Overview
11 DESCRIPTION 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.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Orlistat is a reversible 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 residue 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 may have a positive effect on weight control. 12.2 Pharmacodynamics Dose-response Relationship The dose-response relationship for orlistat in human volunteers is shown in Figure 1 .
Indications
- 1 INDICATIONS AND USAGE 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.
Common Doses
- 120 mg
Dosage
2 DOSAGE AND ADMINISTRATION One 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). ( 2 ) Advise patients to take a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. ( 2 ) Distribute the daily intake of fat, carbohydrate, and protein over three main meals. ( 2 ) Advise patients to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. ( 2 ) Take the vitamin supplement at least 2 hours before or after the administration of XENICAL, such as at bedtime.
Contraindications
- 4 CONTRAINDICATIONS XENICAL is contraindicated in: Pregnancy [see Use in Specific Populations (8.1) ] Patients with chronic malabsorption syndrome Patients with cholestasis Patients with known hypersensitivity to XENICAL or to any component of this product Pregnancy ( 4 , 8.1 ) Chronic malabsorption syndrome ( 4 ) Cholestasis ( 4 ) Known hypersensitivity to XENICAL or to any component of this product ( 4 )
Side Effects
- 6 ADVERSE REACTIONS Most common treatment emergent adverse reactions (≥5% and at least twice that of placebo) include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact the Safety Call Center at 1-888-236-5445 or FDA at 1‑800‑FDA‑1088 (1-800-332-1088) or www.fda.gov/medwatch. 6.1 Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared...
Interactions
- 7 DRUG INTERACTIONS Cyclosporine: Reduction in cyclosporine plasma levels was observed when XENICAL was coadministered with cyclosporine. ( 7.1 ) Fat-soluble Vitamin Supplements and Analogues: All patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. ( 7.2 ) Levothyroxine: Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. ( 7.3 ) Warfarin: Patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. ( 7.