CONTRAVE®

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• Contrave contains bupropion, an antidepressant, and naltrexone, an opioid antagonist

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• Appetite suppression
• It's not completely understood how bupropion and naltrexone suppress hunger, but nonclinical studies suggest they affect two separate areas of the brain involved in regulating food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system)

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• Contrave is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of:
• 30 or greater
• 27 or greater in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)

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• Overview
• The effects of Contrave on weight loss were studied in the COR I trial and COR-BMOD trials detailed below

• RCT
  COR-BMOD study - Contrave vs Placebo for Weight Loss Over 56 weeks, Obesity (2011) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=793 | length = 56 weeks) in adults (average BMI 37 | average weight 222 lbs) with BMI 30 - 45 or BMI 27 - 45 with hypertension or dyslipidemia
• Treatment: Contrave (naltrexone 32 mg/day + bupropion 360 mg/day) vs Placebo. Patients were randomized in a 3:1 ratio. Both groups received intensive behavior modification (diet, exercise).
• Primary outcome: Co-primary end points were percentage change in weight and the proportion of participants who lost ≥ 5% weight at week 56
• Results:
• Primary outcome (% decrease in weight): Contrave - 7.8%, Placebo - 4.9% (p<0.001)
• Primary outcome (≥ 5% weight loss): Contrave - 54.3%, Placebo - 41.6% (p=0.001)
• Discontinuations: Contrave - 42%, Placebo - 42%
• Findings: The present findings support the efficacy of combined naltrexone/bupropion therapy as an adjunct to intensive behavior modification for obesity

• Summary
• In the two 56-week trials above, Contrave enhanced weight loss by 3 - 5% compared to placebo. Dropout rates were high in both trials, with about half of participants discontinuing their assigned treatment.

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

Common side effects
Side effect	Contrave 16/180 mg twice a day (N=2545)	Placebo (N=1515)
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, serum creatinine increased more in Contrave-treated patients than placebo-treated patients (0.07 mg/dl vs 0.01 mg/dl). This 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
• In trials, Contrave-treated patients had a slight transient increase in blood pressure. At Weeks 4 and 8, average SBP and DBP were 1 mmHg higher than baseline. At Week 12, blood pressures were similar to baseline, and by Weeks 24 and 56, they were 1 mmHg below baseline.

• Heart rate increase
• In trials lasting 52 weeks, the average heart rate increased by 1 - 3 bpm in Contrave-treated patients

• Liver toxicity
• Cases of hepatotoxicity have been reported in patients receiving naltrexone. Affected patients often had pre-existing liver disease, making causality difficult to establish. 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 bupropion trials. Furthermore, rare reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also occurred. Contrave should be discontinued if signs of hypersensitivity (e.g. rash, itching, hives, edema) develop.

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• 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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• Kidney disease
• CrCl ≥ 60 ml/min: no dose adjustment necessary
• CrCl 16 - 59 ml/min: dose should not exceed 1 tablet twice daily
• 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 daily
• Child-Pugh C: DO NOT USE

• Older patients
• In trials, Contrave-treated patients 65 and older had a higher incidence of psychiatric and sleep disorders (29% vs 6% with placebo). Use caution in susceptible patients.

• 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 seizures. In trials, seizures were reported in 0.1% of Contrave-treated patients and 0% of placebo-treated patients. Contrave is contraindicated in patients with a history of seizures and should be used with caution in patients with risk factors, including head trauma, history of stroke, history of severe hypoglycemia, other seizure-provoking medications, excessive alcohol and/or sedative use.

• Opioid medications
• Patients receiving chronic opioid therapy
• Patients receiving chronic opioid therapy should not take Contrave because it contains naltrexone, an opioid antagonist that blocks the effects of opioid medications. Contrave may also precipitate withdrawal in opioid-treated patients, and a minimum opioid-free interval of 7 to 10 days is recommended before Contrave is initiated.
• Increased sensitivity to opioids
• Taking naltrexone for a period and then discontuining it may increase opioid sensitivity. Patients should be warned that the risk of opioid overdose after stopping naltrexone may be heightened.
• Overcoming naltrexone blockade
• Naltrexone opioid blockade is competitive and can be overcome by high opioid doses. Patients who try to overcome naltrexone with large opioid doses are at increased risk of overdose, which can be fatal.

• Acute pain control
• Acute pain control in patients taking naltrexone may be achieved through regional analgesia, conscious sedation with a benzodiazepine, non-opioid analgesics, or general anesthesia. If opioid analgesia is needed, larger opioid doses may be required, and the resulting respiratory depression may be deeper and more prolonged.

• 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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• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).

• Antidepressants - bupropion is an antidepressant and caution should be used when combining with other antidepressants
• CYP2D6 substrates - bupropion is a strong CYP2D6 inhibitor and may increase CYP2D6 substrate exposure. Use caution when combining Contrave with CYP2D6 substrates and lower substrate doses when appropriate.
• CYP2B6 inhibitors - bupropion is a CYP2B6 sensitive substrate, and CYP2B6 inhibitors may increase its exposure. Do not exceed one Contrave tablet twice daily when combining.
• Digoxin - Contrave may reduce digoxin exposure. Monitor digoxin levels closely when combining.
• Dopaminergic agents (e.g. levodopa, amantadine, etc.) - bupropion may potentiate the effects of other dopaminergic agents, leading to symptoms of dopaminergic excess (e.g. restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, dizziness). Use caution when combining.
• MAO inhibitors - DO NOT COMBINE. Bupropion inhibits the reuptake of dopamine and norepinephrine and can increase the risk for hypertensive reactions when used with MAO inhibitors. MAO inhibitors and bupropion should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
• OCT2 substrates - bupropion inhibits organic cation transporter (OCT2) in vitro and may increase exposure to OCT2 substrates, including amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, and oxaliplatin
• Opioid pain medications - see opioid medications above
• Clopidogrel and ticlopidine - clopidogrel and ticlopidine, both CYP2B6 inhibitors, increase bupropion exposure. Do not exceed one Contrave tablet twice daily when combining.
• Ritonavir, Lopinavir, and Efavirenz - ritonavir, lopinavir, and efavirenz induce CYP2B6, reducing bupropion exposure. Concomitant use is not recommended.

• Drug-laboratory interactions
• Bupropion
• False-positive urine immunoassays for amphetamine have been reported in patients receiving bupropion. If a false-positive result is suspected, gas chromatography/mass spectrometry testing can be used to distinguish between bupropion and amphetamine.
• Naltrexone
• Naltrexone may cause some urine drug screens to show a positive opioid result. 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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• 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

• Kidney disease
• CrCl ≥ 60 ml/min: no dose adjustment necessary
• CrCl 16 - 59 ml/min: dose should not exceed 1 tablet twice daily
• 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 daily
• Child-Pugh C: DO NOT USE

• Price
• The Contrave manufacturer has set up a website that allows cash-pay patients to purchase 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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• Bupropion and naltrexone were approved in the 1980s and are proven safe when prescribed appropriately

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