CONTRAVE®

• ACRONYMS AND DEFINITIONS

• BMI - Body mass index
• bpm - beats per minute
• SPAQI - Society for Perioperative Assessment and Quality Improvement

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• DRUGS IN CLASS

• Contrave contains bupropion and naltrexone
• Bupropion is a norepinephrine-dopamine reuptake inhibitor. It is the active ingredient in the antidepressant Wellbutrin®.
• Naltrexone is an opioid antagonist used to treat alcohol dependence and opiate overdose

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• MECHANISM OF ACTION

• Appetite suppression
• Contrave contains bupropion and naltrexone
• Bupropion is a norepinephrine-dopamine reuptake inhibitor. It is the active ingredient in the antidepressant Wellbutrin®.
• Naltrexone is an opioid antagonist used to treat alcohol dependence and opiate overdose
• The mechanism by which Contrave suppresses appetite is not completely understood
• 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)

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• FDA-APPROVED INDICATION

• Contrave is indicated for chronic weight management in the following adults:
• Adults with BMI ≥ 30
• Adults with BMI ≥ 27 in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)

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• WEIGHT LOSS

• Overview
• The effects of Contrave on weight loss were studied in the COR II trial detailed below

• Summary
• In the COR II trial, Contrave increased weight loss by about 4.5% when compared to placebo. In a 220 pound patient, this equates to about 10 pounds.
• Based on the COR II trial, providers can expect the following when they prescribe Contrave:
• About half of patients will discontinue the drug
• On average, patients will lose around 6.5% of their body weight at 28 weeks

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• SIDE EFFECTS

• Side effects presented are those that occurred in > 4% of patients or at a difference of ≥ 3% when compared to placebo
• Reference [2]

Common side effects
Side effect	Contrave 16/180 mg twice a day (2545 patients)	Placebo (1515 patients)
Nausea	32.5%	6.7%
Constipation	19.2%	7.2%
Headache	17.6%	10.4%
Vomiting	10.7%	2.9%
Dizziness	9.9%	3.4%
Insomnia	9.2%	5.9%
Dry mouth	8.1%	2.3%
Diarrhea	7.1%	5.2%
Anxiety	4.2%	2.8%
Hot flush	4.2%	1.2%
Fatigue	4.0%	3.4%
Tremor	4.0%	0.7%

• Serum creatinine increase
• In trials, patients taking Contrave had a greater average increase in serum creatinine when compared to patients on placebo (0.07 mg/dl vs 0.01 mg/dl)
• The increase may be related to bupropion's inhibition of organic cation transporter 2 (OCT2) which is involved in tubular secretion of creatinine [2]

• Blood pressure increase
• Contrave may cause an increase in blood pressure
• In trials, average blood pressure was higher in the Contrave group by 1.8 - 2.4/1.7 - 2.1 mmHg during the first 12 weeks of therapy when compared to placebo. Beyond 12 weeks, average blood pressure was 1 mmHg lower than baseline in the Contrave group.

• Heart rate increase
• Contrave may cause an increase in heart rate
• In trials, patients on Contrave had an average heart rate that was approximately 2 bpm higher when compared to placebo

• Liver toxicity
• Naltrexone has been associated with cases of hepatitis in clinical trials. It's unclear if naltrexone was the causative agent in these cases.
• In Contrave trials, there were no cases of elevated transaminases greater than three times the upper limit of normal (ULN) in conjunction with an increase in bilirubin greater than two times ULN.

• Allergic reactions
• Allergic reactions including pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, rare reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also occurred.

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• CONTRAINDICATIONS

• Known hypersensitivity to naltrexone or bupropion
• Uncontrolled hypertension
• Seizure disorder or history of seizure
• Concomitant bupropion products (Wellbutrin®, etc.)
• Bulimia or anorexia nervosa
• Chronic opioid or opiate agonist (e.g., methadone) or partial agonists (e.g., buprenorphine) use, or acute opiate withdrawal
• Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs
• Concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with Contrave.

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• PRECAUTIONS

• Kidney disease
• CrCl ≥ 60 ml/min: no dose adjustment necessary
• CrCl 16 - 59 ml/min: dose should not exceed 1 tablet twice a day
• CrCl ≤ 15 ml/min: DO NOT USE

• Liver disease
• Child-Pugh A: no dose adjustment necessary
• Child-Pugh B: dose should not exceed 1 tablet twice a day
• Child-Pugh C: DO NOT USE

• Older patients
• Psychiatric and sleep disorders may be more common in older patients (≥ 65 years) taking Contrave
• In Contrave trials, 28.6% of patients who were ≥ 65 years reported a psychiatric or sleep disorder compared to 6.3% on placebo

• Suicidal thoughts and behavior
• Antidepressants may increase the risk of suicidal thoughts and behavior
• In placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18 to 24 year olds. There were no suicides in any of the pediatric trials.

• Seizures and epilepsy
• Bupropion may increase the risk of seizure in susceptible patients.
• In trials, the incidence of seizure was 0.1% in Contrave-treated patients compared to 0% in placebo-treated patients
• Contrave is contraindicated in patients with a history of seizures
• Use caution in patients who are at an increased risk of seizure. Risk factors for seizures include history of head trauma, history of stroke, high-risk for hypoglycemia (diabetics on insulin, etc), certain concomitant meds (see drug interactions below), and excessive alcohol and sedative use.

