General 
Pretreatment Screening
- Assess blood pressure prior to treatment.1
- Screen patients for a personal or family history of bipolar disorder, mania, or hypomania.1
- Screen patients for risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression).1
- Screen patients for concomitant use of other medications that contain bupropion or dextromethorphan.1
Patient Monitoring
- Monitor blood pressure periodically during treatment.1
- 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.1
- 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).1
Administration
The commercially available fixed combination of dextromethorphan hydrobromide and bupropion hydrochloride (dextromethorphan/bupropion; Auvelity®) is administered orally as extended-release tablets without regard to food.1 The extended-release tablets should be swallowed whole and should not be crushed, divided, or chewed.1
Dextromethorphan/bupropion is intended for oral use only.1 Seizures and/or deaths have been reported when bupropion has been administered intranasally or by parenteral injection.1
Dosage
Commercially available as bilayer extended-release tablets (Auvelity®) containing 45 mg of immediate-release dextromethorphan hydrobromide and 105 mg of extended-release bupropion hydrochloride.1 Dosage of both drugs is expressed in terms of the salt.1
For the treatment of major depressive disorder in adults, the recommended initial dosage of the fixed combination of dextromethorphan/bupropion is dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning for the first 3 days of therapy.1 On the fourth day of therapy and thereafter, dosage of the fixed combination should be increased to the maximum recommended dosage of dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg twice daily given at least 8 hours apart.1 Do not exceed 2 doses within the same day.1
Special Populations
Hepatic Impairment
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
Renal Impairment
In patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/minute per 1.73 m2), the recommended dosage of dextromethorphan/bupropion is dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning.1
Geriatric Patients
The manufacturer makes no specific dosage recommendations for geriatric patients.1
CYP2D6 Poor Metabolizers
In patients who are known poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 substrates, the recommended dosage of dextromethorphan/bupropion is dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning.1
Patients Receiving Potent CYP2D6 Inhibitors
In patients who are receiving concomitant treatment with potent CYP2D6 inhibitors, the recommended dosage of dextromethorphan/bupropion is dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg once daily in the morning.1
Contraindications
- Seizure disorder.1
- Current or past diagnosis of bulimia or anorexia nervosa.1
- Patients undergoing abrupt discontinuance of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.1
- Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor.1 Initiating dextromethorphan/bupropion in patients receiving reversible MAO inhibitors (e.g., linezolid, IV methylene blue) also is contraindicated.1
- Known hypersensitivity to bupropion, dextromethorphan, or to any other ingredient in the formulation.1
Warnings/Precautions
Warnings
Suicidal Thoughts and Behaviors
A boxed warning about suicidal thinking and behavior (suicidality) has been included in the prescribing information for dextromethorphan/bupropion.1 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidal thoughts and behaviors (suicidality) in pediatric patients and young adults up to 24 years of age receiving antidepressants for major depressive disorder and other indications.1 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults >24 years of age, and a reduced risk was observed in adults ≥65 years of age.1 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 from placebo-controlled maintenance studies in adults with major depressive disorder indicates that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidality.1
Monitor all patients being treated with antidepressants for clinical worsening and emergence of suicidality, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 Advise families and caregivers of patients being treated with antidepressants to monitor patients for changes in behavior and to report such changes immediately to a health-care provider.1 Consideration should be given to changing the therapeutic regimen, including possible discontinuance of dextromethorphan/bupropion, in patients whose depression is persistently worse or in patients experiencing emergent suicidality.1
Dextromethorphan/bupropion is not labeled for use in pediatric patients.1
Other Warnings and Precautions
