XENICAL (orlistat), when used in conjunction with a mildly hypocaloric diet, is indicated for:

• obesity management including weight loss and weight maintenance

  
  

• reducing the risk of weight regain in obese patients after prior weight loss.

  
  

 

These indications for the use of XENICAL apply to obese patients with a BMI{*The BMI is calculated by dividing weight in kilograms by height in metres squared.} ≥30 kg/m² or a BMI ≥27 kg/m² in the presence of other risk factors (e.g., hypertension, type 2 diabetes, dyslipidemia, excess visceral fat).

The weight loss induced by the combination of XENICAL and a mildly hypocaloric diet results in an improvement of risk factors and comorbidities including hypercholesterolemia, impaired glucose tolerance, hyperinsulinemia, hypertension, reduction of visceral fat and waist circumference.

The weight loss induced by XENICAL improves glycemic control in diabetic patients and reduces the risk of developing type 2 diabetes in obese patients (BMI* ≥30 kg/m²) with impaired glucose tolerance. The effect of XENICAL on weight loss is adjunctive to that of diet and exercise.

XENICAL can be used in combination with anti-diabetic agents (sulphonylureas, metformin, insulin) to improve blood glucose control in overweight or obese type 2 diabetes patients who are inadequately controlled on diet, exercise, and one or more of a sulphonylurea, metformin, or insulin.

XENICAL (orlistat) is contraindicated in patients with chronic malabsorption syndrome, cholestasis and in patients with known hypersensitivity to XENICAL or to any component of this product (for a complete listing of components, see Dosage Forms, Composition and Packaging).

Patients should be advised to adhere to dietary guidelines (see Dosage and Administration).

No serious adverse reactions or safety hazards related to the use of XENICAL (orlistat) have been reported to date during large, long-term clinical trials (up to 4 years) (see Adverse Reactions).

As with any weight-loss agent, the potential exists for misuse of XENICAL in inappropriate patient populations (e.g. patients with anorexia nervosa or bulimia). See the Indications and Clinical Use for appropriate prescribing guidelines.

When using XENICAL in combination with insulin or oral hypoglycemic agents in the treatment of type 2 diabetes, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to the patient, family members, caregiver or others.

For warnings and precautions involving drug interactions, see Drug Interactions.

XENICAL should be used with caution in patients with pre-existing disease of the large bowel or rectum.

The possibility of experiencing gastrointestinal events (see Adverse Reactions) may increase when XENICAL is taken with a diet high in fat (e.g. in a 2000 Calorie/day diet, a diet high in fat would contain >30% calories from fat, which equates to >67g 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. XENICAL only inhibits the absorption of dietary fat. Patients should be advised that if the resulting caloric reduction is compensated by an increase in calories from protein or carbohydrates, the expected weight loss will not occur.

Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Caution should be exercised when prescribing XENICAL to patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.

Teratogenicity studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 22 and 43 times the daily human dose calculated, on a body surface area (mg/m²) basis, for rats and rabbits, respectively.

There are no adequate and well-controlled studies of orlistat in pregnant women. Because animal reproductive studies are not always predictive of human response, XENICAL should be used during pregnancy only if the benefit clearly outweighs any potential harm.

It is not known if orlistat is secreted in human milk. Therefore, XENICAL should not be used by nursing women unless the benefit to the mother clearly outweighs any potential for harm to the nursing infant.

XENICAL has not been studied in pediatric patients below the age of 12 years.

Diabetic patients treated with orlistat should have tests for fasting glucose and HbA1c as required.

The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains no more than 30% of calories from fat. The daily intake of fat, carbohydrate and protein should be distributed over three main meals (see Drug Interactions, Drug-Drug Interactions, Fat-soluble Vitamin Supplements and Analogues).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Commonly Observed: (based on first year and second year data—120 mg versus placebo):

Gastrointestinal symptoms are the most commonly observed treatment-emergent adverse events associated with the use of XENICAL (orlistat) in double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of ≥5% and an incidence in the XENICAL 120 mg group that is at least twice that of placebo.) (See Warnings and Precautions). See Table 1.

