Naltrexone/bupropion

Naltrexone/bupropion
	Skeletal structures of bupropion (top) and naltrexone (bottom)
Combination of
Naltrexone	Opioid receptor antagonist
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; US: WARNINGRx-only; EU: Rx-only;
Identifiers
CAS Number	1201668-08-7;
PubChem CID	11556075;
KEGG	D10751 ;
	(what is this?) (verify)

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.^[4]^[6] It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone atypical antidepressant.^[4] It is taken by mouth.^[4] 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.^[7]

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]

30 kg/m² (obese), or^[4]^[5]
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^[4]^[5]

Available forms

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 treating overweight 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 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.^[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 reuptake inhibitor 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 the combination to the FDA in 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 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.^[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 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 March 2015.^[10]

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.^[21] 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.^[22]

In 2018, Orexigen sold its assets, including Contrave, to Nalpropion Pharmaceuticals.^[23]^[24]

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.^[25]

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
^ "Regulatory Decision Summary — Contrave". Health Canada. 23 October 2014. Archived from the original on 4 December 2020. Retrieved 7 June 2022.
^ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Archived from the original on 17 April 2024. Retrieved 17 April 2024.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Contrave Extended-Release- naltrexone hydrochloride and bupropion hydrochloride tablet, extended release". DailyMed. 26 April 2019. Archived from the original on 4 June 2020. Retrieved 5 August 2020.
^ ^a ^b ^c ^d ^e "Mysimba EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 22 October 2020. Retrieved 5 August 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ 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. PMID 19364254. S2CID 56625956.
^ Tek C (2016). "Naltrexone HCI/bupropion HCI for chronic weight management in obese adults: patient selection and perspectives". Patient Preference and Adherence. 10: 751–9. doi:10.2147/PPA.S84778. PMC 4862388. PMID 27217728.
^ "Drug Approval Package: Contrave (naltrexone hydrochloride/bupropion hydrochloride) Extended-Release Tablets NDA #200063". U.S. Food and Drug Administration (FDA). 12 November 2014. Archived from the original on 4 June 2020. Retrieved 5 August 2020.
^ ^a ^b ^c "FDA approves weight-management drug Contrave" (Press release). FDA. 10 September 2014. Archived from the original on 17 February 2017. Retrieved 16 December 2019.
^ ^a ^b Orexigen Therapeutics, Inc. (26 March 2015). "Orexigen's Mysimba Approved in Europe for the Treatment of Obesity". Yahoo! Finance. PR Newswire. Archived from the original on 31 March 2015. Retrieved 28 March 2015.
^ "Regulatory Decision Summary — Contrave — Health Canada". Health Canada. 13 February 2018. Archived from the original on 4 December 2020. Retrieved 5 September 2021.
^ ^a ^b "CONTRAVE (naltrexone HCl and bupropion HCl)" (PDF). Archived (PDF) from the original on 2 October 2021. Retrieved 10 July 2024.
^ "Suicidality in Children and Adolescents Being Treated With Antidepressant Medications". United States Food and Drug Administration. 3 November 2018. Archived from the original on 23 August 2020. Retrieved 21 February 2024.
^ Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, et al. (January 2009). "Rational design of a combination medication for the treatment of obesity". Obesity. 17 (1): 30–9. doi:10.1038/oby.2008.461. PMID 18997675. S2CID 24856014.
^ Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. (May 2013). "A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II)". Obesity. 21 (5): 935–43. doi:10.1002/oby.20309. PMC 3739931. PMID 23408728.
^ "Obesity expert named Life Scientist of the Year". Monash University. 29 October 2009. Archived from the original on 2 November 2009.
^ "Orexigen Therapeutics Submits Contrave New Drug Application to FDA for the Treatment of Obesity" (Press release). Orexigen Therapeutics. Archived from the original on 25 April 2023. Retrieved 2 July 2024 – via PR Newswire.
^ "Press Release". Orexigen Therapeutics, Inc. 7 December 2010. Retrieved 29 December 2016.^{[permanent dead link]}
^ Contrave Archived 30 December 2016 at the Wayback Machine, Drugs.com
^ "Orexigen's weight-loss drug gets thumbs-up from CHMP". Fierce Pharma. 19 December 2014. Archived from the original on 30 December 2016. Retrieved 29 December 2016.
^ Silverman E (12 May 2015). "Orexigen Study for Diet Drug Ends Over Premature Data Disclosure". WSJ. Archived from the original on 30 December 2016. Retrieved 29 December 2016.
^ O'Riordan M (14 April 2016). "Another CV Outcomes Trial Testing Weight-Loss Drug Contrave Terminated Early". TCTMD. Cardiovascular Research Foundation. Archived from the original on 20 May 2024. Retrieved 20 May 2024.
^ "Orexigen, seller of weight-loss drug Contrave, agrees to sale for $75 million". San Diego Union-Tribune. 23 April 2018. Archived from the original on 13 October 2018. Retrieved 5 August 2020.
^ "Nalpropion Pharmaceuticals, Inc. Expands Agreement with iNova Pharmaceuticals for Exclusive Commercialization Rights for Contrave (naltrexone HCl / bupropion HCl extended release) to include Select Markets in Southeast Asia, Africa and the Pacific" (Press release). Nalpropion Pharmaceuticals. 19 December 2018. Archived from the original on 28 October 2021. Retrieved 5 August 2020 – via GlobeNewswire.
^ Osborne S (8 May 2015). "Orexigen Posts Loss — Revenue Will Be The Story". Seeking Alpha (blog). Archived from the original on 10 May 2015. Retrieved 9 May 2015.

