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Capsule, hard.
Xenical 120mg hard capsules have a turquoise cap and turquoise body bearing the imprint of "ROCHE XENICAL 120".

Microcrystalline cellulose, sodium starch glycollate, polyvidone K30, sodium lauryl sulphate and talc.

Xenical is indicated for long-term treatment of significantly obese patients, including patients with risk factors associated with obesity, in conjunction with a mildly hypocaloric diet

Xenical is effective in long-term weight control (weight loss, weight maintenance and prevention of weight regain). Treatment with Xenical results in an improvement of risk factors and comorbidities associated with obesity, including hypercholesterolemia, noninsulin dependent diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, hypertension and in a reduction of visceral fat.

In Type 2 diabetic patients who are overweight (BMI =27) or obese (BMI =30), Xenical, in conjunction with a mildly hypocaloric diet, provides additional glycaemic control when used in combination with insulin, metformin or sulphonylurea medicines.

The efficacy of orlistat as a monotherapy treatment for Type 2 diabetes has not been established.

The recommended dose of Xenical is one 120 mg capsule with each main meal (during or up to one hour after the meal). If a meal is missed or contains no fat, the dose of Xenical may be omitted. The therapeutic benefits of Xenical are continued with long-term 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.

Clinical investigations in patients with hepatic and/or renal impairment have not been undertaken.

Xenical is contraindicated in patients with chronic malabsorption syndrome, cholestasis and in patients with known hypersensitivity to orlistat or any of the components contained in the medicinal product.

The majority of patients in up to two full years of treatment had vitamin A, D, E and K and beta-carotene levels stay within normal range. In order to ensure adequate nutrition, the use of a multivitamin supplement could be considered.

Patients should be advised to adhere to dietary guidelines (see Dosage and Method of Administration). The possibility of experiencing gastrointestinal events (see Undesirable Effects) may increase when Xenical is taken with a diet high in fat (e.g. in a 2000 calories/day diet, > 30% of calories from fat equates to > 67 g of fat). The daily intake of fat should be distributed over three main meals. If Xenical is taken with any one meal very high in fat, the possibility of gastrointestinal effects may increase. Weight loss induced by Xenical is accompanied by improved metabolic control in type 2 diabetics which might allow or require reduction in the dose of oral hypoglycaemic medication (e.g. sulfonylureas).

A reduction in cyclosporin plasma levels has been observed when Xenical is co-administered. Therefore it is recommended to monitor more frequently than usual the cyclosporin plasma levels when Xenical is co-administered (see Interactions).

Coagulation parameters should be monitored in patients treated with concomitant oral anticoagulants.

In a PK study, oral administration of amiodarone during orlistat treatment demonstrated a 25 - 30% reduction in the systemic exposure to amiodarone and desethylamiodarone. Due to the complex pharmacokinetics of amiodarone, the clinical effect of this is unclear. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. A potential reduced therapeutic effect of amiodarone is possible.

During pharmacokinetic studies no interactions with alcohol, digoxin, nifedipine, oral contraceptives, phenytoin, pravastatin, warfarin or metformin have been observed.

However, when warfarin or other anticoagulants are given in combination with orlistat, international normalised ratio (INR) values should be monitored.

Decreases in the absorption of vitamin D, E and ß-carotene have been observed when co-administered with Xenical. If a multivitamin supplement is recommended, it should be taken at least two hours after the administration of Xenical or at bedtime.

In a PK study, oral administration of amiodarone during orlistat treatment demonstrated a 25 - 30% reduction in the systemic exposure to amiodarone and desethylamiodarone. Due to the complex pharmacokinetics of amiodarone, the clinical effect of this is unclear. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. A reduced therapeutic effect of amiodarone is possible.

In animal reproductive studies, no embryotoxic or teratogenic effects were observed with orlistat. In absence of a teratogenic effect in animals, no malformative effect is expected in human beings. However, Xenical is not recommended for use during pregnancy in the absence of clinical data.

The secretion of orlistat in human breast milk has not been investigated. Xenical should not be taken during breast-feeding.

