Naltrexone / Bupropion (Contrave)

1. Health Canada Product Monograph — Naltrexone / Bupropion

• Naltrexone / Bupropion is indicated, along with a reduced-calorie diet and increased physical activity, for chronic weight management in adults with a body mass index of 30 kg/m² or greater, or 27 kg/m² or greater with at least one weight-related condition such as controlled high blood pressure, type 2 diabetes, or high cholesterol.
• Treatment should be reassessed after 12 weeks at the full maintenance dose, and stopped if the patient has not lost at least 5% of their starting body weight, since continuing is unlikely to produce meaningful further weight loss.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Naltrexone / Bupropion should not be used during pregnancy, because weight loss offers no benefit to a pregnant woman and could harm the developing baby.
• A minimum weight gain, not weight loss, is recommended for all pregnant women, including those who are overweight or obese.

• Naltrexone / Bupropion should not be used while breastfeeding, since both naltrexone and bupropion, along with their breakdown products, pass into human breast milk.

• Clinical studies of Naltrexone / Bupropion did not include enough patients aged 65 and older to know whether they respond differently, but older adults may be more sensitive to central nervous system side effects and to reduced kidney function, so this medicine should be used with caution in this age group.

• Naltrexone / Bupropion is not approved for use in patients under 18 years of age, since no data are available in this population.

• Dosing is increased gradually over 4 weeks: one tablet in the morning only during week 1, one tablet morning and evening during week 2, two tablets in the morning and one in the evening during week 3, and two tablets twice daily (the full maintenance dose) from week 4 onward.
• The maximum daily dose is two tablets twice daily, for a total of 32 mg naltrexone and 360 mg bupropion.
• In moderate or severe kidney impairment, the maximum recommended daily dose is one tablet in the morning and one in the evening.
• In mild or moderate liver impairment, the maximum recommended daily dose is one tablet in the morning only.
• When combined with a CYP2B6 inhibitor, such as ticlopidine or clopidogrel, the maximum recommended daily dose is one tablet in the morning and one in the evening.
• Tablets should not be cut, chewed, or crushed.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• There is no clinical experience with overdose of the combination product, but the bupropion component is expected to cause the most serious effects.
• Bupropion overdose has been associated with seizures in about one-third of reported cases.
• Other reported effects of bupropion overdose include hallucinations, loss of consciousness, a fast heart rhythm, abnormal ECG changes, fever, muscle rigidity, muscle breakdown, low blood pressure, and, in severe or multi-drug cases, coma and breathing failure.
• Naltrexone alone has shown low toxicity even at doses far higher than the recommended daily amount.
• There is no specific antidote; treatment includes airway support, heart monitoring, and activated charcoal if given soon after ingestion.

• Nausea is very common, especially during the first few weeks of treatment.
• Constipation is common.
• Vomiting is common.
• Headache is common.
• Dizziness is common.
• Dry mouth is common.
• Diarrhea may occur.
• Tremor may occur.
• Excessive sweating may occur.
• Insomnia may occur.
• Hot flushes may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Seizures can occur, and the risk increases with higher doses; this medicine should be stopped and not restarted if a seizure occurs.
• Increases in blood pressure and heart rate can occur, particularly in the first three months of treatment.
• Bupropion carries an increased risk of suicidal thinking and behaviour, similar to other antidepressant-related medicines, even though this product is not used to treat depression.
• Serious allergic reactions, including hives, swelling, and difficulty breathing, have been reported.
• Severe skin reactions, including cutaneous or systemic lupus-like reactions, have been reported.
• Liver injury, including hepatitis, has been reported.
• Serotonin syndrome, a potentially life-threatening condition with symptoms such as agitation, high fever, and muscle twitching, can occur, particularly when combined with other serotonergic medicines.
• Unmasking of an underlying heart rhythm disorder called Brugada syndrome has been reported.
• If this medicine is used to try to overcome its own opioid-blocking effect by taking large amounts of opioids, this can result in life-threatening opioid overdose.
• Seek urgent medical attention for a seizure, chest pain, severe allergic reaction, thoughts of self-harm, or fainting.

