In September 2014, the United States FDA gave the final approval for the new weight loss drug – Contrave, an extended release combination of Naltrexone and Bupropion.
Contrave (referred to as “NB” hereafter), a novel combination product for the treatment of obesity, is composed of bupropion combined with naltrexone.
CLINICAL PERSPECTIVE ON OBESITY AND ITS TREATMENT
Obesity is a rapidly growing epidemic among adults, adolescents, and children in the United States.
Currently, there are three main approaches to the treatment of obesity:
(1) diet, physical activity, and behavioral modification (diet and exercise);
(2) pharmacotherapy; and
(3) nariatric surgery.
Diet and exercise is the mainstay of weight management and generally precedes other measures.
Unfortunately, diet and exercise alone yield mostly limited and transient weight loss, with many individuals finding it difficult to adhere to such regimens.
The strategy to implement pharmacotherapeutic or surgical approaches in addition to diet and exercise depends upon the patient’s BMI as well as the presence of obesity-related comorbidities.
However, unlike the situation for other metabolic diseases such as hypertension and type 2 diabetes, there are very limited obesity pharmacotherapies available.
Although orlistat is approved for long-term use and provides efficacy beyond that usually achievable using diet and exercise alone, it is not tolerated well by some patients.
The other available pharmacotherapies, e.g. phentermine, are approved for short-term use only.
While more invasive options (e.g., gastric banding, bariatric surgery) do result in greater weight loss than is achievable with pharmacotherapy, these are targeted primarily to those patients with the highest BMI.
The benefit of surgery is also offset by greater expense and risk. In the face of such limited options, patients often resort to the use of off-label medications or dietary supplements that may be ineffective or unsafe. In this context, agents such as NB may offer viable alternatives for many obese patients.
Contrave approved for weight loss
Contrave is a combination of two FDA-approved drugs, naltrexone and bupropion, in an extended-release formulation. Naltrexone is approved to treat alcohol and opioid dependence. Bupropion is approved to treat depression and seasonal affective disorder and as an aid to smoking cessation treatment.
The effectiveness of Contrave was evaluated in multiple clinical trials that included approximately 4,500 obese and overweight patients with and without significant weight-related conditions treated for one year. All patients received lifestyle modification that consisted of a reduced- calorie diet and regular physical activity.
Results from a clinical trial that enrolled patients without diabetes showed that patients had an average weight loss of 4.1 percent over treatment with placebo (inactive pill) at one year. In this trial, 42 percent of patients treated with Contrave lost at least 5 percent of their body weight compared with 17 percent of patients treated with placebo. Results from another clinical trial that enrolled patients with type 2 diabetes showed that patients had an average weight loss of 2 percent over treatment with placebo at one year. In this trial, 36 percent of patients treated with Contrave lost at least 5 percent of their body weight compared with 18 percent of patients treated with placebo.
Side effects of Contrave
The most common adverse reactions reported with Contrave include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.
Cost of Contrave
Priced at an affordable maximum of $45.00 with insurance to $75.00 without insurance per month, Contrave is probably one of the most cost effective new combination weight loss medications and compares favorably well with Belviq that can cost up to $225.00 per month, or Qsymia, that can cost up to $150.00 per month.
BENEFIT/RISK OF USE OF CONTRAVE
Key benefits following treatment with Contrave(NB) are summarized below:
- Clinically meaningful weight loss was apparent early in treatment, and was greater than that observed with either naltrexone or bupropion alone. Weight loss was on average sustained, and those patients who continued treatment through 56 weeks experienced the most substantial weight loss. The efficacy of NB was observed across all demographic and clinical subgroups evaluated, including patients with hypertension, dyslipidemia, history of cardiovascular disease, type 2 diabetes, impaired fasting glucose, or history of depression.
- Significant effects of NB treatment were observed on a number of weight-related cardiometabolic parameters (e.g., waist circumference, triglycerides, HDL-cholesterol, and hs-CRP); HDL increases and triglyceride reductions were observed irrespective of history of dyslipidemia or treatment for this condition.
- Patients with type 2 diabetes benefitted from weight loss, improvements in waist circumference, HDL and triglycerides, and clinically significant improvements in glycemic control (particularly decreased HbA1c). A lower proportion of NB-treated patients required adjustments to their antidiabetic medications due to poor glycemic control.
