Naltrexone/bupropion

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Naltrexone/bupropion
Bupropion and naltrexone.svg
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
Legal status
Legal status
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CAS Number
PubChem CID
KEGG
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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]

Contents

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]

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 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]

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.

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]

Related Research Articles

<span class="mw-page-title-main">Bupropion</span> Medication mainly used for depression and smoking cessation

Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cases of "incomplete response" to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue. Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder.

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<span class="mw-page-title-main">Oxymorphone</span> Opioid analgesic drug

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<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

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<span class="mw-page-title-main">Naltrexone</span> Medication

Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found effective in the treatment of other addictions and may be used for them off-label. An opioid-dependent person should not receive naltrexone before detoxification. It is taken by mouth or by injection into a muscle. Effects begin within 30 minutes, though a decreased desire for opioids may take a few weeks to occur. Side effects may include trouble sleeping, anxiety, nausea, and headaches. In those still on opioids, opioid withdrawal may occur. Use is not recommended in people with liver failure. It is unclear if use is safe during pregnancy. Naltrexone is an opioid antagonist and works by blocking the effects of opioids, including both opioid drugs as well as opioids naturally produced in the brain.

<span class="mw-page-title-main">Mecamylamine</span> Antihypertensive drug

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<span class="mw-page-title-main">Lofexidine</span> Medication used for opioid withdrawal

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<span class="mw-page-title-main">Nalmefene</span> Opioid antagonist

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<span class="mw-page-title-main">Lorcaserin</span> Antiobesity drug

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Michael Cowley FTSE is an Australian physiologist. He is best known for his mapping of the neural circuits involved in metabolism and obesity and diabetes treatment. He is a professor in the Department of Physiology at Monash University in the Faculty of Biomedical and Psychological Sciences. He is also a director of the Australian diabetes drug development company, Verva Inc, and director of the Monash Obesity & Diabetes Institute] (modi).

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<span class="mw-page-title-main">Dextromethorphan/bupropion</span> Combination medication

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References

  1. ↑ "Regulatory Decision Summary - Contrave". Health Canada. 23 October 2014. Retrieved 7 June 2022.
  2. ↑ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada . 14 October 2020. Retrieved 17 April 2024.
  3. ↑ "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 Oct 2023.
  4. 1 2 3 4 5 6 7 8 9 10 "Contrave Extended-Release- naltrexone hydrochloride and bupropion hydrochloride tablet, extended release". DailyMed. 26 April 2019. Retrieved 5 August 2020.
  5. 1 2 3 4 5 "Mysimba EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 5 August 2020. Text was copied from this source which is © 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. Retrieved 5 August 2020.
  9. 1 2 3 "FDA approves weight-management drug Contrave" (Press release). FDA. 10 September 2014. Archived from the original on 17 February 2017. Retrieved 16 December 2019.
  10. 1 2 Orexigen Therapeutics, Inc. (March 26, 2015). "Orexigen's Mysimba Approved in Europe for the Treatment of Obesity". Yahoo! Finance. PR Newswire. Retrieved 28 March 2015.
  11. ↑ "Regulatory Decision Summary - Contrave - Health Canada". Health Canada . 13 February 2018. Retrieved 5 September 2021.
  12. 1 2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf [ bare URL PDF ]
  13. ↑ "Suicidality in Children and Adolescents Being Treated With Antidepressant Medications". United States Food and Drug Administration. 3 November 2018. 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.
  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
  18. ↑ "Press Release". Orexigen Therapeutics, Inc. 2010-12-07. Retrieved 2016-12-29.[ permanent dead link ]
  19. ↑ Contrave, Drugs.com
  20. ↑ "Orexigen's weight-loss drug gets thumbs-up from CHMP". Fierce Pharma. 2014-12-19. Retrieved 2016-12-29.
  21. ↑ Silverman E (2015-05-12). "Orexigen Study for Diet Drug Ends Over Premature Data Disclosure". WSJ. Retrieved 2016-12-29.
  22. ↑ "Orexigen, seller of weight-loss drug Contrave, agrees to sale for $75 million". San Diego Union-Tribune. 23 April 2018. Retrieved 5 August 2020.
  23. ↑ "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. Retrieved 5 August 2020– via GlobeNewswire.
  24. ↑ "Nalpropion Pharmaceuticals LLC - 09/22/2020". Food and Drug Administration . 23 March 2021.
  25. ↑ "Archived copy". Archived from the original on 2022-12-15. Retrieved 2022-12-15.{{cite web}}: CS1 maint: archived copy as title (link)
  26. 1 2 Osborne S (May 8, 2015). "Orexigen Posts Loss - Revenue Will Be The Story". Seeking Alpha (blog). Retrieved May 9, 2015.
  27. ↑ Grover N (September 10, 2014). "Reuters More: Reuters Health Long-awaited Diet Pill Gets U.S. Approval Reuters". Business Insider. Reuters. Archived from the original on April 2, 2015. Retrieved March 28, 2015.
  28. ↑ Osborne S (December 12, 2014). "Contrave Sales Continue To Impress". Seeking Alpha (blog). Retrieved March 28, 2015.
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