|Naltrexone||Opioid receptor antagonist|
|Bupropion||Norepinephrine-dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist|
|Trade names||Contrave, Mysimba|
|Side effects||Nausea, constipation, dizziness, trouble sleeping, dry mouth, headache|
|(what is this?)|
Naltrexone/bupropion, sold under the brand name Contrave among others, is a combination medication used to treat obesity together with diet and exercise. Such use; however, is not recommended in the United Kingdom. It is taken by mouth.
Common side effects include nausea, constipation, dizziness, trouble sleeping, dry mouth, and headache. Other side effects may include suicide, psychosis, seizures, high blood pressure, and liver problems. Use during pregnancy is not recommended. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant.
The combination was approved for medical use in the United States in 2014, Europe in 2015, and Canada in 2018. In the United States it costs 330 USD per month as of 2021. This amount in the United Kingdom costs about £78.
- 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
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.
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.
The manufacturer recommends against its use in people that have/are:
- History of seizures
- History of an eating disorder such as bulimia nervosa or anorexia nervosa
- Taking opioid pain medicines, taking medicines to stop opioid addiction, or are in opiate withdrawal
- Taking an MAOI or have taken an MAOI in the last 14 days
- Abruptly stopped using: alcohol, benzodiazepines, barbiturates, or antiepileptic drugs
The Food and Drug Administration (FDA) has put a boxed warning onto this medicine because it may affect mood and increase the likelihood of suicidal thoughts in people under 25 years old. This is attributed to the bupropion component, as antidepressants have been associated with increased risk of suicidal thoughts, but not suicide, and only in people younger than 25.
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.[medical citation needed]
- 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.
Orexigen submitted a New Drug Application (NDA) for this drug combination to the U.S. Food and Drug Administration (FDA) on 31 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 31 January 2011. On 7 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 the fall of 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 late March 2015.
In May 2015, Orexigen ended a safety study of its diet drug earlier than planned, because an independent panel of experts says the drug maker “inappropriately” compromised the trial by prematurely releasing interim data. The early data release reported a reduction in heart attacks that was no longer observed when a more complete view of the data was analyzed.
Society and culture
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.
At the time of its approval by FDA, Wells Fargo analyst Matthew Andrews estimated that Contrave's U.S. sales would reach approximately US$200,000,000 in 2016, exceeding that of the dominant alternative obesity medications lorcaserin and phentermine/topiramate. Despite being initially impeded by technical issues, the growth in filled prescriptions in the first months after approval was very rapid — substantially exceeding the equivalent early uptake of either of the two alternative medications just cited. The first quarter of sales for Contrave (Q1 2015) showed net sales of US$11,500,000.
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