Alli (orlistat)

The recommended dosage of prescription orlistat (e.g., Xenical(R)) for the management of obesity and weight regain in adults and adolescents 12 years of age and older is 120 mg 3 times daily with each main meal containing fat. Patients should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. Daily intake of fat, carbohydrate, and protein should be distributed over 3 main meals. If a meal occasionally is missed or contains no fat, the dose of orlistat may be omitted. Dosages exceeding 120 mg 3 times daily have not been shown to provide additional benefit.

For self-medication for weight loss, the usual dosage of orlistat (Alli(R)) in overweight adults 18 years of age and older is 60 mg 3 times daily with each meal containing fat. If a meal occasionally is missed or contains no fat, the dose of orlistat may be omitted. Dosage for self-medication should not exceed three 60-mg capsules daily.

Orlistat is administered orally 3 times daily, during (or up to 1 hour after) each main meal containing fat. However, administering the drug up to 2 hours after midmeal does not appear to affect efficacy.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Orlistat/Triheptanoin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Triheptanoin is hydrolyzed by pancreatic enzymes in the intestines to heptanoate and glycerol, which are then absorbed. Pancreatic lipase inhibitors (i.e., orlistat) can reduce the formation of heptanoate from triheptanoin.(1)

CLINICAL EFFECTS: Orlistat may reduce absorption of heptanoate, leading to insufficient supplementation of medium-chain fatty acids.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of triheptanoin states that concurrent use of pancreatic lipase inhibitors should be avoided.(1)

DISCUSSION: Orlistat may decrease exposure to the triheptanoin metabolite, heptanoate, and decrease the effectiveness of triheptanoin.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Orlistat/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Orlistat may bind with cyclosporine in the stomach or small intestine, thus decreasing the absorption of cyclosporine.

CLINICAL EFFECTS: The concurrent administration of cyclosporine and orlistat may result in a decrease in the levels and clinical effects of cyclosporine.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of orlistat states that cyclosporine should be administered either at least 3 hours before or after orlistat and that cyclosporine levels should be carefully monitored.(1)

DISCUSSION: In a case report, a heart-transplant patient experienced a decrease in cyclosporine trough concentration, maximum concentration (Cmax), and area-under-curve (AUC) by 47%, 86%, and 75%, respectively, following the addition of orlistat to his regimen.(3) In a case report, larger than normal doses of cyclosporine were required in a renal transplant patient who had been maintained on orlistat.(4) In a case report, a renal transplant patient experienced decreased cyclosporine levels following the addition of orlistat to her regimen, despite the administration of orlistat 2 hours before cyclosporine. However, the authors note that the patient did not follow a low-fat diet and experienced severe diarrhea which may have also contributed to poor cyclosporine absorption.(5) There are other case reports of decreased cyclosporine levels following the addition of orlistat,(6-9) including six reports received by the US Food and Drug Administration.(6) In a multiple dose study, orlistat (120 mg TID) decreased the Cmax and AUC of cyclosporine (50 mg BID) by 25% and 31%, respectively. When separated by 3 hours, orlistat (120 mg TID) decreased the Cmax and AUC of cyclosporine (50 mg BID) by 4% and 17%, respectively.(1,10)

Orlistat/Selected Antiretrovirals

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Orlistat may reduce the absorption of lipophilic antiretroviral HIV drugs by retention in the gastrointestinal tract or reduced gastrointestinal tract transit time.

CLINICAL EFFECTS: The concurrent administration of orlistat and atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, or tenofovir may result in a decrease in the levels and clinical effects of the antiretroviral, including loss of virological control.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: HIV RNA levels should be frequently monitored in patients taking orlistat while being treated for HIV infection. If there is a confirmed increase in HIV viral load, orlistat should be discontinued.(1)

DISCUSSION: Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with lipophilic antiretroviral drugs.(1) There are three case reports of patients having an increased HIV viral load after taking orlistat concomitantly with their HIV therapy.(2-4) Antiretrovirals included in this monograph are atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, and tenofovir.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Orlistat/Fat Soluble Vitamins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The acetate ester forms of vitamin A and vitamin E must undergo hydrolysis for absorption from the gastrointestinal tract.(1) The enzyme responsible for this hydrolysis is inhibited by orlistat.(2)

CLINICAL EFFECTS: Orlistat may reduce absorption of fat soluble vitamins, leading to a deficiency state.

