Dextromethorphan and Bupropion (Monograph)

Brand name: Auvelity
Drug class: Antidepressants, Miscellaneous
Chemical name: Morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α)-hydrobromide monohydrate
Molecular formula: C₁₈H₂₅NO•HBr•H₂OC₁₃H₁₈ClNO•HCl
CAS number: 6700-34-1

Medically reviewed by Drugs.com on Feb 25, 2023. Written by ASHP.

Introduction

Antidepressant; fixed combination containing dextromethorphan (a potent sigma-1 [σ₁] receptor agonist and N-methyl-d-aspartate [NMDA] receptor antagonist) and bupropion (an aminoketone antidepressant and competitive inhibitor of CYP2D6).

Uses for Dextromethorphan and Bupropion

Major Depressive Disorder

Treatment of major depressive disorder in adults.

Substantially improved depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) compared with placebo and with bupropion alone in short-term clinical trials.

Dextromethorphan and Bupropion Dosage and Administration

General

Pretreatment Screening

• Assess blood pressure prior to treatment.

• Screen patients for a personal or family history of bipolar disorder, mania, or hypomania.

• Screen patients for risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression).

• Screen patients for concomitant use of other medications that contain bupropion or dextromethorphan.

Patient Monitoring

• Monitor blood pressure periodically during treatment.

• Monitor patients for clinical worsening and emergence of suicidality, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.

• Monitor patients with a history of drug abuse for signs of dextromethorphan/bupropion misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Administration

Oral Administration

Administer orally without regard to food. Swallow tablets whole; do not crush, divide, or chew.

Dosage

Available as bilayer extended-release tablets; each tablet contains 45 mg of immediate-release dextromethorphan hydrobromide and 105 mg of extended-release bupropion hydrochloride. Dosage of both drugs expressed in terms of the salt.

Adults

Major Depressive Disorder

Oral

Initially, dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning for the first 3 days of therapy. On the fourth day of therapy and thereafter, increase dosage to dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg twice daily given at least 8 hours apart.

Prescribing Limits

Adults

Major Depressive Disorder

Oral

Dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg twice daily.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.

Renal Impairment

Moderate renal impairment (eGFR 30–59 mL/minute per 1.73 m²): Dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

CYP2D6 Poor Metabolizers

Known CYP2D6 poor metabolizers: Dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning.

Patients Receiving Potent CYP2D6 Inhibitors

Patients receiving concomitant treatment with potent CYP2D6 inhibitors: Dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning.

Related/similar drugs

Trintellix, Rexulti, Vraylar, sertraline, trazodone, Lexapro, Zoloft

Cautions for Dextromethorphan and Bupropion

Contraindications

• Seizure disorder.

• Current or past diagnosis of bulimia or anorexia nervosa.

• Patients undergoing abrupt discontinuance of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

• Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor. Initiating dextromethorphan/bupropion in patients receiving reversible MAO inhibitors (e.g., linezolid, IV methylene blue) also is contraindicated.

• Known hypersensitivity to bupropion, dextromethorphan, or to any other ingredient in the formulation.

Warnings/Precautions

Warnings

Suicidal Thoughts and Behaviors

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality). Increased risk of suicidality in pediatric patients and young adults (18–24 years of age) in short-term, placebo-controlled studies receiving antidepressants for major depressive disorder and other indications. Risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo. It is not known whether the risk of suicidality in children, adolescents, and young adults extends to longer-term use (i.e., >4 months) of antidepressants; however, substantial evidence indicates that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidality.

Monitor all patients being treated with antidepressants for any indication for clinical worsening and emergence of suicidality, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Advise family members and caregivers of patients being treated with antidepressants to monitor patients for changes in behavior and to alert the clinician if such changes occur.

Consider changing the therapeutic regimen, including possible discontinuance of dextromethorphan/bupropion, in patients whose depression is persistently worse or who are experiencing emergent suicidality.

Dextromethorphan/bupropion is not labeled for use in pediatric patients.

