ATC Class:A08AB01
VA Class:GA900
Orlistat, a reversible inhibitor of gastric and pancreatic lipases,1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 18, 19, 21, 22, 47, 51 exhibits antiobesity1, 6, 7, 8, 17, 23, 36 and antilipemic activity.1, 3, 4, 5, 6, 7, 8, 20, 36
Orlistat is used as an adjunct to caloric restriction, increased physical activity, and behavioral modification in the treatment of exogenous obesity as well as to reduce the risk for weight regain subsequent to initial loss.1, 6, 7, 8, 15, 17, 27, 36 Although orlistat can reduce caloric intake by reducing dietary fat absorption from the GI tract and thus promote weight loss,1, 6, 7, 8, 15, 17 pharmacotherapy with the drug is an adjunct to not a substitute for a reduced (at least mildly)-calorie diet.1, 7, 8, 15, 27 Candidates for orlistat therapy include patients with a pretreatment body mass index (BMI) of 30 kg/m2 or greater or, in the presence of an underlying risk factor or disease (e.g., hypertension, diabetes mellitus, hyperlipidemia), a BMI of 27 kg/m2 or greater.1, 15, 27 BMI is calculated by dividing the patient's weight in kilograms (kg) by their height in meters (m) squared.1
Efficacy of orlistat (120 mg 3 times daily) for managing obesity (assessed by evaluating weight loss, weight maintenance, and weight regain and improvement in certain comorbidities such as diabetes mellitus, hyperlipidemia, and hypertension) has been established in 7 long-term (1- to 2-years' duration) controlled trials in over 2800 patients who received behavioral therapy and were instructed to consume a reduced-calorie diet intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat.1, 6, 7, 8, 15, 17, 36 After 2 years of treatment, approximately 25-45% of orlistat-treated patients versus approximately 15-28% of placebo recipients lost at least 5% of baseline weight, with about 17-25% of orlistat-treated patients versus about 4-12% of placebo recipients achieving at least a 10% weight loss.1 In the 3 studies that evaluated the effect of orlistat on weight regain, orlistat-treated patients regained 26-35% of the weight they had previously lost compared with 52-63% for patients receiving placebo.1, 7, 8 Relative improvement in several risk factors (e.g., serum glucose and lipoproteins) (see Description) was maintained for 2 years of orlistat therapy.1, 7, 8 In obese type 2 diabetics, in addition to weight loss and cardiovascular risk improvement, orlistat therapy was associated with improved glycemic control and dosage reduction for oral antidiabetic (sulfonylurea) therapy,1, 17, 37 with discontinuance of sulfonylurea therapy in about 12% of patients.1 Effects on dietary fat absorption with orlistat are evident within 1-2 days after therapy is initiated.1
The effect of orlistat (120 mg 3 times daily) on time to onset of type 2 diabetes mellitus and body weight has been evaluated in a 4-year randomized, prospective, double-blind, placebo-controlled study (XENDOS study) in 3304 obese (BMI of 30 kg/m2 or greater), nondiabetic adult patients with normal (79% of patients) or impaired glucose tolerance (21% of patients) at baseline.1, 39, 45 All study participants were instructed to consume a reduced-calorie diet intended to provide 30% of calories from fat.39, 45 At study endpoint, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes mellitus than placebo (6.2 versus 9%, respectively), translating into a 37.3% decreased risk of developing diabetes with orlistat.39, 45, 51 This finding was principally due to efficacy of orlistat in delaying onset of type 2 diabetes mellitus in patients with impaired glucose tolerance at baseline.1, 39, 51 At study endpoint, the incidence of type 2 diabetes mellitus was 18.8% in orlistat-treated patients with impaired glucose tolerance at baseline and 28.8% in placebo recipients with impaired glucose tolerance at baseline.39 Treatment with orlistat did not reduce the risk for development of type 2 diabetes mellitus in patients with normal glucose tolerance at baseline (2.6% in those receiving orlistat versus 2.7% in those receiving placebo).1, 39 After 4 years of treatment, 52.8% of orlistat-treated patients versus 37.3% of placebo recipients lost at least 5% of baseline weight, with 26.2% of orlistat-treated patients versus 15.6% of placebo recipients achieving at least a 10% weight loss.39, 45 Weight loss in those with impaired glucose tolerance at baseline was similar to that in patients with normal glucose tolerance at baseline.39 Mean difference in weight loss between orlistat-treated patients and placebo recipients was 2.5%.1 Relative improvement in several risk factors (e.g., blood pressure, waist circumference, serum lipoproteins) (see Description) was maintained throughout the study.39, 51
