Zimulti

Generic Name: rimonabant
Company: Sanofi-Aventis

Sanofi-Aventis has withdrawn rimonabant from the market globally and it is no longer under development.1 In June of 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee recommended against the approval of rimonabant (known in the United States as Zimulti) due to concerns over dangerous psychological side effects, including suicidality and depression. Subsequently, the FDA did not approve rimonabant, and it has never been marketed in the United States. Acomplia, the brand name of rimonabant in Europe, was officially withdrawn by the European Medicines Agency (EMEA) in January 2009 due to the risks of these side effects. Previously, the EMEA had suspended Acomplia from the UK market in 2008 because the agency felt the benefits did not outweigh the risks.

What is Zimulti?

  • Zimulti (rimonabant) was the first in a new class of therapeutic agents called Cannabinoid-1 Receptor Blockers (CB1).
  • Zimulti was studied in the treatment of obesity, as an aid for smoking cessation, and related conditions.

How does Zimulti work?

  • Zimulti acts by selectively blocking CB1 receptors found in the brain and in peripheral organs important in glucose and lipid (or fat) metabolism, including adipose tissue, the liver, gastrointestinal tract and muscle.2
  • CB1 receptor blockade with Zimulti acts to decrease the overactivity of the endocannabinoid system (EC system).3,4 The EC system is a recently characterised physiological system that includes receptors such as the CB1 receptor and it has been shown to play an important role in regulating body weight and in controlling energy balance, as well as glucose and lipid (or fat) metabolism.
  • Zimulti switches off the same brain circuits that make people hungry when they smoke cannabis. As a result, people who take Zimulti eat less and lose weight.

What is Zimulti used for?

  • Zimulti was studied to be used complementary to diet and exercise to treat obese or overweight patients who suffer from Type 2 diabetes and abnormal levels of fat in the blood.
  • Sanofi argued that Zimulti could also prevent the risk of cardiovascular disease.

Does Zimulti also aid smoking cessation?

  • Zimulti had been studied by Sanofi-Aventis as an aid to smoking cessation based on studies for up to one year in over 6,500 smokers motivated to quit smoking.
  • Sanofi-Aventis submitted a New Drug Application for Zimulti to the FDA, who in turn issued a non-approvable letter for Zimulti use in smoking cessation, and an approvable letter for use in weight management. However, in June of 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee recommended against the approval of rimonabant for any indication due to concerns over dangerous psychological side effects, including suicidality and depression. Subsequently, the FDA did not approve rimonabant, and it has never been marketed in the United States.

What were the results of the clinical studies?

  • In clinical studies, Zimulti was shown to improve a wide array of cardiometabolic risk factors as well as promote sustained weight loss.5,6
  • Approximately half of the observed improvement in HDL-cholesterol, triglycerides and HbA1C (an indicator of blood sugar control) in patients who received Zimulti 20mg was beyond that expected from weight loss alone.7

Zimulti side effects

  • Side effects in the trial on Zimulti in obesity were vomiting and nausea, forcing about 19 percent of patients to leave the trial versus 13 percent of those who took placebo.
  • Clinical studies found that 26 percent of people taking Zimulti reported psychiatric symptoms, including anxiety, insomnia, panic attacks as well as increases in aggression and agitation compared to patients given a placebo.
  • Zimulti has also been shown to cause increased suicidal tendencies and other depressive symptoms.8

References:

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  1. Personal Communication. Sanofi-Aventis Medical Information Department. Rimonabant availability. September 12, 2011
  2. Pagotto U. Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet. 2005; 365: 1363-64.
  3. Van Gaal LF, Rissanen, AM, Scheen AJ, Ziegler O, Rössner S for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365: 1389-97.
  4. Marzo V, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410:822-825.
  5. Després, J.P. et al. Effect of Rimonabant on Body Weight and the Metabolic Syndrome in Overweight Patients. New England Journal of Medicine, November, 16, 2005.
  6. Van Gaal L, et al. Effects Of The Cannabinoid-1 Receptor Blocker Rimonabant On Weight Reduction And Cardiovascular Risk Factors In Overweight Patients: 1-Year Experience From The RIO-Europe Study. The Lancet. 365;1389-1397.
  7. Zimulti Summary of Product Characteristics
  8. Testimony Before FDA Advisory Committee Meeting on Rimonabant (HRG Publication #1815), Testimony of Sidney Wolfe, M.D., Ben Wolpaw and Elizabeth Barbehenn Ph.D. Health Research Group of Public Citizen. FDA Endocrine Metabolic Drugs Advisory Committee Meeting on Rimonabant: June 13, 2007

Sources:

Rimonabant Accepted for Filing By the FDA June 23, 2005

Sanofi-aventis Received from the FDA an Approvable Letter for Rimonabant for Weight Management and a Non Approvable Letter for Smoking Cessation February 17, 2006

Acomplia (rimonabant) receives marketing authorisation in the European Union (PDF)
Sanofi-Aventis Press Release June 21, 2006

FDA Advisory Committee Did Not Recommend Approval of Rimonabant (Zimulti) for Use in Obese and Overweight Patients With Associated Risk Factors June 13, 2007

Weight Loss Drug Zimulti (rimonabant) Can Cause Serious Physical and Psychological Harm and Birth Defects, Public Citizen Tells FDA June 13, 2007

Sanofi-Aventis to Discontinue Rimonabant Trials for All Indications November 6, 2008

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