Other Warnings/Precautions

When dextromethorphan/bupropion is used, consider the cautions, precautions, and contraindications associated with each drug in the fixed combination.

Seizures

Bupropion is associated with a dose-related risk of seizures.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold; consider these risks before initiating treatment with dextromethorphan/bupropion. Risk factors include a history of severe head injury or stroke, arteriovenous malformation, CNS tumor or infection, metabolic disorders (e.g., hypoglycemia, hyponatremia), severe hepatic impairment, hypoxia, use of illicit drugs (e.g., cocaine), abuse or misuse of prescription drugs such as CNS stimulants, use of drugs that can cause hypoglycemia (e.g., insulin, sulfonylureas, meglitinides), and concomitant use of drugs that lower the seizure threshold (e.g., antipsychotics, tricyclic antidepressants [TCAs], theophylline, systemic corticosteroids, other drugs containing bupropion).

Screen patients for use of other bupropion-containing products prior to initiating dextromethorphan/bupropion. If concomitant use of other bupropion-containing products is clinically warranted, inform patient of risk of seizures. If a seizure occurs, permanently discontinue dextromethorphan/bupropion.

Dextromethorphan/bupropion is contraindicated in patients with a seizure disorder or prior history of seizures, current or past diagnosis of bulimia or anorexia nervosa, and in patients undergoing abrupt discontinuance of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Increased Blood Pressure

Risk of elevated BP and hypertension reported with bupropion. Risk increased with concomitant use of MAO inhibitors or other drugs that increase dopaminergic or noradrenergic activity.

Exacerbation of preexisting hypertension leading to discontinuance of bupropion reported in patients with major depressive disorder and stable CHF receiving immediate-release bupropion. Safety of bupropion in patients with a recent history of MI or unstable cardiac disease not studied.

Monitor BP prior to and periodically during therapy.

Activation of Mania

Possible precipitation of mania, hypomania, or mixed episode, particularly in patients with bipolar disorder or risk factors for bipolar disorder. Screen patients for bipolar disorder or risk factors (e.g., family history of bipolar disorder, suicide, or depression).

Dextromethorphan/bupropion is not labeled for treatment of bipolar depression.

Psychosis and Other Neuropsychiatric Reactions

Risk of dose-related neuropsychiatric signs and symptoms (e.g., delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion) with use of bupropion in patients with depression (with or without bipolar disorder). In addition, dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability.

Screen patients for use of other bupropion- or dextromethorphan-containing products prior to initiating dextromethorphan/bupropion. If concomitant use of other bupropion- or dextromethorphan-containing products is clinically warranted, monitor patients for neuropsychiatric reactions; advise patients to contact a healthcare provider if such reactions occur.

Angle-closure Glaucoma

Pupillary dilation (mydriasis) occurs with many antidepressants, including bupropion, and may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.

Avoid use of antidepressants, including dextromethorphan/bupropion, in patients with untreated anatomically narrow angles.

Dizziness

May cause dizziness. Take precautions to reduce the risk of falls, especially in patients with motor impairment affecting gait or with a history of falls.

Caution patients about operating hazardous machinery, including motor vehicles, until they know how dextromethorphan/bupropion will affect them.

Serotonin Syndrome

Concomitant use of dextromethorphan/bupropion with SSRIs, TCAs (e.g., clomipramine, imipramine), or MAO inhibitors may result in serotonin syndrome. Manifestations may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.

Screen patients for use of other dextromethorphan-containing products prior to initiating dextromethorphan/bupropion. If concomitant use of other serotonergic agents is clinically warranted, inform patient of increased risk for serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome occur, immediately discontinue dextromethorphan/bupropion and/or other serotonergic drugs and initiate supportive symptomatic treatment.

Concomitant use of dextromethorphan/bupropion with MAO inhibitors, including linezolid or IV methylene blue, is contraindicated. If it is necessary to initiate an MAO inhibitor such as linezolid or IV methylene blue, discontinue dextromethorphan/bupropion before initiating treatment with the MAO inhibitor.

