REDUCTIL (sibutramine hydrochloride ) is the first orally administered serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline reuptake inhibitor (SNRI) to be used for the management of obesity.

Sibutramine produces its therapeutic effects predominantly via its active secondary and primary amine metabolites (metabolites 1 and 2 respectively) which are inhibitors of noradrenaline, serotonin (5-hydroxytryptamine; 5-HT) and dopamine reuptake. In human brain tissue, metabolites 1 and 2 are ~3-fold more potent as in vitro inhibitors of noradrenaline and serotonin reuptake than of dopamine. Plasma samples taken from sibutramine-treated volunteers caused significant inhibition of both noradrenaline reuptake (73%) and serotonin reuptake (54%) with no significant inhibition of dopamine reuptake (16%). Sibutramine and its metabolites are neither monoamine-releasing agents nor are they monoamine oxidase inhibitors. They have no affinity with a large number of neurotransmitter receptors, including serotonergic (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), adrenergic (ß1, ß2, ß3,a1, a2), dopaminergic (D1-like, D2-like), muscarinic, histaminergic (H1), benzodiazepine and NMDA receptors.

In animal models, it potently reduces body weight gain by a dual action to decrease calorie intake through enhancement of post-ingestive satiety responses and to increase energy expenditure by enhancing resting metabolic rate. It is postulated that sibutramine decreases food intake by enhancing central noradrenaline and 5-HT function mediated through a-1 and 5-HT2A/2C receptors, respectively, and increases metabolic rate by enhancing peripheral noradrenaline function through a-3 adrenoreceptors. In man dose-dependant reductions in bodyweight are seen following treatment with sibutramine.

Pharmacodynamics/Clinical Studies

Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.

The long-term effects of REDUCTIL on the morbidity and mortality associated with obesity have not been established. Sibutramine's effect on weight loss was examined in double-blind, placebo-controlled obesity trials with study durations of 8 weeks to 18 months and doses ranging from 1 to 30mg once daily. A total of 8052 patients were included in these studies; 5335 patients being treated with REDUCTIL and 2717 patients with placebo. The patients involved in these studies either had uncomplicated obesity with Body Mass Index (BMI) ranging from 27 to 40 kg/m2 or were obese with comorbid condition(s) and BMI = 27kg/m2. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5mg to 30mg once daily. In two 12-month studies (one of these studies only involved obese patients who had lost at least 6 kg on a 4-week very low calorie diet), maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of weight loss achieved with REDUCTIL was consistent across studies.

Data from two 12-month studies in uncomplicated obese patients and obese patients with type 2 diabetes mellitus indicate that patients who lose at least 2 kg in the first 4 weeks with a given dose of Reductil are most likely to achieve long-term weight loss on that dose of Reductil. Approximately 75% of such patients went on to achieve a weight loss of =5% of their initial bodyweight at month 12. Conversely, uncomplicated obese and obese type 2 diabetic patients, who did not lose =2 kg after 4 weeks treatment with Reductil did not lose at least 5% of their initial bodyweight by month 12 (see Dosage and Administration ).

Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months treatment with REDUCTIL in placebo-controlled clinical trials. These data were consistent with more objective measurements of abdominal visceral adiposity such as computed tomography (CT) scans; CT scans on obese patients in a 2-year study provide evidence of a significant decrease in abdominal visceral fat of 24% and in subcutaneous fat of 17% after Reductil 10 mg, compared to baseline. These changes were associated with significant reductions from baseline in mean weight, waist circumference and fasting blood glucose, insulin, C-peptide and triglycerides.

Double-blind, placebo-controlled obesity trials with study durations of 12 weeks to 18 months have provided evidence that the weight loss resulting from treatment with REDUCTIL was associated with improvements in patients' glycaemic control, serum lipid profiles (similar to those seen with non-pharmacological mediated weight loss), and serum uric acid. Treatment with REDUCTIL (5 to 20mg once daily) is associated with mean increases in blood pressure of 1 to 3mmHg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings, which were not associated with any clinically significant outcomes, are similar in normotensives and in patients with hypertension controlled with medication. With the latter patients, control of blood pressure was not adversely affected. Those patients who lose significant ( =5% weight loss) amounts of weight on REDUCTIL tend to have smaller increases in blood pressure and pulse rate (see Warnings and Precautions ).

Studies in healthy volunteers indicate that REDUCTIL does not affect the sympathoadrenal system, the hypothalamic-pituitary-end organ axes and other endocrine parameters including testosterone and postprandial cholecystokinin.

Echocardiographic Data: Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with cardiac valve dysfunction. The possible occurrence of cardiac valve disease with REDUCTIL was specifically investigated in two studies using echocardiography. In the first study 209 patients (mean age, 54 years) received REDUCTIL 15mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a prior history of valvular heart disease, the incidence of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In a second study, 104 patients received either sibutramine 10 mg or sibutramine 20 mg and 52 patients received placebo daily for 6 months. Echocardiography was performed at baseline and at month 6. In patients with normal valves at baseline, no sibutramine-treated patient compared to one placebo-treated patient (moderate mitral regurgitation) had valvular heart disease at month 6.

