Rimonabant
Encyclopedia
Rimonabant is an anorectic
antiobesity drug that has been withdrawn from the market. It is an inverse agonist
for the cannabinoid receptor CB1. Its main effect is reduction in appetite
.
Rimonabant was the first selective CB1 receptor
blocker to be approved for use anywhere in the world. In Europe, it was indicated for use in conjunction with diet and exercise for patients with a body mass index
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. In the UK, it was available beginning in July 2006. As of 2008, the drug was available in 56 countries. On 23 October 2008, the European Medicines Agency (EMEA)
issued a press release stating its Committee for Medical Products for Human Use (CHMP) had concluded the benefits of Acomplia no longer outweighed its risks, and subsequently recommended the product be suspended from the UK market. Sanofi-Aventis
later released a press statement stating the drug had been suspended. Approval of the drug was officially withdrawn by the EMEA on 16 January 2009.
in 2006. The French pharma firm Sanofi-Aventis
disclosed a complete response to the FDA's approvable letter was submitted on 26 October 2006, triggering a Class I (two-month) or Class II (six-month) review process. On 13 June 2007, FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval. Subsequently, Sanofi-Aventis announced it was suspending the new drug application (NDA) for rimonabant, and that it would resubmit an application at some point in the future.
On 21 June 2006, the European Commission
approved the sale of rimonabant in the then-25-member European Union
. Sanofi announced the first country in which Acomplia would be sold was the United Kingdom
as a prescription drug. Sales began in July 2006. Sanofi also announced it projected that the drug would be sold shortly thereafter in Denmark
, Ireland
, Germany
, Finland
, and Norway
. It was expected in Belgium
and Sweden
in 2007. Ordinary obesity would, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there would be additional requirements concerning abnormal blood lipid levels.
The EU's approval was not a blanket approval, nor did it approve Acomplia for nonobesity-related problems, such as smoking cessation
, although off-label use
of the drug was still possible. The approval was, in combination with diet and exercise, for the treatment of obese patients (BMI
greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
In October 2008, the European Medicines Agency
recommended doctors not prescribe the drug due to the risk of serious psychiatric problems and even suicide. The drug was subsequently suspended.
On 15 June 2007, BBC News
reported a committee advising the U.S. FDA had voted not to recommend the drug's approval because of concerns over suicidality, depression, and other related side effects associated with use of the drug.
. The Studies with Rimonabant and Tobacco Use (STRATUS) program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi-Aventis that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy.
According to a Cochrane
review in 2007, rimonabant "may increase the odds of quitting approximately 11/2-fold".
- and opiate
-seeking behavior.
. It was therefore hypothesised that rimonabant may improve short-term memory. Indeed, in animal studies, it significantly improved the performance of rats to encode information in the short-term memory.
(THC) in humans without affecting the pharmacokinetics
.
motility and viability in vitro.
Anorectic
An anorectic or anorexic , also known as anorexigenic or appetite suppressant, is a dietary supplement and/or drug which reduces appetite, food consumption, and as a result, causes weight loss to occur.-List of anorectics:Numerous pharmaceutical compounds are marketed as appetite suppressants.The...
antiobesity drug that has been withdrawn from the market. It is an inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
for the cannabinoid receptor CB1. Its main effect is reduction in appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
.
Rimonabant was the first selective CB1 receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
blocker to be approved for use anywhere in the world. In Europe, it was indicated for use in conjunction with diet and exercise for patients with a body mass index
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
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. In the UK, it was available beginning in July 2006. As of 2008, the drug was available in 56 countries. On 23 October 2008, the European Medicines Agency (EMEA)
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
issued a press release stating its Committee for Medical Products for Human Use (CHMP) had concluded the benefits of Acomplia no longer outweighed its risks, and subsequently recommended the product be suspended from the UK market. Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
later released a press statement stating the drug had been suspended. Approval of the drug was officially withdrawn by the EMEA on 16 January 2009.
History
Despite the FDA's issuing an approvable letter in February 2006 for the obesity indication, and a nonapprovable letter for smoking cessation, the drug did not enter the market in the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in 2006. The French pharma firm Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
disclosed a complete response to the FDA's approvable letter was submitted on 26 October 2006, triggering a Class I (two-month) or Class II (six-month) review process. On 13 June 2007, FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval. Subsequently, Sanofi-Aventis announced it was suspending the new drug application (NDA) for rimonabant, and that it would resubmit an application at some point in the future.
On 21 June 2006, the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
approved the sale of rimonabant in the then-25-member European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
. Sanofi announced the first country in which Acomplia would be sold was the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
as a prescription drug. Sales began in July 2006. Sanofi also announced it projected that the drug would be sold shortly thereafter in Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
, Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
, Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
, Finland
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
, and Norway
Norway
Norway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...
. It was expected in Belgium
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
and Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
in 2007. Ordinary obesity would, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there would be additional requirements concerning abnormal blood lipid levels.
The EU's approval was not a blanket approval, nor did it approve Acomplia for nonobesity-related problems, such as smoking cessation
Smoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
, although off-label use
Off-label use
Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
of the drug was still possible. The approval was, in combination with diet and exercise, for the treatment of obese patients (BMI
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
In October 2008, the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
recommended doctors not prescribe the drug due to the risk of serious psychiatric problems and even suicide. The drug was subsequently suspended.
Side effects
Shortly after market introduction, press reports and independent studies suggested side effects occurred more intensely and more commonly than shown by the manufacturer in their clinical studies. Resulting from drug actions at CB1 receptors in the brain, reports of severe depression and suicidal thoughts are frequent. As CB1 receptors are fairly ubiquitous throughout the central nervous system, it is not currently understood where exactly the inverse agonist is acting to cause these side-effects.On 15 June 2007, BBC News
BBC News
BBC News is the department of the British Broadcasting Corporation responsible for the gathering and broadcasting of news and current affairs. The department is the world's largest broadcast news organisation and generates about 120 hours of radio and television output each day, as well as online...
reported a committee advising the U.S. FDA had voted not to recommend the drug's approval because of concerns over suicidality, depression, and other related side effects associated with use of the drug.
Smoking cessation
Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi-Aventis is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapySmoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
. The Studies with Rimonabant and Tobacco Use (STRATUS) program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi-Aventis that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy.
According to a Cochrane
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
review in 2007, rimonabant "may increase the odds of quitting approximately 11/2-fold".
Addiction
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans: priming and cues. It may also reduce ethanolAlcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
- and opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
-seeking behavior.
Memory
Tetrahydrocannabinol (THC) is known to impair short-term memoryShort-term memory
Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...
. It was therefore hypothesised that rimonabant may improve short-term memory. Indeed, in animal studies, it significantly improved the performance of rats to encode information in the short-term memory.
Blockage of cannabis effects
Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9-tetrahydrocannabinolTetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(THC) in humans without affecting the pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
.
Effect on male fertility
Rimonabant significantly increased human spermSperm
The term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
motility and viability in vitro.