Naltrexone Hydrochloride and Bupropion Hydrochloride

[Section Outline]

Chronic Weight Management

Chronic Weight Management

The fixed combination of naltrexone hydrochloride and bupropion hydrochloride (naltrexone/bupropion; commercially available as Contrave^®) is 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 in patients who are overweight (pretreatment BMI ≥27 kg/m²) and have at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus).1,2,3,4,5

Efficacy and safety of naltrexone/bupropion in combination with other products used to promote weight loss, including prescription and nonprescription (OTC) drugs and herbal preparations, have not been established.1 The effect of naltrexone/bupropion on cardiovascular morbidity and mortality has not been established.1,6

Efficacy and safety of naltrexone/bupropion for the management of body weight were established in 4 randomized, double-blind, placebo-controlled studies (COR-I, COR-II, COR-BMOD, COR-Diabetes) of up to 56 week's duration in a total of 4536 adults who were obese (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) and had at least one comorbid condition such as hypertension, dyslipidemia, or type 2 diabetes mellitus.1 In all studies, patients were randomized to receive naltrexone/bupropion or placebo in conjunction with lifestyle modification.1,2,3,4,5 In the COR-I, COR-II, and COR-Diabetes studies, lifestyle modification consisted of behavioral modification advice and instructions for patients to follow a reduced-calorie diet (approximately 500 kcal/day deficit) and to increase physical activity.1,2,3,5 In COR-BMOD, lifestyle modification consisted of an intensive behavioral modification program that included group counseling sessions and a prescribed diet and exercise regimen.1,4 The 2 co-primary efficacy endpoints in these studies were percent change in body weight from baseline and the proportion of patients achieving a reduction in body weight of at least 5%, evaluated at 56 weeks in COR-I, COR-BMOD, and COR-Diabetes1,2,4,5 and at 28 weeks in COR-II.3,6 Other measures of efficacy included the proportion of patients achieving a reduction in body weight of at least 10% and changes in waist circumference, lipids, blood pressure, heart rate, and glycemic control.1,2,3,4,5 Across all 4 studies, the mean baseline BMI was 36 kg/m² and waist circumference was 110 cm.1 Apart from COR-Diabetes, which only enrolled patients with type 2 diabetes, the demographic characteristics of patients were similar across all 4 trials.1 The mean age of patients was 46 years, 83% were female, 77% were Caucasian, 18% were Black, 24% had hypertension, 54% had dyslipidemia, and 10% had type 2 diabetes mellitus.1 Overall study discontinuance rates were 46 or 45% in patients randomized to naltrexone/bupropion or placebo, respectively; most discontinuances occurred during the first 12 weeks of treatment.1 Approximately 24 or 12% of patients receiving naltrexone/bupropion or placebo, respectively, discontinued treatment due to an adverse reaction.1 In all 4 studies, treatment with fixed-combination naltrexone 32 mg and bupropion 360 mg daily resulted in substantially greater reduction in body weight from baseline compared with placebo in patients with or without diabetes who were obese or overweight.1,2,3,4,5 A substantially greater proportion of patients receiving naltrexone/bupropion lost at least 5 or 10% of their baseline body weight compared with patients receiving placebo.1,2,3,4,5 Serum lipids were improved but did not differ substantially between naltrexone/bupropion and placebo groups.1 In patients with type 2 diabetes mellitus, treatment with naltrexone/bupropion resulted in greater reduction in glycosylated hemoglobin (HbA_1c) compared with placebo.1,5

In COR-I, patients were randomized in a 1:1:1 ratio to receive fixed-dose naltrexone hydrochloride 32 mg/bupropion hydrochloride 360 mg daily, naltrexone hydrochloride 16 mg/bupropion hydrochloride 360 mg daily, or placebo for 52 weeks following a 4-week dosage titration period.2 At 56 weeks, patients receiving naltrexone/bupropion lost a greater percentage of baseline body weight compared with placebo; the mean reduction from baseline was 5.4% in patients receiving naltrexone hydrochloride 32 mg/bupropion hydrochloride 360 mg daily compared with 1.3% in those receiving placebo.1 A substantially greater percentage of patients receiving naltrexone hydrochloride 32 mg/bupropion hydrochloride 360 mg daily lost 5% or more of their baseline body weight compared with patients receiving placebo (42 versus 17%, respectively).1 In addition, the percentage of patients who lost 10% or more of their baseline body weight was substantially greater in the naltrexone hydrochloride 32 mg/bupropion hydrochloride 360 mg daily group compared with placebo (21 versus 7%, respectively), and waist circumference was also substantially reduced in patients receiving the combination treatment compared with placebo (mean reduction of 6.2 versus 2.5 cm, respectively).1

