Naltrexone and Bupropion

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release 12 Hour, Oral:

Contrave: Naltrexone hydrochloride 8 mg and bupropion hydrochloride 90 mg [contains edetate disodium, fd&c blue #2 aluminum lake]

Pharmacology

Mechanism of Action

Naltrexone is a pure opioid antagonist, and bupropion is a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. The exact neurochemical effects of naltrexone/bupropion leading to weight loss are not fully understood. Effects may result from action on areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system).

Use: Labeled Indications

Weight management: Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of ≥30 kg/m² or ≥27 kg/m² in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, and/or dyslipidemia)

Limitations of use: The effect of naltrexone/bupropion on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of naltrexone/bupropion in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

Contraindications

Hypersensitivity to bupropion, naltrexone, or any other component of the formulation; concomitant use of other bupropion-containing products (eg, including [but not limited to] Wellbutrin, Wellbutrin SR, Wellbutrin XL, Aplenzin, Zyban); chronic opioid, opiate agonist (eg, methadone) or partial agonist (eg, buprenorphine) use; acute opioid withdrawal; uncontrolled hypertension; seizure disorder or a history of seizures; bulimia or anorexia nervosa; abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; concomitant use of MAOIs (concurrently or within 14 days of discontinuing the MAOI or naltrexone/bupropion); initiation of naltrexone/bupropion in a patient receiving linezolid or IV methylene blue; pregnancy

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use of thioridazine; severe hepatic impairment; end-stage renal failure

Dosage and Administration

Dosing: Adult

Weight management: Oral:

Initial: One tablet (naltrexone 8 mg/bupropion 90 mg) once daily in the morning for 1 week; at week 2, increase to 1 tablet twice daily administered in the morning and evening and continue for 1 week; at week 3, increase to 2 tablets in the morning and 1 tablet in the evening and continue for 1 week; at week 4, increase to 2 tablets twice daily administered in the morning and evening and continue for the remainder of the treatment course.

Usual dosage: Two tablets (naltrexone 16 mg/bupropion 180 mg) twice daily (maximum dose: naltrexone 32 mg/bupropion 360 mg/day).

Concomitant Use with CYP2B6 inhibitors (eg, ticlopidine, clopidogrel): Maximum dose: 1 tablet (naltrexone 8 mg/bupropion 90 mg) twice daily

Discontinuation of therapy: If the patient has not lost at least 5% of baseline body weight after 12 weeks at the maintenance dosage, discontinue therapy; clinically meaningful weight loss is unlikely with continued treatment.

Dosing: Geriatric

Refer to adult dosing.

Administration

Administer twice daily doses in the morning and in the evening; do not administer with high-fat meals. Do not cut, chew, or crush tablets.

Dietary Considerations

Do not administer with high-fat meals; may result in a significant increase in bupropion and naltrexone systemic exposure.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Agents With Seizure Threshold Lowering Potential: BuPROPion may enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Monitor therapy

Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of BuPROPion. Specifically, seizure threshold may be lowered. BuPROPion may enhance the adverse/toxic effect 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. Consider therapy modification

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Monitor therapy

Antihepaciviral Combination Products: May decrease the serum concentration of BuPROPion. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): May enhance the adverse/toxic effect of BuPROPion. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (adult doses -- patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Consider therapy modification

Bremelanotide: May decrease the serum concentration of Naltrexone. Avoid combination

Brexanolone: BuPROPion may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP2D6 inhibitor, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder. Consider therapy modification

Citalopram: BuPROPion may enhance the adverse/toxic effect of Citalopram. Specifically, the risk for seizures and serotonin syndrome may be increased with this combination. BuPROPion may increase the 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. Consider therapy modification

CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification

CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Monitor therapy

CYP2B6 Inhibitors (Weak): May increase the serum concentration of BuPROPion. Monitor therapy

CYP2D6 Substrates (High risk with Inhibitors): CYP2D6 Inhibitors (Strong) may decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Exceptions: Ajmaline; Dapoxetine; Indoramin; Metoprolol; Tamoxifen; Timolol (Ophthalmic); Tropisetron. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Monitor therapy

Dapoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Monitor therapy

Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg with concurrent use of a strong CYP2D6 inhibitor. Consider therapy modification

