Naltrexone/bupropion

Naltrexone/bupropion

Norepinephrine-dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist
Clinical data
Trade names	Contrave, Mysimba
AHFS/Drugs.com	Monograph
Routes of administration	By mouth
ATC code	A08AA62 (WHO)
Legal status
Legal status	CA: ℞-only[2][3] US: WARNING[1]Rx-only[4] EU: Rx-only[5]
Identifiers
CAS Number	1201668-08-7
PubChem CID	11556075
KEGG	D10751 N
NY (what is this?)  (verify)

Naltrexone/bupropion, sold under the brand name Contrave among others, is a

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:^[4][5]

• 30 kg/m² (obese), or^[4][5]
• 27 kg/m² to < 30 kg/m², (overweight) in the presence of one or more weight-related
  dyslipidaemia, or controlled high blood pressure^[4][5]

Each Contrave tablet contains 8 mg naltrexone and 90 mg bupropion.[12] 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.^[12]

Contraindications

According to the U.S. Food and Drug Administration (FDA), naltrexone/bupropion is contraindicated in patients who have/are:^[4]

• 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
  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.^[4] This is attributed to the bupropion component, as the FDA requires all antidepressants to include that boxed warning on medication package inserts.^[13]

The safety and effectiveness in children under the age of 18 has not been studied.^[4]

Mechanism of action

Individually, naltrexone and bupropion each target pathways in the central nervous system that influence appetite and energy use.

• Bupropion is a
  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.[14]

Combined, naltrexone/bupropion has an effect on the reward pathway that results in reduced food craving.^[15] 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.^[16]

History

Orexigen submitted a New Drug Application (NDA) for this drug combination to the FDA on 31 March 2010.^[17] 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.^[18] 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.^[19] It was ultimately approved in the United States in the fall of 2014.^[9]

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.^[20] Approval was granted in late March 2015.^[10]

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.^[21]

In 2018, Orexigen sold its assets, including Contrave, to Nalpropion Pharmaceuticals.^[22][23]

On 22 September 2020, the FDA issued a Warning Letter to Nalpropion Pharmaceuticals LLC on concerns of a sponsored Google link making "false or misleading claims about the risks associated with and efficacy of Contrave"^[24] on multiple issues. Nalproprion subsequently issued "An important correction from CONTRAVE® (naltrexone HCl/bupropion HCl) Extended-Release Tablets" ^[25]

Society and culture

Economics

The sustained-release formulation, Contrave, is marketed by Takeda under license from the combination medication's developer, Orexigen Therapeutics.^[9] As of 2015, Orexigen received 20% of net sales from Takeda.^[26]

At the time of its approval by the FDA, Wells Fargo analyst Matthew Andrews estimated that Contrave's US sales would reach approximately US$200 million in 2016, exceeding that of the dominant alternative obesity medications lorcaserin and phentermine/topiramate.^[27] 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.^[28] The first quarter of sales for Contrave (Q1 2015) showed net sales of US$11,500,000.^[26]

References