In COR-II, patients were randomized in a 2:1 ratio to receive naltrexone hydrochloride 32 mg/bupropion hydrochloride 360 mg daily or placebo; patients in the active treatment group who did not experience a weight loss of at least 5% of body weight between 28-44 weeks were re-randomized to continue the same dosage or increase to naltrexone hydrochloride 48 mg/bupropion hydrochloride 360 mg daily.3,6 The primary endpoints in this study were evaluated at week 28;3,6 treatment with naltrexone 32 mg/bupropion 360 mg daily resulted in a greater percentage of baseline body weight loss and a greater percentage of patients losing at least 5 or 10% of their baseline body weight, compared with placebo.3,6

In COR-BMOD, patients were randomized in a 3:1 ratio to receive naltrexone hydrochloride 32 mg/bupropion hydrochloride 360 mg daily following a 4-week dosage titration period or placebo in addition to an intensive lifestyle modification program.1,4 At 56 weeks, naltrexone/bupropion-treated patients lost a mean of 8.1% of baseline body weight compared with 4.9% in those receiving placebo, and 57% of patients receiving the drug lost at least 5% of their baseline body weight compared with 43% of patients receiving placebo.1 In addition, a greater percentage of naltrexone/bupropion-treated patients lost at least 10% of their baseline body weight compared with placebo (35 versus 21%, respectively), and waist circumference was substantially reduced in patients receiving the combination treatment compared with placebo (mean reduction of 10 versus 6.8 cm, respectively).1

COR-Diabetes compared naltrexone/bupropion with placebo in overweight or obese patients with type 2 diabetes mellitus who were inadequately controlled (i.e., HbA_1c≥7%) with oral antidiabetic agents or with diet and exercise alone.1,5 Approximately 49% of patients were receiving a sulfonylurea, 31% were receiving a thiazolidinedione, and 79% were receiving metformin at the start of the study; baseline HbA_1c was 8% in both groups.1 At 56 weeks, naltrexone/bupropion-treated patients lost a mean of 3.7% of baseline body weight compared with 1.7% in those receiving placebo, and a substantially greater percentage of patients receiving naltrexone/bupropion compared with placebo lost at least 5% (36 versus 18%, respectively) or 10% (15 versus 5%, respectively) of their baseline body weight.1 In addition, HbA_1c was reduced to a greater extent in patients receiving the combination treatment compared with placebo (mean reduction of 0.6 versus 0.1%, respectively).1

Clinical Perspective

Clinical practice guidelines recommend treatment for obesity in patients with excess body weight and associated health risks.50,51 A comprehensive lifestyle intervention is an essential component of therapy and should be provided to all patients; pharmacologic therapy may be considered as an adjunct to behavioral modification in patients who fail to achieve or sustain clinically meaningful weight loss (generally defined as a loss of more than 4-5% of total body weight) 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).50,51 Response to drug therapy should be evaluated after 3-4 months of treatment; if clinically meaningful weight loss is not achieved, it is generally recommended that a new treatment plan be considered because the patient is likely not responding to the drug.50,51

Dosage and Administration ⬆ ⬇

[Section Outline]

General
Administration
Dosage
Special Populations

General

Pretreatment Screening

Monitor blood pressure and heart rate prior to treatment.1
Screen patients for a history of bipolar disorder and risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression).1
In patients with type 2 diabetes mellitus, monitor blood glucose concentrations prior to initiating therapy.1
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.1 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.1

Patient Monitoring

Monitor blood pressure and heart rate regularly throughout treatment, particularly in patients with hypertension, who may be at increased risk of blood pressure elevations.1
Monitor for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1
In patients with type 2 diabetes mellitus, monitor blood glucose concentrations during treatment.1

Administration

Administer fixed-combination naltrexone/bupropion extended-release tablets orally twice daily in the morning and in the evening.1 The fixed-combination drug may be taken with meals; however, avoid administration with a high-fat meal because this may increase systemic exposures of bupropion and naltrexone systemic.1 Swallow tablets whole and do not cut, chew, or crush.1

Dosage

Naltrexone/bupropion is available as extended-release tablets; each tablet contains 8 mg of naltrexone hydrochloride and 90 mg of bupropion hydrochloride.1 Dosages of both drugs are expressed in terms of the salt.1 Dosage should be titrated slowly over several weeks to the recommended dosage to reduce the risk of seizures.1