When dextromethorphan and bupropion is used, the cautions, precautions, and contraindications associated with each drug in the fixed combination should be considered.1
Seizures
Bupropion has been associated with a dose-related risk of seizures.1 With administration of bupropion hydrochloride sustained-release tablets at a dosage of up to 300 mg daily (approximately 1.5 times the bupropion dosage at the maximum recommended daily dosage of dextromethorphan/bupropion), the incidence of seizures was approximately 0.1%; at a dosage of 400 mg daily (approximately 2 times the maximum recommended daily dosage of dextromethorphan/bupropion), the incidence of seizures increased to approximately 0.4%.1
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.1 Conditions that increase the risk of seizures 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, theophylline, systemic corticosteroids, other drugs containing bupropion).1
Screen patients for use of other bupropion-containing products prior to initiating dextromethorphan/bupropion.1 If concomitant use of dextromethorphan/bupropion with other bupropion-containing products is clinically warranted, inform patients of the risk of seizures.1 If a seizure occurs, permanently discontinue dextromethorphan/bupropion.1
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.1
Increased Blood Pressure
Bupropion has been associated with a risk of elevated blood pressure and hypertension.1 The risk of hypertension is increased if dextromethorphan/bupropion is used concomitantly with monoamine oxidase (MAO) inhibitors or other drugs that increase dopaminergic or noradrenergic activity.1
Exacerbation of preexisting hypertension leading to discontinuance of bupropion has been reported in patients with major depressive disorder and stable congestive heart failure receiving immediate-release bupropion.1 There are no controlled trials to date assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.1
Monitor blood pressure prior to initiating therapy and periodically during dextromethorphan/bupropion therapy.1
Activation of Mania
Treatment with antidepressants, including bupropion, can precipitate a manic, mixed, or hypomanic episode, particularly in patients with bipolar disorder or risk factors for bipolar disorder.1
Prior to initiating therapy with dextromethorphan/bupropion, screen patients for bipolar disorder or risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression).1 Dextromethorphan/bupropion is not labeled for the treatment of bipolar depression.1
Psychosis and Other Neuropsychiatric Reactions
Use of bupropion in patients with depression, including some with bipolar disorder, has been associated with a variety of neuropsychiatric signs and symptoms (e.g., delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion).1 In some cases, these symptoms abated upon dosage reduction and/or withdrawal of treatment.1
Dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability.1
Because the risks of neuropsychiatric reactions are dose-related, patients should be screened for use of other bupropion- or dextromethorphan-containing products prior to initiating dextromethorphan/bupropion.1 If concomitant use of dextromethorphan/bupropion with other bupropion- or dextromethorphan-containing products is clinically warranted, monitor patients for neuropsychiatric reactions and instruct patients to contact a healthcare provider if such reactions occur.1
Angle-closure Glaucoma
The pupillary dilation (mydriasis) that occurs following the use of many antidepressant agents, including bupropion, 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.1
Avoid use of antidepressants, including dextromethorphan/bupropion, in patients with untreated anatomically narrow angles.1
Dizziness
Dextromethorphan/bupropion may cause dizziness.1 In controlled studies, dizziness was reported in 14% of patients receiving dextromethorphan/bupropion compared with 6% of patients receiving placebo.1
Take precautions to reduce the risk of falls during therapy, particularly in patients with motor impairment affecting gait or with a history of falls.1 Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that dextromethorphan/bupropion therapy does not affect them adversely.1
Serotonin Syndrome
Concomitant use of dextromethorphan/bupropion with selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants (e.g., clomipramine, imipramine), or monoamine oxidase (MAO) inhibitors may result in serotonin syndrome, which can be life-threatening.1 Manifestations of serotonin syndrome may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.1
Screen patients for use of other dextromethorphan-containing products prior to initiating dextromethorphan/bupropion.1 If concomitant use of dextromethorphan/bupropion with other serotonergic agents is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.1 If symptoms of serotonin syndrome occur, immediately discontinue dextromethorphan/bupropion and/or other serotonergic drugs and initiate supportive symptomatic treatment.1