Orlistat also may be used for self-medication to promote weight loss in overweight adults 18 years of age or older; orlistat is used in conjunction with a reduced-calorie, low-fat diet.46 Efficacy of orlistat (60 mg 3 times daily) in promoting weight loss has been established in 3 randomized, double-blind, placebo-controlled studies of up to 2 years' duration in over 1500 overweight and obese patients maintained on a reduced-calorie diet intended to provide 30% of calories from fat.48, 49, 50 In these studies, patients receiving orlistat lost more weight than those receiving placebo during the first year; in addition, weight regain during year 2 (weight maintenance diet phase) was less for patients receiving orlistat.49, 50 In one study in obese individuals, 48.8% of orlistat-treated patients versus 30.7% of placebo recipients lost at least 5% of baseline weight, with 24.4% of orlistat-treated patients versus 11.3% of placebo recipients achieving at least a 10% weight loss after 1 year of treatment.49 After 2 years of treatment, 33.8% of orlistat-treated patients versus 24.1% of placebo recipients lost at least 5% of baseline weight, with 14.6% of orlistat-treated patients versus 6.6% of placebo recipients achieving at least a 10% weight loss.49 In another study in obese individuals, 31.2% of orlistat-treated patients versus 18.8% of placebo recipients achieved at least a 10% weight loss after 1 year of treatment, and 29% of orlistat-treated patients versus 18.6% of placebo recipients achieved at least a 10% weight loss after 2 years of treatment.50 Relative improvement in several risk factors (e.g., blood pressure, serum lipoproteins) (see Description) was maintained until study endpoint.48, 49, 50
Because of the tendency to regain weight after initial loss, long-term maintenance therapy with orlistat may be indicated in certain patients.15 However, because safety and efficacy beyond 4 years of therapy have not been established, periodic reassessment of weight management and therapy should be conducted.7, 27, 39 If orlistat is effective in helping the patient lose weight and/or maintain weight loss and there are no serious adverse effects, it can be continued as long as clinically indicated.17 The manufacturer states that the long-term effects of orlistat therapy on morbidity and mortality associated with obesity have not been established.1
Orlistat is administered orally 3 times daily, during (or up to 1 hour after) each main meal containing fat.1, 8, 19, 20, 23, 27, 46, 47 However, administering the drug up to 2 hours after midmeal does not appear to affect efficacy.19, 20
The recommended dosage of prescription orlistat (e.g., Xenical®) 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.1, 6, 7, 8, 17, 23, 27, 36 Patients should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat.1, 27 Daily intake of fat, carbohydrate, and protein should be distributed over 3 main meals.1 If a meal occasionally is missed or contains no fat, the dose of orlistat may be omitted.1, 27 Dosages exceeding 120 mg 3 times daily have not been shown to provide additional benefit.1, 23
For self-medication for weight loss, the usual dosage of orlistat (Alli®) in overweight adults 18 years of age and older is 60 mg 3 times daily with each meal containing fat.46 If a meal occasionally is missed or contains no fat, the dose of orlistat may be omitted.47 Dosage for self-medication should not exceed three 60-mg capsules daily.46
The manufacturers recommend that a multivitamin supplement containing fat-soluble vitamins (A, D, E, and K) and beta carotene be used during orlistat therapy,1, 46, 59 since the drug may reduce GI absorption of such vitamins and beta carotene.1, 59 However, in clinical and other studies, fat-soluble vitamin concentrations remained within the normal range for most individuals despite decreases, and supplementation was only occasionally needed.7, 8, 17, 25, 26, 36 At least 2 hours should elapse before or after any orlistat dose and multivitamin administration; administering the multivitamin supplement at bedtime is a convenient time.1, 8, 27, 37, 46
Concomitant Therapy with Cyclosporine and Levothyroxine
In patients receiving prescription orlistat, cyclosporine should be administered at least 3 hours before or after orlistat.1 Orlistat should not be used for self-medication in organ transplant recipients because of possible interactions with the immunosuppressive agents used to prevent organ rejection, including cyclosporine.46 (See Concomitant Drug Therapy and Vitamin Use under Cautions: Warnings/Precautions and also see Drug Interactions: Cyclosporine and Other Immunosuppressive Agents.)
In patients receiving prescription orlistat and levothyroxine concomitantly, the drugs should be administered at least 4 hours apart.1 Patients receiving orlistat for self-medication should consult a clinician or pharmacist before initiating orlistat if they are receiving therapy for thyroid disease; dosage adjustment may be needed in such patients.46 (See Drug Interactions: Thyroid Agents.)