Embryofetal Toxicity

Based on findings in pregnant animals exposed to dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan/quinidine), dextromethorphan/bupropion may cause fetal harm when administered to pregnant women.

Discontinue treatment in pregnant women and advise of potential fetal risk. Use alternative treatment in women who are planning to become pregnant.

Laboratory Test Interferences

False-positive results for urine immunoassay screening tests for amphetamines reported in patients receiving bupropion and following discontinuance of the drug. Confirmatory tests (e.g., gas chromatography/mass spectrometry) can distinguish bupropion from amphetamines.

Abuse Potential and Dependence

Dextromethorphan and bupropion are not controlled substances. No systematic studies of potential for abuse, tolerance, or physical dependence with dextromethorphan/bupropion available; however, cases of dextromethorphan abuse have been reported. No drug-seeking behavior observed in clinical studies of dextromethorphan/bupropion; however, potential for misuse, diversion, and/or abuse cannot be excluded. Closely monitor patients with a history of drug abuse for signs of dextromethorphan/bupropion misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Specific Populations

Pregnancy

Clinical data on use of dextromethorphan/bupropion during pregnancy insufficient to evaluate for drug-associated risk of major birth malformations, miscarriage, or other adverse maternal or fetal outcomes. Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an overall increased risk of congenital malformations. Based on animal studies, dextromethorphan/bupropion may cause fetal harm when administered to women during pregnancy. If a patient becomes pregnant, discontinue drug and advise patient of potential fetal risk.

Pregnancy exposure registry: National Pregnancy Registry for Antidepressants at 1-866-961-2388 or [Web].

Lactation

Bupropion and its metabolites are distributed into human milk. Effects of bupropion or its metabolites on milk production not known. Not known whether dextromethorphan is distributed into human milk; effects of dextromethorphan on the breast-fed infant or on milk production also not known.

Potential for neurotoxicity in nursing infants. Avoid breast-feeding during treatment and for 5 days following final dose of dextromethorphan/bupropion.

Females and Males of Reproductive Potential

May cause fetal harm when administered during pregnancy. Use alternative treatment in women who are planning to become pregnant.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Clinical trials did not include patients ≥65 years of age; unknown whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: No dosage adjustment necessary.

Severe (Child-Pugh class C) hepatic impairment: Not studied; use not recommended.

Renal Impairment

Moderate renal impairment (eGFR 30–59 mL/minute per 1.73 m²): Dosage adjustment recommended.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²): Not studied; use not recommended.

CYP2D6 Poor Metabolizers

Known CYP2D6 poor metabolizers: Dosage adjustment recommended.

Common Adverse Effects

Common adverse effects (reported in ≥5% of patients): Dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, hyperhidrosis.

Drug Interactions

When dextromethorphan/bupropion is used, interactions associated with each drug in the fixed combination should be considered.

Bupropion is metabolized to hydroxybupropion, principally by CYP2B6; CYP isoenzymes not involved in the formation of other bupropion metabolites. Dextromethorphan is metabolized primarily by CYP2D6 to dextrorphan.

Bupropion and its metabolites inhibit CYP2D6. At therapeutically relevant concentrations, dextromethorphan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Dextromethorphan does not induce CYP1A2, CYP3A4, or CYP2B6.

Dextromethorphan is a substrate of the P-glycoprotein (P-gp) transporter. Dextromethorphan does not inhibit transporters at therapeutically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: Potent CYP2D6 inhibitors: Increased plasma concentrations of dextromethorphan. Dosage adjustment of dextromethorphan/bupropion required; monitor for adverse reactions to dextromethorphan (e.g., somnolence, dizziness).

Inducers of CYP2B6: Potent CYP2B6 inducers: Decreased plasma concentrations of dextromethorphan and bupropion; possible reduced efficacy. Avoid concomitant use; consider alternatives to potent CYP2B6 inducers as clinically necessary.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: CYP2D6 substrates: Possible increased concentrations of the CYP2D6 substrate. Dosage reduction of CYP2D6 substrates, particularly those with a relatively narrow therapeutic index, may be necessary.