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.1

The recommended initial adult dosage of the fixed combination of naltrexone/bupropion for chronic weight management is 1 tablet once daily in the morning for 1 week; dosage should then be titrated until a maintenance dosage of 2 tablets twice daily (total daily dose of naltrexone 32 mg and bupropion 360 mg) is reached.1 (See Table 1.) Do not take more than 4 tablets (32 mg of naltrexone hydrochloride and 360 mg of bupropion hydrochloride) in one day, and do not take more than 2 tablets at one time.1 In patients receiving a CYP2B6 inhibitor (e.g., clopidogrel, ticlopidine) concomitantly, the maximum recommended daily dosage of naltrexone/bupropion is 2 tablets (administered as 1 tablet twice daily).1

Table 1. Naltrexone/Bupropion Dosage Titration Schedule1

	Morning Dose	Evening Dose
Week 1	1 tablet	None
Week 2	1 tablet	1 tablet
Week 3	2 tablets	1 tablet
Week 4 - Onward	2 tablets	2 tablets

Evaluate patient response after 12 weeks of treatment at the recommended maintenance dosage.1 Discontinuance of therapy is recommended in patients who have not lost at least 5% of their baseline body weight since such patients are unlikely to achieve and sustain meaningful weight loss with continued therapy.1

Special Populations

Hepatic Impairment

The maximum recommended maintenance dosage of naltrexone/bupropion in patients with moderate hepatic impairment is 2 tablets daily (one tablet each in the morning and evening).1

Naltrexone/bupropion is not recommended in patients with severe hepatic impairment.1

Renal Impairment

In patients with moderate or severe renal impairment, the maximum recommended dosage of naltrexone/bupropion is 2 tablets daily (i.e., one tablet each in the morning and evening).1

Naltrexone/bupropion is not recommended in patients with end-stage renal disease.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Cautions ⬆ ⬇

[Section Outline]

Contraindications
Warnings/Precautions
Common Adverse Effects

Contraindications

Uncontrolled hypertension.1
Seizure disorder or history of seizures.1
Concurrent use of any other bupropion-containing products (e.g., Aplenzin^®, Forfivo XL^®, Wellbutrin^®, Wellbutrin^® SR, Wellbutrin^® XL, Zyban^®).1
Current or past diagnosis of bulimia or anorexia nervosa.1
Chronic use of opiate agonists or opiate partial agonists, or acute opiate withdrawal.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 naltrexone/bupropion in patients receiving reversible MAO inhibitors such as linezolid or IV methylene blue is also contraindicated.1
Known hypersensitivity to bupropion, naltrexone, or to any other ingredient in the formulation.1

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.1

A boxed warning about suicidal thinking and behavior (suicidality) has been included in the prescribing information for naltrexone/bupropion.1 Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder whether or not they are taking antidepressants.1 This risk may persist until clinically important remission occurs.1 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.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 suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.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

Depression, suicide, suicide attempt, and suicidal ideation also have been reported during postmarketing experience in patients receiving naltrexone for the treatment of opiate dependence, although a causal relationship has not been established.1

In controlled studies of the fixed combination of naltrexone/bupropion in obese/overweight adults, no suicides or suicide attempts were reported; suicidal ideation was reported in one patient (0.03%) who received the naltrexone/bupropion combination compared with 3 patients (0.2%) who received placebo.1

Appropriately monitor all patients being treated with antidepressants, including naltrexone/bupropion, 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.1 Advise families and caregivers of patients treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1

The manufacturer recommends that naltrexone/bupropion be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1

Other Warnings and Precautions

When the fixed-combination of naltrexone and bupropion is used, the cautions, precautions, and contraindications associated with each ingredient should be considered.1

Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment

The fixed combination of naltrexone/bupropion is not approved for smoking cessation treatment.1

Serious neuropsychiatric symptoms, including changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic as well as suicidal ideation, suicide attempt, and completed suicide, have been reported during postmarketing experience in patients receiving bupropion for smoking cessation.1 Such events have occurred in patients with or without preexisting psychiatric disease, and some patients experienced worsening of their psychiatric illness.1 While some of the cases may have been confounded by symptoms of nicotine withdrawal typically seen in individuals who have stopped smoking, these effects were also observed in patients who continued to smoke.1

Monitor patients for neuropsychiatric symptoms.1 Patients who experience agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient or who develop suicidal ideation or suicidal behavior should discontinue naltrexone/bupropion and immediately contact a clinician.1 Although resolution of symptoms after bupropion discontinuance was reported in many postmarketing reports, manifestations persisted in some cases.1 Therefore, ongoing patient monitoring and supportive care should be provided until symptoms resolve.1