Table 1: XENICAL

Percentage of Patients with Commonly Observed GI Adverse Events (based on first and second year data) Which Occurred with a Frequency of ≥5% in XENICAL 120 mg or Placebo

Adverse Event	Year One		Year Two
	XENICAL (% patients) (n=1913)	Placebo (% patients) (n=1466)	XENICAL (% patients) (n=613)	Placebo (% patients) (n=524)
Oily Spotting	26.6	1.3	4.4	0.2
Flatus with Discharge	23.9	1.4	2.1	0.2
Fecal Urgency	22.1	6.7	2.8	1.7
Fatty/Oily Stool	20.0	2.9	5.5	0.6
Oily Evacuation	11.9	0.8	2.3	0.2
Increased Defecation	10.8	4.1	2.6	0.8
Fecal Incontinence	7.7	0.9	1.8	0.2

These and other commonly observed adverse reactions were generally mild and transient, and decreased during the second year of treatment. Events occurred early in treatment (within 3 months) and most patients experienced only one episode. Only 3% experienced more than two episodes of any one adverse event. The incidence of these effects is directly related to the amount of dietary fat ingested and increases or decreases with the fat content of the diet. Patients should be counselled as to the possibility of the occurrence of gastrointestinal effects and how to minimize them, such as reinforcing the diet, particularly the percentage of fat it contains. Consumption of a diet low in fat (<30%) will decrease the likelihood of experiencing the gastrointestinal effects. The occurrence of gastrointestinal effects may actually help demonstrate to patients that the medication is working and help them monitor and regulate their fat intake.

In the 4-year double-blind, placebo-controlled XENDOS study, the incidence and duration of the commonly observed adverse reactions were comparable to those observed in the 1- and 2- year studies shown above.

In controlled obesity management clinical trials of 1-, and 2- year duration, 8.8% of patients treated with XENICAL discontinued treatment due to adverse events, compared to 5.0% of placebo treated patients. Similarly, in the 4-year XENDOS clinical trial, 8.0% and 4.0% of patients treated with XENICAL and placebo, respectively, discontinued treatment due to adverse events. For XENICAL, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.

The following Table 2 and Table 3 list other treatment-emergent adverse events from seven Phase III, multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥1% among patients treated with XENICAL 120 mg tid and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.

Table 2: XENICAL

Other Treatment-Emergent Adverse Events From Phase III Placebo-Controlled Obesity Management Clinical Trials Year One Treatment



Table 3: XENICAL

Other Treatment-Emergent Adverse Events From Phase III Placebo-Controlled Obesity Management Clinical Trials Year Two Treatment

In the 4-year XENDOS study, the pattern and distribution of adverse events was similar to that reported for the 1 and 2 year studies. The total incidence of gastrointestinal related adverse events occurring in year 1 decreased progressively with each additional year of treatment, over the four year period.

In clinical trials with XENICAL in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.

Commonly observed adverse events: Mild and transient gastrointestinal effects of the same type as those seen in the obesity management trials were observed in the double-blind, placebo-controlled clinical trials for type 2 diabetes management. However, the overall difference in incidence of these adverse events between patients treated with XENICAL and patients receiving placebo was generally less than in the overall obesity trials. Marked decreases were seen in the trials in patients with type 2 diabetes in the incidence of oily spotting, fecal urgency and flatus with discharge (15.8%, 10.5%, 9.4%){†These values are the treatment difference between XENICAL and placebo.}, compared to those for obesity management (25.3%, 15.4% and 22.5% respectively)†. Recurrence also decreased in the diabetes trials: 4% of the patients experienced more than one episode of each gastrointestinal event compared to 6% in the obesity trials. The 2 sets of trials were not run concurrently and thus may not be directly comparable.

Of the other treatment-emergent adverse events reported in the diabetes trials, all were similar in type and generally occurred at a lower incidence compared to those of the obesity management trials, with the exception of cough (2.8% in XENICAL vs 2.4% in placebo), abdominal distension (5.8% vs 4.1%) and hypoglycemia (13.2% vs 9.5%). The majority of hypoglycemic events were mild to moderate in intensity and most patients could control the symptoms themselves. Only two patients in the placebo treatment group and three patients in the orlistat treatment group had hypoglycemic events that would be considered severe.

