Rimonabant

Overview

Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious neurological and psychiatric side effects; it was never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor CB₁ and was first-in-class.[1–5] WP

Risks and side effects

Adverse effects

Data from clinical trials submitted to regulatory authorities showed that rimonabant caused depressive disorders or mood alterations in up to 10% of subjects and suicidal ideation in around 1%, and in Europe it was contraindicated for people with any psychiatric disorder, including clinical depression. Data from a large, randomized, clinical trial (CRESCENDO) with > 9,000 patients receiving rimonabant treatment demonstrated a rate of psychiatric adverse events (anxiety, depression, depressed mood, or insomnia) of greater than 30%.[6][7] WP

Additionally, nausea and upper respiratory tract infections were very common adverse effects (occurring in more than 10% of people); common adverse effects (occurring in between 1% and 10% of people) included gastroenteritis, anxiety, irritability, insomnia and other sleep disorders, hot flushes, diarrhea, vomiting, dry or itchy skin, tendonitis, muscle cramps and spasms, fatigue, flu-like symptoms, and increased risk of falling. WP

The FDA's advisory committee concurred with concerns raised by the review divisions. Based on human and on animal data, it appeared that the therapeutic window was narrow.[3][8][9] WP

EMA postmarketing surveillance data suggested that the risk of psychiatric disorders in people taking rimonabant was doubled.[3] WP

Pharmacology

Pharmacology

Rimonabant is an inverse agonist of the cannabinoid CB₁ receptor. Originally thought to be selective for the CB₁ receptor, rimonabant was subsequently also found to act as an antagonist of the μ-opioid receptor.[10] WP

These properties may make this drug useful in cases of cannabinoid or opioid overdose but more research and safety testing is required. WP

Research

Research

Along with the clinical trials in obesity that generated the data submitted to regulatory authorities, rimonabant was also studied in clinical trials for diabetes, atherosclerosis, and smoking cessation.[3][11][12][13] WP

History

History

Rimonabant was discovered and developed by Sanofi-Aventis.[14] WP

On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union as a prescription drug for use in conjunction with diet and exercise for patients with a body mass index (BMI) greater than 30 kg/m², or patients with a BMI greater than 27 kg/m² with associated risk factors, such as type 2 diabetes or dyslipidaemia. It was first in its class to be approved anywhere in the world.[5][6] WP

Rimonabant was submitted to the Food and Drug Administration (FDA) for approval in the United States in 2005; in 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval. The application was deemed not-approvable by FDA, and the company cancelled plans for a re-submission.[15][16] WP

The drug was approved in Brazil in April 2007.[3] WP

In October 2008, the European Medicines Agency recommended the suspension of Acomplia after the Committee for Medicinal Products for Human Use (CHMP) had determined that the risks of Acomplia outweighed its benefits due to the risk of serious psychiatric problems, including suicide. In November 2008 an advisory committee in Brazil recommended suspension as well, and that month Sanofi-Aventis suspended sale of the drug worldwide. The EMA approval was withdrawn in January 2009. In 2009 India prohibited the manufacture and sale of the drug.[3][17–20] WP

Chemistry

Formula

C22H21Cl3N4O PC

CAS number

168273-06-1 PC

Molar mass (g/mol)

463.8 PC

IUPAC name (computed by PubChem)

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidin-1-ylpyrazole-3-carboxamide PC

SMILES

CC1=C(N(N=C1C(=O)NN2CCCCC2)C3=C(C=C(C=C3)Cl)Cl)C4=CC=C(C=C4)Cl PC

InChIKey

JZCPYUJPEARBJL-UHFFFAOYSA-N PC

PubChem CID

104850

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Rimonabant
2. Journal / agency Sam AH, Salem V, Ghatei MA. Rimonabant: From RIO to Ban. Journal of Obesity. 2011. doi:10.1155/2011/432607 · PMID 21773005 · PMC3136184
3. Journal / agency Moreira FA, Crippa JA. The psychiatric side-effects of rimonabant. Revista Brasileira de Psiquiatria. June 2009. doi:10.1590/s1516-44462009000200012 · PMID 19578688
4. Journal / agency Fong TM, Heymsfield SB. Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. International Journal of Obesity. September 2009. doi:10.1038/ijo.2009.132 · PMID 19597516
5. Other European Approval Comes Early for Sanofi-Aventis' Acomplia. June 23, 2006
6. Journal / agency Acomplia EPAR. January 30, 2009
7. Journal / agency Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD, Hamm CW, Montalescot G, Steg PG, Pearson TA, Cohen E, Gaudin C, Job B, Murphy JH, Bhatt DL. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet. August 2010. doi:10.1016/S0140-6736(10)60935-X · PMID 20709233
8. Journal / agency FDA Briefing Document NDA 21-888 Zimulti (rimonabant) Tablets, 20. June 13, 2007
9. Journal / agency Davis-Bruno K. Nonclinical Overview: CNS Toxicity with Rimonabant. June 13, 2007
10. Journal / agency Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL. AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies. Neuropharmacology. October 2012. doi:10.1016/j.neuropharm.2012.06.046 · PMID 22771770 · PMC3408547
11. Journal / agency Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. February 2006. doi:10.1001/jama.295.7.761 · PMID 16478899
12. Journal / agency Cahill K, Ussher MH. Cannabinoid type 1 receptor antagonists for smoking cessation. The Cochrane Database of Systematic Reviews. March 2011. doi:10.1002/14651858.CD005353.pub4 · PMID 21412887 · PMC6486173
13. Journal / agency Maldonado R, Valverde O, Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends in Neurosciences. April 2006. doi:10.1016/j.tins.2006.01.008 · PMID 16483675
14. Journal / agency Barth F, Rinaldi-Carmona M. The development of cannabinoid antagonists. Current Medicinal Chemistry. August 1999. doi:10.2174/0929867306666220401143808 · PMID 10469889
15. Other Saul S. F.D.A. Panel Rejects Drug for Obesity. 14 June 2007
16. Other Sanofi-Aventis Drops Application for Drug. 30 June 2007
17. Journal / agency The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia. 23 October 2008
18. Other Anti-obesity drug use suspended. 23 October 2008
19. Journal / agency Public Statement on Acomplia (rimonabant) Withdrawal of the Marketing Authorisation in the European Union. 30 January 2009
20. Other Drugs banned in India

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.