Seizures

Bupropion has been associated with a dose-related risk of seizures.1 In controlled clinical studies, seizure was reported in approximately 0.1% of patients receiving naltrexone/bupropion compared with none of the patients receiving placebo.1

Use naltrexone/bupropion 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).1 Carefully consider these risks before initiating therapy with naltrexone/bupropion.1

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.1

Follow recommended dosage titration and administration instructions carefully to minimize the risk of seizures with naltrexone/bupropion.1 Permanently discontinue the drug in patients who experience a seizure during therapy.1

Patients Receiving Opiates

Because naltrexone is an opiate antagonist, naltrexone/bupropion should not be used in patients receiving chronic opiate therapy.1 If a patient receiving naltrexone/bupropion requires chronic opiate therapy, discontinue naltrexone/bupropion.1 If a patient requires intermittent opiate therapy, temporarily discontinue naltrexone/bupropion; lower dosages of the opiate may be necessary.1 Advise patients that they may be more sensitive to opiates after naltrexone/bupropion is discontinued.1

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).1 Patients should be warned about the serious consequences of trying to overcome opiate blockade.1

When opiate withdrawal is precipitated abruptly (e.g., with naltrexone), the resulting withdrawal syndrome can be severe enough to require hospitalization.1 To prevent occurrence of precipitated withdrawal in patients who are physically dependent on opiates or exacerbation of preexisting subclinical withdrawal symptoms, patients should be opiate-free before starting treatment with naltrexone/bupropion, including those being treated for alcohol dependence.1 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.1 Patients should be apprised of the risks associated with precipitated opiate withdrawal and encouraged to give an accurate account of last opiate use.1

Increased Blood Pressure and Heart Rate

Elevations in systolic and/or diastolic blood pressure and resting heart rate may occur during treatment with naltrexone/bupropion; the risk may be greater during the first 3 months of therapy.1 Hypertension, in some cases severe and requiring acute treatment, has been reported in patients receiving bupropion.1

In controlled studies, statistically significant differences in mean blood pressure were observed between patients receiving naltrexone/bupropion compared with those receiving placebo.1 The largest mean differences between the groups were observed during the first 12 weeks of treatment.1 Naltrexone/bupropion treatment also was associated with statistically significant higher mean heart rate compared with placebo.1 Adverse reactions related to blood pressure or heart rate occurred in a greater percentage of patients receiving naltrexone/bupropion than those receiving placebo (6.3 versus 4.2%, respectively) and were observed in patients with and without preexisting hypertension.1 In a study in patients with type 2 diabetes mellitus, blood pressure-related adverse reactions occurred in 12% of naltrexone/bupropion-treated patients compared with 6.5% of those receiving placebo.1

In an ambulatory blood pressure monitoring substudy in 182 patients, systolic blood pressure decreased by 0.2 or 2.8 mm Hg after 52 weeks of treatment with naltrexone/bupropion or placebo, respectively; diastolic blood pressure increased by 0.8 mm Hg in patients receiving naltrexone/bupropion compared with a decrease of 2.1 mm Hg in those receiving placebo.1

The clinical importance of increased blood pressure and heart rate associated with naltrexone/bupropion therapy, particularly in patients with cardiac and cerebrovascular disease, is not known; patients with recent (i.e., within 6 months) MI or stroke, life-threatening arrhythmias, or congestive heart failure were not included in clinical studies of naltrexone/bupropion.1

Naltrexone/bupropion is contraindicated in patients with uncontrolled hypertension.1 Preexisting hypertension should be controlled before initiating therapy with naltrexone/bupropion.1 Monitor blood pressure and heart rate prior to initiating therapy and regularly during treatment, particularly in patients with controlled hypertension prior to naltrexone/bupropion treatment.1

Hypersensitivity Reactions

Anaphylactic or anaphylactoid reactions with symptoms including pruritus, urticaria, angioedema, and dyspnea have occurred in patients receiving bupropion in clinical trials.1 In addition, erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with use of bupropion have been reported rarely.1 Symptoms suggestive of delayed hypersensitivity (e.g., arthralgia, myalgia, fever with rash), which may resemble serum sickness, also have been reported in association with bupropion.1

