Naltrexone/bupropion: Difference between revisions

{{Short description|Medication for treatment of obesity}}

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| image = Bupropion and naltrexone.svg

| width = 200

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| caption = Skeletal structures of bupropion (top) and naltrexone (bottom)

<!-- Combo data -->

| type = combo

| component1 = Naltrexone

| class1 = [[Opioid antagonist|Opioid receptor antagonist]]

| component2 = Bupropion

| class2 = [[Norepinephrine-dopamine reuptake inhibitor]] and [[nicotinic acetylcholine receptor]] [[receptor antagonist|antagonist]]

<!-- Clinical data -->

| tradename = Contrave, Mysimba

| Drugs.com = {{drugs.com|monograph|naltrexone-hydrochloride-and-bupropion-hydrochloride}}

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

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| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = A08

| ATC_suffix = AA62

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| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Regulatory Decision Summary - Contrave | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00417 | access-date=7 June 2022}}</ref><ref>{{cite web | title=Drug and medical device highlights 2018: Helping you maintain and improve your health | website=[[Health Canada]] | date=14 October 2020 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html | access-date=17 April 2024}}</ref>

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| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Contrave FDA label">{{cite web | title=Contrave Extended-Release- naltrexone hydrochloride and bupropion hydrochloride tablet, extended release | website=DailyMed | date=26 April 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b | access-date=5 August 2020}}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Mysimba EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

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| legal_status = <!-- For countries not listed above -->

<!-- Identifiers -->

| CAS_number = 1201668-08-7

| PubChem = 11556075

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| KEGG = D10751

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<!-- Chemical and physical data -->

'''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 [[calorie restriction|reduced-calorie diet]] and increased [[exercise|physical activity]].<ref name="Contrave FDA label" /><ref>{{cite journal | vauthors = Plodkowski RA, Nguyen Q, Sundaram U, Nguyen L, Chau DL, St Jeor S | title = Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 6 | pages = 1069–81 | date = April 2009 | pmid = 19364254 | doi = 10.1517/14656560902775750 | s2cid = 56625956 }}</ref> It contains [[naltrexone]], an opioid antagonist, and [[bupropion]], an [[aminoketone]] [[atypical antidepressant]].<ref name="Contrave FDA label" /> It is taken [[Oral administration|by mouth]].<ref name="Contrave FDA label" /> Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some [[synergy|synergistic]] effects on weight.<ref>{{cite journal | vauthors = Tek C | title = Naltrexone HCI/bupropion HCI for chronic weight management in obese adults: patient selection and perspectives | journal = Patient Preference and Adherence | volume = 10 | pages = 751–9 | date = 2016 | pmid = 27217728 | pmc = 4862388 | doi = 10.2147/PPA.S84778 | doi-access = free }}</ref>

In September 2014, a [[sustained release]] formulation of the drug was approved for marketing in the United States under the brand name '''Contrave'''.<ref>{{cite web | title=Drug Approval Package: Contrave (naltrexone hydrochloride/bupropion hydrochloride) Extended-Release Tablets NDA #200063 | website=U.S. [[Food and Drug Administration]] (FDA) | date=12 November 2014 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000TOC.cfm | access-date=5 August 2020 }}</ref><ref name=fda20140911 /> The combination was subsequently approved in the [[European Union]] in the spring of 2015, where it is sold under the name Mysimba.<ref name="Mysimba EPAR">{{cite web | title=Mysimba EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/mysimba | access-date=5 August 2020}} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref name=Orexigen2015>{{cite news|last1=Orexigen Therapeutics, Inc.|title=Orexigen's Mysimba Approved in Europe for the Treatment of Obesity|url=https://finance.yahoo.com/news/orexigens-mysimba-approved-europe-treatment-182200956.html|access-date=28 March 2015|work=Yahoo! Finance|agency=PR Newswire|date=March 26, 2015}}</ref> It was approved in Canada under the Contrave brand name in 2018.<ref>{{cite web | title=Regulatory Decision Summary - Contrave - Health Canada | website=[[Health Canada]] | date=13 February 2018| url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00417 | access-date=5 September 2021}}</ref>

==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:<ref name="Contrave FDA label"/><ref name="Mysimba EPAR" />

* 30&nbsp;kg/m² (obese), or<ref name="Contrave FDA label"/><ref name="Mysimba EPAR" />

* 27&nbsp;kg/m² to < 30&nbsp;kg/m², (overweight) in the presence of one or more weight-related [[comorbidity|comorbidities]], like [[type 2 diabetes]], [[dyslipidaemia]], or controlled [[hypertension|high blood pressure]]<ref name="Contrave FDA label"/><ref name="Mysimba EPAR" />

===Available forms===

Each Contrave tablet contains 8&nbsp;mg naltrexone and 90&nbsp;mg bupropion.<ref name="ContraveLabel">https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf {{Bare URL PDF|date=March 2022}}</ref> Once full dosing is reached (after 4&nbsp;weeks of administration), the total dosage of Contrave for overweightness or obesity is two tablets twice daily or 32&nbsp;mg naltrexone and 360&nbsp;mg bupropion per day.<ref name="ContraveLabel" />

==Contraindications==

According to the [[Food and Drug Administration|U.S. Food and Drug Administration]] (FDA), naltrexone/bupropion is contraindicated in patients who have/are:<ref name ="Contrave FDA label"/>

* History of [[seizures]]

* History of an eating disorder such as [[bulimia nervosa]] or [[anorexia nervosa]]

* Taking [[opioid|opioids]], or are in opiate withdrawal.

