Contrave

— THERAPEUTIC CATEGORIES —
  • Obesity
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Contrave Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Naltrexone HCl, bupropion HCl 8mg/90mg; ext-rel tabs.

    Pharmacological Class

    Opioid antagonist + aminoketone.

    How Supplied

    Tabs—120

    How Supplied

    Contrave 8mg/90mg extended-release tablets are blue, round, bi-convex, film-coated tablets debossed with “NB-890” on one side.

    • Bottles of 120

    Storage

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

    Manufacturer

    Currax Pharmaceuticals LLC

    Generic Availability

    NO

    Mechanism of Action

    Contrave has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of Contrave leading to weight loss are not fully understood.

    Contrave Indications

    Indications

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

    Limitations of Use

    The effect on cardiovascular morbidity and mortality has not been established. Safety and efficacy in combination with other weight loss products, including Rx or OTC drugs, and herbal preps, have not been established.

    Contrave Dosage and Administration

    Adult

    Swallow whole. Avoid high-fat meals. Escalate dose gradually. ≥18yrs: Week 1: 1 tab daily in the AM; Week 2: 1 tab daily in the AM and 1 tab daily in the PM; Week 3: 2 tabs in the AM and 1 tab in the PM; Week 4 and thereafter: 2 tabs in the AM and 2 tabs in the PM. Max 32mg/360mg per day. Evaluate response after 12 weeks. Discontinue if ≥5% weight loss is not achieved. Concomitant CYP2B6 inhibitors (eg, ticlopidine, clopidogrel), renal impairment (moderate or severe), hepatic impairment (moderate): max 2 tabs daily (1 tab each AM & PM).

    Adult

     ≥18yrs: Escalate dose according to the following schedule:

    • Week 1: 1 tab daily in the AM; 

    • Week 2: 1 tab daily in the AM and 1 tab daily in the PM; 

    • Week 3: 2 tabs in the AM and 1 tab in the PM; 

    • Week 4 - Onward: 2 tabs in the AM and 2 tabs in the PM. 

    A total daily dosage of two Contrave 8 mg/90 mg tablets twice daily (32 mg/360 mg) is reached at the start of Week 4.

    Total daily doses greater than 32 mg/360 mg per day (two tablets twice daily) are not recommended. 

    Because patients with hypertension may be at increased risk for developing blood pressure elevations, such patients should be monitored for this potential effect when initiating treatment with Contrave. 

    Response to therapy should be evaluated after 12 weeks at the maintenance dosage. If a patient has not lost at least 5% of baseline body weight, discontinue Contrave, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. 

    Children

    <18yrs: not recommended.

    Administration

    Contrave should be taken by mouth in the morning and in the evening. The tablets should not be cut, chewed, or crushed.  

    In clinical trials, Contrave was administered with meals. However, Contrave should not be taken with a high-fat meal because of a resulting significant increase in bupropion and naltrexone systemic exposure.

    Contrave Contraindications

    Contraindications

    Uncontrolled hypertension. Seizure disorder. Concomitant other bupropion-containing products. Bulimia. Anorexia nervosa. Use of chronic opioid or opiate agonist (eg, methadone), or partial agonists (eg, buprenorphine). Acute opiate withdrawal. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptics. During or within 14 days of discontinuing MAOIs. Concomitant linezolid or IV methylene blue.

    Contrave Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Boxed Warning

    Suicidal thoughts and behaviors

    Contrave is not approved for use in the treatment of major depressive disorder or other psychiatric disorders. Contrave contains bupropion, the same active ingredient as some antidepressant medications (including, but not limited to, Wellbutrin, Wellbutrin SR, Wellbutrin XL, and Aplenzin). 

    Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients >24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on Contrave, monitor closely for worsening, and for the emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.

    Contrave is not approved for use in pediatric patients.