Digoxin: BuPROPion may decrease the serum concentration of Digoxin. Monitor therapy

Dipyrone: May decrease the serum concentration of BuPROPion. Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Monitor therapy

Efavirenz: May decrease the serum concentration of BuPROPion. Management: Monitor for decreased response to bupropion in patients treated with efavirenz. Increased bupropion doses may be required. Avoid the use of naltrexone/bupropion for weight management in patients receiving efavirenz. Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Escitalopram: BuPROPion may enhance the adverse/toxic effect of Escitalopram. Specifically, the risk for seizures and serotonin syndrome may be increased. Monitor therapy

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

FLUoxetine: May enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of FLUoxetine. Monitor therapy

FluvoxaMINE: BuPROPion may enhance the adverse/toxic effect of FluvoxaMINE. Specifically, the risk for seizures and serotonin syndrome may be increased. Monitor therapy

Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Monitor therapy

Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor. Consider therapy modification

Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Monitor therapy

Iobenguane Radiopharmaceutical Products: BuPROPion may diminish the therapeutic effect 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. Avoid combination

Ioflupane I 123: BuPROPion may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 anticonvulsants. Consider therapy modification

Isavuconazonium Sulfate: May decrease the serum concentration of BuPROPion. Monitor therapy

Lofexidine: May decrease the serum concentration of Naltrexone. Monitor therapy

Lopinavir: May decrease the serum concentration of BuPROPion. Concentrations of the active metabolite, hydroxybupropion, may also be decreased. Management: Monitor bupropion response closely. Significant bupropion dose adjustments may be necessary to maintain adequate response. Avoid the use of naltrexone/bupropion for weight management in patients receiving lopinavir. Monitor therapy

Lorcaserin: BuPROPion may enhance the serotonergic effect of Lorcaserin. This could result in serotonin syndrome. Management: Seek alternatives to this combination when possible. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Monitor therapy

Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination

Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: Reduce metoclopramide dose to 5 mg 4 times daily (30 minutes before each meal and at bedtime) and limit the maximum daily dose to 20 mg if combined with strong CYP2D6 inhibitors. Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of BuPROPion. Avoid combination

Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Monitor therapy

Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Monitor therapy

Opioid Agonists: Naltrexone may diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

PARoxetine: BuPROPion may enhance the adverse/toxic effect of PARoxetine. Specifically, the risk for seizures and serotonin syndrome may be increased. Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Consider therapy modification

Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. Management: Monitor for signs and symptoms of possible treatment failure with primaquine in patients who are taking strong CYP2D6 inhibitors. If efficacy of primaquine is compromised, may consider adjusting therapies. Consider therapy modification

Ritonavir: May decrease the serum concentration of BuPROPion. Mixed effects on concentrations of the active hydroxybupropion metabolite have been reported. Management: Monitor for decreased bupropion effects. Significant bupropion dose adjustments may be necessary to maintain adequate response. Avoid the use of naltrexone/bupropion for weight management in patients receiving ritonavir. Monitor therapy

Sertraline: BuPROPion may enhance the adverse/toxic effect of Sertraline. Specifically, the risk for seizures and serotonin syndrome may be increased. Monitor therapy

Sibutramine: May enhance the adverse/toxic effect of Centrally Acting Weight Loss Agents. Avoid combination

Solriamfetol: BuPROPion may enhance the hypertensive effect of Solriamfetol. Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Avoid combination

Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy

Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Tetrabenazine adult dose should be reduced by 50% when starting a strong CYP2D6 inhibitor. Maximum tetrabenazine adult dose is 50 mg/day when used with a strong CYP2D6 inhibitor. Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Monitor therapy

Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Monitor therapy

Tricyclic Antidepressants: May enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of Tricyclic Antidepressants. Exceptions: Amoxapine; Protriptyline. Monitor therapy

Tropisetron: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tropisetron. Monitor therapy

Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Monitor therapy

Vilazodone: BuPROPion may enhance the adverse/toxic effect of Vilazodone. Specifically, the risk for seizures and serotonin syndrome may be increased. Monitor therapy

Vortioxetine: BuPROPion may enhance the adverse/toxic effect of Vortioxetine. Specifically, the risk for seizures and serotonin syndrome may be increased. BuPROPion may increase the 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. Consider therapy modification

Adverse Reactions

Also see individual agents.