Discontinue naltrexone/bupropion if a hypersensitivity reaction occurs.1

Hepatotoxicity

Hepatitis and clinically significant liver dysfunction have been reported with naltrexone during clinical trials and postmarketing experience with the drug.1 Transient, asymptomatic elevations in hepatic transaminase concentrations also have been observed with naltrexone although potential causative or contributory etiologies often were identified (e.g., preexisting alcoholic liver disease, hepatitis B and/or C virus infection, concomitant use of other potentially hepatotoxic drugs).1 In controlled studies of naltrexone/bupropion for weight management, there were no cases of elevated transaminase concentrations >3 times the upper limit of normal (ULN) in conjunction with bilirubin concentrations >2 times the ULN.1 Although clinically important liver dysfunction typically is not associated with opiate withdrawal, precipitated opiate withdrawal may lead to systemic effects, including acute liver injury.1

Discontinue naltrexone/bupropion if manifestations of acute hepatitis occur.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 Activation of mania or hypomania was not reported in controlled studies of naltrexone/bupropion for the treatment of obesity; these studies excluded patients receiving antidepressants and patients with a history of bipolar disorder or recent hospitalization because of psychiatric illness.1

Prior to initiating therapy with naltrexone/bupropion, screen patients for bipolar disorder or risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression).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

Hypoglycemia

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus who are treated with insulin and/or insulin secretagogues (e.g., sulfonylureas).1 In patients with type 2 diabetes mellitus, monitor blood glucose concentrations prior to and during treatment with naltrexone/bupropion.1 Clinicians should consider reductions in dosage of concomitant non-glucose-dependent antidiabetic agents to minimize the risk of hypoglycemia.1 If hypoglycemia develops following initiation of naltrexone/bupropion therapy, appropriately adjust the antidiabetic drug regimen.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

Specific Populations

Pregnancy

Weight loss offers no potential benefit to pregnant women and may result in fetal harm.1 If a patient becomes pregnant, discontinue naltrexone/bupropion and advise the patient of the risk to the fetus.1 Available pharmacovigilance data and data from clinical trials with the individual components of the combination drug in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcome.1

Lactation

Naltrexone, bupropion, and their metabolites are distributed into human milk.1 There is no information regarding whether the drugs have an effect on milk production.1 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.1

Pediatric Use

Safety and efficacy of naltrexone/bupropion in patients <18 years of age have not been established; use of naltrexone/bupropion is not recommended in pediatric patients.1

Geriatric Use

Clinical trials of naltrexone/bupropion did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; in controlled studies in obese and overweight patients, 2% of patients were ≥65 years of age and none were ≥75 years of age.1 Older individuals may be more sensitive to CNS effects of naltrexone/bupropion.1 Because geriatric patients may have decreased renal function, use naltrexone/bupropion with caution in such patients.1

Hepatic Impairment

In a pharmacokinetic study in patients with hepatic impairment (mild, moderate, and severe), exposure to naltrexone, bupropion, and their metabolites were increased.1 Therefore, the 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).1 Use of naltrexone/bupropion is not recommended in patients with severe hepatic impairment.1

Renal Impairment

In a pharmacokinetic study in patients with renal impairment (mild, moderate and severe), exposure to naltrexone and bupropion metabolites were increased.1 Therefore, the 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).1 Use of naltrexone/bupropion is not recommended in patients with end-stage renal disease.1

Common Adverse Effects

Common adverse reactions reported in ≥5% of patients receiving naltrexone/bupropion in clinical studies include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.1

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting Hepatic Microsomal Enzymes
Drugs Metabolized by Hepatic Microsomal Enzymes
Drugs Affecting the Seizure Threshold
Alcohol
Atorvastatin
Cimetidine
Citalopram
Clopidogrel
Desipramine
Digoxin
Dopaminergic Drugs
Glyburide
Lamotrigine
Lisinopril
Metformin
Metoprolol
Monoamine Oxidase Inhibitors
Nifedipine
Opiate Agonists
Prasugrel
Ticlopidine
Valsartan

When naltrexone/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 the other bupropion metabolites.1

Bupropion and its metabolites inhibit CYP2D6.1 Naltrexone and its major metabolite do not inhibit CYP1A2, 2B6, 2C8, 2E1, 2C9, 2C19, 2D6 or 3A4 nor induce CYP1A2, 2B6, or 3A4.1

Bupropion and its metabolites inhibit renal organic cation transporter (OCT) 2 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions are possible if naltrexone/bupropion is used concomitantly with inhibitors or inducers of CYP2B6 (altered bupropion and/or hydroxybupropion concentrations).1

In vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.1

Although not systematically studied, carbamazepine, phenobarbital, or phenytoin may induce the metabolism of bupropion.1

Inhibitors of CYP2B6

Concomitant use of naltrexone/bupropion with CYP2B6 inhibitors (e.g., ticlopidine, clopidogrel) may result in increased systemic exposure of bupropion and decreased systemic exposure of hydroxybupropion.1