    Contrave Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults; monitor for clinical worsening or unusual changes in all patients. Monitor for neuropsychiatric reactions; discontinue if occurs. Increased risk of seizures with predisposing risk factors (eg, history of head trauma, prior seizure, severe stroke, arteriovenous malformation, CNS tumor or infection, others: see full labeling); discontinue if seizure occurs and do not restart. Diabetes. Hypoglycemia. Cardiac or cerebrovascular disease. Monitor BP, pulse, and blood glucose levels prior to starting and during treatment. Risk of hepatic injury; discontinue if signs/symptoms of acute hepatitis occur. Screen for bipolar disorder. Angle-closure glaucoma. ESRD or severe hepatic impairment: not recommended. Elderly. Pregnancy: discontinue if occurs. Nursing mothers.

    Warnings/Precautions

    Suicidal Behavior and Ideation

    Contrave contains bupropion, a dopamine and norepinephrine re-uptake inhibitor that is similar to some drugs used for the treatment of depression.

    Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

    All patients should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Prescriptions for Contrave should be written for the smallest quantity of tablets in order to reduce the risk of overdose.

    Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

    Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events.

    Seizures

    Consider these risks before initiating treatment with Contrave. Contrave is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Caution should be used when prescribing Contrave to patients with predisposing factors that may increase the risk of seizure including:

    • history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (eg, hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia)
    • excessive use of alcohol or sedatives, addiction to cocaine or stimulants, or withdrawal from sedatives 
    • patients with diabetes treated with insulin and/or oral diabetic medications (sulfonylureas and meglitinides) that may cause hypoglycemia 
    • concomitant administration of medications that may lower the seizure threshold, including other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, systemic steroids 

    Patients Receiving Opioid Analgesics 

    Vulnerability to Opioid Overdose:

    • Contrave should not be administered to those receiving chronic opioids, due to the naltrexone component, which is an opioid receptor antagonist.
    • Discontinue Contrave if chronic opiate therapy is required. In those requiring intermittent opiate treatment, Contrave therapy should be temporarily discontinued and lower doses of opioids may be needed.
    • Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after Contrave treatment is discontinued.

    Precipitated Opioid Withdrawal:

    • To prevent occurrence of either precipitated withdrawal in patients dependent on opioids or exacerbation of a pre-existing subclinical withdrawal symptoms, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting Contrave treatment.
    • An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short acting opioids, and those patients transitioning from buprenorphine or methadone may need as long as two weeks.

    Increase in Blood Pressure and Heart Rate 

    Contrave can cause an increase in systolic and/or diastolic blood pressure as well as an increase in resting heart rate. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. The clinical significance of the increases in blood pressure and heart rate observed with Contrave treatment is unclear, especially for patients with cardiac and cerebrovascular disease, since patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure were excluded from Contrave clinical trials. Blood pressure and pulse should be measured prior to starting Contrave; monitor at regular intervals consistent with usual clinical practice, particularly among patients with controlled hypertension prior to treatment.

    Allergic Reactions 

    Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. 

    Hepatotoxicity

    Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone exposure during naltrexone clinical trials and in postmarketing reports for patients using naltrexone. Transient, asymptomatic hepatic transaminase elevations were also observed. Use of Contrave should be discontinued in the event of symptoms and/or signs of acute hepatitis. 

    Activation of Mania 

    Bupropion, a component of Contrave, is a drug used for the treatment of depression. Antidepressant treatment can precipitate a manic, mixed, or hypomanic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiation, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (eg, family history of bipolar disorder, suicide, or depression). 

    Angle-Closure Glaucoma 

    The pupillary dilation that occurs following use of many antidepressant drugs including bupropion, a component of Contrave, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

    Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Antidiabetic Therapy

    Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Measurement of blood glucose levels prior to starting and during Contrave treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Contrave, appropriate changes should be made to the antidiabetic drug regimen. 