No special population dosage recommendations at this time.1
Orlistat is contraindicated in women who are pregnant.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)
Patients with chronic malabsorption syndrome.1, 27
Patients with cholestasis.1, 27
Patients with known hypersensitivity to orlistat or any ingredient in the formulations.1, 27, 46 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)
Hypersensitivity reactions reported rarely in orlistat-treated patients during the postmarketing period include pruritus, rash, urticaria, angioedema, bronchospasm, and anaphylaxis.1 Very rare cases of bullous eruption also have been reported with the drug.1
Rare cases of leukocytoclastic vasculitis have been reported in patients receiving orlistat.1, 68, 69 Clinical signs have included palpable purpura, maculopapular lesions, arthralgia/myalgia, and bullous eruption.1, 68, 69 In one case of cutaneous leukocytoclastic vasculitis that developed 3 days following initiation of orlistat therapy, the condition rapidly improved following drug discontinuance, bed rest, and administration of nonsteroidal anti-inflammatory agents.68
Concomitant Drug Therapy and Vitamin Use
Concomitant administration of orlistat and cyclosporine can result in decreased plasma concentrations of cyclosporine.1, 40, 41, 42, 43, 44 Orlistat should not be used for self-medication in organ transplant recipients because of possible interactions with the immunosuppressive agents used to prevent organ rejection.46 (See Concomitant Therapy with Cyclosporine and Levothyroxine under Dosage and Administration: Dosage and see also Drug Interactions: Cyclosporine and Other Immunosuppressive Agents.)
Fat-soluble vitamin deficiency during orlistat therapy is unlikely but possible,1, 7, 8, 17, 25, 26, 27 and the manufacturers consider routine multivitamin supplementation a prudent precaution.1, 27, 37, 46
Weight loss may improve glycemic control in orlistat-treated patients with diabetes mellitus.1 Dosage reduction or discontinuance of concurrent antidiabetic agents (e.g., sulfonylureas, metformin, insulin) may be therefore necessary in some patients.1, 17, 29 (See Drug Interactions: Antidiabetic Agents.)
Severe hepatotoxicity (e.g., hepatocellular necrosis, acute hepatic failure), sometimes resulting in liver transplantation or death, has been reported rarely during postmarketing experience with orlistat.1, 52, 53, 55, 56, 57, 58, 61, 62, 63, 65, 66 Other adverse hepatic effects that have occurred rarely in patients receiving the drug include elevations in serum aminotransferase (transaminase) and alkaline phosphatase concentrations and hepatitis.1, 55
In August 2009, the US Food and Drug Administration (FDA) reported that it was conducting an ongoing safety review of orlistat prompted by reports of adverse hepatic-related effects in patients receiving the drug.52, 53, 55, 56, 57, 58, 61, 62, 63 Between 1999 and October 2008, FDA had received 32 reports of serious hepatic injury associated with orlistat, including 27 cases requiring hospitalization and 6 cases that resulted in liver failure.52, 53, 62, 66 Thirty of those cases occurred outside the US.52, 53 The most commonly reported adverse effects described in these reports included jaundice, weakness, and abdominal pain.52, 53, 55 In May 2010, FDA's completed safety review of the available data (including preclinical, clinical, postmarketing, and drug utilization data) identified 13 cases of severe liver injury reported in orlistat-treated patients; 12 of these cases occurred outside the US with prescription orlistat (Xenical®) and 1 case occurred in the US with the over-the-counter (OTC) preparation (Alli®).65, 66 Among the 13 reported cases, 2 resulted in death and 3 resulted in liver transplantation.65, 66 Because of the possibility that other drugs or factors may have contributed to the development of severe hepatic injury in some of these cases, FDA states that a causal relationship to orlistat cannot be established at this time.65, 66 However, because of the seriousness of severe liver injury, the agency has directed the manufacturers of orlistat to add information to the labeling of their orlistat products to inform clinicians and patients about this potential risk.65, 66
Clinicians should weigh the benefits of weight loss with orlistat against the potential risks of therapy when considering whether the drug is appropriate for patients.65, 66 Clinicians should also instruct patients to report any signs or symptoms possibly associated with the development of hepatic injury (e.g., anorexia, pruritus, jaundice, dark urine, light-colored stools, right upper quadrant pain) (see Advice to Patients).1, 27, 52, 53, 65, 66 If such manifestations occur or liver injury is suspected, orlistat and any other suspect drugs should be immediately discontinued and liver function tests (including serum ALT [SGPT] and AST [SGOT] concentrations) should be performed.1, 65, 66
Increased concentrations of urinary oxalate may develop in some patients receiving orlistat therapy.1, 67 Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported in patients treated with the drug.1, 67 The manufacturer states that if prescription orlistat is used in patients at risk for renal impairment, renal function should be monitored.1 In addition, the drug should be used with caution in patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.1 (See Advice to Patients.)
Substantial weight loss may increase risk of cholelithiasis.1 Cholelithiasis was reported in 2.9% of patients receiving orlistat and in 1.8% of placebo recipients in the clinical trial that evaluated the effect of orlistat on the time to onset of type 2 diabetes mellitus.1
Clinicians should rule out organic causes of obesity (e.g., hypothyroidism) before prescribing orlistat.1
Adherence to dietary recommendations minimizes adverse GI effects related to high fat intake as well as contributing to weight loss.1, 27, 46 (See Dosage under Dosage and Administration.)