* Taken [[Monoamine oxidase inhibitor|monoamine oxidase inhibitors]] in the last 14 days

* [[Pregnancy|Pregnant]]

* Abruptly stopped use of [[alcoholic beverages|alcohol]], [[benzodiazepines]], [[barbiturates]], or [[anticonvulsants|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.<ref name ="Contrave FDA label" /> This is attributed to the bupropion component, as the FDA requires all [[Antidepressant|antidepressants]] to include that boxed warning on [[Medication package insert|medication package inserts.]]<ref>{{Cite web |title=Suicidality in Children and Adolescents Being Treated With Antidepressant Medications |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications |access-date=21 February 2024 |website=United States Food and Drug Administration.|date=3 November 2018 }}</ref>

The safety and effectiveness in children under the age of 18 has not been studied.<ref name="Contrave FDA label" />

==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 reuptake inhibitor|dopamine]], and a [[nicotinic acetylcholine receptor]] [[receptor antagonist|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 [[Opioid#Endogenous opioids|endogenous opioids]] via opioid-mediated [[negative feedback]].{{medcn|date=August 2020}}

*Naltrexone is a pure opioid antagonist, which further augments bupropion's activation of the POMC.<ref>{{cite journal | vauthors = Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, Gadde KM, Gupta AK, O'Neil P, Schumacher D, Smith D, Dunayevich E, Tollefson GD, Weber E, Cowley MA | title = Rational design of a combination medication for the treatment of obesity | journal = Obesity | volume = 17 | issue = 1 | pages = 30–9 | date = January 2009 | pmid = 18997675 | doi = 10.1038/oby.2008.461 | s2cid = 24856014 | doi-access = free }}</ref>

Combined, naltrexone/bupropion has an effect on the reward pathway that results in reduced food craving.<ref>{{cite journal | vauthors = Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E | title = A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II) | journal = Obesity | volume = 21 | issue = 5 | pages = 935–43 | date = May 2013 | pmid = 23408728 | pmc = 3739931 | doi = 10.1002/oby.20309 }}</ref> 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.<ref name=monashnews2009>{{cite web |url=http://www.monash.edu.au/news/newsline/story/1534 |title=Obesity expert named Life Scientist of the Year |publisher=[[Monash University]] |url-status=dead |date=29 October 2009 |archive-date=2 November 2009 |archive-url=https://web.archive.org/web/20091102061153/http://www.monash.edu.au/news/newsline/story/1534 }}</ref>

==History==

[[Orexigen Therapeutics|Orexigen]] submitted a [[New Drug Application]] (NDA) for this drug combination to the FDA on 31 March 2010.<ref>[http://www.prnewswire.com/news-releases/orexigenr-therapeutics-submits-contraver-new-drug-application-to-fda-for-the-treatment-of-obesity-89626217.html Orexigen Therapeutics Submits Contrave New Drug Application to FDA for the Treatment of Obesity]</ref> 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.<ref name="Orexigen Therapeutics, Inc. 2010">{{cite web | title=Press Release | website=Orexigen Therapeutics, Inc. | date=2010-12-07 | url=http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1505602&highlight= | access-date=2016-12-29 }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 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.<ref>[https://www.drugs.com/nda/contrave_110204.html Contrave], [[Drugs.com]]</ref> It was ultimately approved in the United States in the fall of 2014.<ref name=fda20140911>{{cite press release |publisher=[[Food and Drug Administration|FDA]] |date=10 September 2014 |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm413896.htm |title=FDA approves weight-management drug Contrave |access-date=16 December 2019 |archive-date=17 February 2017 |archive-url=https://web.archive.org/web/20170217225439/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm413896.htm |url-status=dead }}</ref>

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.<ref name=Palmer2014>{{cite news | title=Orexigen's weight-loss drug gets thumbs-up from CHMP | newspaper=Fierce Pharma | date=2014-12-19 | url=http://www.fiercepharma.com/regulatory/orexigen-s-weight-loss-drug-gets-thumbs-up-from-chmp | access-date=2016-12-29}}</ref> Approval was granted in late March 2015.<ref name=Orexigen2015 />