Concomitant use of dextromethorphan/bupropion with MAO inhibitors is contraindicated.1 In addition, do not initiate dextromethorphan/bupropion in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 If it is necessary to initiate treatment with an MAO inhibitor such as linezolid or IV methylene blue in a patient receiving dextromethorphan/bupropion, discontinue dextromethorphan/bupropion before initiating treatment with the MAO inhibitor.1
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.1
In developmental toxicity studies, administration of dextromethorphan/quinidine in pregnant rats and rabbits resulted in fetal malformations (rabbits) and embryolethality in offspring.1 Neurotoxicity was observed in juvenile rats administered dextromethorphan/quinidine on postnatal day 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first 3 years of life in humans.1 The separate effect of dextromethorphan on developmental toxicity at the recommended clinical dose is unclear.1
Discontinue dextromethorphan/bupropion in pregnant females and advise the patient about the potential risk to a fetus.1 Use alternative treatment in females who are planning to become pregnant.1
Laboratory Test Interferences
False-positive results for urine immunoassay screening tests for amphetamines have been reported in patients receiving bupropion and even following discontinuance of the drug.1 Confirmatory tests (e.g., gas chromatography/mass spectrometry) can distinguish bupropion from amphetamines.1
Abuse Potential and Dependence
Dextromethorphan and bupropion are not controlled substances.1 The fixed combination of dextromethorphan/bupropion has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence; however, cases of dextromethorphan abuse have been reported.1 While clinical studies with dextromethorphan/bupropion did not reveal drug-seeking behavior, a potential for misuse, diversion, and/or abuse of the drug cannot be excluded.1 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).1
Specific Populations
Pregnancy
Clinical data on the use of dextromethorphan/bupropion during pregnancy are insufficient to evaluate for a drug-associated risk of major birth malformations, miscarriage, or other adverse maternal or fetal outcomes; however, data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an overall increased risk of congenital malformations.1 Based on animal studies, dextromethorphan/bupropion may cause fetal harm when administered to women during pregnancy.1 If a patient becomes pregnant, discontinue dextromethorphan/bupropion and advise the patient of the risk to the fetus.1
In studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including fetal malformations (rabbits) and embryolethality, when administered to pregnant animals.1 When bupropion alone was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 21 times the maximum recommended human dose (MRHD) of 210 mg daily.1 When bupropion alone was given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately 2-5 times the MRHD and greater.1 Decreased fetal weights were seen at bupropion doses approximately 5 times the MRHD and greater.1
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.1 Clinicians are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or [Web].1
Lactation
Bupropion and its metabolites are distributed into human milk.1 The effects of bupropion or its metabolites on milk production are not known.1 It is not known whether dextromethorphan is distributed into human milk; the effects of dextromethorphan on the breast-fed infant or on milk production also are not known.1
Limited data from postmarketing reports of bupropion use in nursing women have not identified a clear association of adverse reactions in the breast-fed infant.1 Neurotoxicity findings have been observed in juvenile rats treated with dextromethorphan/quinidine on postnatal day 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first 3 years of life in humans.1
Because of the potential for neurotoxicity in nursing infants, breast-feeding is not recommended during treatment with dextromethorphan/bupropion and for 5 days following the final dose.1
Females and Males of Reproductive Potential
Dextromethorphan/bupropion may cause fetal harm when administered during pregnancy.1 Use alternative treatment in females who are planning to become pregnant.1
Pediatric Use
Safety and efficacy of dextromethorphan/bupropion in pediatric patients have not been established.1 Antidepressants, including bupropion, increase the risk of suicidal thoughts and behaviors in pediatric patients.1
The pharmacokinetics of dextromethorphan/bupropion have not been studied in pediatric patients.1