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 hypoglycemic medication (see Warnings and Precautions and Drug Interactions, Diabetes Agents).

Rare cases of hypersensitivity have been reported. The main clinical symptoms were pruritus, rash, urticaria, angioedema, bronchospasm 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 physicopathological mechanism between hepatitis and orlistat therapy have been established.

Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of haemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.

A reduction in cyclosporine plasma levels has been observed when XENICAL (orlistat) is co-administered. Therefore, it is recommended to monitor cyclosporine plasma levels more frequently than usual if XENICAL is co-administered.

A pharmacokinetic interaction study with β-carotene showed a 30% reduction in β-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A and nutritionally derived vitamin K is not known at this time. Obesity management studies indicated that some patients required vitamin D supplementation with a multivitamin to achieve desirable blood levels. The decreases in vitamin D were modest (measured by 25-OH-D) and were not associated with any changes in vitamin D metabolism, as evidenced by total or ionized calcium and parathyroid levels. Clinical studies did not reveal any interference with blood coagulation that would indicate vitamin K deficiency.

During obesity management studies, there were decreases in the levels of some fat soluble vitamins and β-carotene based on the pharmacologic action of the drug. The vast majority of patients in up to four full years of treatment had vitamin levels (vitamins A, D, E, and K, and beta-carotene) that stayed well within normal range, and there was no evidence of clinical sequelae.

The vitamin status of obese patients in general and patients on a weight control regimen, including pharmacotherapy with XENICAL, may be low. Therefore patients should be counselled to take a multivitamin which includes fat-soluble vitamins and β-carotene to ensure adequate nutrition. Pediatric patients should be instructed to take a multivitamin. The supplement should be taken at least two hours before or after the administration of XENICAL, or at bedtime.

As treatment with orlistat may potentially impair the GI absorption of vitamin K, close monitoring of the coagulation parameters is recommended when oral anticoagulants are co-administered.

(Extended-Release Tablets): In 17 normal weight subjects receiving XENICAL 120 mg tid for 6 days, XENICAL did not alter the bioavailability of nifedipine extended-release tablets.

At 50 mg tid for 7-8 days, orlistat did not significantly alter the pharmacokinetics of atenolol, captopril, furosemide and nifedipine retard.

In a pharmacokinetic (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 effects of this are 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.

No interactions based on specific drug-drug interaction studies have been observed with losartan, fibrates, or atorvastatin.

Weight loss induced by XENICAL is accompanied by improved metabolic control in non-insulin dependent diabetics, which might allow or require reduction in dose of oral hypoglycemic medication (e.g. sulfonylureas).

In 12 normal weight subjects receiving XENICAL 80 mg tid for 4 1/3 days, XENICAL did not alter the pharmacokinetics or pharmacodynamics (blood-glucose-lowering) of glyburide.

In 20 normal weight subjects receiving XENICAL 120 mg tid for 6 days in a two way crossover study, XENICAL did not alter the pharmacokinetics of metformin.

Drug interaction studies were performed with XENICAL and a number of drugs with a narrow therapeutic index. XENICAL had no inhibitory effects on pharmacokinetic or pharmacodynamic parameters of the following drugs:

In 12 normal weight subjects receiving XENICAL 120 mg tid for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin.

In 12 normal weight subjects, administration of XENICAL 120 mg tid for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although Vitamin K nutritional status parameters (ratios of vitamin K₁ epoxide to vitamin K₁ and undercarboxylated osteocalcin to osteocalcin) were also unaltered by orlistat, treatment with orlistat may potentially impair the GI absorption of vitamin K. Close monitoring of the coagulation parameters, including international normalised ratio (INR) values, is recommended when oral anticoagulants are co-administered.

In 12 normal weight subjects receiving XENICAL 120 mg tid for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin.

In a multiple-dose study in 30 normal weight subjects, coadministration of orlistat and 40 grams of alcohol (e.g. approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), and systemic exposure to orlistat.

A reduction in cyclosporine plasma levels has been observed when XENICAL is co-administered. Therefore, it is recommended to monitor cyclosporine plasma levels more frequently than usual if XENICAL is co-administered.