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.<ref name="Silverman 2015">{{cite web | last=Silverman | first=Ed | title=Orexigen Study for Diet Drug Ends Over Premature Data Disclosure | website=WSJ | date=2015-05-12 | url=https://blogs.wsj.com/pharmalot/2015/05/12/orexigen-safety-study-for-diet-pill-ends-due-to-premature-data-disclosure/ | access-date=2016-12-29}}</ref> 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.<ref name="ORiordan2016">{{cite news |last1=O'Riordan |first1=Michael |title=Another CV Outcomes Trial Testing Weight-Loss Drug Contrave Terminated Early |url=https://www.tctmd.com/news/another-cv-outcomes-trial-testing-weight-loss-drug-contrave-terminated-early |access-date=20 May 2024 |work=[[TCTMD]] |publisher=[[ Cardiovascular Research Foundation]] |date=April 14, 2016}}</ref>

In 2018, Orexigen sold its assets, including Contrave, to Nalpropion Pharmaceuticals.<ref>{{cite news | title=Orexigen, seller of weight-loss drug Contrave, agrees to sale for $75 million | website=San Diego Union-Tribune | date=23 April 2018 | url=https://www.sandiegouniontribune.com/business/biotech/sd-me-orexigen-sold-nalpropion-20180423-story.html | access-date=5 August 2020}}</ref><ref>{{cite press release| title=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 | publisher=Nalpropion Pharmaceuticals | via=GlobeNewswire| date=19 December 2018 | url=http://www.globenewswire.com/news-release/2018/12/19/1669738/0/en/Nalpropion-Pharmaceuticals-Inc-Expands-Agreement-with-iNova-Pharmaceuticals-for-Exclusive-Commercialization-Rights-for-Contrave-naltrexone-HCl-bupropion-HCl-extended-release-to-inc.html | access-date=5 August 2020}}</ref>

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"<ref>{{cite web | url=https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/nalpropion-pharmaceuticals-llc-09222020 | title=Nalpropion Pharmaceuticals LLC - 09/22/2020 | website=[[Food and Drug Administration]] | date=23 March 2021 }}</ref> on multiple issues. Nalproprion subsequently issued "An important correction from CONTRAVE® (naltrexone HCl/bupropion HCl) Extended-Release Tablets" <ref>{{Cite web |url=https://www.correctiveadvertisementforcontrave.com/ |title=Archived copy |access-date=2022-12-15 |archive-date=2022-12-15 |archive-url=https://web.archive.org/web/20221215012723/https://www.correctiveadvertisementforcontrave.com/ |url-status=dead }}</ref>

== Society and culture ==

=== Economics ===

The sustained-release formulation, Contrave, is marketed by [[Takeda Pharmaceutical Company|Takeda]] under license from the combination medication's developer, Orexigen Therapeutics.<ref name=fda20140911 /> As of 2015, Orexigen received 20% of net sales from Takeda.<ref name="osborne2015">{{cite web |url=http://seekingalpha.com/article/3159646-orexigen-posts-loss-revenue-will-be-the-story |title=Orexigen Posts Loss - Revenue Will Be The Story |website=Seeking Alpha |date=May 8, 2015 | last = Osborne | first = Spencer |type=blog |access-date=May 9, 2015 }}</ref>

At the time of its approval by the FDA, [[Wells Fargo]] [[Financial analyst|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]].<ref name=Grover2014>{{cite news |last1=Grover |first1=Natalie |title=Reuters More: Reuters Health Long-awaited Diet Pill Gets U.S. Approval Reuters |url=http://www.businessinsider.com/r-long-awaited-diet-pill-gets-us-approval-2014-9 |access-date=March 28, 2015 |work=Business Insider |agency=Reuters |date=September 10, 2014 |archive-date=April 2, 2015 |archive-url=https://web.archive.org/web/20150402142214/http://www.businessinsider.com/r-long-awaited-diet-pill-gets-us-approval-2014-9 |url-status=dead }}</ref> 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.<ref name=Osborne2014>{{cite web |last1=Osborne |first1=Spencer |title=Contrave Sales Continue To Impress |url=http://seekingalpha.com/article/2752575-contrave-sales-continue-to-impress |access-date=March 28, 2015 |website=Seeking Alpha |date=December 12, 2014 |type=blog }}</ref> The first quarter of sales for Contrave (Q1 2015) showed net sales of {{currency|11.5 million}}.<ref name="osborne2015" />

{{Reflist}}

{{Anorectics}}

{{Adrenergics}}

{{Cholinergics}}

{{Opioidergics}}

{{Portal bar|Medicine}}

{{DEFAULTSORT:Naltrexone Bupropion}}

[[Category:Anti-obesity drugs]]

[[Category:Combination anti-obesity drugs]]

[[Category:Kappa-opioid receptor antagonists]]

[[Category:Mu-opioid receptor antagonists]]

[[Category:Norepinephrine releasing agents]]

[[Category:Norepinephrine reuptake inhibitors]]

[[Category:Nicotinic antagonists]]