Orlistat - Drug Monograph

Introduction

Orlistat is a lipase inhibitor medication used for weight management in conjunction with a reduced-calorie diet. It is available by prescription (Xenical® 120 mg) and over-the-counter (Alli® 60 mg). Orlistat works locally in the gastrointestinal tract to prevent the absorption of dietary fats, making it a unique pharmacological approach to weight management that differs from centrally-acting appetite suppressants.

Mechanism of Action

Orlistat is a potent and specific inhibitor of gastrointestinal lipases, primarily pancreatic and gastric lipases. These enzymes are essential for the hydrolysis of dietary triglycerides into absorbable free fatty acids and monoglycerides. By covalently binding to the active serine residue site of these lipases, orlistat forms an inactive complex that prevents the enzymatic breakdown of approximately 30% of ingested dietary fats. The undigested triglycerides are not absorbed and are eliminated in the feces, resulting in a calorie deficit.

Indications

• FDA-approved: Management of obesity in adults with an initial body mass index (BMI) ≥30 kg/m², or ≥27 kg/m² in the presence of other risk factors (such as hypertension, diabetes, or dyslipidemia)
• Adjunct to a reduced-calorie, low-fat diet and increased physical activity
• Long-term weight management when significant weight loss has been achieved

Dosage and Administration

• Adults: 120 mg orally three times daily with each main meal containing fat
• Timing: Should be taken during the meal or up to one hour after eating
• Dose omission: If a meal is missed or contains no fat, the dose should be skipped
• Maximum daily dose: 360 mg (three 120 mg capsules)
• Special populations: No dosage adjustment required for renal or hepatic impairment, elderly patients, or different racial groups

Pharmacokinetics

• Absorption: Minimal systemic absorption (<1%); primarily localized to GI tract
• Distribution: >99% protein bound; minimal volume of distribution
• Metabolism: Primarily within gastrointestinal wall; main metabolites M1 (hydrolyzed β-lactone ring) and M3 (cleaved N-formyl leucine side chain)
• Elimination: Primarily fecal excretion (97%); renal excretion of metabolites <2%
• Half-life: 1-2 hours

Contraindications

• Chronic malabsorption syndrome
• Cholestasis
• Hypersensitivity to orlistat or any component of the formulation
• Pregnancy and breastfeeding
• Organ transplant recipients (due to potential effects on cyclosporine absorption)

Warnings and Precautions

• Gastrointestinal effects: May cause oily spotting, flatus with discharge, fecal urgency, and steatorrhea, especially with high-fat meals
• Hepatic effects: Rare cases of severe liver injury have been reported; monitor for symptoms of liver dysfunction
• Renal effects: Cases of oxalate nephropathy reported in patients with underlying risk factors
• Fat-soluble vitamin deficiency: May decrease absorption of vitamins A, D, E, and K; recommend multivitamin supplementation
• Pancreatitis: Has been reported; discontinue if symptoms occur
• Gallbladder disease: May increase risk of cholelithiasis

Drug Interactions

• Cyclosporine: Decreased absorption; administer cyclosporine at least 2 hours before or after orlistat
• Warfarin: Possible increased INR due to reduced vitamin K absorption; monitor INR closely
• Antidiabetic medications: May enhance hypoglycemic effects; dose adjustments may be necessary
• Amiodarone: Possible reduced absorption
• Levothyroxine: Reduced absorption; separate administration by at least 4 hours
• Antiepileptics: Possible reduced absorption of fat-soluble antiepileptics
• Oral contraceptives: Theoretical risk of reduced efficacy; recommend alternative contraception

Adverse Effects

• Oily spotting from rectum
• Flatus with discharge
• Fecal urgency
• Fatty/oily stool
• Oily evacuation
• Increased defecation

• Abdominal pain/discomfort
• Nausea
• Infectious diarrhea
• Headache
• Upper respiratory infection

• Severe liver injury
• Oxalate nephropathy
• Pancreatitis
• Hypersensitivity reactions
• Subacute cutaneous lupus erythematosus

Monitoring Parameters

• Weight and BMI: At baseline and regularly during treatment
• Nutritional status: Monitor for signs of fat-soluble vitamin deficiency
• Liver function tests: Baseline and periodically; more frequently if symptoms suggest hepatic dysfunction
• INR: In patients taking warfarin
• Renal function: In patients with risk factors for oxalate nephropathy
• Glycemic control: In diabetic patients
• Adherence and tolerance: Assess gastrointestinal side effects and dietary compliance

Patient Education

• Take with meals containing fat, but follow a reduced-calorie, low-fat diet (<30% of calories from fat)
• Expect common gastrointestinal side effects, which may decrease over time with proper dietary compliance
• Take a daily multivitamin containing fat-soluble vitamins at least 2 hours before or after orlistat
• Report symptoms of liver injury (jaundice, dark urine, light-colored stools, itching, loss of appetite)
• Notify all healthcare providers about orlistat use, especially before starting new medications
• Understand that orlistat is most effective when combined with comprehensive lifestyle modifications
• Continue regular physical activity as part of weight management program
• Discontinue use and consult healthcare provider if pregnancy is suspected

References

1. FDA Prescribing Information: Xenical (orlistat) capsules. 2019. 2. Zhi J, et al. Pharmacokinetic evaluation of orlistat. Clin Pharmacokinet. 1995;29(6):397-404. 3. Torgerson JS, et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study. Diabetes Care. 2004;27(1):155-161. 4. Rössner S, et al. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat. Obes Res. 2000;8(1):49-61. 5. Hutton B, et al. The efficacy and safety of orlistat: a systematic review. Obes Rev. 2006;7(1):1-17. 6. Sjöström L, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998;352(9123):167-172. 7. McDuffie JR, et al. Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions. J Pediatr Endocrinol Metab. 2004;17(3):307-319.