    Pregnancy Considerations

    When a pregnancy is recognized, advise the pregnant patient of the risk to the fetus, and discontinue Contrave. Available pharmacovigilance data and data from clinical trials with the individual components of Contrave use in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

    Nursing Mother Considerations

    Data from published literature report the presence of bupropion and its metabolites in human milk. Limited data from postmarketing reports with bupropion use during lactation have not identified a clear association of adverse effects on a breastfed infant. Naltrexone and its major metabolite, 6β-naltrexol, are present in human milk. There are no data on bupropion, naltrexone, or their metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Contrave and any potential adverse effects on the breastfed infant from Contrave or from the mother’s underlying condition.

    Pediatric Considerations

    The safety and effectiveness of Contrave in pediatric patients <18 years of age have not been established and the use of Contrave is not recommended in pediatric patients.

    Geriatric Considerations

    Clinical studies of Contrave did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. 

    Naltrexone and bupropion are known to be substantially excreted by the kidney, and the risk of adverse reactions to Contrave may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Contrave should be used with caution in patients >65 years of age.

    Renal Impairment Considerations

    Contrave is not recommended for use in patients with end-stage renal disease.

    Hepatic Impairment Considerations

    Contrave is not recommended for use in patients with severe hepatic impairment.

    Contrave Pharmacokinetics

    Absorption

    When Contrave was administered with a high-fat meal, the AUC and Cmax for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and Cmax for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and Cmax for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and Cmax for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, Contrave should not be taken with high-fat meals because of the resulting significant increases in bupropion and naltrexone systemic exposure.

    Distribution

    Naltrexone is 21% plasma protein bound. The mean apparent volume of distribution at steady state for naltrexone (Vss/F) is 5,697 liters. 

    Bupropion is 84% plasma protein bound. The mean apparent volume of distribution at steady state for bupropion (Vss/F) is 880 liters.

    Metabolism

    Hepatic.

    Elimination

    Naltrexone:

    Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose). Fecal excretion is a minor elimination pathway. Following single oral administration of Contrave, mean elimination half-life (T½) was ~5 hours for naltrexone. 

    Bupropion:

    Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Following single oral administration of Contrave, mean elimination half-life (T½) was ~21 hours for bupropion.

    Contrave Interactions

    Interactions

    See Contraindications. Vulnerability to opioid overdose with concurrent opioid analgesics; if chronic therapy needed, discontinue Contrave. To prevent precipitation of withdrawal: discontinue chronic opioids 7–10 days prior to initiation. Reduced benefit with opioid-containing drugs (eg, antitussives, antidiarrheals, analgesics). May be potentiated by CYP2B6 inhibitors (see Adults). Avoid concomitant CYP2B6 inducers (eg, ritonavir, lopinavir, efavirenz). Caution with CYP2D6 substrates (eg, tricyclics, SSRIs, antipsychotics [eg, haloperidol, risperidone, thioridazine], β-blockers [eg, metoprolol], Class 1C antiarrhythmics [eg, propafenone, flecainide]); consider dose reduction (esp. drugs with a narrow therapeutic index). Caution with drugs that lower seizure threshold (eg, antipsychotics, antidepressants, theophylline, steroids). Monitor for CNS toxicity with levodopa, amantadine. Avoid alcohol. May antagonize digoxin levels; monitor. Concomitant antidiabetics; adjust dose if hypoglycemia develops. May cause false (+) test results in urine immunoassay for amphetamines.

    Contrave Adverse Reactions

    Adverse Reactions

    Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, diarrhea; allergic reactions.

    Contrave Clinical Trials

    Clinical Trials

    The effects of Contrave on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in double-blind, placebo-controlled trials (BMI range 27 to 45 kg/m2) with study durations of 16 to 56 weeks randomized to naltrexone and/or bupropion or placebo.  

    Four 56-week multicenter, double-blind, placebo-controlled obesity trials (Contrave Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of Contrave in conjunction with lifestyle modification in 4,536 patients randomized to Contrave or placebo. The COR-I, COR-II, and COR-BMOD trials enrolled patients with obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one comorbidity (hypertension or dyslipidemia). The COR-Diabetes trial enrolled patients with BMI >27 kg/m2 with type 2 diabetes with or without hypertension and/or dyslipidemia.