When the CYP2B6 inhibitor ticlopidine (200 mg twice daily for 4 days) was administered concomitantly with bupropion, AUC and peak plasma concentrations of bupropion increased by 85 and 35%, respectively, and AUC and peak plasma concentrations of hydroxybupropion decreased by 84 and 78%, respectively.1

When clopidogrel (75 mg once daily for 4 days) was administered concomitantly with bupropion, AUC and peak plasma concentrations of bupropion increased by 60 and 40%, respectively, and AUC and peak plasma concentrations of hydroxybupropion decreased by 52 and 50%, respectively.1

If naltrexone/bupropion is used concomitantly with a CYP2B6 inhibitor (e.g., ticlopidine, clopidogrel), the maximum daily dosage of naltrexone/bupropion is 2 tablets (i.e., one tablet twice daily).1

Inducers of CYP2B6

Concomitant use of naltrexone/bupropion with CYP2B6 inducers (e.g., carbamazepine, efavirenz, lopinavir, phenobarbital, phenytoin, ritonavir) may result in decreased systemic exposure of bupropion and potentially reduced efficacy of naltrexone/bupropion.1 Concomitant use of bupropion and ritonavir (100 mg twice daily for 17 days or 600 mg twice daily for 8 days) or the fixed combination of lopinavir and ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 14 days) has resulted in decreased systemic exposure of bupropion and its metabolites.1 Concomitant administration of efavirenz (600 mg once daily for 2 weeks) and bupropion decreased peak plasma concentrations and AUC of bupropion by 55 and 34%, respectively, increased peak plasma concentrations of hydroxybupropion by 50%, but had no substantial effect on hydroxybupropion AUC.1

The manufacturer states that concomitant use of naltrexone/bupropion and CYP2B6 inducers should be avoided.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Bupropion and its metabolites hydroxybupropion, erythrohydrobupropion, and threohydrobupropion inhibit CYP2D6 and may increase systemic exposure of other drugs metabolized by CYP2D6 including certain antidepressants (e.g., SSRIs, tricyclic antidepressants), antipsychotic agents (e.g., haloperidol, risperidone, thioridazine), β-adrenergic blocking agents (e.g., metoprolol), and class IC antiarrhythmic agents (e.g., flecainide, propafenone).1 When the CYP2D6 substrate metoprolol (single 50-mg dose) was administered concomitantly with the fixed combination naltrexone/bupropion (16 mg of naltrexone/180 mg of bupropion twice daily) in healthy individuals, AUC and peak plasma concentrations of metoprolol were increased four- and twofold, respectively.1 Similar pharmacokinetic interactions have been observed with concomitant use of bupropion and the CYP2D6 substrates desipramine and venlafaxine.1

If a CYP2D6 substrate is initiated in a patient receiving naltrexone/bupropion, the CYP2D6 substrate should be initiated at the lower end of the recommended dosage range.1 If naltrexone/bupropion is initiated in a patient receiving a CYP2D6 substrate, dosage reduction of the CYP2D6 substrate should be considered, particularly if the drug has a narrow therapeutic index.1

Drugs Affecting the Seizure Threshold

Naltrexone/bupropion should be used with extreme caution in patients receiving concomitant therapy with other drugs that lower the seizure threshold (e.g., antidepressants, antipsychotics, systemic corticosteroids, theophylline).1 Naltrexone/bupropion therapy should be initiated with a low dosage in such patients and dosage should be increased gradually.1 Naltrexone/bupropion is contraindicated patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs.1

Alcohol

Adverse neuropsychiatric events or reduced alcohol tolerance have been reported rarely in patients who ingested alcohol during bupropion therapy.1 Because excessive use or abrupt discontinuation of alcohol can increase the risk of seizure, consumption of alcohol should be minimized or avoided during therapy with naltrexone/bupropion.1 Naltrexone/bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.1

Atorvastatin

Concomitant use of atorvastatin and naltrexone/bupropion does not result in clinically important interactions.1 Dosage adjustments are not needed in patients receiving these drugs concurrently.1

Cimetidine

Concomitant use of cimetidine and bupropion does not substantially affect the pharmacokinetics of bupropion.1 Dosage adjustment of naltrexone/bupropion is not needed in patients receiving cimetidine.1