• Opiate pain medication
• Contrave contains naltrexone, an opioid antagonist. Contrave is contraindicated in patients on chronic opioid therapy because it can block analgesia and precipitate withdrawal. If short-term opioids are required for pain relief, Contrave should be discontinued during their use.

• Surgery / Procedures
• SPAQI guidelines recommend that Contrave be held for at least 72 hours before a surgery or procedure requiring opioid analgesia. After surgery, patients should be off opioids for 3 - 7 days before restarting Contrave.
• If the procedure does not require opioid use, Contrave may be continued uninterrupted

• Manic episodes
• Bupropion may precipitate manic episodes in susceptible patients. Use caution in patients with bipolar or a history of mania.

• Angle-closure glaucoma
• Bupropion may cause pupil dilation that precipitates angle-closure glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma.

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• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.

• Antidepressants - bupropion is an antidepressant. Caution should be used when combining with other antidepressants
• CYP2D6 substrates - bupropion is a strong CYP2D6 inhibitor, and it may increase blood levels of CYP2D6 substrates. When Contrave is taken with medications that undergo significant CYP2D6 metabolism, caution should be used and drug doses should be lowered
• CYP2B6 inhibitors and inducers - bupropion is a CYP2B6 sensitive substrate. CYP2B6 inhibitors may raise bupropion levels and CYP2B6 inducers may lower bupropion levels.
• Dopaminergic agents (levodopa, amantadine, etc.) - bupropion increases dopaminergic activity. Concomitant dopaminergic agents may potentiate dopaminergic effects. Excessive dopaminergic activity may cause symptoms that include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.
• MAO inhibitors - bupropion inhibits the reuptake of dopamine and norepinephrine and can increase the risk for hypertensive reactions when used concomitantly with drugs that also inhibit the reuptake of dopamine or norepinephrine, including MAO inhibitors. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with Contrave. Conversely, at least 14 days should be allowed after stopping Contrave before starting an MAO inhibitor.
• OCT2 substrates - bupropion inhibits organic cation transporter (OCT2) in vitro. Blood levels of OCT2 substrates may be increased when taken with Contrave. OCT2 substrates include amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, and oxaliplatin
• Opiate pain medications - Contrave contains naltrexone which is an opiate antagonist. Patients on chronic opiate therapy may experience withdrawal symptoms when taking Contrave. Contrave is contraindicated in these patients. For patients who require short-term opiate therapy, Contrave should be discontinued during the opiate therapy.
• P2Y12 inhibitors (clopidogrel and ticlopidine) - Clopidogrel and ticlopidine are CYP2B6 inhibitors. When taking Contrave with clopidogrel or ticlopidine, the maximum dose of Contrave is 1 tablet twice a day.
• Ritonavir, Lopinavir, and Efavirenz - Ritonavir, Lopinavir, and Efavirenz are CYP2B6 inducers, and they may decrease bupropion exposure. Contrave should not be taken with these medications

• Drug-laboratory interactions
• Bupropion
• Bupropion may cause a false-positive amphetamine urine drug test
• False-positive test results may result even following discontinuation of bupropion therapy
• Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines
• Naltrexone
• Naltrexone does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone or quinine in the urine
• Naltrexone may or may not interfere with enzymatic methods for the detection of opioids depending on the specificity of the test. Please consult the test manufacturer for specific details.

• Metabolism and clearance
• Bupropion
• CYP2B6 - sensitive substrate
• CYP2D6 - strong inhibitor
• OCT2 - inhibitor
• Naltrexone
• Does not undergo CYP metabolism

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• DOSING

• Dosage form
• Contrave® extended-release tablet: 8 mg naltrexone / 90 mg bupropion

• Dosing
• Contrave is titrated over 4 weeks using the schedule in the table below. The maximum dose is 2 tablets twice daily.
• Response to therapy should be evaluated after 12 weeks. If the patient has not lost at least 5% of their baseline weight, Contrave should be discontinued. It has been studied for up to 56 weeks in trials.
• Contrave was taken with food in trials; however, it should not be taken with a high-fat meal because absorption and systemic exposure are increased substantially

Contrave titration schedule
	Morning dose	Evening dose
Week 1	1 tablet	None
Week 2	1 tablet	1 tablet
Week 3	2 tablets	1 tablet
Week 4 and on	2 tablets	2 tablets

• Price
• The Contrave manufacturer has set up a website that allows cash-pay patients to get Contrave for $99/month through a mail-order pharmacy (Contrave CurxAccess program). However, it's usually cheaper to prescribe the individual components (bupropion and naltrexone) separately since they both have cheap generics.

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• LONG-TERM SAFETY

• Contrave® is a new medication - FDA-approved 2014
• Bupropion was FDA-approved in 1985. It has been prescribed widely and is generally considered safe.
• Naltrexone was FDA-approved in 1984. It is generally considered safe when prescribed correctly.

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• BIBLIOGRAPHY

• 1 - PMID 23408728 - COR II study
• 2 - Contrave PI®