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4. Pharmacological Properties and effects
4.1 Pharmacodynamic Properties

4.1.1 Mechanism of Action
Xenical is a potent, specific and long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of the gastric and pancreatic lipases. The inactivated enzyme is thus unable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit has a positive effect on weight control. Based on fecal fat measurements, the effect of Xenical is seen as soon as 24-48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pre-treatment levels, within 48-72 hours.

4.1.2 Efficacy/Clinical Studies
Obese Adults
Clinical trials have demonstrated that orlistat promotes weight loss, exceeding that achieved with diet alone. Weight loss was apparent within 2 weeks of initiation of treatment and continued for a duration of 6 to 12 months, even in individuals who failed to respond to dieting alone. Over 2 years, statistically significant improvements in metabolic risk factors associated with obesity were observed. Furthermore, significant improvements in body fat were observed in comparison to placebo. Orlistat was also effective in preventing of weight regain, with approximately half of the patients regaining no ,more than 25% of lost weight and about half of these regaining no weight or even continuing to lose weight.

Obese Patients with Type 2 Diabetes
Clinical trials conducted over a period of 6 months to one year showed that overweight or obese patients with type 2 diabetes had greater weight loss compared to dieting alone. It was also demonstrated that the weight loss was primarily due to decreased body fat. Additionally, despite receiving anti-diabetic medication, the average patient had poor glycemic control, prior to study entry, but showed statistically significant (and clinically meaningful) improvements in glycemic control following treatment with orlistat. Furthermore, anti-diabetic medication usage decreased, insulin levels were lower and decreased insulin resistance was apparent

Delay in Onset of Type 2 Diabetes in Obese Patients
A clinical trial conducted over a 4-year period, showed that orlistat significantly reduced the risk of onset of type 2 diabetes, with the risk decreased by approximately 37%, compared to the placebo group. The decrease in risk for patients with impaired glucose tolerance at baseline was even more marked, at approximately 45%. Additionally, weight loss was significantly greater in the orlistat group than in the placebo group, and was maintained throughout the 4-year study period. Furthermore, orlistat-treated patients showed significant reductions in metabolic risk factors compared to placebo.

Obese Adolescents
A clinical trial conducted over 1 year, showed that obese adolescents treated with orlistat had a decreased BMI, compared to those in the placebo group, who had an increased BMI. Furthermore, those in the orlistat group had significantly decreased fat mass and waist and hip circumference compared to those in the placebo group. Diastolic blood pressure was also significantly reduced in the orlistat group compared to placebo.

Efficacy in patients with type 2 diabetes
Pooled data from four one year studies and three six month studies in type 2 diabetic patients showed that the percentage of responders (? 10% of body weight loss) was 11.3% with orlistat as compared to 4.5% with placebo. The mean difference in weight loss with the drug compared to placebo was - 2.47 kg in these patients. The pooled data from the four one year studies and three six month studies of Xenical as an adjunct to antidiabetic medications are summarised in the following table:

LSM = Least squares mean; ND=Not done

^*p<0.05 based on LSM differences xenical v. placebo, ^**p<0.05 based on Coch-ran-Mantel-Haentzel test.

⁺p value <0.05 for overall change in anti-diabetic medication

4.2 Pharmacokinetics
4.2.1 Absorption
In normal weight and obese volunteers, the systemic absorption of orlistat was minimal Plasma concentrations of intact orlistat were non-measurable (< 5 ng/ml) following a single oral administration 360mg of orlistat.

In general, after long term treatment at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/ml or 0.02 µm), without evidence of accumulation, and consistent with negligible absorption.

4.2.2 Distribution
The volume of distribution cannot be determined because the drug is minimally absorbed. In vitro orlistat is > 99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

4.2.3 Metabolism
Based on animal data, it is likely that the metabolism of orlistat occurs mainly presystemically. Two major metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total radioactivity in plasma resulting from the minute fraction of the dose that was absorbed systemically in obese patients. These two major metabolites have very weak lipase inhibitory activity (1000 and 2500 fold less than orlistat respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 ng/ml and 108 ng/ml respectively), these metabolites are pharmacologically inconsequential.

4.2.4 Elimination
Studies in normal weight and obese subjects have shown that fecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97% of-the administered dose was excreted in feces and 83% of that as unchanged orlistat. The cumulative renal excretion of total orlistat-related materials was < 2% of the given dose. The time to reach complete excretion (fecal plus urinary) was 3-5 days. The disposition of orlistat appeared to be similar between normal-weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.

4.2.5 Pharmacokinetics in Special Populations
Plasma concentrations of orlistat and its metabolites M1 and M3 were similar in pediatric patients compared to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat and placebo treatment groups, respectively.

4.2.6 Preclinical safety
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. In animal reproductive studies, no teratogenic effect was observed. In the absence of a teratogenic effect in animals, no malformation effect is expected in men.

5. Pharmaceutical Particular
5.1 Stability
This medicine should not be used after the expiry date (EXP) shown on the pack.
See also outer pack for storage remark.

5.2 Packs

Capsules 120 mg

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