PREDISPOSING FACTORS: A pre-existing deficiency of fat soluble vitamins (A,D,E and K) or chronic malabsorption syndrome.

PATIENT MANAGEMENT: The inhibition of fat soluble vitamin absorption by orlistat should be borne in mind during implementation of a vitamin supplementation strategy. Patients should be strongly encouraged to take a multivitamin supplement which contains fat soluble vitamins, particularly Vitamin D as it appears most susceptible to this interaction.(4,5) Multivitamin supplements should be taken at least two hours before or after the dose of orlistat, or at bedtime.(4) Patients with chronic malabsorption syndromes should not receive orlistat.(4)

DISCUSSION: Adult patients taking orlistat without supplementation showed a greater reduction in vitamin A,D,E and beta-carotene levels compared to placebo during two or more consecutive visits in studies of 1-2 years duration; these patients had normal baseline values prior to orlistat therapy. Low vitamin values in orlistat patients were as follows: low Vitamin D 12%, low beta-carotene 6.1%, low Vitamin E 5.8%, low Vitamin A 2.2%.(4) A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption and a 60% decreased in vitamin E acetate absorption with concomitant orlistat.(4) In a study, orlistat produced the vitamin net concentration by approximately 43%.(1) In a study, no statistically significant decrease in vitamin A absorption was observed with concurrent orlistat.(2) In a study, mean vitamin D levels were significantly reduced compared with baseline after one month of orlistat therapy despite multivitamin supplementation.(5)

Orlistat/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Orlistat may bind to the thyroid preparation in the small intestine, decreasing systemic absorption.(1-4)

CLINICAL EFFECTS: Concurrent administration of orlistat and thyroid preparations may decrease the clinical effects of the thyroid agent.(1-4) Hypothyroidism has been reported.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration times of orlistat and thyroid preparations by at least 4 hours. Patients receiving concurrent therapy should be monitored for changes in thyroid function.(1-3)

DISCUSSION: In a case report, a post-thyroidectomy patient on a stable dose of levothyroxine (250 mcg daily) started concurrent orlistat therapy. Within two weeks of starting orlistat therapy, she felt experienced cold intolerance and felt lethargic and tired. She was found be severely hypothyroid and the orlistat was discontinued. Within two weeks, her symptoms improved and, within 4 weeks, her thyroid levels normalized.(4)

Orlistat is contraindicated in women who are pregnant. (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Patients with chronic malabsorption syndrome.

Patients with cholestasis.

Patients with known hypersensitivity to orlistat or any ingredient in the formulations. (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

• Cholestasis
• Drug-induced hepatitis
• Malabsorption states
• Pregnancy

• Anorexia nervosa
• Bulimia nervosa

• Calcium oxalate renal calculi
• Hyperoxaluria
• Hypothyroidism
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)

Adverse effects of orlistat occurring in 5% or more of patients and with an incidence at least twice that of placebo include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence. Such effects usually develop within 3 months of starting therapy and persist for less than one to no more than 4 weeks; occasionally adverse GI effects may occur over a 6-month period or longer. In controlled clinical trials that evaluated orlistat 120 mg three times daily, 8.8% of patients discontinued orlistat because of adverse effects, compared with 5% for placebo. In trials that evaluated orlistat 60 mg three times daily, 3.2% of patients discontinued orlistat because of adverse effects. The most common adverse effects resulting in discontinuance were GI effects.

In clinical studies, adverse effects reported in individuals receiving orlistat 60 mg 3 times daily were similar to those reported in patients receiving 120 mg 3 times daily, and were primarily GI related.

Adverse effects reported in the long-term 4-year study were similar to those reported for the 1- and 2-year studies; the total incidence of GI effects decreased each year over the 4-year study period.

