Takeda Pharmaceuticals USA and Orexigen Therapeutics have won FDA approval for their chronic weight management drug Contrave® (naltrexone HCI and bupropion HCI) extended-release tablets as an adjunct to a reduced-calorie diet and more physical activity. The approval has come with a boxed warning agreed upon by the companies, and numerous additional postmarketing studies required by FDA.

Takeda said it is planning a fall commercial launch for Contrave, which FDA approved yesterday, some three years after the agency held off on a decision while requesting additional data assessing the drug’s safety effects.

Contrave indicated for adults with an initial body mass index (BMI) of 30 kg/m2 or greater, defined as obese, and “overweight” adults with a BMI of 27 kg/m2 or greater, who have at least one weight-related condition such as hypertension, type 2 diabetes, or high cholesterol.

Contrave combines two drugs previously approved by the FDA: Naltrexone, indicated for alcohol and opioid dependence; and bupropion, for depression and seasonal affective disorder and as an aid to smoking cessation treatment.

Because it contains bupropion, Contrave was approved with a boxed warning about increased risk of suicidal thoughts and behaviors associated with antidepressant drugs. Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation, the warning also notes, “including changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety and panic, as well as suicidal ideation, suicide attempt, and completed suicide.”

The label also warns against Contrave use in patients who have seizure disorders, patients with uncontrolled high blood pressure, patients with bulimia or anorexia nervosa, patients using opioids or treatments for opioid dependence or experiencing acute opiate withdrawal, patients who abruptly discontinue alcohol, benzodiazepines, barbiturates and antiepileptic drugs, and women who are pregnant or trying to become pregnant.

Takeda and Orexigen also agreed to several post-marketing studies to assess the safety and efficacy of Contrave, including:

  • A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use;
  • Two efficacy, safety, and clinical pharmacology studies in pediatric patients—one in patients 7–11 years of age, the other in patients ages 12–17;
  • A nonclinical animal juvenile toxicity study, focused on growth and development as well as behavior, learning, and memory;
  • A study to evaluate the effect of Contrave on cardiac conduction;
  • Clinical trials to evaluate dosing in patients with hepatic or renal impairment;
  • A clinical trial to evaluate the potential for interactions between Contrave and other drugs.

Patients with a history of heart attack or stroke in the previous six months, life-threatening arrhythmias, or congestive heart failure were excluded from the clinical trials. As a result, the clinical significance of blood-pressure and heart-rate increases seen with Contrave treatment is unclear, the FDA said, especially for patients with heart-related and cerebrovascular disease.

Contrave was approved despite its developers acknowledging that neither its effect on cardiovascular morbidity and mortality, nor its safety and effectiveness in combination with other medications intended for weight loss, have been established. Last year Orexigen disclosed successful results from a cardiovascular outcomes trial that randomized approximately 8,900 patients. Contrave LIGHT was designed to rule out excess cardiovascular risk in overweight and obese patients receiving Contrave.

The exact neurochemical effects by which Contrave use leads to weight loss are not fully understood, Takeda and Orexigen said.

FDA said it based its approval on data from four clinical trials, in which a total 4,536 obese and overweight patients—both with and without significant weight-related conditions—were treated for a year. All patients carried out a reduced-calorie diet and regular physical activity.

In one trial, Contrave-using participants without diabetes had an average weight loss 4.1% higher than that of patients treated with placebo after one year, while 42% of patients treated with Contrave lost at least 5% of their body weight compared with 17% of patients treated with placebo.

Another clinical trial, which included patients with type 2 diabetes, showed that patients had an average weight loss of 2% over treatment with placebo at one year. In this trial, 36% of patients treated with Contrave lost at least 5% of their body weight compared with 18% of patients treated with placebo.

Contrave enters a weight-loss drug market reshaped in recent years by the introduction of several new products, including Vivus’ Qsymia (phentermine and topiramate extended-release), and Belviq (lorcaserin hydrochloride), which is manufactured by Arena Pharmaceuticals and marketed by Japan’s Eisai.

Novo Nordisk was to present data today before FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on its application for a new 3 mg dosage of liraglitude, a once-daily human GLP-1 analog, for chronic weight management in adults with obesity or overweight with comorbidities, also as adjunct to diet and exercise. Liraglutide is now marketed as Victoza® for type 2 diabetes at 1.2 and 1.8 mg once-daily, as well as at 0.9 mg in Japan.