Naltrexone And Bupropion (Monograph)

Brand name: Contrave
Drug class: Anorexigenic Agents, Miscellaneous
Chemical name: 17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride
Molecular formula: C₂₀H₂₃NO₄•HClC₁₃H₁₈ClNO•HCl
CAS number: 16676-29-2

Medically reviewed by Drugs.com on Nov 27, 2022. Written by ASHP.

Introduction

Anorexigenic agent; fixed combination containing naltrexone (an opiate antagonist) and bupropion (an antidepressant agent).

Uses for Naltrexone And Bupropion

Chronic Weight Management

Used as an adjunct to caloric restriction and increased physical activity for chronic weight management in patients who are obese (pretreatment body mass index [BMI] ≥30 kg/m²) or who are overweight (pretreatment BMI ≥27 kg/m²) and have at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia).

Safety and efficacy in combination with other weight-loss products (prescription or OTC drugs, herbal preparations) not established.

Effects on cardiovascular morbidity and mortality not established.

Clinical practice guidelines recommend that patients with excess body weight and associated health risks be treated for obesity. Essential component of therapy is a comprehensive lifestyle intervention; may consider pharmacologic therapy as an adjunct in patients who fail to achieve or sustain clinically meaningful weight loss (generally defined as loss of >4–5% of total body weight) with behavioral modification alone and who also meet regulatory prescribing guidelines (BMI ≥27 kg/m² with one or more comorbidities or a BMI >30 kg/m² with or without associated metabolic effects). Evaluate response to drug therapy after 3–4 months; if clinically meaningful weight loss not achieved, consider new treatment plan.

Related/similar drugs

Mounjaro, semaglutide, phentermine, Wegovy, Saxenda, Alli

Naltrexone And Bupropion Dosage and Administration

General

Pretreatment Screening

• Monitor BP and heart rate prior to treatment.

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

• In patients with type 2 diabetes mellitus, monitor blood glucose concentrations prior to initiating therapy.

• To prevent withdrawal symptoms in patients who are physically dependent on opiates, patients should be opiate-free before starting treatment with naltrexone/bupropion, including those being treated for alcohol dependence. The manufacturer recommends an opiate-free interval of at least 7–10 days in patients who may be dependent on short-acting opiates; patients transitioning from buprenorphine or methadone may require up to 2 weeks.

Patient Monitoring

• Monitor BP and heart rate regularly throughout treatment, particularly in patients with hypertension, who may be at risk of developing BP elevations.

• Monitor for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.

• In patients with type 2 diabetes mellitus, monitor blood glucose concentrations during treatment.

Administration

Oral Administration

Administer orally twice daily (in the morning and evening). May take with meals; however, avoid administration with a high-fat meal because this may increase systemic exposures of bupropion and naltrexone.

Swallow tablets whole; do not cut, chew or crush.

Dosage

Available as extended-release tablets; each tablet contains 8 mg of naltrexone hydrochloride and 90 mg of bupropion hydrochloride. Dosage of both drugs are expressed in terms of the salt.

If a dose of naltrexone/bupropion is missed, skip the missed dose and take the next dose at the regularly scheduled time.

Adults

Chronic Weight Management

Oral

Initially, 1 tablet (naltrexone hydrochloride 8 mg/bupropion hydrochloride 90 mg) taken once daily in the morning for the first week. Increase dosage according to the recommended dosage escalation schedule (see Table 1) until a maintenance dosage of 2 tablets twice daily (total daily dose of naltrexone hydrochloride 32 mg and bupropion hydrochloride 360 mg) is reached at the start of week 4. Higher dosages not recommended.

In patients receiving a CYP2B6 inhibitor (e.g., clopidogrel, ticlopidine) concomitantly, the maximum recommended dosage of naltrexone/bupropion is 2 tablets (administered as 1 tablet twice daily).

Evaluate patient response after 12 weeks of treatment at the recommended maintenance dosage. Discontinue treatment if weight loss is <5% of the patient’s baseline body weight because continued therapy is unlikely to result in sustained meaningful weight loss.

Prescribing Limits

Adults

Chronic Weight Management

Oral

Do not take more than 4 tablets (32 mg of naltrexone and 360 mg of bupropion) in one day and do not take more than 2 tablets at one time.

Special Populations

Hepatic Impairment

Moderate hepatic impairment: Maximum 2 tablets daily (one tablet each in the morning and evening).