Prodrugs dependent on CYP2D6 for activation: Possible reduced clinical efficacy of the prodrug. An increase in dosage of the prodrug may be necessary.

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome) with serotonergic agents. Monitor for symptoms of serotonin syndrome; if serotonin syndrome occurs, consider discontinuance of dextromethorphan/bupropion and/or concomitant serotonergic drugs.

Specific Drugs

Dextromethorphan and Bupropion Pharmacokinetics

Absorption

Bioavailability

Dextromethorphan administered with bupropion displays nonlinear pharmacokinetics at steady state, with greater than dose-proportional changes in AUC and peak concentrations at dextromethorphan doses of 60–120 mg (0.67–1.33 times the maximum recommended dose of dextromethorphan/bupropion) and less than dose-proportional changes at bupropion doses of 150–300 mg (0.71-1.43 times the maximum recommended dose of dextromethorphan/bupropion).

Steady-state plasma concentrations of dextromethorphan and bupropion given as fixed combination achieved within 8 days.

When administered as dextromethorphan/bupropion, accumulation ratios for dextromethorphan at steady state based on peak concentration and AUC are 20 and 32, respectively; when administered alone, accumulation ratios for dextromethorphan at steady state based on peak concentration and AUC are 1.3 and 1.4, respectively.

Accumulation ratios for bupropion at steady state based on peak concentration and AUC are 1.1 and 1.5, respectively.

Following oral administration of the fixed combination, time to peak concentrations for dextromethorphan or bupropion is 3 or 2 hours, respectively.

Food

When administered with food, AUC of dextromethorphan is decreased by 14% and peak plasma concentrations are not affected; AUC and peak plasma concentrations of bupropion are increased by 3 and 6%, respectively.

Special Populations

Exposure to dextromethorphan and bupropion not substantially altered in patients with moderate (Child-Pugh class B) hepatic impairment.

Exposure to dextromethorphan and bupropion increased approximately 2.2- and 1.8-fold, respectively, in patients with moderate renal impairment (eGFR 30–59 mL/minute per 1.73 m²). Pharmacokinetics of dextromethorphan/bupropion not evaluated in patients with severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²).

Exposure to dextromethorphan increased approximately 3.4-fold in poor CYP2D6 metabolizers compared with extensive/intermediate CYP2D6 metabolizers.

Pharmacokinetics do not appear to be affected by race or sex.

Distribution

Extent

Bupropion and its metabolites are distributed into human milk.

Not known whether dextromethorphan is distributed into human milk.

Plasma Protein Binding

Dextromethorphan: 60–70%.

Bupropion: 84%.

Elimination

Metabolism

Bupropion is extensively metabolized to 3 active metabolites: hydroxybupropion (principally mediated by CYP2B6), and threohydrobupropion and erythrohydrobupropion (formed through non-CYP pathways). Bupropion metabolites have a longer elimination half-life than the parent drug and account for majority of bupropion exposure.

Elimination Route

Approximately 37–52% of an orally administered dose of dextromethorphan recovered in urine in CYP2D6 extensive metabolizers; <2% excreted in urine as parent drug.

In CYP2D6 poor metabolizers, approximately 45–83% of an orally administered dose of dextromethorphan recovered in urine; approximately 26% excreted in urine as parent drug.

Half-life

Dextromethorphan: 22 hours. Mean elimination half-life of 22 hours following 8 days of administration of dextromethorphan/bupropion in extensive metabolizers is approximately 3-fold that observed for dextromethorphan administered without bupropion.

Bupropion: 15 hours.

Stability

Storage

Oral

Tablets

20–25°C in original bottle; excursions permitted to 15–30°C.

Actions

• Combination of dextromethorphan (a σ₁ receptor agonist and uncompetitive NMDA receptor antagonist) and bupropion (an aminoketone antidepressant and competitive inhibitor of CYP2D6).

• Mechanism of antidepressant activity not fully established.

