Naltrexone-Bupropion (CONTRAVE): Another Dangerous Weight-Loss Drug

Naltrexone-bupropion (CONTRAVE) is not really a new drug but a new fixed-dose combination of two older drugs: the opioid antagonist naltrexone and the antidepressant bupropion (APLENZIN, FORFIVO XL, WELLBUTRIN, ZYBAN). Naltrexone and bupropion often are used separately in the treatment of opioid and nicotine addiction, respectively.

In 2014, the Food and Drug Administration (FDA) approved naltrexone-bupropion for weight loss in obese adults or overweight adults who also have at least one weightrelated health condition (such as diabetes or high blood pressure).[1] It is supposed to be prescribed in conjunction with a reduced-calorie diet and increased physical activity.

In clinical trials, subjects taking naltrexone-bupropion on average experienced only 4 percent more weight loss than those taking a placebo.[2] Public Citizen’s Health Research Group has designated this drug as Do Not Use because its longterm cardiovascular safety has not been established, and it also causes serious adverse effects that outweigh its minimal weight-loss benefits.

Cardiovascular risk

In 2011, the FDA rejected Orexigen Therapeutics’ initial application for naltrexone-bupropion due to evidence from clinical trials that raised “concern about the cardiovascular safety profile of naltrexonebupropion when used long-term in a population of overweight and obese subjects.”[3] Particularly concerning to the FDA was the fact that the drug can cause significant elevations in blood pressure and heart rate. Indeed, during the clinical trials, 21 subjects taking naltrexone-bupropion developed either hypertension or heart palpitations (which can be caused by a rapid heart rate or other abnormal heart rhythm) that was severe enough to require withdrawal from the trial, whereas no such events occurred in subjects taking a placebo.[4]

Even modest increases in blood pressure and heart rate are associated with an elevated risk of serious adverse cardiovascular events, including heart attacks and strokes. Because of these concerns, the FDA required that Orexigen conduct an additional large randomized clinical trial to evaluate the risk of serious adverse cardiovascular events. This trial was named the LIGHT trial.

In response to pushback from the company, the FDA agreed to reconsider approval of naltrexone-bupropion based on a preliminary analysis of data from the LIGHT trial after it was only 25 percent completed.[5] Thus, in 2013, Orexigen submitted to the FDA a second application for the drug that included the preliminary results from the LIGHT trial. Because these results showed that it was unlikely that naltrexonebupropion would cause a twofold or greater increase in the risk of major adverse cardiovascular events, the FDA approved the drug in 2014 — despite the fact that the drug may cause a smaller but still unacceptable increase in the risk of such adverse events.

Disturbingly, prior to its approval of the drug, the FDA also had discovered that Orexigen had failed to appropriately maintain the confidentiality of the preliminary LIGHT trial results, raising serious concerns that the “LIGHT trial [was] not being conducted to the highest of scientific standards.”[6] For this reason, the LIGHT trial was stopped, and the FDA required that Orexigen start a new clinical trial to evaluate the long-term cardiovascular safety of naltrexone-bupropion. The results of this new trial will not be available until at least 2022.[7]

Importantly, the product labeling indicates that “the effect of naltrexone- bupropion on cardiovascular [risks] has not been established.”[8]

Other adverse effects[9]

Naltrexone-bupropion is associated with adverse psychiatric effects and sleep disorders, particularly in older adults. During clinical trials, the total incidence of adverse psychiatric effects (primarily depression) and sleep disorders (primarily insomnia) in patients 65 years and older who were using naltrexone-bupropion was more than four times higher (29 percent) than in those receiving a placebo (6 percent). Although product labeling for the other diet drugs liraglutide (SAXENDA), phentermine- topiramate (QSYMIA) and lorcaserin (BELVIQ) briefly mention an increase in suicidal thoughts and behaviors, naltrexone-bupropion is the only product that includes a black-box warning (the strongest warning required by the FDA) for these adverse effects.

* This warning has been paraphrased from the FDA-approved drug labeling.

Naltrexone-bupropion also is associated with an increased risk of several neurologic and cognitive adverse reactions, including problems with attention, dizziness and syncope (sudden loss of consciousness). Such events occurred nearly three times more frequently in patients using the drug (15 percent) than in those receiving a placebo (6 percent). Bupropion also is known to cause seizures.

Naltrexone-bupropion, like liraglutide and phentermine-topiramate, is associated with worsening kidney function. Patients in clinical trials were six times more likely to have significant increases in blood creatinine levels (indicating a decline in kidney function) when using naltrexonebupropion (0.6 percent) than when using a placebo (0.1 percent).

In addition, the drug’s product label warns about an increased risk of liver damage and glaucoma (a serious eye disorder that can impair vision and lead to permanent blindness).

Alongside these dangerous adverse effects, the drug’s labeling mentions a number of additional risks. For example, naltrexone-bupropion commonly causes nausea, vomiting, constipation, dry mouth and headache.

What You Can Do

As with the other weight-loss drugs, we recommend that you not use naltrexone-bupropion because it has serious risks. Instead, talk with your doctor about how to lose weight by safer means, including lifestyle changes, diet and exercise.

References

[1] Orexigen Therapeutics. Label: naltrexone HCl and bupropion HCl (CONTRAVE). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200063s009lbl.pdf. Accessed June 1, 2017.

[2] Wharton S, Serodio KJ. Next generation of weight management medications: Implications for diabetes and CVD risk. Curr Cardiol Rep. 2015;17(5):35.

[3] Food and Drug Administration. Complete response letter to Orexigen Therapeutics, NDA 200063. January 1, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000OtherActionLtrs.pdf. Accessed June 2, 2017.

[4] Food and Drug Administration. Clinical review, NDA 200063. December 20, 2010. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000MedR.pdf. Accessed June 5, 2017. PDF page 312.

[5] Food and Drug Administration. Summary review, NDA 200063. September 10, 2014. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200063Orig1s000SumR.pdf. Accessed June 2, 2017.

[6] Ibid.

[7] Sharfstein JM, Psaty BM. Evaluation of the cardiovascular risk of naltrexone-bupropion: A study interrupted. JAMA. 2016;315(10):984-986.

[8] Orexigen Therapeutics. Label: naltrexone HCl and bupropion HCl (CONTRAVE). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200063s009lbl.pdf. Accessed June 1, 2017.

[9] Ibid.