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FDA approves Contrave for chronic weight management
The FDA granted approval for naltrexone hydrochloride and bupropion hydrochloride extended-release tablets for adults to use, in conjunction with reducing calories and exercising, for chronic weight management, according to a statement from the agency.
Naltrexone hydrochloride and bupropion hydrochloride (Contrave, Orexigen) is designed for adults with obesity (BMI ≥30) or adults who are overweight (BMI ≥27) with at least one weight-related condition including hypertension, type 2 diabetes or high cholesterol.
“As the number of Americans affected by severe obesity continues to rise, equipping our nation’s doctors with proven and effective tools to treat patients for this disease is increasingly important,” Lee Kaplan, MD, PhD, chair of the clinical committee for The Obesity Society, said in a statement. “The FDA announcement that Contrave has been approved for long-term treatment of obesity is an important step toward this goal and can help improve the health and weight of our nation.”
The therapeutic combines two drugs already approved by the FDA in an extended-release formulation. Naltrexone was approved to treat alcohol and opioid dependence, and bupropion was approved to treat depression and seasonal affective disorder and to aid in smoking cessation.
The effectiveness of the drug has been demonstrated in multiple clinical trials, involving approximately 4,500 patients with obesity or overweight with and without weight-related conditions, which included diet and exercise lifestyle modifications.
Over one year, patients without diabetes lost, on average, 4.1% body weight compared with placebo; 42% of patients treated with naltrexone hydrochloride and bupropion hydrochloride lost ≥5%body weight vs. only 17% of patients with placebo.
Patients with type 2 diabetes lost, on average, 2% body weight over the same time period; 36 percent of patients receiving therapy lost ≥5% body weight vs. 18% with placebo.
In the statement, the FDA advised clinicians to evaluate patients receiving the maintenance dose at 12 weeks to determine effectiveness and to discontinue treatment if 5% body weight loss was not reached; this is because it is unlikely patients would sustain clinically meaningful results by continuing treatment.
A boxed warning alerts clinicians and patients to the increased risk of suicidal thoughts and behaviors associated with antidepressant therapies. The drug could cause seizures and is not for use in patients with seizure disorders, according to the statement.
Naltrexone hydrochloride and bupropion hydrochloride could raise both blood pressure and heart rate and is not for use in patients with uncontrolled high blood pressure; the clinical significance of these increases remain unclear as patients with these conditions were excluded from the trials.
Common adverse reactions with therapy include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea, according to the statement.
Six post-marketing requirements were set forth by the FDA: a cardiovascular outcomes trial; efficacy, safety and clinical pharmacology studies in children (aged 7 to 11 years) and adolescents (aged 12 to 17 years); an animal juvenile toxicity study focusing on growth and development, behavior, learning and memory; a study to evaluate cardiac conduction effect; clinical trials to assess dosing with hepatic or renal impairment; a clinical trial to determine potential interactions between this and other drugs.
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This compound is a combination of naltrexone and bupropion which works synergistically to promote weight loss. This is the first compound for obesity treatment in which the mechanisms of action of two drugs enhance one another to achieve greater weight loss. Bupropion causes some weight loss on its own, and naltrexone blocks the feedback inhibition at the proopiomelanocortin (POMC) neuron level, thus promoting more weight loss.
This new approval increases the number of drugs available for use in obesity and gives providers a panoply of options for nonsurgical treatment of obesity. Contrave now joins Belviq, Qsymia, Xenical and Phentermine in the armamentarium that a provider can utilize as medications for weight loss.
All of these drugs have been studied along with behavior modification including dietary counseling, exercise prescription and lifestyle change, and they are meant to be used as adjuncts to these interventions.
Any patient with obesity would be eligible for Contrave if they have BMI over 30, or over 27 with one comorbidity. However, in particular patients with a binge eating component to their eating behavior, Contrave might be selected as a first choice if there are no other contraindications.
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The FDA approval of Contrave is welcome news and reflects efficacy and safety demonstrated in phase 3 clinical trials. This adds another option for pharmacotherapy to our existing armamentarium including orlistat, phentermine/topiramate ER, and lorcaserin.
All four medications have relative advantages and disadvantages, and vary with respect to efficacy (i.e., placebo-subtracted weight loss during clinical trials) and the side effect/safety profile with different warnings and cautions. As we individualize treatment for our patients, these factors should all be considered when selecting the initial medication as an adjunct to lifestyle intervention. All medications have a certain rate of primary failure and the FDA has provided an “off-ramp” when any weight loss medication does not produce clinically sufficient weight loss. Specifically, if the patient has not lost 5% or more weight on the maximal dose of the medication over a 12 week period, then discontinue the drug. With the approval of Contrave, we now have four drugs, each of which can be considered for initial therapy, and can also be considered for alternative therapy if and when patients exhibit primary failure to the first line medication.
The addition of Contrave strengthens our clinical ability to treat obesity as a chronic disease. The patients who will most benefit from weight loss therapy are those patients with obesity related complications that can be ameliorated by weight loss, such as metabolic syndrome, prediabetes, type 2 Diabetes, hepatic steatosis, sleep apnea and osteoarthritis.
Hopefully, Takeda will move quickly to obtain safety and efficacy data in adolescents and children with obesity where therapeutic needs are unmet. Takeda will also conduct cardiovascular outcome trials and we should follow these results with interest.
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The approval is obviously very welcomed news. It needs to be interpreted within the context of the obesity epidemic, not only in America but globally.
The context is that we have prevalence rates that remain high, that are not being significantly bent downwards, and that reflects not only a disease state that we’re still trying to understand but a dominant role of cultural influences —from the built environment in the context of obesity, but also shortcomings in our armamentarium to manage obesity.
Those shortcomings can be viewed as involving lifestyle and lack of coordinated approaches in structured lifestyle education of physicians and other health care professionals, as well as an expanded portfolio of safe and effective procedures to complement the existing bariatric procedures.
But the third group, which is germane to a discussion of Contrave, is a paucity of drugs that are FDA approved for long-term use for obesity. Right now we have over-the-counter branded Ali or Orlistat, and then the relatively newly-released extended-release, topiramate phentermine and Lorcaserin. Now having the FDA approve the Contrave product, buprion and naltrexone, adds to the suite of drugs that clinicians have available.
It’s welcome. It gives us more choices. It gives us a greater ability to tailor our management of patients with obesity. It is not intended to be viewed in the context that all patients with obesity must be treated with anti-obesity medications, but rather that the management of obesity is comprehensive and includes lifestyle in all aspects, complication-centric consistent with AACE guidelines and personalized based on individualities and variances that one sees from person to person.
There are multiple drivers that are complex for obesity, and not every patient is treated the same way. Therefore, not being pigeon-holed into just having access to one or two drugs, having a third and hopefully others entering into the anti-obesity pharmacopeia space, is something that will be beneficial to all of healthcare, since there are many other aspects of healthcare that are influenced by the obese state.
The incidence rates of cancer, cardiovascular disease, degenerative disease of the joints, and behavioral and psychiatric disorders are all the types of obesity-related comorbidities that can be expected to improve with successful weight loss.