Severe hepatic impairment: Use not recommended.

Renal Impairment

Mild renal impairment: Manufacturer makes no specific dosage recommendations.

Moderate or severe renal impairment: Maximum 2 tablets daily (one tablet each in the morning and evening).

End-stage renal disease: Use not recommended.

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Naltrexone And Bupropion

Contraindications

• Uncontrolled hypertension.

• Seizure disorder or history of seizures.

• Concurrent use of any other bupropion-containing products (e.g., Aplenzin, Forfivo XL, Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban).

• Current or past diagnosis of bulimia or anorexia nervosa.

• Chronic use of opiate agonists or opiate partial agonists, or acute opiate withdrawal.

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

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

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

Warnings/Precautions

Warnings

Suicidal Thoughts and Behaviors

Bupropion is an antidepressant agent used in the treatment of major depressive disorder; however, the fixed combination of naltrexone/bupropion is not indicated for the treatment of major depressive disorder or other psychiatric disorders.

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs. However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. (See Boxed Warning.)

Depression, suicide, suicide attempt, and suicidal ideation reported in patients receiving naltrexone for the treatment of opiate dependence; causal relationship not established.

Appropriately monitor and closely observe patients for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.

Prescribe naltrexone/bupropion in smallest quantity consistent with good patient management to reduce risk of overdosage.

Other Warnings and Precautions

When naltrexone/bupropion is used, consider the cautions, precautions, and contraindications associated with each ingredient.

Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment

The fixed combination of naltrexone/bupropion is not approved for smoking cessation treatment.

Serious neuropsychiatric symptoms, including mood changes (e.g., depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, and suicidality (e.g., suicidal ideation, attempted and completed suicide) reported in patients receiving bupropion for smoking cessation; occurred in patients with or without psychiatric history.

Monitor patients for neuropsychiatric symptoms. Discontinue naltrexone/bupropion in patients who develop agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient or who develop suicidal ideation or suicidal behavior and provide ongoing monitoring and supportive care until symptoms resolve.

Seizures

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

Use with caution in patients with risk factors predisposing to seizures, including a history of head trauma or prior seizure, arteriovenous malformation, CNS tumor or infection, metabolic disorders (e.g., hypoglycemia, hyponatremia), severe hepatic impairment, hypoxia, excessive use of alcohol or sedatives, withdrawal from sedatives, addiction to cocaine or stimulants, 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).

Naltrexone/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.

Carefully titrate dosage of naltrexone/bupropion to minimize risk of seizure. If patients experience a seizure, permanently discontinue naltrexone/bupropion.

Patients Receiving Opiates

Naltrexone is an opiate antagonist.

Discontinue naltrexone/bupropion in patients requiring chronic opiate therapy; in patients requiring intermittent opiate therapy, temporarily discontinue naltrexone/bupropion and consider use of lower dosages of the opiate. Patients may be more sensitive to opiates after naltrexone/bupropion is discontinued.

An attempt by a patient to overcome naltrexone opiate blockade by administering large doses of opiates is particularly dangerous and can result in fatal overdosage or life-threatening effects (e.g., respiratory arrest, circulatory collapse). Apprise patients of the serious consequences of trying to overcome opiate blockade.

When opiate withdrawal is precipitated abruptly (e.g., with naltrexone), the resulting withdrawal syndrome can be severe and require hospitalization. To prevent or minimize exacerbation of withdrawal symptoms in patients who are physically dependent on opiates, patients should be opiate-free for ≥7–10 days; patients transitioning from buprenorphine or methadone may require up to 2 weeks.

Apprise patients of the risks associated with precipitated opiate withdrawal and obtain accurate account of last opiate use.

Increased Blood Pressure and Heart Rate

Possible increased systolic BP, diastolic BP, and resting heart rate; risk may be greater during the first 3 months of therapy. Hypertension (sometimes severe) reported with bupropion. Clinical importance of increased BP and heart rate, particularly in patients with cardiac and cerebrovascular disease, not known.

Naltrexone/bupropion has not been studied in patients with recent (i.e., within 6 months) MI or stroke, life-threatening arrhythmias, or CHF.

Naltrexone/bupropion is contraindicated in patients with uncontrolled hypertension. Control preexisting hypertension before initiating naltrexone/bupropion therapy.

