This column is dedicated to providing information on the medical management of obesity, which includes diet, exercise, behavioral change, and medication.
Craig Primack, MD, FACP, FAAP, Medical Bariatrician/Certified Medical Obesity Specialist/Co-Medical Director, Scottsdale Weight Loss Center PLLC, Scottsdale, Arizona
Wendy Scinta, MD, MS, FAAFP, Medical Director, Medical Weight Loss of NY, BOUNCE Program for Childhood Obesity, Fayetteville, New York; Clinical Assistant Professor of Family Medicine, Upstate Medical University, Syracuse, New York
This month: Contrave: A New Tool for the Medical Weight Loss Community
by Craig Primack, MD, FACP, FAAP
FUNDING: No funding was provided for this article.
FINANCIAL DISCLOSURES: Dr. Primack is on the Takeda Speakers Bureau
Bariatric Times. 2014;11(12):11
Its been a great couple of years in the field of medical weight loss since we started this column. In 2012 and 2013, the United States Food and Drug Administration (FDA) approved two drugs for weight loss: 1) lorcaserin (Belviq, Eisai Inc., Woodcliff Lake, New Jersey) and 2) phentermine/extended-release topiramate (Qysmia, Vivus, Inc., Mountain View, California).
Recently, we saw a third drug approved: Contrave® (Takeda Pharmaceuticals America, Inc., Deerfield, Illionois). This month’s column provides a brief overview of this new tool for the chronic medical treatment of obesity.
Contrave is an extended-release formulation of naltrexone HCL, an opioid antagonist, and bupropion HCL, an inhibitor of the reuptake of dopamine and norepinephrine. It likely works on both the hypothalamus (appetite) and mesolimbic dopamine circuit (reward center). Contrave is indicated along with a reduced calorie diet and adequate physical activity for patients with a BMI>30kg/m2 and patients with body mass index (BMI) more than 27kg/m2 with a weight-related disease (e.g., diabetes, hypertension, hyperlipidemia). It is also the first of the new weight loss medications that is not on a restricted schedule by the FDA. It has been classified as schedule V, the least restricted, by the FDA.
Contrave is supplied in a fixed-dose pill in extended-release formulation comprised of 8mg of naltrexone HCL and 90mg of bupropion HCL. Its dosing instructions are as follows: Week 1: one tablet in the morning; Week 2: one tablet BID; Week 3: two tablets in the morning and one tablet in the evening; and Week 4 and onward: two tablets BID. It can be taken with or without food but a high fat meal should be avoided as it increases absorption.
Contrave was studied in four trials1–4 that were pooled and submitted to the FDA. These studies included 4,536 patients. The Contrave Obesity Research I (COR-I) and Contrave Obesity Research II (COR-II) studied a 500kcal/day decrease in calories, standard behavior modification, and increased exercise with naltrexone plus bupropion or placebo.
A third trial, Contrave Obesity Research behavior modification (COR-BMOD) examined the efficacy and safety of naltrexone plus bupropion as an adjunct to intensive behavior modification. Lastly, COR-Diabetes specifically looked at patients with poorly controlled diabetes, whereas patients with diabetes were specifically excluded from the first three COR studies.
The studies included the following primary endpoints, which were consistent with other recent medications studies: 1) Percent change from baseline body weight and 2) proportion of patients achieving at least a five-percent reduction in body weight. All studies were double blinded, placebo-controlled, multi-center studies. In COR-I, the mean weight change from baseline was -5.4 percent in Contrave treated patients with the placebo group achieving just -1.3 percent.1 In the COR-BMOD, the group that received Contrave saw a -8.1 percent decrease in weight versus the placebo at -4.9 percent. In the COR-Diabetes group Contrave patients saw a weight reduction of -3.7 percent versus -1.7 percent in the placebo group. The participants who completed the trials did better than the intention-to-treat/Last-Observation-Carried-Forward (ITT-LOCF) population in all of the studies. This resembles what we see in the office. If a patient stops the drug, we do not expect them to continue benefit from it. In addition, triglycerides, HDL, LDL, and waist circumference showed benefit in the Contrave treated group versus the placebo group. In the COR-Diabetes group, HgA1c decreased significantly in the patients with diabetes on Contrave versus the placebo group with diabetes.
It is important to note that the FDA declined to approve Contrave in 2011 because there were signs that it raised patients’ pulse rates and blood pressure. Although there is still no evidence that can prove that the new anti-obesity drug can pose risk on the heart, the Food and Drug Administration requires the company to finish its research including a cardiovascular outcomes trial known as the LIGHT study. The company is also tasked to investigate more on the effect of Contrave when taken with other drugs.
When looking at pooled data, heart rate, systolic and diastolic blood pressures were higher than baseline in the Contrave treated patients for the first eight weeks, equal to the baseline by Week 12, and below baseline by the end of 56 weeks. Placebo groups had decreased heart rate and blood pressure throughout.
The most common side effects leading to discontinuation of the drug were nausea, headache, and vomiting. It is pregnancy category X, meaning the drug is contraindicated in women who are, or may become pregnant.
Contrave has received a black box warning, which is common among antidepressants, in regard to suicidal thoughts and behaviors and neuropsychiatric reactions. Bupropion decreases seizure threshold and should be avoided in patients with a seizure disorder. Also, as naltrexone is an opioid antagonist, it should not be given to patients on chronic opioids. If opioid therapy is needed, the patient should inform his or her healthcare provider. There are also several interactions with drugs metabolized by the CYP2D6 and CYP2B6 enzymes, which include but are not limited to selective serotonin reuptake inhibitors (SSRIs), antipsychotics, beta blockers, Type 1C antiarrhythmics, ticlodipine, clopidogrel, carbamazepine and phenobarbital. The recommendations vary depending on the enzyme affected. Patients and healthcare providers should see the package insert for more details.
As Contrave is quite new to the market, over the next several months and years experience in practice will determine where its full clinical utility rests. For now, we are excited to have another option for the medical management of obesity.
- COR-I Greenway FL et al. Lancet. 2010; 376(9741):595-605
- COR-II Apovian CM et al. Obesity 2013; 21(5):935-9435
- COR-BMOD Wadden TA et al. Obesity 2011;19(1):110-120
- COR-Diabetes Hollander P et al. Diabetes. 2010; 59(suppl 1):A15
- Castaño-Monsalve B. [Antidepressants in epilepsy]. Rev Neurol. 2013 Aug 1;57(3):117–122.
- Contrave prescribing information. 2014. Takeda Pharmaceuticals America, Inc.