XENICAL (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C 29 H 53 NO 5 , and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is: Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no p K a within the physiological pH range. XENICAL is available for oral administration as a turquoise hard-gelatin capsule. The capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide. chemical structure

XENICAL is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. XENICAL is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m 2 or ≥27 kg/m 2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia). Table 1 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5 ' 5 " would have a BMI of 30. Table 1 Body Mass Index (BMI), kg/m 2 Conversion Factors: Weight in lbs ÷ 2.2 = weight in kilograms (kg) Height in inches × 0.0254 = height in meters (m) 1 foot = 12 inches XENICAL is a reversible inhibitor of gastrointestinal lipases indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. Table 1

XENICAL 120 mg turquoise capsules imprinted with XENICAL 120 in black ink. Capsules: 120 mg.

One 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). Advise patients to take a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. Distribute the daily intake of fat, carbohydrate, and protein over three main meals. Advise patients to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. Take the vitamin supplement at least 2 hours before or after the administration of XENICAL, such as at bedtime. For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL. For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart

Recommended Dosing The recommended dose of XENICAL is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of XENICAL can be omitted. Because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition . The vitamin supplement should be taken at least 2 hours before or after the administration of XENICAL, such as at bedtime. For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL. For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. Doses above 120 mg three times a day have not been shown to provide additional benefit. 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.

XENICAL has drug interactions and can decrease vitamin absorption. ( 5.1 , 7 ) Take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition. Rare cases of severe liver injury with hepatocellular necrosis or acute hepatic failure have been reported. Patients may develop oxalate nephrolithiasis and oxalate nephropathy following treatment with XENICAL. Monitor renal function in patients at risk for renal insufficiency. Discontinue XENICAL if oxalate nephropathy develops. Substantial weight loss can increase the risk of cholelithiasis. Exclude organic causes of obesity (eg, hypothyroidism) before prescribing XENICAL. Gastrointestinal events may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat). 5.1 Drug Interactions and Decreased Vitamin Absorption XENICAL may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs . Data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Therefore, XENICAL and cyclosporine should not be simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after XENICAL in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered. Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene . In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of XENICAL, such as at bedtime. Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients

Liver Injury There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking XENICAL. When these symptoms occur, XENICAL and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained

Oxalate Nephrolithiasis and Oxalate Nephropathy with Renal Failure Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing XENICAL to patients at increased risk for oxalate nephropathy, including patients with renal impairment and in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Discontinue XENICAL in patients who develop oxalate nephropathy

Cholelithiasis Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of XENICAL for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to XENICAL and 1.8% (30/1655) for patients randomized to placebo

Miscellaneous Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing XENICAL. Patients should be advised to adhere to dietary guidelines . Gastrointestinal events may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from 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 increases.

Cyclosporine: Reduction in cyclosporine plasma levels was observed when XENICAL was coadministered with cyclosporine. Fat-soluble Vitamin Supplements and Analogues: All patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. Levothyroxine: Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. Warfarin: Patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. Amiodarone: A reduction in exposure to amiodarone was observed when XENICAL was co-administered. Antiepileptic Drugs: Convulsions have been reported in patients taking XENICAL with antiepileptic drugs. Patients should be monitored for possible changes in frequency or severity of convulsions. Antiretroviral Drugs: Loss of virological control has been reported in HIV-infected patients. Patients should be monitored frequently for changes in HIV RNA levels

Cyclosporine Data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. XENICAL and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of XENICAL

Fat-soluble Vitamin Supplements and Analogues Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement. The effect of XENICAL on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time

Levothyroxine Hypothyroidism has been reported in patients treated concomitantly with XENICAL and levothyroxine postmarketing. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and XENICAL at least 4 hours apart

Anticoagulants including Warfarin Vitamin K absorption may be decreased with XENICAL. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with XENICAL and anticoagulants. Patients on chronic stable doses of warfarin or other anticoagulants who are prescribed XENICAL should be monitored closely for changes in coagulation parameters

Amiodarone A pharmacokinetic study, where amiodarone was orally administered during orlistat treatment, demonstrated a reduction in exposure to amiodarone and its metabolite, desethylamiodarone . A reduced therapeutic effect of amiodarone is possible. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied

Antiepileptic Drugs Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions

Antiretroviral Drugs Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate. The exact mechanism for this is unclear, but may include a drug-drug interaction that inhibits systemic absorption of the antiretroviral drug. HIV RNA levels should be frequently monitored in patients who take XENICAL while being treated for HIV infection. If there is a confirmed increase in HIV viral load, XENICAL should be discontinued.