Potential for abuse in inappropriate patient populations (e.g., anorexia nervosa, bulimia).1
Category X.1 (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.1 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.1
Embryotoxicity and teratogenicity have not been observed in animals at dosages substantially higher than the recommended human dosage.1 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.1
It is not known if orlistat is distributed in breast milk; therefore, the drug should be used with caution in nursing women.1, 27, 46, 47
Safety and efficacy of prescription orlistat (Xenical®) in children younger than 12 years of age have not been established.1
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.1
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.1, 45, 51 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.1, 45, 51 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.1 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).1, 45, 51 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.1, 45 Adverse effects of orlistat in adolescent patients were similar to those observed in adults.1
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.1 A decrease in iron balance was observed in orlistat-treated patients and placebo recipients (64.7 versus 40.4 µmol/24 hours, respectively).1
Plasma concentrations of orlistat and its metabolites M1 and M3 in adolescents were similar to those observed in adults receiving an equivalent dosage.1 Daily fecal fat excretion was 27% of dietary intake in orlistat-treated pediatric patients compared with 7% in those receiving placebo.1
Orlistat should not be used for self-medication in children younger than 18 years of age.46
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.1
The pharmacokinetics of orlistat have not been specifically studied in geriatric patients to date.1
The pharmacokinetics of orlistat have not been specifically studied in patients with renal impairment to date.1
Because cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported in orlistat-treated patients,1, 67 the manufacturer of prescription orlistat states that renal function should be monitored in patients at risk for renal impairment during therapy.1 (See Hyperoxaluria under Cautions: Warnings/Precautions.)1
Adverse effects of orlistat occurring in 5% or more of patients and with an incidence at least twice that of placebo include oily spotting,1, 7, 8, 48, 49 flatus with discharge,1, 7, 8, 46, 48 fecal urgency,1, 7, 8, 48, 49 fatty/oily stool,1, 7, 8, 48, 49 oily evacuation,1, 8, 49 increased defecation,1, 7, 8, 46, 48, 49 and fecal incontinence.1, 7, 8, 46, 49 Such effects usually develop within 3 months of starting therapy1, 47, 49, 50 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.1, 7, 8 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.1 In trials that evaluated orlistat 60 mg three times daily, 3.2% of patients discontinued orlistat because of adverse effects.47 The most common adverse effects resulting in discontinuance were GI effects.1, 7, 8
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.49, 50
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.1
Potential pharmacokinetic interaction with beta-carotene and vitamin E acetate supplements (decreased absorption).1, 7, 8, 17, 25, 26, 27 The effect of orlistat on the absorption of other fat-soluble vitamins (A, D, and K) has not been established.1 (See Multivitamin Supplementation under Dosage and Administration: Dosage and also see Advice to Patients.)
In a controlled study in healthy individuals, multiple-dose orlistat decreased the systemic exposure of a single dose of amiodarone (a highly lipophilic drug) and its metabolite desethylamiodarone by 23-27%.1, 64 The effect of initiating orlistat therapy in patients receiving a stable dosage of amiodarone has not been studied to date.1
Orlistat potentially may decrease the absorption of anticonvulsants, which may increase the risk of seizures.70 Seizures have been observed in some patients treated concomitantly with orlistat and anticonvulsants (e.g., lamotrigine, valproic acid).1, 70 The manufacturer of prescription orlistat recommends monitoring for possible changes in the frequency and/or severity of seizures in patients receiving anticonvulsants and orlistat in combination.1, 70
Patients receiving an anticonvulsant should consult a clinician or pharmacist before initiating orlistat for self-medication .46
In normal-weight individuals, orlistat (120 mg given 3 times daily for 7 days) did not affect the pharmacokinetics of phenytoin (single 300-mg dose) during concomitant administration.1, 34
Weight loss may improve glycemic control; antidiabetic (e.g., insulin, metformin, sulfonylureas) dosage reduction or discontinuance may be necessary.1, 17, 29
Patients receiving an antidiabetic agent should consult a clinician or pharmacist before initiating orlistat for self-medication ; dosage adjustment of the antidiabetic agent may be needed.46
In normal-weight individuals, orlistat (80 mg given 3 times daily for 5 days) did not affect the pharmacokinetics or pharmacodynamics (i.e., blood glucose-lowering effect) of glyburide during concomitant administration.1
In normal-weight, mildly hypercholesterolemic patients, orlistat (120 mg given 3 times daily for 6 days) did not affect the pharmacokinetics of pravastatin during concurrent administration.1