>10%:

Central nervous system: Headache (18%), sleep disorder (14%)

Gastrointestinal: Nausea (33%), constipation (19%), vomiting (11%)

1% to 10%:

Cardiovascular: Hypertension (≤6%), increased blood pressure (≤6%), palpitations (2%), myocardial infarction (<2%), presyncope (<2%), tachycardia (<2%)

Central nervous system: Dizziness (10%), insomnia (9%; ≥65 years of age: 11%), depression (6%; ≥ 65 years of age: 7%), anxiety (4% to 6%), fatigue (4%), irritability (3%), disturbance in attention (<2% to 3%), abnormal dreams (<2%), agitation (<2%), altered mental status (<2%), amnesia (<2%), derealization (<2%), emotional lability (<2%), equilibrium disturbance (<2%), feeling abnormal (<2%), feeling hot (<2%), intention tremor (<2%), jitteriness (<2%), lethargy (<2%), memory impairment (<2%), nervousness (<2%), tension (<2%), vertigo (<2%)

Dermatologic: Hyperhidrosis (3%), alopecia (<2%)

Endocrine: Hot flash (4%), dehydration (<2%), increased thirst (<2%)

Gastrointestinal: Xerostomia (8%), diarrhea (7%), upper abdominal pain (4%), viral gastroenteritis (4%), abdominal pain (3%), dysgeusia (2%), cholecystitis (<2%), eructation (<2%), hematochezia (<2%), hernia (<2%), lower abdominal pain (<2%), motion sickness (<2%), swelling of lips (<2%)

Genitourinary: Urinary tract infection (3%), erectile dysfunction (<2%), irregular menses (<2%), urinary urgency (<2%), vaginal dryness (<2%), vaginal hemorrhage (<2%)

Hematologic & oncologic: Decreased hematocrit (<2%)

Hepatic: Increased liver enzymes (<2%)

Infection: Kidney infection (<2%), staphylococcal infection (<2%)

Neuromuscular & skeletal: Tremor (4%), strain (2%), herniated disk (<2%), jaw pain (<2%), weakness (<2%)

Otic: Tinnitus (3%)

Renal: Increased serum creatinine (<2%)

Respiratory: Pneumonia (<2%)

<1%, postmarketing, and/or case reports: Increased heart rate (resting), loss of consciousness, malaise, syncope

Warnings/Precautions

Major psychiatric warnings (use in treating psychiatric disorders):