Monitor BP and heart rate prior to and periodically during treatment.

Hypersensitivity Reactions

Anaphylactoid reactions (e.g., pruritus, urticaria, angioedema, dyspnea) reported with bupropion. Postmarketing reports include erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock. Symptoms suggestive of delayed hypersensitivity (e.g., arthralgia, myalgia, fever with rash) which may resemble serum sickness also reported.

Discontinue naltrexone/bupropion if hypersensitivity reaction occurs.

Hepatotoxicity

Hepatitis and liver dysfunction reported with naltrexone; elevations in hepatic transaminase concentrations also observed with naltrexone in presence of other potential causative or contributory etiologies. No cases of transaminase concentrations >3 times the ULN with bilirubin concentrations >2 times the ULN reported with naltrexone/bupropion in clinical studies.

Discontinue naltrexone/bupropion if manifestations of acute hepatitis occur.

Abrupt, precipitated opiate withdrawal may lead to systemic effects, including acute liver injury.

Activation of Mania

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

Angle-closure Glaucoma

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

Hypoglycemia

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas).

Monitor blood glucose concentrations prior to and during therapy in patients with type 2 diabetes mellitus. Consider reducing dosage of concomitant non-glucose-dependent antidiabetic agents.

If hypoglycemia develops, adjust antidiabetic drug regimen as needed.

Specific Populations

Pregnancy

Weight loss offers no benefit to a pregnant patient and may cause fetal harm. If a patient becomes pregnant, discontinue the drug and advise the patient of the risk to the fetus. Available data have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Lactation

Naltrexone, bupropion, and their metabolites are distributed into human milk. No information regarding whether the drugs have an effect on milk production.

Consider the known benefits of breastfeeding along with the mother's need for naltrexone/bupropion and any potential adverse effects on the infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in patients <18 years of age. Use not recommended.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Use with caution in geriatric patients; older individuals may be more sensitive to CNS effects of naltrexone/bupropion. Consider possibility of decreased renal function in geriatric patients.

Hepatic Impairment

In patients with hepatic impairment (mild, moderate, and severe), exposure to naltrexone, bupropion, and metabolites are increased. Therefore, maximum recommended daily maintenance dose of naltrexone/bupropion in patients with moderate hepatic impairment is 2 tablets (one tablet each in the morning and evening). Not recommended in patients with severe hepatic impairment.

Renal Impairment

In patients with renal impairment (mild, moderate and severe), exposure to naltrexone and bupropion metabolites are increased. Therefore, maximum recommended daily maintenance dose of naltrexone/bupropion in patients with moderate or severe renal impairment is 2 tablets (one tablet each in the morning and evening). Not recommended in patients with end-stage renal disease.

Common Adverse Effects

Reported in ≥5% of patients: Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, diarrhea.

Drug Interactions

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

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

Bupropion and its metabolites inhibit CYP2D6. Naltrexone and its major metabolite do not inhibit CYP1A2, 2B6, 2C8, 2E1, 2C9, 2C19, 2D6 or 3A4 nor induce CYP1A2, 2B6, or 3A4.

Bupropion and its metabolites inhibit renal organic cation transporter (OCT) 2 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

CYP2B6 inhibitors: Potential pharmacokinetic interaction (increased systemic exposure of bupropion and decreased systemic exposure of hydroxybupropion). Maximum recommended dosage of naltrexone/bupropion is one tablet twice daily if used concomitantly with a CYP2B6 inhibitor.

CYP2B6 inducers: Potential pharmacokinetic interaction (decreased systemic exposure of bupropion). Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Potential pharmacokinetic interaction (increased systemic exposure of the CYP2D6 substrate). In patients receiving naltrexone/bupropion, initiate CYP2D6 substrates at the lower end of the recommended dosage range. When initiating naltrexone/bupropion in patients receiving a CYP2D6 substrate, consider reducing dosage of the CYP2D6 substrate, particularly if the drug has a narrow therapeutic index.

Specific Drugs

Naltrexone And Bupropion Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of naltrexone and bupropion occur at 2 and 3 hours, respectively, following administration of a single dose of the fixed combination of naltrexone/bupropion.

Food

Administration of naltrexone/bupropion extended-release tablets with a high-fat meal increases peak plasma concentrations of naltrexone and bupropion by 1.4- and 1.8-fold, respectively, and increases AUC of naltrexone and bupropion by 2.1- and 3.7-fold, respectively.

