: 15 hours; hydroxybupropion (active metabolite): 35 hours; erythrohydroxybupropion (active metabolite): 44 hours; threohydroxybupropion (active metabolite): 33 hours.
Dextromethorphan: 22 hours.
Time to peak:
Bupropion: 2 hours; hydroxybupropion (active metabolite): ~3 hours; erythrohydroxybupropion and threohydroxybupropion (active metabolites): ~4 hours.
Dextromethorphan: 3 hours.
Excretion:
Bupropion: Urine (87%); feces (10%); 0.5% of total dose excreted as unchanged drug.
Dextromethorphan: CYP2D6 extensive metabolizers: Urine (37% to 52% of dose; <2% of dose is excreted as unchanged drug); CYP2D6 poor metabolizers: Urine (45% to 83% of dose; ~26% of dose is excreted as unchanged drug).