• Blockade of the NMDA receptor and agonism of the σ₁ receptor by dextromethorphan modulate glutamate signaling in the CNS; dextromethorphan also acts as a weak serotonin reuptake inhibitor.

• Mechanism of action of bupropion may relate to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine; does not inhibit monoamine oxidase or reuptake of serotonin.

• Both dextromethorphan and bupropion increase the availability of norepinephrine by inhibiting its reuptake and also act as α4β2 nicotinic acetylcholine receptor antagonists.

• Bupropion increases plasma concentrations of dextromethorphan by competitively inhibiting CYP2D6.

Advice to Patients

• Importance of advising patients to read the FDA-approved patient labeling (medication guide).

• Advise patients to swallow dextromethorphan/bupropion tablets whole and not to crush, chew, or divide the tablets.

• Importance of advising patients to take dextromethorphan/bupropion exactly as prescribed, with an interval of at least 8 hours between doses and no more than 2 tablets (each containing dextromethorphan hydrobromide 45 mg and bupropion hydrochloride 105 mg) in 1 day. Importance of advising patients not to take a double dose if they miss a dose and to take the next dose at the regularly scheduled time.

• Importance of advising patients and caregivers to monitor for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down, and to report such symptoms to their clinician.

• Risk of immediate and delayed hypersensitivity reactions to dextromethorphan/bupropion. Instruct patients to seek immediate medical attention if they experience symptoms indicative of hypersensitivity (e.g., skin rash, pruritus, hives, chest pain, edema, shortness of breath, arthralgia, myalgia, or fever).

• Importance of advising patients that dextromethorphan/bupropion can cause seizures and that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk. Advise patients to minimize or avoid use of alcohol. Instruct patients to use dextromethorphan/bupropion as directed and to permanently discontinue dextromethorphan/bupropion if they experience a seizure while on treatment.

• Risk of increased blood pressure, which is increased with concomitant use of some other drugs such as MAO inhibitors and drugs that increase dopaminergic or noradrenergic activity. Advise patients to inform a clinician if they experience increased blood pressure during dextromethorphan/bupropion therapy.

• Advise patients to monitor for signs of activation of mania/hypomania and to report such symptoms to their clinician.

• Inform patients that changes in mood including delusions, hallucinations, psychosis, concentration disturbances, paranoia, and confusion have occurred with use of bupropion. Instruct patients to notify their clinician if such symptoms occur.

• Advise patients that dextromethorphan/bupropion can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.

• Advise patients that dextromethorphan/bupropion may cause dizziness. Advise patients to take precautions to reduce the risk of falls, particularly if they have motor impairment affecting gait or a history of falls. Caution patients about operating hazardous machinery, including motor vehicles, until they know how the drug will affect them.

• Risk of serotonin syndrome, particularly with concomitant use of selective serotonin-reuptake inhibitors (SSRIs) or tricyclic antidepressants. Instruct patients to contact their clinician or seek emergency medical care if they experience signs or symptoms of serotonin syndrome.

• Advise patients that dextromethorphan/bupropion can increase adverse neuropsychiatric reactions or reduce alcohol tolerance and to avoid or limit use of alcohol during treatment with dextromethorphan/bupropion.

• Advise females of reproductive potential to inform their clinician if they are or plan to become pregnant. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to dextromethorphan/bupropion during pregnancy.

• Advise female patients to inform their clinician if they plan to breast-feed. Advise patients not to breast-feed during treatment with dextromethorphan/bupropion and for 5 days after the final dose.

• Inform patients that dextromethorphan/bupropion increases the risk of drug interactions. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant or past illnesses (e.g., seizure disorder, eating disorder, bipolar disorder, substance abuse). Before taking any new medications, patients should tell their clinician that they are taking dextromethorphan/bupropion.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• Does Auvelity work better than Wellbutrin?
• Auvelity vs. Wellbutrin: Effectiveness for Depression?
• How does Auvelity work / moa?
• What makes Auvelity different from other antidepressants?
• Does Auvelity cause weight gain or loss?

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