Rimonabant ( Acomplia ) is an oral selective cannabinoid CB1 receptor antagonist. It is licensed as an adjunct to diet and exercise for the treatment of obese patients( BMI >30Kg/m2 ), or overweight patients ( BMI >27Kg/m2 ) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

The endocannabinoid system is a physiological system present in brain and peripheral tissues ( including adipocytes ) that affects energy balance, glucose and lipid metabolism and body weight, and in neurons of the mesolimbic system modulates the intake of highly palatable, sweet or fatty foods.

Obesity is one of several important risk factors in the development of cardiovascular disease.
The aims of management should be modest weight loss maintained in the long term, with methods and goals tailored to the individual. Initial approaches should include supervised diet and exercise, which can be effective. However, they must be continued to maintain weight loss, including throughout treatment with adjunctive therapies.

Orlistat ( Xenical ) and Sibutramine ( Meridia/Reductil ) were previously the only drugs licensed for obesity in the UK.
However, gastrointestinal side-effects can limit Orlistat's acceptability to patients, and Sibutramine can increase blood pressure and is contraindicated in patients with cardiovascular disease.


Efficacy

Four large, double-blind, randomised controlled trials have compared Rimonabant 20mg/day against placebo for up to 2 years in obese subjects, or overweight subjects with additional cardiovascular risk factors, whose diets were reduced by 600 kcal/day.
Only people who were able to comply with a reduced calorie diet during a 4-week run-in period were entered into the trials, and they received frequent ( at least monthly ) dietary and exercise advice throughout.
These trials showed that 1-year weight loss ( the primary endpoint ) was statistically significantly greater with Rimonabant than placebo ( P<0.001 ).
In the 2-year studies, no additional weight loss was achieved in the second year, and continued treatment with Rimonabant was necessary to maintain the 1-year weight loss.
Statistically significant improvements in some metabolic parameters ( secondary endpoints ), including HDL-cholesterol and triglyceride levels, glycemic control and the incidence of metabolic syndrome, were reported with Rimonabant compared with placebo.
In general, there was no significant effect on total-cholesterol or LDL-cholesterol.
Metabolic syndrome has been characterised by the co-occurrence of abdominal obesity ( assessed by waist circumference ), dyslipidaemia ( raised triglycerides and low HDL-cholesterol ), hyperglycaemia and hypertension.
As with other anti-obesity drugs, long-term effects on morbidity and mortality are unknown.
There are no trials comparing Rimonabant against other drugs.


Safety

Rimonabant has been evaluated for safety in approximately 2500 patients enrolled in studies that examined the metabolic and weight loss effects in overweight and obese patients and in approximately 3800 patients in other indications.
In placebo-controlled studies, the discontinuation rate due to adverse reactions was 15.7% for patients receiving Rimonabant.
The most common adverse reactions resulting in discontinuation were: nausea, mood alteration with depressive symptoms, depressive disorders, anxiety and dizziness.
All trials excluded people with a history of psychiatric disorders or severe depression.


Warning and precautions

Rimonabant is metabolised by the liver, thus caution is advised in patients with moderate hepatic impairment. The pharmacokinetics and safety of Rimonabant have not been studied in patients with severe hepatic impairment; its use in these patients is not recommended.
There are limited data in patients with moderate renal impairment and no data in patients with severe renal impairment. Rimonabant should not be used in patients with severe renal impairment.
The efficacy and safety of Rimonabant treatment in patients over 75 years of age has not sufficiently been established. Rimonabant should be used with caution in this population.
Rimonabant has not been studied in patients being treated for epilepsy. In clinical trials no difference in the incidence of seizures was seen in patients receiving Rimonabant or placebo. Rimonabant, however, should be used with caution in these patients.
The clinical effect ( weight loss ) of Rimonabant in Black patients was lower than in Caucasians. This could be caused by a higher Rimonabant clearance than in Caucasians resulting in a lower exposure.
Rimonabant should be used with caution in combination with potent CYP3A4 inhibitors ( e.g. Ketoconazole, Itraconazole, Ritonavir, Telithromycin, Clarithromycin, Nefazodone ).
Since Acomplia tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
Therapy with Rimonabant should not be initiated in patients with uncontrolled serious psychiatric illness such as a major depression. Appropriate treatment of this condition should be initiated first and therapy with Rimonabant considered once this psychiatric condition is controlled.
As there is limited data in patients with antidepressant medication in combination with Rimonabant, use of Rimonabant is not recommended in these patients.
Patients who had a cardiovascular event ( myocardial infarction, stroke, etc. ) less than 6 months ago were excluded in the studies for Rimonabant.

Source:

1) Medicines Compendium UK, 2006

2) National Prescribing Centre UK, 2006

XagenaMedicine2006