Orlistat did not substantially affect the pharmacokinetics of simvastatin and its active metabolite during concomitant administration in healthy individuals.64
Cyclosporine and Other Immunosuppressive Agents
Pharmacokinetic interaction with cyclosporine (decreased plasma cyclosporine concentrations).1, 40, 41, 42, 43, 44 In a multiple-dose study, orlistat (120 mg given 3 times daily) decreased the area under the concentration-time curve (AUC) and peak plasma concentration of cyclosporine (50 mg twice daily) by 31 and 25%, respectively.1 When cyclosporine was administered 3 hours after orlistat in the same study, AUC and peak plasma concentration of cyclosporine decreased by 17 and 4%, respectively.1 Prescription orlistat should therefore not be administered at the same time as cyclosporine.1 Cyclosporine should be taken at least 3 hours before or after orlistat.1 In addition, more frequent monitoring of plasma or blood concentrations of cyclosporine in patients receiving these drugs in combination should be considered.1, 41, 43
Organ transplant recipients should not use orlistat for self-medication because of possible interactions with the immunosuppressive agents used to prevent organ rejection, including cyclosporine.46
In normal-weight individuals, orlistat (120 mg given 3 times daily for 6 days) did not affect the pharmacokinetics of single-dose digoxin during concomitant administration.1, 30
Orlistat did not substantially affect the pharmacokinetics of fluoxetine and its metabolite norfluoxetine during concurrent administration in healthy volunteers.64
In normal-weight individuals, orlistat (120 mg given 3 times daily for 6 days) did not affect the bioavailability of extended-release nifedipine tablets during concomitant administration.1, 31, 32
In normal-weight, healthy women, orlistat (120 mg given 3 times daily for 23 days) did not affect the ovulation-suppressing activity of oral contraceptives during concomitant administration.1, 33
Hypothyroidism has been reported in patients concurrently receiving orlistat and levothyroxine during postmarketing surveillance.1, 60, 61 Patients receiving prescription orlistat and levothyroxine concomitantly should be monitored for changes in thyroid function, and the drugs should be administered at least 4 hours apart.1
Patients receiving therapy for thyroid disease should consult a clinician or pharmacist before initiating orlistat for self-medication ; dosage adjustment of the thyroid agent may be needed.46
In normal-weight individuals, orlistat (120 mg given 3 times daily for 16 days) did not affect the pharmacokinetics or pharmacodynamics of R -warfarin and S -warfarin during concomitant administration with warfarin sodium.1, 28 Although undercarboxylated osteocalcin, which is a marker of vitamin K nutritional status, was not affected by orlistat administration, vitamin K concentrations tended to decline in individuals receiving the drug.1, 28 In addition, decreased prothrombin, increased international normalized ratio (INR), and unbalanced anticoagulant therapy resulting in changes in hemostatic parameters have been reported in patients concurrently receiving orlistat and anticoagulants.1 Therefore, patients receiving chronic stable dosages of warfarin should be monitored closely for possible changes in coagulation parameters during prescription orlistat therapy.1 Dosage adjustment of warfarin may be necessary.46
Patients receiving warfarin should consult a clinician or pharmacist before initiating orlistat for self-medication ; dosage adjustment of warfarin may be needed.46
In healthy, normal-weight individuals, concurrent administration of orlistat and ethanol (40 g; equivalent to approximately 3 glasses of wine) did not affect the pharmacokinetics of ethanol or the systemic exposure and pharmacodynamics (i.e., fecal fat excretion) of orlistat.1, 35
Orlistat, a reversible inhibitor of gastric and pancreatic lipases,1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 18, 19, 21, 22, 47, 51 exhibits antiobesity1, 6, 7, 8, 17, 23, 36 and antilipemic activity.1, 3, 4, 5, 6, 7, 8, 20, 36 The drug also inhibits certain other (e.g., microbial, carboxylester [for hydrolysis of vitamin esters]) lipases.4, 9, 12, 14 Orlistat is a synthetic derivative of naturally occurring lipstatin.2, 4, 6, 9, 12, 18, 21, 37
Unlike most other currently available antiobesity agents, orlistat does not exert anorexigenic (appetite suppressant) effects.15 Instead, orlistat exerts its antiobesity effect by decreasing the absorption of dietary fats (triacylglycerols) in the gastric and intestinal lumen via inhibition of triglyceride hydrolysis;1, 2, 4, 6, 12, 18, 19, 20, 21, 22, 51 at recommended dosages, approximately one-fourth to one-third of dietary fat will not be absorbed.1, 6, 12, 18, 19, 20, 47 By preventing triglyceride hydrolysis, the drug decreases intestinal concentrations of absorbable free fatty acids and monoglycerides.1, 4, 6, 12
Effects of orlistat on serum lipoproteins include decreased concentrations of LDL1, 3, 4, 5, 6, 7, 8, 20, 36, 51 and total1, 4, 5, 6, 7, 8, 20, 36 cholesterol; effects on serum triglyceride concentrations are variable,1, 3, 4, 5, 6, 7, 20 despite reductions in postprandial serum concentrations,3 as are those on HDL cholesterol.3, 4, 6, 7 In obese patients, with6, 17 or without5, 7, 8 diagnosed diabetes mellitus, improved glucose tolerance and glycemic control can occur.51 Short-term orlistat use does not affect gallbladder motility1, 6, 12, 16 or bile composition or lithogenicity1, 12 in obese or normal-weight individuals; whether long-term therapy reduces the risk of gallstones is unknown.16