Pharmacokinetics

The pharmacokinetics of sibutramine and its pharmacologically active metabolites are similar in obese subjects to those in normal weight subjects, and there is no evidence of any clinically significant difference in the pharmacokinetics of males and females. The pharmacokinetic profile observed in elderly healthy subjects (mean age 70 years) is similar to that seen in young healthy subjects. Nevertheless, REDUCTIL is not intended for use in the elderly over 65 years of age as safety and efficacy in this population has not been established. Based on steady-state trough plasma concentrations of the active metabolites of sibutramine, there was no evidence of any clinically significant pharmacokinetic difference seen between Afro-Americans and Caucasians.

Absorption

Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 hours) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.

The effect of food on steady-state kinetics of sibutramine and its two active metabolites, during long-term treatment with REDUCTIL, will not be significant. Administration of sibutramine with food in a single dose study resulted in reduced Cmax for each of the two active metabolites and delayed Tmax whilst the AUCs were not significantly altered.

Distribution

In vitro, sibutramine and its metabolites 1 and 2 are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses. Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. Tissue distribution was unaffected by pregnancy, with relatively low transfer to the foetus.

Metabolism

Sibutramine is metabolised in the liver principally by the cytochrome P450 isoenzyme CYP3A4 to, principally, two demethylated active metabolites which are secondary and primary amines. These active metabolites are further metabolised to pharmacologically inactive conjugated hydroxy-metabolites. Based on in-vitro studies there was no indication of sibutramine's affinity for the CYP2D6 isoenzyme - a low capacity enzyme involved in pharmacokinetic interactions of numerous drugs. Further in-vitro studies revealed that sibutramine had no significant effect on the activity of the major P450 isoenzymes, including CYP3A4.

In-vivo, co-administration of CYP3A4 inhibitors (ie ketaconazole or erythromycin) with REDUCTIL increased plasma concentrations of the active metabolites and this was accompanied by recorded modest increase in heart rate.

The high capacity of the CYP3A4 and the low therapeutic dose of sibutramine suggest a relatively low potential for sibutramine to affect the metabolism of other drugs metabolised by this isoenzyme. However, caution should be exercised on concomitant administration of REDUCTIL with drugs that affect CYP3A4 isoenzyme activity (see Interactions).

The plasma concentrations of the active metabolites reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of the secondary- and primary amine metabolites (14 and 16 hours, respectively) were unchanged following repeated dosing.

Elimination

Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and faeces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were two inactive conjugated hydroxy-metabolites; unchanged sibutramine, and the active secondary and primary amine metabolites were not detected. The primary route of excretion for the active metabolites is hepatic metabolism and for the inactive hydroxy-metabolites is renal excretion. The plasma levels of the two active metabolites (ie the secondary and primary amine metabolites) peaked in 3 hours (Tmax) with elimination t1/2 of 14 hours and 16 hours respectively. Linear kinetics have been demonstrated over the dose range 10mg to 30mg. Steady-state for the two active metabolites was achieved within 4 days with an approximate two-fold accumulation.

Renal Insufficiency: The effect of renal disease has not been studied. However, since sibutramine and its two active metabolites are eliminated by hepatic metabolism, renal disease is unlikely to have a significant effect on their disposition. Elimination of the inactive hydroxy-metabolites, which are renally excreted, may be affected in this population. REDUCTIL should not be used in patients with severe renal impairment

Hepatic Insufficiency: In a study, with patients with moderate hepatic impairment receiving a single 15mg oral dose of sibutramine, the combined AUCs of the two active metabolites were increased by 24% compared to healthy subjects while plasma concentrations of the two inactive hydroxy-metabolites were unchanged. The observed differences in concentrations of the active metabolites do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. REDUCTIL should not be used in patients with severe hepatic dysfunction.

Indications

REDUCTIL is indicated for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet. REDUCTIL is recommended for obese patients with an initial body mass index =30kg/m2, or = 27kg/m2 in the presence of other obesity-related risk factors (e.g., diabetes, dyslipidaemia, hypertension).

Reductil may only be prescribed to patients who have not adequately responded to an appropriate weight-reducing regimen alone (hypocaloric diet and/or exercise) i.e patients who have difficulty achieving or maintaining >5% weight loss within 3 months.

BMI is calculated by taking the patient's weight, in kg, and dividing by the patient's height, in meters, squared.

REDUCTIL is not intended for use in obese children under 18 years as safety and efficacy in this population has not been established.

REDUCTIL is not intended for use in elderly patients over 65 years of age as safety and efficacy in this population has not been established.

 

 

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