Citalopram

Concomitant use of citalopram (40 mg once daily for 14 days) and bupropion (300 mg of an extended-release formulation once daily for 14 days) increased AUC and peak plasma concentrations of citalopram by 40 and 30%, respectively; systemic exposures of bupropion or its metabolites were not affected.1 In patients receiving naltrexone/bupropion, citalopram should be initiated at the lower end of the recommended dosage range.1 If naltrexone/bupropion is initiated in a patient receiving citalopram, dosage reduction of citalopram should be considered.1 Dosage adjustment of naltrexone/bupropion is not necessary.1

Clopidogrel

Concomitant use of clopidogrel (75 mg once daily for 4 days) and bupropion increased AUC and peak plasma concentrations of bupropion by 60 and 40%, respectively, and decreased AUC and peak plasma concentrations of hydroxybupropion by 52 and 50%, respectively.1 If naltrexone/bupropion is used concomitantly with clopidogrel, dosage of naltrexone/bupropion should not exceed 2 tablets daily (one tablet twice daily).1

Desipramine

Concomitant use of desipramine (single 50-mg dose) and bupropion (150 mg twice daily for 10 days) increased desipramine AUC and peak plasma concentrations five- and twofold, respectively.1 In patients receiving naltrexone/bupropion, desipramine should be initiated at the lower end of the recommended dosage range.1 If naltrexone/bupropion is initiated in a patient receiving desipramine, dosage reduction of desipramine should be considered.1

Digoxin

Concomitant use of naltrexone/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 naltrexone/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 naltrexone/bupropion is used concomitantly with dopaminergic drugs such as levodopa or amantadine; patients should be monitored for adverse reactions.1

Glyburide

Concomitant use of glyburide (single 6-mg dose) and naltrexone/bupropion resulted in twofold increases in naltrexone AUC and peak plasma concentrations, and a 36 and 22% increase in bupropion and hydroxybupropion AUC, respectively; pharmacokinetics of glyburide were not affected.1 Naltrexone/bupropion should be used with caution in patients concurrently receiving glyburide.1 In addition, weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus receiving glyburide; blood glucose concentrations should be monitored and dosage reduction of glyburide should be considered.1

Lamotrigine

Concomitant use of lamotrigine and bupropion does not affect the pharmacokinetics lamotrigine.1 Dosage adjustment of lamotrigine is not needed in patients receiving naltrexone/bupropion.1

Lisinopril

Concomitant use of lisinopril and naltrexone/bupropion does not result in clinically important interactions.1 Dosage adjustments are not needed in patients receiving these drugs concurrently.1

Metformin

No effects on bupropion or naltrexone pharmacokinetics were observed with concomitant administration of naltrexone/bupropion and metformin.1 No dosage adjustment of metformin or naltrexone/bupropion is necessary.1

Metoprolol

Concomitant use of metoprolol (single 50-mg dose) and naltrexone/bupropion increased metoprolol AUC and peak plasma concentrations four- and twofold, respectively and decreased naltrexone AUC and peak plasma concentrations by 25 and 29%, respectively; pharmacokinetics of bupropion were not affected.1 In patients receiving naltrexone/bupropion, metoprolol should be initiated at the lower end of the recommended dosage range.1 If naltrexone/bupropion is initiated in a patient receiving metoprolol, dosage reduction of metoprolol should be considered.1 Dosage adjustment of naltrexone/bupropion is not necessary.1

Monoamine Oxidase Inhibitors

Concomitant use of bupropion and monoamine oxidase (MAO) inhibitors can increase the risk of hypertensive reactions.1 In animals, phenelzine enhanced the acute toxicity of bupropion.1 Concomitant use of bupropion and MAO inhibitors is contraindicated; at least 2 weeks should elapse between discontinuance of an MAO inhibitor and initiation of naltrexone/bupropion and vice versa.1 Initiation of naltrexone/bupropion in a patient treated with reversible MAO inhibitors such as linezolid or IV methylene blue also is contraindicated.1

Nifedipine

Concomitant use of nifedipine and naltrexone/bupropion resulted in increased systemic exposure of naltrexone; pharmacokinetics of bupropion and nifedipine were not affected.1 Dosage adjustments are not needed in patients receiving nifedipine and naltrexone/bupropion concurrently.1

Opiate Agonists

Patients receiving naltrexone/bupropion may not benefit therapeutically from opiate-containing preparations, including those used for the management of cough and cold, diarrhea, and pain.1 Naltrexone/bupropion is contraindicated in patients requiring chronic opiate therapy.1 In patients requiring intermittent opiate therapy, naltrexone/bupropion should be temporarily discontinued.1 Patients may be more sensitive to opiates following discontinuance of naltrexone/bupropion.1 In such patients, recommended dosages of opiates should not be exceeded and lower dosages of the opiate may be necessary.1 Because naltrexone can precipitate opiate withdrawal, naltrexone/bupropion should be used with caution only after chronic opiate therapy has been discontinued for at least 7-10 days in patients who may be dependent on short-acting opiates or up to 2 weeks in patients previously treated with buprenorphine or methadone.1