Special Populations

Hepatic impairment: Exposure to naltrexone, bupropion, and metabolites increased.

Renal impairment: Exposure to naltrexone and bupropion metabolites increased.

Distribution

Extent

Naltrexone, bupropion, and their metabolites distribute into milk.

Plasma Protein Binding

Naltrexone: 21%.

Bupropion: 84%.

Elimination

Metabolism

Naltrexone: Metabolized to a major active metabolite, 6-β-naltrexol, through non-CYP pathways.

Bupropion: Extensively metabolized to 3 active metabolites: hydroxybupropion (principally by CYP2B6), threohydrobupropion, and erythrohydrobupropion.

Elimination Route

Naltrexone: Excreted primarily in urine (53–79%); <2% excreted in urine as unchanged drug.

Bupropion: Excreted in urine (87%) and feces (10%), principally as metabolites; 0.5% excreted as unchanged drug.

Half-life

Following administration of naltrexone/bupropion extended-release tablet, elimination half-lives of naltrexone and bupropion were approximately 5 and 21 hours, respectively.

Stability

Storage

Oral

Extended-Release Tablets

25°C (excursions permitted to 15–30°C).

Actions

• Combination of naltrexone, an opiate antagonist, and bupropion, an aminoketone antidepressant agent that has weak dopamine and norepinephrine reuptake inhibitor properties.

• Precise mechanism of action in producing weight loss not known; both drugs decrease food intake through independent and complementary effects on areas of the brain involved in regulating food intake: the hypothalamic melanocortin system and the mesolimbic dopamine system (reward system). The drugs have been shown in animal studies to produce a synergistic effect on food intake when combined.

Advice to Patients

• Advise patients to take naltrexone/bupropion exactly as prescribed and not to take more than the recommend dosage. Inform patients that the dosage of naltrexone/bupropion should be titrated according to the weekly schedule when initiating therapy.

• Inform patients that naltrexone/bupropion can be taken with or without food; however the drug should not be taken with a high-fat meal. Advise patients to swallow naltrexone/bupropion tablets whole and not to chew, cut, crush the tablets.

• If a dose of naltrexone/bupropion is missed, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.

• Advise patients that naltrexone/bupropion contains bupropion and should not be used concomitantly with any other products that contain bupropion (e.g., Aplenzin, Forfivo XL, Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban).

• Inform patients that changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide, have been reported in patients attempting to quit smoking while receiving bupropion. Advise patients to discontinue naltrexone/bupropion and notify a clinician if they experience such symptoms or sudden changes in mood, behavior, thoughts or feelings.

• Risk of seizures, particularly in patients with certain medical conditions, those taking certain drugs concomitantly, and those receiving higher dosages of bupropion. Advise patients to permanently discontinue naltrexone/bupropion and notify a clinician if they have a seizure.

• Advise patients to minimize or avoid consumption of alcohol; use of alcohol or abrupt cessation of alcohol, benzodiazepines, antiepileptic drugs, or sedative/hypnotic agents can increase the risk of seizure.

• Inform patients that the naltrexone component of the fixed combination of naltrexone and bupropion is an opiate antagonist and that they may be more sensitive to opiates after treatment with naltrexone/bupropion is discontinued.

• Risk of increased blood pressure and heart rate. Advise patients to inform a clinician if they experience increased blood pressure or heart rate during naltrexone/bupropion therapy.

• Risk of hypersensitivity reactions. Advise patients to discontinue naltrexone/bupropion and contact a clinician if they experience skin rash, pruritus, hives, chest pain, edema, shortness of breath, or other allergic reactions during treatment with the drug.

• Risk of hepatotoxicity. Advise patients to contact a clinician if manifestations of acute hepatitis (e.g., abdominal pain lasting more than a few days, dark urine, yellowing of the eyes, fatigue) occur.

• Advise patients that bupropion can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals. Possible symptoms include eye pain, vision changes, and swelling or redness in or around the eye. Preexisting glaucoma is almost always open-angle glaucoma since angle-closure glaucoma can be treated definitively with iridectomy when diagnosed; open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure glaucoma and have a prophylactic procedure (e.g., iridectomy) if they are susceptible.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.

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

Preparations

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

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

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Frequently asked questions

• Does naltrexone cause weight gain?

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