Naltrexone and Bupropion
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- Bupropion and Naltrexone
- Bupropion Hydrochloride and Naltrexone Hydrochloride
- Naltrexone HCl/Bupropion HCl
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]
Brand Names: U.S.
- Antidepressant, Dopamine/Norepinephrine-Reuptake Inhibitor
- Opioid Antagonist
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.
Hypersensitivity to bupropion, naltrexone, or any other component of the formulation; concomitant use of other bupropion-containing products; 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 MAO inhibitors (concurrently or within 14 days of discontinuing the MAO inhibitor or naltrexone/bupropion); initiation of naltrexone/bupropion in a patient receiving linezolid or intravenous (IV) methylene blue; pregnancy
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 daily).
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.
MAO inhibitor recommendations:
Switching to or from an MAO inhibitor antidepressant:
Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat depression and initiation of naltrexone/bupropion.
Allow 14 days to elapse between discontinuing naltrexone/bupropion and initiation of an MAO inhibitor intended to treat depression.
Use with reversible MAO inhibitors (such as linezolid or IV methylene blue):
Do not initiate naltrexone/bupropion in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.
If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving naltrexone/bupropion and potential benefits outweigh potential risks, discontinue naltrexone/bupropion promptly and administer linezolid or IV methylene blue. Monitor for increased risk of hypertensive reactions for 2 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume naltrexone/bupropion 24 hours after the last dose of linezolid or IV methylene blue (Wellbutrin prescribing information, 2013).
Refer to adult dosing.
Dosing: Renal Impairment
Mild impairment: There are no dosage adjustment provided in the manufacturer’s labeling (has not been studied); use with caution.
Moderate or severe impairment: Maximum dose: One tablet (naltrexone 8 mg/bupropion 90 mg) twice daily
End-stage renal disease (ESRD): Use is not recommended.
Dosing: Hepatic Impairment
Maximum dose: One tablet (naltrexone 8 mg/bupropion 90 mg) daily
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.
Do not administer with high-fat meals; may result in a significant increase in bupropion and naltrexone systemic exposure.
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Ajmaline: CYP2D6 Inhibitors (Moderate) 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
Analgesics (Opioid): Naltrexone may diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification
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 (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy
Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy
Citalopram: BuPROPion may enhance the adverse/toxic effect of Citalopram. 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
CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy
CYP2B6 Inhibitors (Weak): May increase the serum concentration of BuPROPion. Exceptions: Prasugrel. Monitor therapy
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
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 (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy
FLUoxetine: BuPROPion may enhance the adverse/toxic effect of FLUoxetine. BuPROPion may increase the serum concentration of FLUoxetine. Monitor therapy
FluvoxaMINE: BuPROPion may enhance the adverse/toxic effect of FluvoxaMINE. BuPROPion may increase the serum concentration of FluvoxaMINE. Monitor therapy
Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Monitor therapy
Ioflupane I 123: BuPROPion may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy
Isavuconazonium Sulfate: May decrease the serum concentration of BuPROPion. 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: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy
MAO Inhibitors: May enhance the hypertensive effect of BuPROPion. Avoid combination
Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination
Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification
MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy
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 (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy
Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy
OCT2 Substrates: BuPROPion may increase the serum concentration of OCT2 Substrates. Monitor therapy
PARoxetine: BuPROPion may enhance the adverse/toxic effect of PARoxetine. BuPROPion may increase the serum concentration of PARoxetine. 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
Propafenone: May increase the serum concentration of CYP2D6 Inhibitors (Moderate). Monitor therapy
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
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification
Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination
Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy
Tricyclic Antidepressants: BuPROPion may decrease the metabolism of Tricyclic Antidepressants. Management: Seek alternatives when possible. Monitor patients receiving these combinations closely for increased serum concentrations (when testing is available) and toxic effects of the tricyclic antidepressant. Exceptions: Amoxapine; Protriptyline. Consider therapy modification
Vortioxetine: BuPROPion may enhance the adverse/toxic effect of Vortioxetine. 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
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% (Limited to important or life-threatening): Hypoglycemia (concomitant use of antidiabetic medications), increased heart rate (resting), syncope
Major psychiatric warnings (use in treating psychiatric disorders):
• Suicidal thinking/behavior (use in treating psychiatric disorders): [U.S. 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(SJS), 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: [U.S. Boxed Warning]: 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. Observe all patients taking bupropion for neuropsychiatric reactions. Instruct patients to 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.
• 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.
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.
• Elderly: Use with caution in the elderly; may be at greater risk of drug accumulation during chronic dosing.
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 Risk Factor
Animal reproduction studies have not been conducted with this combination. Adverse fetal events following maternal use of bupropion during pregnancy have been reported in some studies. Weight-loss therapy is not recommended for pregnant women. Obese and overweight women should be encouraged to participate in weight reduction programs prior to attempting pregnancy; weight gain during pregnancy should be determined by their prepregnancy BMI and current guidelines (ADA, 2009; IOM, 2009). Use of this product is contraindicated in pregnant women.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, constipation, xerostomia, diarrhea, or insomnia. Have patient report immediately to prescriber signs of hepatic impairment, behavioral changes, illogical thinking, severe dizziness, significant syncope, hallucinations, akathisia, intolerable headache, considerable fatigue, severe anxiety, angina, tachycardia, arrhythmia, swollen lymph nodes, myalgia, arthralgia, dyspnea, or Stevens-Johnson syndrome (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
More about bupropion/naltrexone
- Other brands: Contrave