Prasugrel

Concomitant use of prasugrel (10 mg once daily for 6 days) and bupropion increased AUC and peak plasma concentrations of bupropion by 18 and 14%, respectively, and decreased AUC and peak plasma concentrations of hydroxybupropion by 21 and 32%, respectively.1 The manufacturer states that dosage adjustment of naltrexone/bupropion is not necessary if used concomitantly with prasugrel.1

Ticlopidine

Concomitant use of ticlopidine (250 mg twice daily for 4 days) and bupropion increased AUC and peak plasma concentrations of bupropion by 85 and 38%, respectively, and decreased AUC and peak plasma concentrations of hydroxybupropion by 84 and 78%, respectively.1 If naltrexone/bupropion is used concomitantly with ticlopidine, dosage of naltrexone/bupropion should not exceed 2 tablets daily (one tablet twice daily).1

Valsartan

Concomitant use of valsartan and naltrexone/bupropion does not result in clinically important interactions.1 Dosage adjustments are not needed in patients receiving these drugs concurrently.1

Other Information ⬆ ⬇

Description

Naltrexone/bupropion is a fixed combination extended-release preparation consisting of naltrexone, an opiate antagonist, and bupropion, an aminoketone antidepressant agent with weak dopamine and norepinephrine reuptake inhibitor properties; the fixed combination preparation is an anorexigenic agent.1,8 The precise mechanism of action of naltrexone/bupropion in producing weight loss has not been fully elucidated.1 Both drugs appear to decrease food intake through independent but complementary effects on two areas of the brain involved in regulating food intake: the hypothalamic melanocortin system and the mesolimbic dopamine system (reward system).1,8 The drugs have been shown in animal studies to produce a synergistic effect on food intake when combined.8

Following single-dose, oral administration of the fixed-combination naltrexone hydrochloride and bupropion hydrochloride extended-release tablets in healthy individuals, peak plasma concentrations of naltrexone and bupropion occur at 2 and 3 hours, respectively.1 When administered with a high fat meal, AUC and peak plasma concentrations of naltrexone and bupropion are increased 2.1- and 3.7-fold, respectively, and 1.4- and 1.8-fold, 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 Naltrexone is metabolized to its major active metabolite, 6-β-naltrexol, through non-CYP pathways.1 Both naltrexone and bupropion are excreted primarily in the urine, mainly as metabolites; less than 2% of an oral dose of naltrexone is excreted in urine as unchanged drug and 0.5% of an oral dose of bupropion is excreted as unchanged drug.1 Following single-dose administration of the fixed-combination naltrexone hydrochloride and bupropion hydrochloride extended-release tablet, elimination half-lives of naltrexone and bupropion, are approximately 5 and 21 hours, respectively.1

Advice to Patients

Advise patients to take naltrexone/bupropion exactly as prescribed and not to take more than the recommend dosage.1 Inform patients that the dosage of naltrexone/bupropion should be titrated according to the weekly schedule when initiating therapy.1
Inform patients that naltrexone/bupropion can be taken with or without food; however the drug should not be taken with a high-fat meal.1 Advise patients to swallow naltrexone/bupropion tablets whole and not to chew, cut, crush the tablets.1
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.1
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^®).1
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.1 Advise patients to discontinue naltrexone/bupropion and notify a clinician if they experience such symptoms or sudden changes in mood, behavior, thoughts or feelings.1
Risk of seizures, particularly in patients with certain medical conditions, those taking certain drugs concomitantly, and those receiving higher dosages of bupropion.1 Advise patients to permanently discontinue naltrexone/bupropion and notify a clinician if they have a seizure.1
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.1
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.1
Risk of increased blood pressure and heart rate.1 Advise patients to inform a clinician if they experience increased blood pressure or heart rate during naltrexone/bupropion therapy.1
Risk of hypersensitivity reactions.1 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.1
Risk of hepatotoxicity.1 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.1
Advise patients that bupropion can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.1 Possible symptoms include eye pain, vision changes, and swelling or redness in or around the eye.1 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.1 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.1
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.1
Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1
Advise 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.

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Table 1. Naltrexone/Bupropion Dosage Titration Schedule1

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Naltrexone Hydrochloride and Bupropion Hydrochloride

Copyright ⬆ ⬇

References ⬆