Orlistat works locally within the GI tract.1, 6, 12, 21, 22 Following oral administration, systemic exposure to orlistat is minimal.1, 6, 21, 22, 47 In vitro, orlistat was more than 99% bound to plasma proteins, mainly lipoproteins and albumin.1 The drug is metabolized to clinically unimportant metabolites, mainly M1 and M3.1 Limited data suggest that the elimination half-life of absorbed orlistat ranges from 1-2 hours.1 Fecal excretion of unabsorbed drug is the major route of elimination.1, 6, 21, 22
Provide copy of manufacturer's patient information for prescription orlistat (Xenical®).1 Importance of advising patient to read patient information before beginning treatment and each time their prescription is refilled.1
When orlistat is used for self-medication (Alli®), importance of reading the product labeling.46 Information for individuals considering therapy with orlistat or starting orlistat is available at [Web].46
In patients taking prescription orlistat, importance of adherence to clinician's dietary and, if applicable, exercise recommendations.1, 15, 17 Importance of patients using a nutritionally balanced, mildly reduced-calorie diet that contains no more than 30% of total daily calories from fat.27 Daily intake of fat, carbohydrates, and protein should be distributed evenly over 3 main meals.1 Omit orlistat dose if meal contains no fat or is skipped.1, 47
Because orlistat works by blocking the absorption of dietary fat, importance of advising patients that they will likely experience some changes in bowel habits.27 These changes usually occur during the first weeks of treatment, particularly after meals containing higher amounts of fat than recommended, but may continue throughout therapy.27 The changes may include oily spotting, gas with discharge, increased number of bowel movements, and inability to control bowel movements.27 Due to the presence of undigested fat, the oil seen in the bowel movement may be clear or orange or brown in color.27
In patients taking prescription orlistat, importance of patients advising clinicians if they consistently have problems absorbing food (chronic malabsorption), gallbladder problems (e.g., cholestasis), hepatic or renal disease (including nephrolithiasis), pancreatitis, eating disorders such as anorexia or bulimia, diabetes mellitus, thyroid disease, a seizure disorder, cardiac arrhythmias, or hypersensitivity to orlistat or any other components of the formulation.1, 27, 46
When used as self-medication , importance of patients advising clinicians if they have problems absorbing food (chronic malabsorption), have gallbladder problems, kidney stones, pancreatitis, or severe or continuous abdominal pain.46, 47
Risk of oxalate nephrolithiasis/nephropathy.1, 27 Importance of advising patients to promptly contact their clinician if they experience any symptoms of kidney stones or other renal problems (e.g., swelling [particularly of legs and feet], reduced or no urine output, frequent or painful urination, blood in the urine, loss of appetite, nausea and vomiting, or severe pain in the back, abdomen, or groin).27
Possible increased risk for the formation of gall stones in some patients.1, 27 Weight loss with orlistat can increase the risk of gall stones.1, 27 Importance of advising patients to promptly report any symptoms of pain in the upper right portion of the abdomen; the pain may be accompanied by nausea and vomiting.27
Importance of informing patients that there have been rare reports of severe liver injury in orlistat-treated patients.1, 27, 52, 53, 65, 66 Importance of advising patients to contact their clinician if they experience any symptoms possibly associated with liver injury, such as weakness or fatigue, fever, jaundice (yellowing of the eyes or skin), or dark urine.1, 52, 53, 65, 66 Other symptoms may include abdominal or right upper quadrant pain, nausea, vomiting, light-colored stools, itching, or loss of appetite.1, 27, 52, 53, 65, 66 (See Hepatic Effects under Cautions: Warnings/Precautions.)
Importance of taking a multivitamin supplement containing vitamins A, D, E, and K and beta carotene once daily at least 2 hours before or after taking orlistat, such as at bedtime.1, 27, 46, 47
Importance of advising clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary supplements (including herbal preparations), particularly other antiobesity agents, anticonvulsants, antidiabetic agents, amiodarone, cyclosporine, warfarin, or thyroid medication.1, 27, 46
Risk of fetal harm because of maternal weight loss if used during pregnancy.1 Importance of advising women that a minimum weight gain and no weight loss is currently recommended for all pregnant women, including those who are already overweight or obese.1 Importance of advising women of childbearing potential to avoid pregnancy.1 Importance of women informing clinicians if they are or plan to become pregnant or are breast-feeding.1, 27, 46 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)
Importance of informing patients of other important precautionary information.1, 46 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 60 mg | Alli® | |
120 mg |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions February 24, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech USA, Inc,. Xenical® (orlistat) capsules prescribing information. South San Francisco, CA; 2015 Aug.