Adverse reactions to Xenical are largely gastrointestinal in nature and related to the pharmacologic effect of orlistat on preventing the absorption of ingested fat. Commonly observed events are oily spotting, flatus with discharge, faecal urgency, fatty/oily stool, oily evacuation, increased defaecation and faecal incontinence. The incidence of these increases the higher the fat content of the diet. 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 to monitor and regulate their fat intake.

These adverse gastrointestinal reactions are generally mild and transient. They occurred early in treatment (within 3 months) and most patients experienced only one episode.

Treatment-emergent GI-adverse events that occurred commonly among patients treated with Xenical were: abdominal pain/discomfort, flatulence, liquid stools, soft stools, rectal pain/discomfort, tooth disorder, gingival disorder.

Other events observed were: upper respiratory infection, lower respiratory infection; influenza; headache; menstrual irregularity; anxiety; fatigue; urinary tract infection.

Rare cases of hypersensitivity have been reported. Main clinical symptoms are pruritus, rash, urticaria, angioedema and anaphylaxis.

Very rare cases of bullous eruption, increase in transaminases and in alkaline phosphatase, and exceptional cases of hepatitis that may be serious have been reported during the post marketing. No causal relationship or physiopathological mechanism between hepatitis and orlistat therapy has been established.

Reports of decreased prothrombin, increased international normalised ratio (INR) and unbalanced anticoagulant treatment resulting in change of haemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants during post-marketing.

In type 2 diabetic patients, adverse event reporting was comparable to that reported in overweight and obese patients. The only unique treatment adverse events that occurred at a frequency of =2% and with an incidence of =1% above placebo were hypoglycaemia (which may occur as a result of improved glycaemic control) and abdominal distention.

Single doses of 800 mg Xenical and multiple doses of up to 400 mg t.i.d. for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg t.i.d. have been administered to obese patients for 6 months without significant increase of adverse findings.

Orlistat overdose cases received during post-marketing reported either no adverse events or adverse events that are similar to those reported with recommended dose.

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.

Xenical is a potent, specific and reversible 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 serine residue of the active site of 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 the weight control.

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 bodyweight loss) was 11.3% with orlistat as compared to 4.5% with placebo. The mean difference in weight loss with the medicine compared to placebo was 2.47kg 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:

Parameter	Sulphonylurea		Metformin		Insulin
	Xenical (n = 741)	Placebo (n = 749)	Xenical (n = 550)	Placebo (n = 538)	Xenical (n = 262)	Placebo (n = 268)
Body Weight (kg)
Baseline mean	94.99	94.45	96.10	96.39	101.93	101.65
LSM change from Baseline	-3.41*	-1.30	-3.80*	-1.24	-3.85*	-1.25
HbA1c (%)
Baseline mean	8.41	8.39	8.65	8.72	8.97	9.01
LSM change from Baseline	-0.62*	-0.20	-0.82*	-0.48	-0.62*	-0.27
% patients with reduction in HbA1c
>= 0.5% decrease	55**	38	61**	49	51**	40
>= 1.0% decrease	39**	25	46**	33	32**	22
Fasting plasma glucose (mmol/l)
Baseline mean	10.18	9.88	10.78	10.49	10.91	11.15
LSM change from Baseline	-1.06	0.12	-1.73*	-0.64	-1.73*	-1.00
Post-prandial plasma glucose (mmol/l)
Baseline mean	14.56	14.01	14.54	13.92	ND	ND
LSM change from Baseline	-1.64	-0.20	-1.28	0.15	ND	ND
Changes in anti-diabetic medication
% patients with decreases	23+	15	16+	13	42+	31
% patients with increases	9+	17	11+	19	14+	32

LSM = Least squares mean; ND = Not done
* p < 0.05 based on LSM differences Xenical v. placebo; ** p < 0.05 based on Cochran-Mantel-Haentzel test
+ P value < 0.05 for overall change in anti-diabetic medication

In normal weight and obese volunteers, the systemic exposure to orlistat was minimal. Plasma concentrations of intact orlistat were nearly non-measurable (< 5 ng/mL) following a single oral administration of 360 mg 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 showing consistency with negligible absorption.

The volume of distribution cannot be determined because orlistat 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.

Based on animal data, it is likely that the metabolism of orlistat occurs mainly presystemically. Two major metabolites (M1 and M3) 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.

Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed orlistat 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 3-5 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.