Naltrexone/bupropion

Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone atypical antidepressant. It is taken by mouth. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight.

In September 2014, a sustained release formulation of the drug was approved for marketing in the United States under the brand name Contrave. The combination was subsequently approved in the European Union in the spring of 2015, where it is sold under the name Mysimba. It was approved in Canada under the Contrave brand name in 2018.

Medical uses
Naltrexone/bupropion is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, as anti-obesity medication for the management of weight in adults with an initial body mass index (BMI) of:


 * 30 kg/m2 (obese), or
 * 27 kg/m2 to < 30 kg/m2, (overweight) in the presence of one or more weight-related comorbidities, like type 2 diabetes, dyslipidaemia, or controlled high blood pressure

Available forms
Each Contrave tablet contains 8 mg naltrexone and 90 mg bupropion. Once full dosing is reached (after 4 weeks of administration), the total dosage of Contrave for overweightness or obesity is two tablets twice daily or 32 mg naltrexone and 360 mg bupropion per day.

Contraindications
According to the U.S. Food and Drug Administration (FDA), naltrexone/bupropion is contraindicated in patients who have/are:
 * History of seizures
 * History of an eating disorder such as bulimia nervosa or anorexia nervosa
 * Taking opioids, or are in opiate withdrawal.
 * Taken monoamine oxidase inhibitors in the last 14 days
 * Pregnant
 * Abruptly stopped use of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs

Adverse effects
The FDA has issued a boxed warning regarding an increased risk for suicidal thoughts and behavior in children, adolescents, and young adults under the age of 25. This is attributed to the bupropion component, as the FDA requires all antidepressants to include that boxed warning on medication package inserts.

The safety and effectiveness in children under the age of 18 has not been studied.

Mechanism of action
Individually, naltrexone and bupropion each target pathways in the central nervous system that influence appetite and energy use.
 * Bupropion is a reuptake inhibitor and releasing agent of both norepinephrine and dopamine, and a nicotinic acetylcholine receptor antagonist, and it activates proopiomelanocortin (POMC) neurons in the hypothalamus which give an effect downstream, resulting in loss of appetite and increased energy output. The POMC is regulated by endogenous opioids via opioid-mediated negative feedback.
 * Naltrexone is a pure opioid antagonist, which further augments bupropion's activation of the POMC.

Combined, naltrexone/bupropion has an effect on the reward pathway that results in reduced food craving. In 2009, Monash University physiologist Michael Cowley was awarded one of Australia's top research honors, the Commonwealth Science Minister's Prize for Life Scientist of the Year, in recognition of his elucidation of these pathways, which led to the development of the combination medication.

History
Orexigen submitted a New Drug Application (NDA) for the combination to the FDA in March 2010. Having paid a fee under the Prescription Drug User Fee Act, Orexigen was given a deadline for the FDA to approve or reject the drug of January 2011. In December 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave, and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study. Subsequently, on 2 February 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered. It was ultimately approved in the United States in 2014.

In December 2014, the EU's Committee for Medicinal Products for Human Use (CHMP) endorsed the combination for licensure as an obesity medication when used alongside diet and exercise. Approval was granted in March 2015.

In May 2015, Orexigen prematurely ended the trial that was intended to test whether naltrexone/bupirion increased the risk of major adverse cardiovascular events in obese patients with cardiovascular disease, because an independent panel of experts said that the drug maker “inappropriately” compromised the trial by prematurely releasing interim data. The early data release reported a reduction in heart attacks, but that advantage was no longer observed when a more complete view of the data was analyzed. The company then initiated a second trial (CONVENE) designed to test this outcome in 2016, but it was terminated in 2016 shortly after Takeda announced that it would sell its rights to the drug in the USA to Orexigen.

In 2018, Orexigen sold its assets, including Contrave, to Nalpropion Pharmaceuticals.

Economics
The sustained-release formulation, Contrave, is marketed by Takeda under license from the combination medication's developer, Orexigen Therapeutics. As of 2015, Orexigen received 20% of net sales from Takeda.