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.

[2] "Regulatory Decision Summary — Contrave". Health Canada. 23 October 2014. Archived from the original on 4 December 2020. Retrieved 7 June 2022.

[3] "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Archived from the original on 17 April 2024. Retrieved 17 April 2024.

[Contrave_FDA_label-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Contrave Extended-Release- naltrexone hydrochloride and bupropion hydrochloride tablet, extended release". DailyMed. 26 April 2019. Archived from the original on 4 June 2020. Retrieved 5 August 2020.

[Mysimba_EPAR-5] "Mysimba EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 22 October 2020. Retrieved 5 August 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[6] 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. PMID 19364254. S2CID 56625956.

[7] Tek C (2016). "Naltrexone HCI/bupropion HCI for chronic weight management in obese adults: patient selection and perspectives". Patient Preference and Adherence. 10: 751–9. doi:10.2147/PPA.S84778. PMC 4862388. PMID 27217728.

[8] "Drug Approval Package: Contrave (naltrexone hydrochloride/bupropion hydrochloride) Extended-Release Tablets NDA #200063". U.S. Food and Drug Administration (FDA). 12 November 2014. Archived from the original on 4 June 2020. Retrieved 5 August 2020.

[fda20140911-9] "FDA approves weight-management drug Contrave" (Press release). FDA. 10 September 2014. Archived from the original on 17 February 2017. Retrieved 16 December 2019.

[Orexigen2015-10] Orexigen Therapeutics, Inc. (26 March 2015). "Orexigen's Mysimba Approved in Europe for the Treatment of Obesity". Yahoo! Finance. PR Newswire. Archived from the original on 31 March 2015. Retrieved 28 March 2015.

[11] "Regulatory Decision Summary — Contrave — Health Canada". Health Canada. 13 February 2018. Archived from the original on 4 December 2020. Retrieved 5 September 2021.

[ContraveLabel-12] "CONTRAVE (naltrexone HCl and bupropion HCl)" (PDF). Archived (PDF) from the original on 2 October 2021. Retrieved 10 July 2024.

[13] "Suicidality in Children and Adolescents Being Treated With Antidepressant Medications". United States Food and Drug Administration. 3 November 2018. Archived from the original on 23 August 2020. Retrieved 21 February 2024.

[14] Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, et al. (January 2009). "Rational design of a combination medication for the treatment of obesity". Obesity. 17 (1): 30–9. doi:10.1038/oby.2008.461. PMID 18997675. S2CID 24856014.

[15] Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. (May 2013). "A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II)". Obesity. 21 (5): 935–43. doi:10.1002/oby.20309. PMC 3739931. PMID 23408728.

[monashnews2009-16] "Obesity expert named Life Scientist of the Year". Monash University. 29 October 2009. Archived from the original on 2 November 2009.

[17] "Orexigen Therapeutics Submits Contrave New Drug Application to FDA for the Treatment of Obesity" (Press release). Orexigen Therapeutics. Archived from the original on 25 April 2023. Retrieved 2 July 2024 – via PR Newswire.

[Orexigen_Therapeutics,_Inc._2010-18] "Press Release". Orexigen Therapeutics, Inc. 7 December 2010. Retrieved 29 December 2016.^{[permanent dead link]}

[19] Contrave Archived 30 December 2016 at the Wayback Machine, Drugs.com

[Palmer2014-20] "Orexigen's weight-loss drug gets thumbs-up from CHMP". Fierce Pharma. 19 December 2014. Archived from the original on 30 December 2016. Retrieved 29 December 2016.

[Silverman_2015-21] Silverman E (12 May 2015). "Orexigen Study for Diet Drug Ends Over Premature Data Disclosure". WSJ. Archived from the original on 30 December 2016. Retrieved 29 December 2016.

[ORiordan2016-22] O'Riordan M (14 April 2016). "Another CV Outcomes Trial Testing Weight-Loss Drug Contrave Terminated Early". TCTMD. Cardiovascular Research Foundation. Archived from the original on 20 May 2024. Retrieved 20 May 2024.

[23] "Orexigen, seller of weight-loss drug Contrave, agrees to sale for $75 million". San Diego Union-Tribune. 23 April 2018. Archived from the original on 13 October 2018. Retrieved 5 August 2020.

[24] "Nalpropion Pharmaceuticals, Inc. Expands Agreement with iNova Pharmaceuticals for Exclusive Commercialization Rights for Contrave (naltrexone HCl / bupropion HCl extended release) to include Select Markets in Southeast Asia, Africa and the Pacific" (Press release). Nalpropion Pharmaceuticals. 19 December 2018. Archived from the original on 28 October 2021. Retrieved 5 August 2020 – via GlobeNewswire.

[osborne2015-25] Osborne S (8 May 2015). "Orexigen Posts Loss — Revenue Will Be The Story". Seeking Alpha (blog). Archived from the original on 10 May 2015. Retrieved 9 May 2015.

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Naltrexone/bupropion

Medical uses

Available forms

Contraindications

Adverse effects

Mechanism of action

History

Society and culture

Economics

References

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