Contrave (bupropion/naltrexone) narrowly recommended for approval

The day job and an illness have kept me away from the blog this week. However, I did want to share with you a very nice article by Jane E. Allen of ABC News on the recent FDA advisory panel recommendation for approval (with a vote of 13-8) of the anti-obesity drug, Contrave (Oxrigen®). A sustained-release combination of the antidepressant bupropion and the orally-active opioid antagonist naltrexone, Contrave acts in the brain on the pro-opiomelanocortin (POMC) axis of appetite regulation. The FDA is not obligated to follow the recommendations of their advisory panels but most often do so.

Allen included a brief quote from me as I am often contacted by the ABC News Medical Unit for commentary on drug safety and pharmacotherapy. The biggest concern with the drug combination has been cardiovascular side effects, especially since such a drug will be much more widely used than the ~4,500 patients who participated in the clinical trials to date, patients who will often have complicating health issues and/or on many other potentially-interacting drugs.

The report published in The Lancet in August 2010 from 1742 patients is the only efficacy and safety data to which I am privy. In that study the drug combination causes an impressive 6-8% weight loss after 56 weeks, 8-13% drop in triglycerides, and a 12-17% in fasting insulin (suggesting improved insulin sensitivity) with very minimal effects on blood pressure.

With that as the only data I can see, I’m surprised that the vote was so equivocal – I suspect that the panel was privy to other data that I cannot access. This makes me worry that there are other concerns from other studies. Moreover, the panel may be concerned that the drug is likely to be quite popular and that any rare side effect not seen in the reported ~4,500 patients tested will be amplified when hundreds of thousands or a couple of million patients take the drug for long periods.

Interestingly, I saw no discussion of seizure risk which has been a low incidence issue with bupropion monotherapy.

With the limited amount of data available to me, my enthusiasm is mixed based on the published efficacy of the combination and the clear concerns reflected in the advisory committee vote. My greatest concern will be the indiscriminant use of the drug among large populations where diet and exercise would be more appropriate. The drug is primarily intended for obese patients with complicating issues such as cardiovascular disease or diabetes whose weight cannot be managed by diet and exercise alone.

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7 Responses to Contrave (bupropion/naltrexone) narrowly recommended for approval

  1. k says:

    Hmmm…naltrexone will effectively eliminate calories from ETOH for Contrave users. For some, bupropion may have other effects in addition to appetite reduction, such as insomnia, feelings of restlessness and jitteriness. (My personal experience from a very short trial of bupropion, which was the closest I have ever gotten to a manic episode. I have BPII, and that was scary., compared to hypomania.)

    Do you know the drop out rate for the Contrave trial? I have a feeling it might be fairly high (no pun intended). This drug is little better than the topiramate-phentermine combo the FDA rejected.

    I don’t mean to pick on primary care docs, but – in my experience it is far better to see a psychiatrist for psychiatric drugs, as they have more experience with usage, side effects, combination therapy, etc. Perhaps FDA should consider restricting Contrave to psychiatrists, to be used only in combination with appropriate counseling and therapy.

  2. Travis Saunders, MSc, CEP says:

    Our colleague Arya Sharma, who is a researcher and practicing bariatric physician, has been blogging about Contrave and other obesity-related medications of late. While the side-effects are not inconsiderable and tend to get a lot of attention, there are almost no approved pharmacological treatments for obesity (save for Orlistat, at least here in Canada). Which means that instead of the side-effects of the drugs, many individuals have to put up with the metabolic dysfunction and decreased quality of life that can accompany obesity. Arya’s latest post on Contrave is here.

    Not that I think that the we should allow products with dangerous side-effects onto the market, but it seems that a drug with known side-effects, properly administered, is better than no pharmacological options at all. When Rimonabant was still being tested (it was eventually pulled from the market because of risk of suicidal ideation), I remember one colleague asking whether a drug could be considered beneficial if it resulted in dramatic improvements in metabolic health for 500 people, but resulted in decreased quality of life or even suicidal ideation for 100. As someone who knows a helluva lot more about this stuff than I do, I’m curious for your thoughts.

  3. sally says:

    After recent rounds with two other obesity drugs, one with evidence of serious preclinical issues (rat cancer!) and the other with marginal efficacy (barely crossed the 5% threshold), it is no surprise that the committee felt compelled to approve Orixigen’s Contrave based on it’s reported efficacious effects.

    While not envying the panel onerous task of wading through all the data a third time this year, I agree that the side effects for a non-life threatening condition are troubling.

    Incidently, years ago while working on rimonabant, a friend was known to call it “Wemonaboudit” instead owing to the difficulties of managing a stressful and demanding client :)

  4. Travis says:

    I’m not sure if I’m reading you correctly, Sally, but I would disagree with the assertion that obesity is *not* a life-threatening condition. In many instances it is (especially for those who are likely to be receiving obesity drugs), with variable levels of urgency.

  5. sally says:

    Travis, sorry I dashed my comment off in a hurry. I meant imminently within the next couple of months in the same way as, say, advanced cancer or a heart transplant might be.

    Undoubtedly, obesity is becoming a chronic epidemic issue, but few affected will have an imminent or immediate life-threatening issue. If left untreated for years, obviously that is an entirely different ballgame altogether.

  6. David Kroll says:

    Sally and Travis – sorry I couldn’t respond during the day but I understood what Sally was trying to say. The issue, of course, is that while the drug is intended for those with severe obesity issues (and indeed potentially life-threatening) that cannot be addressed with diet or exercise, the drug would provide at least one non-surgical option.

    However – and this speaks to Travis’s earlier point on drug approval – one can make risk-benefit decisions based on the intended patient population but we know full well that the drug will be very widely prescribed for a much larger population of people seeking a quick fix to lose those five or ten pounds. When you amplify the patient population, you’re also increasing the denominator for the incidence of adverse reactions.

    But in general, regulatory agencies tend to give greater latitude in risk-benefit to drugs that are first-in-class and/or are the only pharmacological options.

    Thanks to all of you for the very thoughtful discussion.

  7. Debbie says:

    Whatever you think about this medication. I’m a person who needs to loose weight and just read all these messages on this medication which I just received. Well let me tell you folks I really got scared because according to what you wrote this hasn’t been tested yet am I right?

    Does this Bupropione and Naltrexone together with Fluoxetina really make one loose weight?