    • COR-I and COR-II included a program consisting of a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioral counseling, and increased physical activity. 
    • COR-BMOD included an intensive behavioral modification program consisting of 28 group counseling sessions over 56 weeks as well as a prescribed diet and exercise regimen.
    • COR-Diabetes evaluated patients with type 2 diabetes not achieving glycemic goal of a HbA1c less than 7% either with oral antidiabetic agents or with diet and exercise alone. 
    • The co-primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight.

    In the COR-I trial, the mean change in body weight was -5.4% among patients assigned to Contrave 32 mg/360 mg compared with -1.3% among those assigned to placebo (Intent-To-Treat [ITT] population). In this trial, the achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with Contrave 32 mg/360 mg compared with placebo (42% vs 17%). 

    In the COR-BMOD trial, the mean change in body weight was -8.1% among patients assigned to Contrave 32 mg/360 mg compared with -4.9% among those assigned to placebo. The achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with Contrave 32 mg/360 mg compared with placebo (57% vs 43%). 

    In the COR-Diabetes trial, the mean change in body weight was -3.7% among patients assigned to Contrave 32 mg/360 mg compared with -1.7% among those assigned to placebo. The achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with Contrave 32 mg/360 mg compared with placebo (36% vs 18%). 

    The percentages of patients who achieved at least 10% body weight loss from baseline were greater among those assigned to Contrave vs placebo, in all four obesity trials. For more clinical trial data, see full labeling.

    Contrave Note

    Not Applicable

    Contrave Patient Counseling

    Patient Counseling

    Inform patients to follow the dose escalation schedule and not to take more than the recommended dose of Contrave. Patients should be made aware that Contrave contains the same active ingredient (bupropion) found in certain antidepressants and smoking cessation products  (including, but not limited to, Wellbutrin, Wellbutrin SR, Wellbutrin XL, Aplenzin and Zyban) and that Contrave should not be used in combination with any other medications that contain bupropion. 

    Advise patients that some individuals have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking bupropion. Instruct patients to discontinue Contrave and contact a healthcare professional if they experience such symptoms. 

    Advise patients of the potential serious risks associated with the use of Contrave, including suicidality, seizures, and increases in blood pressure or heart rate. 

    Advise patients to call their healthcare provider to report new or sudden changes in mood, behavior, thoughts, or feelings. 

    Advise patients that taking Contrave can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (eg, iridectomy), if they are susceptible.

    Educate patients on the symptoms of hypersensitivity and to discontinue Contrave if they have a severe allergic reaction to Contrave.  

    Inform patients that Contrave should be discontinued and not restarted if they experience a seizure while on treatment. 

    Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. 

    Advise patients to minimize or avoid use of alcohol. 

    Advise patients that if they previously used opioids, they may be more sensitive to lower doses of opioids and at risk of accidental overdose should they use opioids after Contrave treatment is discontinued or temporarily interrupted. 

    Advise patients that because naltrexone, a component of Contrave, can block the effects of opioids, they will not perceive any effect if they attempt to self-administer any opioid drug in small doses while on Contrave. Further advise patients that the attempt to administer large doses of any opioid or to bypass the blockade while on Contrave may lead to serious injury, coma, or death. 

    Patients should be off all opioids for a minimum of 7 to 10 days before starting Contrave in order to avoid precipitation of withdrawal. Advise patients they should not take Contrave if they have any symptoms of opioid withdrawal. 

    Advise patients to call their healthcare provider if they experience increased blood pressure or heart rate. 

    Advise patients to notify their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs. Concern is warranted because Contrave and other drugs may affect each other’s metabolism. 

    Advise pregnant patients and all patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if Contrave should be discontinued. 

    Advise patients with type 2 diabetes mellitus on antidiabetic therapy to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s). 

    Cost Savings Program

    The Contrave savings program is available here.

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