Geriatric Use
Clinical trials of dextromethorphan/bupropion did not include patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 The pharmacokinetics of dextromethorphan/bupropion have not been studied in geriatric patients.1
Hepatic Impairment
No dosage adjustment of dextromethorphan/bupropion is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1 Exposure to dextromethorphan and bupropion is not substantially altered in patients with moderate hepatic impairment.1
The pharmacokinetics of dextromethorphan/bupropion have not been studied in patients with severe (Child-Pugh C) hepatic impairment; use of the drug is not recommended in such patients.1
Renal Impairment
Dosage adjustment of dextromethorphan/bupropion is recommended in patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/minute per 1.73 m2).1 Exposure to dextromethorphan and bupropion is increased approximately 2.2- and 1.8-fold, respectively, in patients with moderate renal impairment.1
The pharmacokinetics of dextromethorphan/bupropion have not been evaluated in patients with severe renal impairment (eGFR 15-29 mL/minute per 1.73 m2); the drug is not recommended in such patients.1
CYP2D6 Poor Metabolizers
Dosage adjustment of dextromethorphan/bupropion is recommended in patients known to be poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 substrates.1 Dextromethorphan concentrations are increased in CYP2D6 poor metabolizers compared with extensive/intermediate CYP2D6 metabolizers.1 Exposure to dextromethorphan is increased approximately 3.4-fold in poor CYP2D6 metabolizers compared with extensive/intermediate CYP2D6 metabolizers.1
Common Adverse Effects
Adverse effects occurring in ≥5% of patients receiving dextromethorphan/bupropion and with an incidence of at least twice that reported with placebo in clinical studies include dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.1
When dextromethorphan/bupropion is used, interactions associated with each drug in the fixed combination should be considered.1
Bupropion is metabolized to hydroxybupropion, principally by cytochrome P-450 (CYP) 2B6; CYP isoenzymes are not involved in the formation of other bupropion metabolites.1 Dextromethorphan is metabolized primarily by CYP2D6 to dextrorphan.1
Bupropion and its metabolites inhibit CYP2D6.1 At therapeutically relevant concentrations, dextromethorphan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.1 Dextromethorphan does not induce CYP1A2, CYP3A4, or CYP2B6.1
Dextromethorphan is a substrate of the P-glycoprotein (P-gp) transporter.1 Dextromethorphan does not inhibit transporters at therapeutically relevant concentrations.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP2D6
Concomitant use of dextromethorphan/bupropion with potent CYP2D6 inhibitors results in increased plasma concentrations of dextromethorphan.1 In a drug interaction study, dextromethorphan AUC and peak plasma concentrations were increased by approximately 2.7- and 2.4-fold, respectively, in individuals receiving paroxetine 20 mg concomitantly with dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg twice daily.1
Dosage adjustment of dextromethorphan/bupropion is required in patients receiving concomitant treatment with potent CYP2D6 inhibitors, and patients should be monitored for adverse reactions to dextromethorphan (e.g., somnolence, dizziness).1
Inducers of CYP2B6
Concomitant use of dextromethorphan/bupropion with potent CYP2B6 inducers results in decreased plasma concentrations of dextromethorphan and bupropion and may reduce the efficacy of the fixed combination.1 In a drug interaction study, dextromethorphan AUC and peak plasma concentrations were decreased by approximately 64 and 59%, respectively, and bupropion AUC and peak plasma concentrations were decreased by approximately 76 and 74%, respectively, in individuals receiving carbamazepine 200 mg concomitantly with dextromethorphan hydrobromide 45 mg/bupropion hydrochloride 105 mg twice daily.1
Avoid concomitant use of potent CYP2B6 inducers with dextromethorphan/bupropion; consider alternatives to potent CYP2B6 inducers as clinically necessary.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2D6
Concomitant use of dextromethorphan/bupropion and drugs that are metabolized by CYP2D6 may result in increased concentrations of the CYP2D6 substrate.1 Dosage reduction of CYP2D6 substrates, particularly those that have a relatively narrow therapeutic index, may be necessary in patients concurrently receiving dextromethorphan/bupropion.1
For prodrugs dependent on CYP2D6 for activation, concomitant therapy with dextromethorphan/bupropion may reduce the clinical efficacy of the prodrug.1 An increase in dosage of the prodrug may be necessary in patients receiving dextromethorphan/bupropion.1
Drugs Affecting the Seizure Threshold
