Bupropion/naltrexone

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Bupropion/naltrexone
Combination of
Bupropion norepinephrine/dopamine reuptake inhibitor
Naltrexone opioid receptor antagonist
Clinical data
Trade names Contrave
Pregnancy cat.
  • X
Legal status
Identifiers
CAS number  YesY
ATC code ?
 YesY (what is this?)  (verify)

Bupropion/Naltrexone is a combination drug treatment for obesity.[1][2] As of 2014, the drug is marketed in the United States in a sustained release formulation under the name Contrave by Takeda for the drug's developer, Orexigen Therapeutics.[1][3] An estimate from Wells Fargo places the potential revenue from this drug at US$600 million per year.[4]

Bupropion/naltrexone is a combination of two FDA approved drugs, bupropion and naltrexone. Both drugs have individually shown some evidence of effectiveness in weight loss, and the combination is expected to have a synergistic effect.[5] In clinical trials, patients taking Contrave combined with diet and exercise lost more weight than patients taking a placebo and following the same diet and exercise program.[6]

Drug Development[edit]

On 31 March 2010, Orexigen submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for this drug combination.[7] 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.[8] Contrave's PDUFA date was 31 January 2011. 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.[9] The recommended daily dose of Contrave is two (8 mg naltrexone/90 mg bupropion) tablets taken twice daily (4 tablets total - 32 mg naltrexone, 360 mg bupropion). Upon initiation, the drug will be started with a quarter-dose (or one tablet) for one week and a pill will be added to the regimen each week until the full recommended dose is reached on Week 4.

During phase 2 testing, different dosages were used in a once daily formula. These include:

  • 16 mg naltrexone - 400 mg bupropion
  • 32 mg naltrexone - 400 mg bupropion
  • 48 mg naltrexone - 400 mg bupropion

The second dosage (32 mg-400 mg) on average showed the best benefit-to-risk ratio.

Treatment is designed to influence the hypothalamus in order to decrease food intake over an extended period of time. Studies of almost 700 patients, 90% female, ran up to 56 weeks. The control group, overall, lost 5% of their initial body weight, or 11-16 lbs. The experimental (medicated) group lost 20-23 lbs during the same amount of time. The average starting weight for participants was 223 lbs.[10] Current medical weight loss medications average 5-22 lbs lost in 6 months.[medical citation needed]

Mechanism of Action[edit]

Combination of both Bupropion and Naltrexone targets CNS pathways that influence food intake. Bupropion is a dopamine and norepinephrine reuptake inhibitor,which also activates pro-opiomelanocortin (POMC) neurons in the hypothalamus which give an effect downstream, resulting in loss of appetite and increased energy output. POMC is regulated by endogenous opioids via opioid-mediated inhibitory feedback. Naltrexone, a pure opioid antagonist, is used to suppress POMC inhibition therefore augmenting greater effect of POMC activation. [11] Bupropion/Naltrexone also has an effect on the reward pathway that result in lessening food craving.[12]

Dosing[edit]

On the market, Contrave is available as an extended-release tablet of 8mg naltrexone HCl and 90mg bupropion HCl.
Week 1: take 1 tablet by mouth, once daily every morning.
Week 2: take 1 tablet by mouth every morning and evening.
Week 3: take 2 tablets by mouth every morning and 1 in the evening.
Week 4 and on: take 2 tablet by mouth every morning and evening. Total daily dose 32mg naltrexone/360mg bupropion. Daily doses higher than that are not recommended. This is the maintenance dose.

It is recommended to stop taking the medicine if the body weight has not decreased by 5% after 12 weeks at maintenance dose.

Safety and effectiveness in children under the age of 18 has not been studied. [13]

Contraindications[edit]

Takeda recommends that Contrave should not be used in anyone who falls into any of the categories below:[13]
• History of seizures
• History of an eating disorder such as bulimia or anorexia
• Taking opioid pain medicines, taking medicines to stop opioid addiction, or are in opiate withdrawal
• Currently taking an MAOI or have taken an MAOI in the last 14 days
Pregnant
• Abrupt termination of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs

Safety Information[edit]

One of the medications in Contrave is bupropion. The FDA has put a boxed warning onto this medicine because it may affect mood and increase the likelihood of suicide. Although rare, signs of mood and behavioral changes should be reported to a doctor.[13]


References[edit]

  1. ^ a b c "FDA approves weight-management drug Contrave" (Press release). FDA. 10 September 2014. 
  2. ^ Plodkowski, Raymond A.; Nguyen, Quang; Sundaram, Umasankari; Nguyen, Loida; Chau, Diane L.; St. Jeor, Sachiko (2009). "Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity". Expert Opinion on Pharmacotherapy 10 (6): 1069–1081. doi:10.1517/14656560902775750. PMID 19364254. 
  3. ^ "Obesity expert named Life Scientist of the Year". Monash University. 29 October 2009. Archived from the original on 2 November 2009. 
  4. ^ Campbell, Todd (12 September 2014). "Surprising New Competitor: Should Arena Pharmaceuticals, Inc. and Orexigen Therapeutics, Inc. Be Afraid?". The Motley Fool. 
  5. ^ Sinnayah P, Wallingford N, Evans A, Crowley MA (2007). "Bupropion and naltrexone interact synergistically to decrease food intake in mice". Obesity 15 (9): A179. 
  6. ^ Positive 24-week Results For Contrave Phase III Obesity Treatment Study Reported By Orexigen, Medical News Today, 28 Sep 2006
  7. ^ Orexigen(R) Therapeutics Submits Contrave(R) New Drug Application to FDA for the Treatment of Obesity
  8. ^ www.orexigen.com
  9. ^ [1]
  10. ^ WebMD.com
  11. ^ Greenway, Frank; Whitehouse, M.J; Guttadauria, Maria; Anderson, James (2008). "Rational Design of a Combination Medication for the Treatment of Obesity". Obesity 17: 30-39. 
  12. ^ Apovian, Caroline; Aronne, Louis; Rubino, Domenica; Still, Christopher (2013). "A randomized, Phase 3 Trial of Naltrexone SR/Bupropion SR on Weight and Obesity-related Risk Factors (COR-II)". Obesity 21: 935-943. 
  13. ^ a b c "Contrave Prescribing Information". Takeda. Retrieved 2 November 2014.