London, UK - The cannabinoid antagonist rimonabant (Acomplia, Sanofi-Aventis) has been associated with five deaths in the UK since its launch there in mid-2006, according to new data from the UK's Medicines and Healthcare products Regulatory Agency (MHRA) [1].

Rimonabant was approved throughout the European Union in June 2006 for the treatment of obesity, but Sanofi-Aventis withdrew its approval application in the US last year after an FDA advisory committee unanimously recommended nonapproval of the drug, citing a "clear" signal of neurological and psychiatric side effects. In June 2007, psychiatric adverse drug reactions were reassessed by the European Medicines Agency, leading to new contraindications in patients with major depressive disorder or those taking antidepressants. Suicidal ideation and aggressiveness were added as adverse reactions to the prescribing information, and it was recommended that rimonabant should be stopped if a patient develops depression.

The latest information on adverse reactions reported with rimonabant recorded on the MHRA website (covering the period from launch of the drug until May 9, 2008) notes that there have been five fatal events associated with this drug. These are classified as two deaths due to cardiac disorders, one classified as "general," one as death due to infection, and one due to psychiatric disorders (suicide).

Sanofi-Aventis confirmed these figures for heartwire and noted that three of the deaths were in fact of cardiac origin (two MI and one sudden death), one was the result of an infection, and one of psychiatric causes. A company spokesperson commented that it was not surprising to see cardiac deaths in a patient group that has cardiac risk factors and that none of the deaths had been causally linked to rimonabant.

Of the 2123 total number of adverse reactions reported, 974 were classified as psychiatric disorders, 241 were classified as nervous-system disorders, and 229 were gastrointestinal disorders.

More information on the type of adverse reactions being reported with rimonabant is given in the May issue of the MHRA's Drug Safety Update, which covers the period until the end of January 2008. At this point there had been four deaths recorded as being associated with the drug—one suicide, two MIs, and one sudden death of unknown cause. There had been 1971 individual reactions received at this time point in the UK, 423 of which were serious, the report states.

It notes that the most common adverse reactions were psychiatric disorders (44% of the total), and the most common psychiatric reactions were depression and related disorders of mood, of which 52 reactions involved suicidal and self-harming thoughts or behaviors. The MHRA says that depressive reactions remain a source of concern. Until the end of January 2008, there had been 211 reports of depression and related mood disorders, and of those for which a time to onset was available, one-third occurred within the first week of starting treatment with rimonabant, and almost half occurred within the first two weeks. Of these 211 patients, 20 were receiving concomitant treatment with antidepressants and 36 were reported to have a history of depression or suicidality, although rimonabant is contraindicated in patients with ongoing major depression or those taking antidepressants.

Other reported suspected adverse reactions, which are not currently in the product information for rimonabant and have been identified as new safety signals, include hypoglycemic reactions (seven reports), which the MHRA says may be due to inadequate monitoring of blood-glucose control in patients who have managed to reduce calorie intake without appropriate adjustment of glucose-lowering medication; paranoia (15 reports); rash; tremor (14 reports); and headache (40 reports).

The MHRA also notes that the UK, Germany, and France are the highest consumers of rimonabant worldwide and that from launch until the end of 2007, the total amount of rimonabant dispensed in the UK equates to about 21 000 patient-treatment-years.

Rimonabant is indicated in Europe for use together with diet and exercise to reduce weight in adult patients who are obese, with a body-mass index (BMI) >30 kg/m², or who have a BMI >27 kg/m² and also have other risk factors, such as type 2 diabetes or dyslipidemia.  The RIO series of clinical trials showed that showed that roughly one-quarter of obese subjects randomized to rimonabant lost 10% of their body weight after one year, while half of subjects lost about 5% of their original body weight. These losses were greater than those achieved on placebo.