PHARMACOLOGY UPDATE
Naltrexone HCl and Bupropion HCl Extended-Release Tablets (Contrave ® )
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved another drug combination for the treatment of chronic weight management, combining two old drugs, naltrexone and bupropion, in a fixed combination. Naltrexone is an opioid antagonist and bupropion is a commonly prescribed antidepressant. The combination is manufactured for Orexigen Therapeutics and marketed by Takeda Pharmaceuticals as Contrave. It joins lorcaserin (Belviq) and phentermine/topiramate (Qsymia), which were both approved in 2012 for the same indication.
INDICATIONS
Naltrexone/bupropion (NB32) is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with a body mass index (BMI) ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes, or dyslipidemia.1
DOSAGE
The recommended dose is one tablet in the morning the first week, one tablet in the morning and evening on week 2, two tablets in the morning and one in the evening on week 3, and two tablets in the morning and evening from week 4 and after.1 Dosage should be reduced in patients with renal impairment, hepatic impairment, and concomitant use with CYP2B6 inhibitors. Dose reduction should be considered for substrates of CYP2D6 if co-administered with naltrexone and bupropion. NB32 is available as an extended-release tablet with 8 mg of naltrexone and 90 mg of bupropion.1
POTENTIAL ADVANTAGES
NB32 provides another option for managing weight loss in obese patients and those who are overweight with weight-related condition(s).
POTENTIAL DISADVANTAGES
Due to the bupropion component, the product carries a box warning for increased risk of suicide ideation and behavior.2 Patients should be monitored for worsening and emergence of suicidal thoughts and behavior. The drug is also contraindicated in people with a seizure disorder. Naltrexone has been associated with the risk of hepatitis and elevation of hepatic transaminases. Since naltrexone is an opioid antagonist, it should not be given to patients using opioids. Most common adverse reactions (vs placebo) are nausea (32.5% vs 6.7%), constipation (19.2% vs 7.2%), headache (17.6% vs 10.4%), and vomiting (10.7% vs 2.9%).
COMMENTS
The combination of naltrexone/bupropion is believed to target the appetite regulatory center in the hypothalamus and reward system in the mesolimbic dopamine circuit.1 The safety and efficacy of naltrexone/bupropion was studied in four (COR-I, COR-II, COR-BMOD, COR-DIABETES) 56-week, double-blind, placebo-controlled trials involving 4536 obese or overweight subjects with at least one weight-related comorbidity. Co-primary efficacy endpoints were percentage change in body weight and proportion of subjects with a decrease in body weight of ≥ 5% from baseline at week 56. COR-I combined two fixed doses of naltrexone/bupropion 32 mg/360 mg (NB32) and 16/180 mg (NB16).1,2 NB32 showed a greater percent of weight loss of ≥ 5% compared to NB16 and is the approved dose. COR-I and COR-II compared NB32 and placebo and a reduced-calorie diet, behavioral counseling, and increased physical activity.1,2,3 Placebo-subtracted weight losses were 4.1% and 5.2%, respectively. Those losing ≥ 5% were 42% vs 17% and 50.5% vs 17%, respectively. COR-BMOD included an intensive behavioral modification program with the mean percent weight loss -3.2% (placebo-subtracted) and percent losing 5% were 57% vs 43%, respectively.1,4 COR-DIABETES enrolled obese or overweight diabetics and had a mean percent weight loss -2% and percent losing ≥ 5% were 36% compared to 18%.1,5 There were generally improvements in cardiometabolic risk markers, weight-related quality of life, and control of eating scores. Risk markers included waist circumference, lipid levels, fasting insulin, and hsCRP. In COR-DIABETES, NB32 showed a greater reduction in HbA1c and a greater percent with HbA1c < 7% (44% vs 26%, P < 0.001).
CLINICAL IMPLICATION
NB32 is the newest addition for the management of weight loss. It has the same indications as lorcaserin and phentermine/topiramate. There are two FDA benchmarks for weight loss efficacy.8 The first is the mean weight loss between drug and placebo needs to be at least 5% and statistically significant. The second is the proportion of subjects whose weight loss is ≥ 5% of baseline weight in the drug group is at least 35% and approximately double the proportion in the placebo-treated group and the difference is statistically significant. Both lorcaserin and NB32 did not meet FDA criteria for the first criteria, but did meet the second criteria for efficacy.1,6 Phentermine/topiramate met both categories and appears to be superior in efficacy.7 All three products are pregnancy category X. The wholesale costs for all three products are the same at $200 for a 30-day supply.
REFERENCES
- Contrave Prescribing Information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; September 2014.
- Greenway FL, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2010;376:595-605.
- Apovian CM, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity 2013;21:935-943.
- Wadden TA, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: The COR-BMOD trial. Obesity 2011;19:110-120.
- Hollander P. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care 2013;36:4022-4029.
- Belviq Prescribing Information. Woodcliff Lake, NJ: Eisai Inc.; August 2012.
- Qsymia Prescribing Information. Mountain View, CA: Vivus Inc.; September 2013.
- Guidance for Industry: Developing products for weight management. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. February 2007.