• Use with caution in patients with high blood pressure that is already controlled, and blood pressure and pulse should be checked before starting and monitored during treatment.
• Use with caution in patients with risk factors for seizures, including head injury, prior seizure, excessive alcohol use, or low blood sugar.
• Use with caution in patients with type 2 diabetes treated with insulin or medicines that can cause low blood sugar, since weight loss can increase this risk.
• Use with caution in patients taking other medicines that lower the seizure threshold, such as antipsychotics, other antidepressants, theophylline, or systemic steroids.
• Use with caution in patients with mild-to-moderate liver or kidney impairment, since dose reduction is needed.
• Use with caution in older adults, who may be more sensitive to central nervous system side effects.
• Avoid alcohol, and avoid stopping alcohol, benzodiazepines, or other sedatives abruptly while on this medicine, due to seizure risk.

• Contraindicated in patients with uncontrolled high blood pressure.
• Contraindicated in patients with a current seizure disorder or history of seizures.
• Contraindicated in patients using other bupropion-containing products, such as Wellbutrin or Zyban.
• Contraindicated in patients with a current or past diagnosis of bulimia or anorexia nervosa.
• Contraindicated in patients using chronic opioids or opiate agonists or partial agonists, or in acute opioid withdrawal.
• Contraindicated during abrupt withdrawal from alcohol, benzodiazepines, other sedatives, or antiepileptic drugs.
• Contraindicated with concurrent use of monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping one.
• Contraindicated with concurrent use of the antipsychotic thioridazine.
• Contraindicated during pregnancy.
• Contraindicated in severe liver impairment.
• Contraindicated in end-stage kidney failure.
• Contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

• Combining with a monoamine oxidase inhibitor (MAOI) is contraindicated and can cause a dangerous rise in blood pressure.
• Because of the naltrexone component, patients taking this medicine may not get the intended effect from opioid-containing medicines, such as cough and cold products, antidiarrheal medicines, or opioid painkillers.
• Combining with other medicines that lower the seizure threshold, such as antipsychotics, antidepressants, theophylline, lithium, or systemic steroids, increases seizure risk and requires caution.
• Combining with levodopa or amantadine can cause central nervous system toxicity, including confusion, agitation, and tremor.
• Bupropion inhibits the CYP2D6 liver enzyme, which can raise levels of drugs processed by that enzyme, such as certain antidepressants and heart medicines.
• Combining with tamoxifen may reduce tamoxifen's effectiveness, since bupropion interferes with the enzyme needed to activate it.
• Combining with the antipsychotic thioridazine is contraindicated, since bupropion can raise thioridazine levels and increase the risk of dangerous heart rhythm problems.
• Drugs that inhibit the CYP2B6 enzyme, such as ticlopidine or clopidogrel, can raise levels of this medicine and require a lower maximum dose.
• Alcohol use should be minimized or avoided, since it may increase the risk of neuropsychiatric side effects or seizures.

• This medicine should be taken with a meal, since clinical trials used it with food, but a high-fat meal should be avoided because it significantly increases the amount of both active ingredients absorbed into the body and raises the risk of side effects, including seizures.

• Naltrexone / Bupropion is taken twice daily, once in the morning and once in the evening, with a meal that is not high in fat, and should be taken at consistent times each day.

• Store at room temperature, between 15°C and 25°C.
• Keep out of the sight and reach of children.

• Naltrexone / Bupropion is used alongside diet and exercise for long-term weight management, with the dose increased gradually over four weeks to reduce side effects.
• Take this medicine with a meal, but avoid high-fat meals, since they increase the amount absorbed and raise the risk of seizures.
• Do not use opioid pain or cough-and-cold medicines while on this medicine without checking with your pharmacist, since the naltrexone component can block their effects or trigger withdrawal in opioid-dependent patients.
• Contact your doctor right away if you notice a seizure, unusual mood changes, or thoughts of self-harm.