In September 2014, a
sustained release formulation of the drug was approved for marketing in the United States under the brand name Contrave.[8][9] The combination was subsequently approved in the
European Union in the spring of 2015, where it is sold under the name Mysimba.[5][10] It was approved in Canada under the Contrave brand name in 2018.[11]
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:[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]
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.
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 Fargoanalyst 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]
^Plodkowski RA, Nguyen Q, Sundaram U, Nguyen L, Chau DL, St Jeor S (April 2009). "Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity". Expert Opinion on Pharmacotherapy. 10 (6): 1069–81.
doi:
10.1517/14656560902775750.
PMID19364254.
S2CID56625956.