Name of medicine
Orlistat 120mg capsule

Presentation
XENICAL 120mg capsules have a turquoise cap and turquoise body with imprint of XENICAL ROCHE 120 on both the cap and body.

Uses/Actions
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. Systemic absorption is therefore not needed for activity.

Single and repeated dose toxicity studies in rodents and dogs have demonstrated a similar pattern of dose related effects across species, none of which is considered relevant to the recommended use in man.

No orlistat associated mutagenicity or genotoxicity has been observed in a standard battery of five different short-term assays.

Carcinogenicity studies in rats and mice have not shown a carcinogenic potential for orlistat at doses up to 1000mg/kg/day and 1500mg/kg/day respectively. These doses are 182 and 125 times the daily human dose calculated on a body surface area (mg/m 2) basis. There was a decreased incidence of mammary fibroadenoma in female rats in the high dose group. No orlistat associated adverse effects were observed in Segment l, ll and Ill reproductive toxicity studies at doses ranging 62-241 times the recommended clinical dose.

Pharmacokinetics

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

Distribution
The volume of distribution cannot be determined because orlistat is minimally absorbed and has no defined systemic pharmacokinetics. In vitro orlistat is >99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Metabolism
Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on a study in obese patients, of the minute fraction of the dose that was absorbed systemically, two major metabolises, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total plasma concentration.

M1and M3 have an open b-lactone ring and extremely weak lipase inhibitory activity (1000 and 2500 fold less than orlistat receptively). 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 considered to be pharmacologically inconsequential.

Elimination
Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed substance was the major route of elimination. Approximately 97% of the administered dose was excreted in faeces 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 (faecal plus urinary) was 3 to 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.

Indications

Dosage and Administration

The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately 30% of calories from fat. It is recommended that the diet should be rich in fruit and vegetables. The daily intake of fat, carbohydrate and protein should be distributed over three main meals. Doses above 120 mg three times daily have not been shown to provide additional benefit. No dose adjustment is necessary for the geriatric patient. Based on faecal fat measurements, the effect of XENICAL is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, faecal fat content usually returns to pre-treatment levels, within 48 to 72 hours.

Hepatic and/or Renal Impairment
Dose adjustment is not required.

Children below the age of 18 years
The safety and efficacy of XENICAL in children have not been established.

Contraindications

Warnings and Precautions

Use during pregnancy and lactation
The safety of XENICAL has not been established in pregnant women. In animal reproductive studies no embryotoxic or teratogenic effects were observed that were considered to be associated with XENICAL. However, because animal studies are not always predictive of human response, XENICAL should not be used during pregnancy unless the potential benefit outweighs the potential risk. XENICAL should not be taken by nursing women, because it is not known whether XENICAL is secreted in human milk, unless the potential benefit outweighs the potential risk.

Effects on ability to drive and use machines
No effects on the patient's ability to drive and use machines have been reported.

Adverse Effects

The incidence of these increases the higher the fat content of the diet and thus faeces. Patients should be counselled as to the possibility of gastrointestinal effects occurring and how best to handle them such as reinforcing the diet, particularly the percentage of fat it contains. Consumption of a diet low in fat will decrease the likelihood of experiencing adverse gastrointestinal events and this may help patients monitor and regulate their fat intake.

In clinical studies, these pharmacological effects were not considered an impediment to continuation of therapy. These adverse reactions are generally mild and transient. Gastrointestinal events occurred early in treatment (within 3 months) and most patients experienced only one episode. Only 3% of patients experienced more than two episodes of any one adverse event.

In a clinical programme with over 4,000 patients treated for up to 2 years, there were a total of 11 reports of breast cancer, all in women 45 years of age or older. There were 10 reports of breast cancer in the XENICAL treated subgroups (N=1063) and 1 in the placebo subgroup (N=579). The total number of patients reporting breast cancer was small but the imbalance seen warranted further evaluation.

All study patients 45 years of age or older were followed up and all available data were thoroughly reviewed by independent clinical experts in the fields of oncology, pathology, radiology and epidemiology. Follow up revealed two more patients with breast cancer in a XENICAL group and two more in the placebo group.

For 6 of the XENICAL patients, mammograms were available from before XENICAL treatment had commenced and in 4 of these 6 it was possible to detect the lesion when the mammogram was re-examined. Most cancers found were 25mm in diameter and, as it takes 8 to 12 years for a cancer to grow from a single cell to 10mm, it is clear that most tumours were pre-existing. A specific marker found in 9 tumours suggests the lesion was at least 5 years old. Of the 12 patients treated with XENICAL 120mg, 60mg or 30mg found to have breast cancer, 9 had tumours which were proved to have been pre-existing. Of the 3 patients treated with placebo who were found to have breast cancer, one tumour was proven to have been pre-existing.

In summary, there were 3 cases of breast cancer possibly related to therapy in patients in the XENICAL treatment groups (N=1063) and 2 cases possibly related to therapy in patients in the placebo treatment group (N=579). Epidemiological data suggest that if XENICAL were a promoter of cancer, one would expect to see other cancers, and if it were an enhancer one would expect to see increased growth around existing tumours. In neither case was this found.

Re-examination of the pre-clinical data (doses 100 to 1,000 fold the human dose) revealed a lower incidence of mammary tumours in female rats on XENICAL than on placebo.

The expert review of the additional data concluded that there was no evidence that XENICAL or its metabolites, directly or indirectly, initiates, promotes or enhances the growth of breast tumours.

Interactions

However, orlistat enhanced the bioavailability (plasma concentrations increased by approximately 30%) and lipid lowering effect of pravastatin.

In clinical studies, a wide variety of concomitant medications were used without evidence of clinically significant adverse interactions.

In pharmacokinetic interaction studies, orlistat inhibited absorption of oral supplements of some fat-soluble nutrients such as b-carotene (about one third) and vitamin E acetate (about one-half) but not vitamin A acetate or the nutritionally-derived levels of vitamin K.

During clinical studies there were decreases in levels of some fat soluble vitamins and analogues. The vast majority of patients in up to two years of treatment had vitamin levels that stayed well within normal range, and there was no evidence of clinical sequelae.

Weight loss induced by XENICAL is accompanied by improved metabolic control in diabetics which might allow or require reduction in the dose of oral hyperglycaemic medication (e.g. sulfonylureas).

Overdosage

Should a significant overdose of XENICAL occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, any systemic effects attributable to the lipase inhibiting properties of orlistat should be rapidly reversible.

Pharaceutical Precautions

Shelf-life
Three years.

Special precautions for storage
Store below 25°C and protect from moisture.

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