2. Hauptman JB, Jeunet FS, Hartmann D. Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin). Am J Clin Nutr . 1992; 55(Suppl):309S-13. [PubMed 1728845]
3. Reitsma JB, Castro Cabezas M, de Bruin TW et al. Relationship between improved postprandial lipemia and low-density lipoprotein metabolism during treatment with tetrahydrolipstatin, a pancreatic lipase inhibitor. Metabolism . 1994; 43:293-8. [PubMed 8139476]
4. Tonstad S, Pometta D. Erkelens DW et al. The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia. Eur J Clin Pharmacol . 1994; 46:405-10. [PubMed 7957533]
5. Zavoral JH. Treatment with orlistat reduces cardiovascular risk in obese patients. J Hypertens . 1998; 16(12 Part 2):2013-7. [PubMed 9886891]
6. McNeely W, Benfield P. Orlistat. Drugs . 1998; 56:241-9. [PubMed 9711448]
7. Sjöström L, Rissanen A, Andersen T et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet . 1998; 352:167-72. [PubMed 9683204]
8. Davidson MH, Hauptman J, DiGirolamo M et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA . 1999; 281:235-42. [PubMed 9918478]
9. Borgstrom B. Mode of action of tetrahydrolipstatin: a derivative of the naturally occurring lipase inhibitor lipstatin. Biochim Biophys Acta . 1988; 962:308-16. [PubMed 3167082]
10. Hadvary P, Lengsfeld H, Wolfer H. Inhibition of pancreatic lipase in vitro by the covalent inhibitor tetrahydrolipstatin. Biochem J . 1988; 256:357-61. [PubMedCentral][PubMed 3223916]
11. Hadvary P, Sidler W, Meister W et al. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase. J Biol Chem . 1991; 266:2021-7. [PubMed 1899234]
12. Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord . 1997; 21(Suppl 3):12S-3.
13. Lookene A, Skottova N, Olivercrona G. Interactions of lipoprotein lipase with the active-site inhibitor tetrahydrolipstatin (Orlistat). Eur J Biochem . 1994; 222:395-403. [PubMed 8020477]
14. Pottoff AP, Haalck L, Spener F. Inhibition of lipases from Chromobacterium viscosum and Rhizopus oryzae by tetrahydrolipstatin. J Mass Spectrom . 1997; 32:739-49. [PubMed 9241856]
15. National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. 1998 Jun.
16. Froelich F, Hartmann D, Guezelhan C et al. Influence of orlistat on the regulation of gallbladder contraction in man: a randomized double-blind placebo-controlled crossover study. Dig Dis Sci . 1996; 41:2404-8. [PubMed 9011450]
17. Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care . 1998; 21:1288-94. [PubMed 9702435]
18. Zhi J, Melia AT, Guerciolini MD et al. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther . 1994; 56:82-5. [PubMed 8033498]
19. Hussain Y, Güzelham C, Odink J et al. Comparison of the inhibition of dietary fat absorption by full versus divided doses of orlistat. J Clin Pharmacol . 1994; 34:1121-5. [PubMed 7876405]
20. Hartmann D, Hussain Y, Güzelhan C et al. Effect on dietary fat absorption of orlistat, administered at different times relative to meal intake. Br J Clin Pharmacol . 1993; 36:266-70. [PubMedCentral][PubMed 9114915]
21. Zhi J, Melia AT, Funk C et al. Metabolic profiles of minimally absorbed orlistat in obese/overweight volunteers. J Clin Pharmacol . 1996; 36:1006-11. [PubMed 8973989]
22. Zhi J, Melia AT, Eggers H et al. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol . 1995; 35:1103-8. [PubMed 8626884]
23. Van Gaal LF, Broom JI, Enzi G et al. Efficacy and tolerability of orlistat in the treatment of obesity: a 6-month dose-ranging study. Eur J Clin Pharmacol . 1998; 54:125-32. [PubMed 9626916]
24. Güzelhan C, Odink J, Niestijl Jansen-Zuidema JJ et al. Influence of dietary composition on the inhibition of fat absorption by orlistat. J Int Med Res . 1994; 22:255-65. [PubMed 7867870]
25. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol . 1996; 36:647-53. [PubMed 8844448]
26. Zhi J, Melia AT, Koss-Twardy SG et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of β-carotene in healthy volunteers. J Clin Pharmacol . 1996; 36:152-9. [PubMed 8852391]