• Suicidal thinking/behavior (use in treating psychiatric disorders): [US Boxed Warning]: Naltrexone/bupropion is not approved for use in the treatment of major depressive or psychiatric disorders; it contains bupropion the same active ingredient in some other antidepressant medications. Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies of antidepressants did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Accidental opioid overdose: Patients treated with naltrexone may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Warn patients that any attempt to overcome opioid blockade during naltrexone therapy is dangerous and could potentially lead to fatal opioid overdose; the opioid competitive receptor blockade produced by naltrexone is potentially surmountable in the presence of large amounts of opioids. If chronic opiate therapy is required, naltrexone/bupropion should be stopped; if intermittent opiate therapy is required, temporarily discontinue naltrexone/bupropion and lower doses of opioids may be needed.
• Acute opioid withdrawal: May precipitate symptoms of acute withdrawal in opioid-dependent patients. An opioid-free interval of a at least 7 to 10 days is recommended for patients previously dependent on short-acting opioids (including tramadol); consider an opioid-free interval of up to 2 weeks in patients transitioning from buprenorphine or methadone.
• Cardiovascular effects: May elevate heart rate, blood pressure and cause hypertension; use is contraindicated in patients with uncontrolled hypertension. Events have been observed in patients with or without evidence of preexisting hypertension. Risks may be greater during the initial 3 months of therapy. Assess heart rate and blood pressure before initiating treatment and monitor periodically.
• Hepatotoxicity: Cases of hepatitis, significant liver dysfunction, and transient, asymptomatic hepatic transaminase elevations have been observed with naltrexone use. Discontinue therapy if signs/symptoms of acute hepatitis develop. Clinicians should note that elevated transaminases may be a result of preexisting alcoholic liver disease, hepatitis B and/or C infection, or concomitant use of other hepatotoxic drugs; abrupt opioid withdrawal may also lead to acute liver injury.
• Hypersensitivity reactions: Anaphylactoid/anaphylactic reactions have occurred, including pruritus, urticaria, angioedema, and dyspnea. Serious reactions have been (rarely) reported with bupropion, including erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock. Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity resembling serum sickness have been reported with bupropion.
• Neuropsychiatric effect: Although naltrexone/bupropion is not approved for smoking cessation, serious neuropsychiatric events have occurred in patients taking bupropion for smoking cessation, including changes in mood (eg, depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide. The majority of these reactions occurred during bupropion treatment; however some occurred during treatment discontinuation. A causal relationship is uncertain as depressed mood may be a symptom of nicotine withdrawal. Some cases also occurred in patients taking bupropion who continued to smoke. Neuropsychiatric effects occurred in patients with and without preexisting psychiatric disease; some patients experienced a worsening of their psychiatric illnesses. Observe all patients taking bupropion for neuropsychiatric reactions. Instruct patients to stop taking naltrexone/bupropion and contact a health care provider if neuropsychiatric reactions occur. Depression, suicide, attempted suicide, and suicidal ideation have also been reported with naltrexone use for the treatment of opioid dependence; however, no causal relationship has been demonstrated.
• Ocular effects: Bupropion 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: Bupropion may cause a dose-related risk of seizures. Use is contraindicated in patients with a seizure disorder or a history of seizures, current or past diagnosis of bulimia or anorexia nervosa, or those undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Use caution with concurrent use of antipsychotics, antidepressants, theophylline, systemic corticosteroids, or hypoglycemic agents, or with excessive use of ethanol, benzodiazepines, sedative/hypnotics, or opioids. Use with caution in seizure-potentiating metabolic disorders (hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), in patients with an addiction to cocaine or stimulants, in patients withdrawing from sedatives, and in patients with a history of head trauma, severe stroke, arteriovenous malformation, or central nervous system tumor or infection. To minimize the risk of seizures, increase the dose gradually, administer the dose twice daily with no more than 2 tablets taken at a time, avoid administration with high-fat meals, skip missed doses, and limit the daily dose of bupropion to ≤360 mg. Use of multiple bupropion formulations is contraindicated. Permanently discontinue if seizure occurs during therapy.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; naltrexone/bupropion may cause an increase in blood pressure and heart rate.
• Diabetes mellitus: Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues. Monitor blood glucose levels at baseline and periodically during treatment. Consider decreases in doses for concurrent antidiabetic medications which are non-glucose-dependent; adjust antidiabetic drug regimens if hypoglycemia develops during treatment.
• Hepatic impairment: Use with caution in patients with hepatic impairment; reduced doses are recommended.
• Mania/hypomania: Bupropion may precipitate a manic, mixed, or hypomanic episode; risk is increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Screen patients for a history of bipolar disorder and the presence of risk factors including a family history of bipolar disorder, suicide, or depression. Naltrexone/bupropion is not FDA approved for bipolar depression.
• Renal impairment: Dosage reductions are necessary with moderate to severe impairment; avoid use in patients with end-stage renal disease.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly; may be at greater risk of drug accumulation during chronic dosing.

Monitoring Parameters

Blood pressure and heart rate (baseline and periodic); blood glucose (baseline and periodic); weight; BMI; renal and liver function (base and periodic); mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, and panic attacks.

Pregnancy

Pregnancy Risk Factor

X

Pregnancy Considerations

An increased risk of adverse maternal and fetal outcomes is associated with obesity. However, moderate weight gain based on prepregnancy BMI is required for positive fetal outcomes. Therefore, medications for weight loss therapy are not recommended at conception or during pregnancy (ACOG 156 2015; Stang 2016). Due to the lack of clinical benefit and potential for fetal harm, use of naltrexone/bupropion is contraindicated in pregnant females.

Also refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to help you lose weight.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Constipation
• Dry mouth
• Diarrhea
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Agitation
• Irritability
• Panic attacks
• Mood changes
• Behavioral changes
• Eye pain
• Vision changes
• Eye swelling
• Eye irritation
• Severe dizziness
• Passing out
• Sensing things that seem real but are not
• Severe headache
• Seizures
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Swollen glands
• Muscle pain
• Joint pain
• Shortness of breath
• Swelling
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.