Contrave

Contrave is a combination of the drugs naltrexone (an anti-addiction drug) and bupropion (an antidepressant).

Contrave is used along with diet and exercise to help people lose weight and keep weight off.

According to the Centers for Disease Control and Prevention (CDC), more than one-third of adults in the United States are obese.

Contrave is approved to use in obese adults with a body mass index (BMI) of 30 or greater. Your BMI is calculated by dividing your weight (in kg) by the square of your height (in meters).

It's also approved for overweight adults with a BMI of 27 or greater who have more than one weight-related medical condition, such as high blood pressure, high cholesterol, or diabetes.

The Food and Drug Administration (FDA) approved Contrave in 2014. It's manufactured by Takeda Pharmaceuticals, Inc.

According to the FDA, results from a clinical trial of patients without diabetes showed that those who took Contrave had an average weight loss of 4.1 percent more than those who were treated with a placebo at one year.

Contrave Black-Box Warning

Contrave contains a black-box warning to alert patients about an increased risk of suicidal thoughts and actions. The ingredient bupropion has been linked to these behaviors.

You should stop taking this medicine and tell your doctor right away if you experience any of the following:

• Thoughts about dying or suicide
• Suicide attempts
• Depression
• Anxiety
• Agitation or restlessness
• Panic attacks
• Insomnia
• Irritability
• Aggressive actions
• Becoming angry or violent
• Acting on dangerous impulses
• Any unusual changes in mood or behavior

Contrave isn't approved for use in children under age 18.

You shouldn't take Contrave if you:

• Have or have had seizures
• Have uncontrolled high blood pressure
• Use other drugs that contain bupropion (such as Wellbutrin)
• Are dependent on opioid pain drugs, are in opiate withdrawal, or use medications to help stop opioid use (such as methadone or buprenorphine)
• Have or have had an eating disorder such as bulimia or anorexia
• Drink large amounts of alcohol and suddenly stop drinking (this can increase chances of seizures)
• Use sedatives, benzodiazepines, or anti-seizure drugs and stop suddenly
• Have taken a monoamine oxidase inhibitor (MAOI) in the last 14 days. These include isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Emsam, Eldepryl, Zelapar), and tranylcypromine (Parnate).

Contrave can cause an increase in blood pressure, an increased heart rate, and an increased risk for seizures. It's not known if Contrave changes your risk of heart problems or stroke.

The medicine can also cause liver damage or hepatitis.

You should stop taking Contrave if you experience stomach pain lasting more than a few days, yellowing of the eyes or skin, dark-colored urine, or extreme fatigue.

Contrave may also cause an eye problem known as angle-closure glaucoma.

You should tell your doctor right away if you experience eye pain, vision changes, or swelling or redness in or around the eye.

The drug may also increase the risk of a low blood sugar episode in people with type 2 diabetes who also take certain drugs to treat their disease.

You should check your blood sugar levels before starting and while taking Contrave.

You should tell your doctor about any medical condition you have before taking Contrave, especially the following:

• Depression or any mental illness
• Seizures
• Head injuries
• A tumor or infection of your brain or spine
• Low blood sugar
• Low levels of sodium in your blood
• Liver or kidney problems
• High blood pressure
• Heart problems or stroke
• Eating disorders

Pregnancy and Contrave

Contrave is an FDA Pregnancy Category X drug, which means it can cause severe harm to an unborn baby.

Do not take Contrave if you are pregnant or plan to become pregnant.

Talk to your doctor before taking this medicine if you're breastfeeding, or if you're already taking Contrave and are considering breastfeeding.

You should tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially those listed in the Warning section.

Contrave interacts with dozens of other drugs. The most severe drug interactions have been found with the following:

• Rasagiline (Azilect)
• Selegiline (Emsam)
• Isocarboxazid (Marplan)
• Phenelzine (Nardil)
• Pimozide (Orap)
• Eliglustat (Cerdelga)
• Tranylcypromine (Parnate)

Contrave and Alcohol

You should avoid consuming large amounts of alcohol while taking Contrave.

Contrave and Other Interactions

You shouldn't take Contrave with high-fat meals, as this can increase your risk of seizures.

Contrave comes as an extended-release tablet to take by mouth. It contains 8 milligrams (mg) of naltrexone HCl and 90 mg of bupropion HCl.

Your doctor will likely start you on a low dose of the medicine and gradually increase it.

Take this medicine exactly as it's prescribed. Don't take more or less of the drug than is recommended.

You shouldn't take more than four tablets in one day.

Swallow the tablets whole. Don't chew, cut, or crush them.

Contrave Overdose

If you suspect an overdose, you should contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at (800) 222-1222.

Missed Dose of Contrave

If you miss a dose of Contrave, wait until your next scheduled time to take it.

Don't take more than one dose at a time.

Contrave is a prescription medication used to assist with weight management in adults who are obese or overweight with weight-related medical problems. It must be used along with a healthy diet and exercise plan.

It is a single product containing 2 medications: naltrexone and bupropion. Naltrexone belongs to a group of drugs called opioid antagonists. These are believed to work by decreasing appetite. Bupropion belongs to a group of drugs called antidepressants. These work by increasing the activity of certain chemicals in the reward pathways of the brain. The exact ways in which naltrexone and bupropion help in weight loss are not understood.

This medication comes in extended-release tablet form and is taken 2 times a day, in the morning and in the evening. Do not take Contrave with high-fat meals. Do not chew, crush, or cut the tablets.

Common side effects of Contrave include nausea, constipation, headache, vomiting, insomnia, dry mouth, and diarrhea.