- Greater proportions of NB-treated patients reported clinically meaningful improvements in weight-related quality of life compared with placebo, providing further evidence of the range of clinical benefits that can be derived from NB treatment.
- Greater effects of NB treatment were observed on multiple items of the COE questionnaire.
Key safety findings from the NB development program include the following:
- The use of NB was generally well-tolerated, with the frequency and distribution of safety findings being consistent with the established profiles for naltrexone and bupropion.
- Common AEs such as nausea and vomiting tended to occur early in treatment (during the dose-escalation phase), were mostly mild to moderate in severity, and were generally self-limiting.
- The incidence of treatment-emergent SAEs overall was low; the vast majority of SAEs in NB-treated patients were considered unrelated to study drug.
- Initiation of treatment with NB was associated with transient increases from baseline of approximately 1 mm Hg in mean blood pressure, followed by small reductions below baseline. These increases are consistent with the known hemodynamic effects of bupropion and were attenuated by weight loss in patients who responded to therapy, although mean blood pressure reductions with NB were always less than that observed with comparable placebo patients. The small elevations in heart rate seen with NB treatment (compared with decreases with placebo) are also consistent with known bupropion effects.
- The hemodynamic effects of NB are due to bupropion. Bupropion has been extensively prescribed since its original approval more than 20 years ago, and has a long history of safe use even in populations considered at risk for CV disease.
- The incidence of major cardiovascular events (cardiovascular death, myocardial infarction and cerebrovascular accident) and revascularization procedures were low and comparable between NB- and placebo-treated patients, although the number of events is too low to draw firm conclusions.
- Seizures occurred infrequently at a rate that is consistent with that observed for the lowest approved dose of bupropion SR.
- Treatment with NB in the target patient population does not appear to be associated with an increased risk for depression or suicidality.
- No hepatotoxicity was observed with long-term NB treatment.
- Clinical laboratory evaluations were generally unremarkable, and values outside of normal ranges tended to be sporadic and unrelated to dose.
- Neither bupropion nor naltrexone has historically been associated with prolongation of QTc intervals, and review of QT, QTc and the other ECG parameters in patients during long-term NB treatment revealed no noteworthy findings.
In summary, the benefits of NB outweigh the risks given the clinically meaningful weight loss and improvement in multiple markers of cardiometabolic risk and patient-reported quality of life.
These benefits in aggregate are expected to be greater in general clinical practice, as proposed labeling would lead to discontinuation of treatment for patients not experiencing at least a 5% decrease from baseline in body weight. Benefits are observed across a range of overweight and obese patient subgroups and in various treatment settings.
Of note, the population of patients receiving currently approved bupropion-containing therapies has important similarities to patients enrolled in the NB clinical program, as well as the population of patients who receive currently marketed obesity pharmacotherapy.
In addition, clinical experience and investigation in relevant patient populations, including those with cardiovascular risk factors or established cardiovascular disease, have not identified specific safety signals for clinical cardiovascular events.
Overall, the NB safety profile is well-understood, with known risks that are predictable and manageable via appropriate risk mitigation approaches. Orexigen is developing a plan for additional clinical studies to assess: 1) prescription utilization patterns, 2) physician and patient adherence to labeling, and 3) the impact of Contrave on cardiovascular outcomes.
Locations for Physicians familiar with Contrave weight loss drug
W8MD Medical Weight Loss Centers of America’s physicians are familiar with this and many other weight loss medications and can offer Contrave as a tool to fight the epidemic of obesity to eligible patients.
Philadelphia Insurance Weight Loss & Sleep Center: 1718, Welsh Rd, Philadelphia, PA, 19115 Ph: 1-215-676-2334
King Of Prussia Weight Loss & Sleep Center: 987 Old Eagle School Rd, Ste 712, Wayne, PA, 19087 Ph: 215-676-2334
NYC Insurance Weight Loss & Sleep Center: 2003, Bath Avenue, Brooklyn, NY, 11214 Ph: 1-718-946-5500.
W8MD weight loss program in New Jersey.
W8MD weight loss program at Vida Sleep Center of Dr. Felix Roque’s office at 543, 45th Street, Union City, New Jersey. 543 45th St, Union City, NJ 07087. Phone: (201) 766-6469. This center bills out of network for insurance.