Concomitant use of dextromethorphan/bupropion with other drugs that lower seizure threshold (e.g., antipsychotics, tricyclic antidepressants, theophylline, systemic corticosteroids, other drugs containing bupropion) may increase risk of seizure.1 Use caution when administering dextromethorphan/bupropion concomitantly with drugs that lower the seizure threshold.1 Permanently discontinue dextromethorphan/bupropion in patients who experience a seizure.1
Drugs Associated with Serotonin Syndrome
Concomitant use of dextromethorphan/bupropion with selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants (e.g., clomipramine, imipramine), or monoamine oxidase (MAO) inhibitors increases the risk of serotonin syndrome.1 Manifestations of serotonin syndrome may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.1
Monitor for symptoms of serotonin syndrome when dextromethorphan/bupropion is used concomitantly with other drugs that may affect serotonergic neurotransmitter systems.1 If serotonin syndrome occurs, consider discontinuance of dextromethorphan/bupropion and/or concomitant serotonergic drugs.1
Alcohol
Adverse neuropsychiatric events or reduced alcohol tolerance have been reported in patients who ingested alcohol during bupropion therapy.1 Consumption of alcohol should be minimized or avoided during therapy with dextromethorphan/bupropion.1 Dextromethorphan/bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.1
Digoxin
Concomitant use of dextromethorphan/bupropion and digoxin may decrease plasma digoxin concentrations.1 Decreased digoxin exposure has been reported when digoxin (single 0.5-mg dose) was administered 24 hours after extended-release bupropion (single 150-mg dose) in healthy individuals.1 Monitor plasma digoxin concentrations in patients treated concomitantly with dextromethorphan/bupropion.1
Dopaminergic Drugs
CNS toxicity (e.g., restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, dizziness) has been reported with concomitant administration of bupropion and dopaminergic drugs such as levodopa or amantadine.1 Caution should be exercised if dextromethorphan/bupropion is used concomitantly with dopaminergic drugs.1
Monoamine Oxidase Inhibitors
Because of the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome, concomitant use of dextromethorphan/bupropion and MAO inhibitors (including reversible MAO inhibitors [e.g., linezolid, IV methylene blue]) is contraindicated; at least 2 weeks should elapse between discontinuance of an MAO inhibitor and initiation of dextromethorphan/bupropion and vice versa.1
Nicotine Replacement Therapy
A higher incidence of hypertension in patients receiving concomitant treatment with sustained-release bupropion and transdermal nicotine compared with placebo or either drug alone has been reported.1 Monitor blood pressure in patients who receive concomitant treatment with bupropion and nicotine replacement therapy.1
Description
Dextromethorphan hydrobromide and bupropion hydrochloride (dextromethorphan/bupropion) is a fixed combination preparation consisting of immediate-release dextromethorphan (a sigma-1 [σ1] receptor agonist and uncompetitive N -methyl-d-aspartate [NMDA] receptor antagonist) and extended-release bupropion (an aminoketone antidepressant and competitive inhibitor of the hepatic cytochrome P-450 [CYP] 2D6 isoenzyme).1,2,3,4 The mechanism of dextromethorphan/bupropion in the treatment of major depressive disorder has not been fully elucidated.1 Blockade of the NMDA receptor and agonism of the σ1 receptor by dextromethorphan modulate glutamate signaling in the CNS.2,3 Dextromethorphan also acts as a weak serotonin reuptake inhibitor.4 The mechanism of action of bupropion in the treatment of major depressive disorder may be related to noradrenergic and/or dopaminergic mechanisms.1 Both dextromethorphan and bupropion increase the availability of norepinephrine by inhibiting its reuptake and also act as α4β2 nicotinic acetylcholine receptor antagonists.4 Bupropion also increases plasma concentrations of dextromethorphan by competitively inhibiting CYP2D6, which catalyzes a major biotransformation pathway for dextromethorphan.1,2,3,4 Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.1