More Frequent

• Upper respiratory infection

Less Frequent

• Biliary calculus
• Infectious diarrhea
• Lower respiratory infection

Rare or Very Rare

• Abnormal hepatic function tests
• Acute kidney injury
• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Bronchospastic pulmonary disease
• Calcium oxalate renal calculi
• Gastrointestinal hemorrhage
• Hepatic failure
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypoglycemic disorder
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Kidney stone
• Skin rash
• Urinary tract infection
• Urticaria

More Frequent

• Acute abdominal pain
• Fecal incontinence
• Fecal urgency
• Flatulence with discharge
• Increased defecation frequency
• Influenza
• Loose stools
• Oily rectal discharge
• Steatorrhea
• Vitamin D deficiency

Less Frequent

• Dizziness
• Fatigue
• Gingival disorders
• Headache disorder
• Menstrual disorder
• Myalgia
• Nausea
• Rectal irritation
• Rectal pain
• Sleep disorder
• Symptoms of anxiety
• Tooth disorder
• Vitamin A deficiency
• Vitamin E deficiency

Rare or Very Rare

• Abdominal distension
• Acute bacterial otitis media
• Anorexia
• Arthritis
• Back pain
• Cutaneous vasculitis
• Edema
• Hyperoxaluria
• Increased alkaline phosphatase
• Pruritus of skin
• Vaginitis
• Vomiting

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Safety and efficacy of prescription orlistat (Xenical(R)) in children younger than 12 years of age have not been established.

Use of orlistat in obese adolescents 12-16 years of age is supported by safety and efficacy data from studies in obese adolescents, evidence from well-controlled studies in adults, and a 21-day mineral balance study in obese adolescents.

The effects of orlistat (120 mg 3 times daily) on body mass index (BMI) and weight loss have been evaluated in a 54-week, double-blind, placebo-controlled trial in 539 obese adolescents (BMI 2 kg/m2 above 95% percentile based on age and gender) 12-16 years of age. All participants received behavioral therapy and were offered exercise counseling, were instructed to consume a reduced-calorie diet intended to provide 30% of calories from fat, and to take a multivitamin containing fat-soluble vitamins (A, D, E, and K) at least 2 hours before or after orlistat ingestion. After 1 year of treatment, BMI decreased by an average of 0.55 kg/m2 in orlistat-treated patients and increased an average of 0.31 kg/m2 in placebo recipients. More orlistat-treated patients than placebo-treated patients lost at least 5 and 10% of baseline BMI (26.5 versus 15.7%, respectively; 13.3 versus 4.5%, respectively). Additionally, 19% of orlistat-treated patients versus 11.7% of placebo recipients lost at least 5% of baseline weight, with 9.5% of orlistat-treated patients versus 3.3% of placebo recipients achieving at least a 10% weight loss. Adverse effects of orlistat in adolescent patients were similar to those observed in adults.

Administration of orlistat (120 mg 3 times daily) did not result in clinically important changes in calcium, magnesium, phosphorus, zinc, or copper balance in a 21-day study in obese adolescents 12-16 years of age. A decrease in iron balance was observed in orlistat-treated patients and placebo recipients (64.7 versus 40.4 mcmol/24 hours, respectively).

Plasma concentrations of orlistat and its metabolites M1 and M3 in adolescents were similar to those observed in adults receiving an equivalent dosage. Daily fecal fat excretion was 27% of dietary intake in orlistat-treated pediatric patients compared with 7% in those receiving placebo.

Orlistat should not be used for self-medication in children younger than 18 years of age.

Category X. (See Users Guide.)

Orlistat is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Because of the obligatory weight gain that occurs in maternal tissues during pregnancy, a minimum weight gain and no weight loss is currently recommended for all pregnant women, including those who are already overweight or obese.

Embryotoxicity and teratogenicity have not been observed in animals at dosages substantially higher than the recommended human dosage. If orlistat is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.

It is not known if orlistat is distributed in breast milk; therefore, the drug should be used with caution in nursing women.

Clinical trial experience with orlistat in geriatric patients 65 years of age and older is insufficient to determine whether they respond differently than younger adults.

The pharmacokinetics of orlistat have not been specifically studied in geriatric patients to date.