What is the recommended dosing for orlistat (Xenical)?

Orlistat Dosing

The recommended dose of orlistat (Xenical) is 120 mg taken orally three times daily with each main meal containing fat, though the 2022 AGA guidelines suggest against its routine use due to modest efficacy and significant gastrointestinal side effects. 1

Standard Dosing Regimen

• Prescription strength (Xenical): 120 mg orally three times daily with each main meal containing fat 1
• Over-the-counter formulation (Alli): 60 mg orally three times daily with each main meal containing fat 1, 2
• The capsule should be taken during the meal or up to 1 hour after eating 1, 2
• If a meal is skipped or contains no fat, the corresponding dose can be omitted 1, 2

Dietary Requirements

• Patients must follow a diet with approximately 30% of calories from fat to minimize gastrointestinal side effects 1
• A hypocaloric diet with 500-800 kcal/day deficit is recommended in conjunction with orlistat 1
• Most weight loss occurs within the first 6 months of treatment 2

Mandatory Vitamin Supplementation

• All patients taking orlistat must take a daily multivitamin containing fat-soluble vitamins (A, D, E, K) 1
• The multivitamin should be taken at least 2 hours apart from orlistat, ideally at bedtime 1, 2
• This is necessary because orlistat blocks absorption of approximately 30% of dietary fat, leading to potential deficiencies in fat-soluble vitamins 1, 3

Drug Interactions Requiring Dose Separation

• Cyclosporine, levothyroxine, and warfarin require longer intervals between doses and closer monitoring 1
• Orlistat should not be taken with cyclosporine; separate by at least 3 hours 1
• Antiepileptic drugs may require monitoring due to potential interaction 1

Important Safety Considerations

• The FDA has issued a warning about potential serious liver injury with orlistat 1
• Contraindicated in pregnancy, chronic malabsorption syndrome, and cholestasis 1
• Patients with chronic diarrhea, celiac disease, inflammatory bowel disease, or history of bariatric surgery are not ideal candidates 1
• Small risk of cholelithiasis with weight loss 1

Expected Efficacy and Tolerability

• The 120 mg dose produces approximately 2.8 kg (2.78% total body weight loss) more than placebo over 48 weeks to 4 years 1
• The 60 mg over-the-counter dose blocks approximately 25% of ingested fat and has about 85% of the efficacy of the 120 mg dose 4
• Most common adverse effects are gastrointestinal: oily spotting, flatulence with discharge, fecal urgency, oily stools, and fecal incontinence 1
• Treatment discontinuation due to GI adverse effects is 2.86 times higher than placebo 1

Clinical Context

The 2022 AGA guidelines conditionally recommend against orlistat use due to modest weight loss benefit (only 2.78% total body weight loss) and high rates of GI side effects, though patients who highly value even small weight loss and can tolerate GI effects may reasonably choose it 1. The over-the-counter 60 mg formulation was not examined in the systematic review due to paucity of long-term data 1.