Dextromethorphan administered concomitantly with bupropion displays nonlinear pharmacokinetics at steady state, with greater than dose-proportional changes in AUC and peak concentrations for varying doses of dextromethorphan (60-120 mg [0.67-1.33 times the maximum recommended dose of dextromethorphan/bupropion]) and less than dose-proportional changes for varying doses of bupropion (150-300 mg [0.71-1.43 times the maximum recommended dose of dextromethorphan/bupropion]).1 Steady-state plasma concentrations of dextromethorphan and bupropion when given as the fixed combination are achieved within 8 days.1 When administered as the fixed combination, the accumulation ratios for dextromethorphan at steady state based on peak concentration and AUC are 20 and 32, respectively; when administered alone, the accumulation ratios for dextromethorphan at steady state based on peak concentration and AUC are 1.3 and 1.4, respectively.1 The accumulation ratios for bupropion at steady state based on peak concentration and AUC are 1.1 and 1.5, respectively.1 Following oral administration of the fixed combination, the time to peak concentrations is 3 or 2 hours for dextromethorphan or bupropion, respectively.1 When administered with food, the 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.1 Plasma protein binding is 60-70 and 84% for dextromethorphan and bupropion, respectively.1 Bupropion is extensively metabolized to 3 active metabolites: hydroxybupropion, which is principally mediated by CYP2B6, and threohydrobupropion and erythrohydrobupropion, which are formed through non-CYP pathways.1 These metabolites have a longer elimination half-life than bupropion and account for the majority of bupropion exposure.1 The mean elimination half-life of dextromethorphan and bupropion is 22 and 15 hours, respectively.1 Following 8 days of administration of dextromethorphan/bupropion in extensive metabolizers, the mean elimination half-life of dextromethorphan of 22 hours is approximately 3-fold that observed for dextromethorphan administered without bupropion.1 Approximately 37-52% of an orally administered dose of dextromethorphan is recovered in the urine in CYP2D6 extensive metabolizers, with <2% of the dose excreted in urine as unchanged parent drug.1 In CYP2D6 poor metabolizers, approximately 45-83% of an orally administered dose of dextromethorphan is recovered in the urine, with approximately 26% of the dose excreted in urine as unchanged parent drug.1 The pharmacokinetics of dextromethorphan/bupropion do not appear to be affected by race or sex.1
Advice to Patients
- Importance of advising patients to read the FDA-approved patient labeling (medication guide).1
- Advise patients to swallow dextromethorphan/bupropion tablets whole and not to crush, chew, or divide the tablets.1
- 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.1 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.1
- 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.1
- Risk of immediate and delayed hypersensitivity reactions to dextromethorphan/bupropion.1 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).1
- 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.1 Advise patients to minimize or avoid use of alcohol.1 Instruct patients to use dextromethorphan/bupropion as directed and to permanently discontinue dextromethorphan/bupropion if they experience a seizure while on treatment.1
- 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.1 Advise patients to inform a clinician if they experience increased blood pressure during dextromethorphan/bupropion therapy.1
- Advise patients to monitor for signs of activation of mania/hypomania and to report such symptoms to their clinician.1
- Inform patients that changes in mood including delusions, hallucinations, psychosis, concentration disturbances, paranoia, and confusion have occurred with use of bupropion.1 Instruct patients to notify their clinician if such symptoms occur.1
- Advise patients that dextromethorphan/bupropion can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.1
- 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.1 Caution patients about operating hazardous machinery, including motor vehicles, until they know how the drug will affect them.1
- Risk of serotonin syndrome, particularly with concomitant use of selective serotonin-reuptake inhibitors (SSRIs) or tricyclic antidepressants.1 Instruct patients to contact their clinician or seek emergency medical care if they experience signs or symptoms of serotonin syndrome.1
- 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.1
- Advise females of reproductive potential to inform their clinician if they are or plan to become pregnant.1 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to dextromethorphan/bupropion during pregnancy.1
- Advise female patients to inform their clinician if they plan to breast-feed.1 Advise patients not to breast-feed during treatment with dextromethorphan/bupropion and for 5 days after the final dose.1
- Inform patients that dextromethorphan/bupropion increases the risk of drug interactions.1 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).1 Before taking any new medications, patients should tell their clinician that they are taking dextromethorphan/bupropion.1
- Importance of informing patients of other important precautionary information.1 (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.