Contrave can also cause changes in vision, drowsiness, and dizziness. Do not drive or operate heavy machinery until you know how Contrave affects you.

Take Contrave exactly as prescribed.

This medication comes in extended-release tablet form and is taken 2 times a day, in the morning and in the evening. Do not take Contrave with high-fat meals. Do not take Contrave with high-fat meals. Do not chew, crush, or cut the tablets.

You should minimize or avoid drinking alcohol while taking Contrave.

If you miss a dose, take the missed dose at your next scheduled time. Do not take 2 doses of Contrave at the same time.

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended. Do not crush, chew, or break the tablet. Swallow it whole. Do not take more than 2 tablets at once.

Do not take this medicine with a high-fat meal, or you may be more likely to have a seizure.

If you need to use narcotic medicine for any reason (such as pain, surgery, or treatment for drug addiction) you may need to stop taking bupropion and naltrexone for a short time. Follow your doctor's dosing instructions very carefully.

Store at room temperature away from moisture and heat.

If you have not lost at least 5% of your starting weight after 16 weeks of treatment, this medicine may not be right for you.

Recommended Dosing

Contrave dosing should be escalated according to the following schedule:

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.

Contrave should be taken by mouth in the morning and in the evening. The tablets should not be cut, chewed, or crushed. Total daily doses greater than 32 mg/360 mg per day (two tablets twice daily) are not recommended. 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Patients may develop elevated blood pressure or heart rate during Contrave treatment; the risk may be greater during the initial three months of therapy [see Warnings and Precautions (5.6)]. 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.

BMI is calculated by dividing weight (in kg) by height (in meters) squared. A BMI chart for determining BMI based on height and weight is provided in Table 1.

Table 1. BMI Conversion Chart

Dose Adjustment in Patients with Renal Impairment

In patients with moderate or severe renal impairment, the maximum recommended daily dose for Contrave is two tablets (one tablet each morning and evening). Contrave is not recommended for use in patients with end-stage renal disease. There is a lack of adequate information to guide dosing in patients with mild renal impairment [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)].

Dose Adjustment in Patients with Hepatic Impairment

In patients with hepatic impairment, the maximum recommended daily dose of Contrave is one tablet in the morning [see Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with Contrave. Conversely, at least 14 days should be allowed after stopping Contrave before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.1)].

Concomitant Use with CYP2B6 Inhibitors

During concomitant use with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel), the maximum recommended daily dose of Contrave is two tablets (one tablet each morning and evening) [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

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

Contrave is contraindicated in

• Uncontrolled hypertension [see Warnings and Precautions (5.5)]
• Seizure disorder or a history of seizures [see Warnings and Precautions (5.3)]
• Use of other bupropion-containing products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN)
• Bulimia or anorexia nervosa, which increase the risk for seizure [see Warnings and Precautions (5.3)]
• Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal [see Warnings and Precautions (5.4) and Drug Interactions (7.2)]
• Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3) and Drug Interactions (7.7)]
• Concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with Contrave. There is an increased risk of hypertensive reactions when Contrave is used concomitantly with MAOIs. Starting Contrave in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated [see Dosage and Administration (2.4), Drug Interactions (7.1)]
• Known allergy to bupropion, naltrexone or any other component of Contrave.
  Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion [see Warnings and Precautions (5.6)]
• Pregnancy [see Use in Specific Populations (8.1)]

Abuse

Humans

Contrave (naltrexone HCl and bupropion HCl) has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. However, in outpatient clinical studies of up to 56 weeks in duration, there was no evidence of euphoric drug intoxication, physical dependence, diversion, or abuse. There was no evidence of an abstinence syndrome following abrupt or tapered drug discontinuation after 56 weeks of double-blind, placebo-controlled, randomized treatment.

Naltrexone is a pure opioid antagonist. It does not lead to physical or psychological dependence. Tolerance to the opioid antagonistic effect is not known to occur.

Controlled clinical trials of bupropion (immediate-release formulation) conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement. In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.

Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers.

The inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection. Contrave (naltrexone HCl and bupropion HCl) extended-release tablets are intended for oral use only.

Animals

Studies in rodents and primates have shown that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increased rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

Contrave 8 mg/90 mg (naltrexone HCl 8 mg and bupropion HCl 90 mg) extended-release, tri-layer tablets are blue, round, bi-convex, film-coated tablets debossed with "NB-890" on one side. Contrave tablets are available as follows:

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Get emergency medical help if you have signs of an allergic reaction to Contrave: fever, swollen glands, mouth sores, muscle or joint pain; hives, rash or itching; chest pain, difficult breathing; swelling of your face, lips, tongue, or throat.

A person caring for you should seek emergency medical attention if you have slow breathing with long pauses, severe drowsiness, or if you are hard to wake up.

Stop taking this medicine and call your doctor right away if you have:

• a seizure (convulsions);

• blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;

• changes in mood or behavior - anxiety, depression, panic attacks, trouble sleeping, agitation, thoughts about suicide or hurting yourself;

• a manic episode - racing thoughts, increased energy, unusual risk-taking behavior, extreme happiness, being irritable or talkative;

• liver problems - upper stomach pain, tiredness, dark urine, jaundice (yellowing of the skin or eyes);

• increased blood pressure - severe headache, blurred vision, pounding in your neck or ears, anxiety, nosebleed; or

• severe skin reaction - fever, mouth or throat pain, burning eyes, skin pain, red or purple rash that spreads and causes blisters and peeling.

Older adults may be more likely to have certain side effects.

Common Contrave side effects may include:

• nausea, vomiting, diarrhea, constipation;

• headache, dizziness;

• dry mouth; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.