(various ethinyl estradiol and gestagen combinations commercially available): In 20 normal weight female subjects, the treatment of XENICAL 120 mg tid for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives.

In 24 normal weight, mildly hypercholesterolemic subjects receiving XENICAL 120 mg tid for 6 days in a two way cross-over study, XENICAL did not affect the pharmacokinetics or pharmacodynamics of pravastatin.

No interactions based on specific drug-drug interaction studies have been observed with amitryptyline, fluoxetine, sibutramine, or phentermine.

• The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains no more than 30% of calories from fat. The daily intake of fat, carbohydrate and protein should be distributed over three main meals (see Drug Interactions, Drug-Drug Interactions, Fat-soluble Vitamin Supplements and Analogues).

  
  

• For patients with type 2 diabetes, the reduced calorie diet should be consistent with the dietary recommendations of the Canadian Diabetes Association Guidelines for the Nutritional Management of Diabetes Mellitis in the New Millennium.

  
  

The recommended dose of XENICAL (orlistat) is one 120 mg capsule three times daily with each main meal (during or up to 1 hour after the meal). If a meal is occasionally missed or contains no fat, the dose of XENICAL may be omitted.

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 fecal fat measurements, the effect of XENICAL is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.

Single doses of 800 mg XENICAL (orlistat) and multiple doses of up to 400 mg tid for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg tid have been administered to obese patients for 6 months without a significant increase in adverse findings.

Orlistat overdose cases received during post-marketing reported either no adverse events or adverse events that are similar to those reported with the 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 (orlistat) is a reversible inhibitor of lipases. It exerts its therapeutic activity non-systemically in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze 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 loss, maintenance and prevention of weight regain. Systemic absorption of the drug is therefore not needed for activity. At the recommended dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.

Systemic exposure to orlistat is negligible. Following oral dosing with 360 mg ¹⁴C- orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were nonmeasurable (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, 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.

Studies in rats and dogs indicated that the absolute bioavailability of orlistat in plasma is <2% at oral doses up to 1000 mg/kg/day.

In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.

Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on a ¹⁴C -orlistat mass balance study in obese patients, of the minute fraction of the radio-labelled dose that was absorbed systemically, the presence of two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open β-lactone ring and extremely weak systemic lipase inhibitory activity (1000 - and 2500 - fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

Following a single oral dose of 360 mg ¹⁴C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Approximately 97% of the administered radioactivity was excreted in feces and 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg ¹⁴C-orlistat.

The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours. Orlistat, M1 and M3 metabolites were also subject to biliary excretion.

Because the drug is minimally absorbed, with no defined pharmacokinetics, studies in special populations (geriatric, pediatric, different races, patients with renal and hepatic insufficiency) were not conducted.

Plasma concentrations of orlistat and its metabolites M1 and M3 were similar 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.

Clinical investigations in patients with hepatic have not been undertaken.

Clinical investigations in patients with renal impairment have not been undertaken.

In several studies of up to 6-weeks duration, the effects of orlistat on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of orlistat in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effect on plasma triglyceride levels, systemic lipases or balance of six minerals (calcium, magnesium, phosphorus, zinc, copper and iron) were observed with administration of orlistat in these studies.

In a 3-week study of 32 obese adolescents aged 12 to 16 years, XENICAL (120 mg, three times a day) did not significantly affect the balance of calcium, magnesium, phosphorous, zinc, or copper. The iron balance was decreased by 64.7 µmol/24 hours and 40.4 µmol/24 hours in orlistat and placebo treatment groups, respectively.

XENICAL should be stored in its original package between 15-25°C. Protect from moisture. This medicine should not be used after the expiry date shown on the pack.

Xenical.

 

Each turquoise cap and turquoise body capsule, with “ROCHE XENICAL 120” printed in black ink, contains: orlistat 120 mg. Nonmedicinal ingredients: gelatin, indigo carmine, microcrystalline cellulose, povidone K30, sodium lauryl sulfate, sodium starch glycolate, talc and titanium dioxide. Blister packages, cartons of 84.