CONTRAVE is a combination of naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant, indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

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30 kg/m 2 or greater (obese) or

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27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). ( 1)

Limitations of Use:

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The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. ( 1)

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The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription and over-the-counter drugs, and herbal preparations, have not been established. ( 1)
DOSAGE AND ADMINISTRATION

CONTRAVE dose escalation schedule (2.1):

Extended-Release Tablets: 8 mg naltrexone HCl /90 mg bupropion HCl (3)
CONTRAINDICATIONS

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Uncontrolled hypertension ( 4)

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Seizure disorders, anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs ( 4)

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Use of other bupropion-containing products ( 4)

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Chronic opioid use ( 4)

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During or within 14 days of taking monoamine oxidase inhibitors (MAOI) ( 4)

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Known allergy to any of the ingredients in CONTRAVE ( 4)

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Pregnancy ( 4)

WARNINGS AND PRECAUTIONS

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Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue CONTRAVE if symptoms develop. ( 5.1)

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Risk of seizure may be minimized by adhering to the recommended dosing schedule and avoiding coadministration with high-fat meal. ( 5.3)

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Increase in Blood Pressure and Heart Rate: Monitor blood pressure and heart rate in all patients, especially those with cardiac or cerebrovascular disease. ( 5.5)

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Hepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction observed with naltrexone exposure. ( 5.7)

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Angle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9)

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Use of Antidiabetic Medications: Weight loss may cause hypoglycemia. Monitor blood glucose. ( 5.10)

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Most common adverse reactions (greater than or equal to 5%): nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly. ( 7.1)

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Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants, (e.g., selective serotonin reuptake inhibitors and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide): Consider dose reduction when using with CONTRAVE. ( 7.3)

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Concomitant Treatment with CYP2B6 Inhibitors (e.g., ticlopidine or clopidogrel) can increase bupropion exposure. Do not exceed one tablet twice daily when taken with CYP2B6 inhibitors. ( 2.5, 7.4)

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CYP2B6 Inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure, avoid concomitant use. ( 7.4)

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Drugs that Lower Seizure Threshold: Dose CONTRAVE with caution. ( 5.3, 7.5)

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Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with CONTRAVE. ( 7.6)

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Drug-Laboratory Test Interactions: CONTRAVE can cause false-positive urine test results for amphetamines. ( 7.8)

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Nursing Mothers: Discontinue drug or nursing. ( 8.3)

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Pediatric Use: Safety and effectiveness not established and use not recommended. ( 8.4)