27. Genentech, Inc. Xenical® (orlistat) capsules patient information. South San Francisco, CA; 2010 May.
28. Zhi J, Melia AT, Guerciolini R et al. The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol . 1996; 36:659-6. [PubMed 8844450]
29. Zhi J, Melia AT, Koss-Twardy SG et al. The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. J Clin Pharmacol . 1995; 35:521-5. [PubMed 7657854]
30. Melia AT, Zhi J, Koss-Twardy SG et al. The influence of reduced dietary fat absorption induced by orlistat on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol . 1995; 35:840-3. [PubMed 8522642]
31. Melia AT, Mulligan TE, Zhi J. Lack of effect of orlistat on the bioavailability of a single dose of nifedipine extended-release tablets (Procardia XL) in healthy volunteers. J Clin Pharmacol . 1996; 36:352-5. [PubMed 8728349]
32. Weber C, Tam YK, Schmidtke-Schrezenmeier G et al. Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers. Eur J Clin Pharmacol . 1996; 51:87-90. [PubMed 8880057]
33. Hartmann D, Gzelhan C, Zuiderwijk PBM et al. Lack of interaction between orlistat and oral contraceptives. Eur J Clin Pharmacol . 1996; 50:421-4. [PubMed 8839667]
34. Melia AT, Mulligan TE, Zhi J. The effect of orlistat on the pharmacokinetics of phenytoin in healthy volunteers. J Clin Pharmacol . 1996; 36:654-8. [PubMed 8844449]
35. Melia AT, Zhi J, Zelasko R et al. The interaction of the lipase inhibitor orlistat with ethanol in healthy volunteers. Eur J Clin Pharmacol . 1998; 54:773-7. [PubMed 9923583]
36. James WP, Avenell A, Broom J et al. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord . 1997; 21(Suppl 3):S24-30. [PubMedCentral][PubMed 9225173]
37. Roche Laboratories Inc, Nutley, NJ: Personal communication.
38. Roche Laboratories Inc. Xenical® (orlistat) capsules prescribing information. Nutley, NJ; 1999 May.
39. Torgerson JS, Hauptman J, Boldrin MN et al. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as ann adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care . 2004; 27:155-61. [PubMed 14693982]
40. Zhi J, Moore R, Kanitra L et al. Pharmacokinetic evaluation of the possible interaction between selected concomitant medication and orlistat at steady state in healthy subjects. J Clin Pharmacol . 2002; 42:1011-9. [PubMed 12211217]
41. Barbaro D, Orsini P, Pallini S et al. Obesity in transplant patients: case report showing interference of orlistat with absorption of cyclosporine and review of literature. Endocr Pract . 2002; 8:124-6. [PubMed 11942778]
42. Nägele H, Petersen B, Bonacker U et al. Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient. Eur J Clin Pharmacol . 1999; 55:667-9.
43. Colman E, Fossler M. Reduction in blood cyclosporine concentrations by orlistat. New Engl J Med . 2000; 342:1141-2. (letter) [PubMed 10766596]
44. Asberg A. Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients. Drugs . 2003; 63:367-78. [PubMed 12558459]
45. Roche Laboratories Inc, Nutley, NJ: Personal communication.
46. GlaxoSmithKline Consumer Healthcare Holdings (US) LLC. Alli® (orlistat) capsules label. Moon Township, PA; 2016 Jun.
47. Alli Key Facts. From Alli Healthcare Professionals web site. [Web]
48. Anderson JW, Schwartz SM, Hauptman J et al. Low-dose orlistat effects on body weight of mildly to moderately overweight individuals: a 16 week, double-blind, placebo-controlled trial. Ann Pharmacother . 2006; 40:1717-23. [PubMed 16940406]
49. Hauptman J, Lucas C, Boldrin MN et al. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med . 2000; 9:160-7. [PubMed 10693734]
50. Rössner S, Sjöström L, Noack R et al. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res . 2000; 8:49-61.
51. Curran MP, Scott LJ. Orlistat: a review of its use in the management of patients with obesity. Drugs . 2004; 64:2845-64. [PubMed 15563254]
52. Food and Drug Administration, Centers for Drug Evaluation and Research. Early communication about an ongoing safety review of orlistat (marketed as Alli and Xenical). Rockville, MD; 2009 Aug 24. From the FDA web site. Accessed 2009 Sep 9. [Web]
53. Food and Drug Administration. FDA News Release: FDA issues early communication about ongoing safety review of weight loss drug orlistat: review includes both prescription drug Xenical and OTC drug Alli. Rockville, MD; 2009 Aug 24. From the FDA web site. Accessed 2009 Oct 28. [Web]
55. Umemura T, Ichijo T, Matsumoto A et al. Severe hepatic injury caused by orlistat. Am J Med . 2006; 119:e7. [PubMed 16887401]
56. Lau G, Chan CL. Massive hepatocellular [correction of hepatocullular] necrosis: was it caused by Orlistat?. Med Sci Law . 2002; 42:309-12. [PubMed 12487515]
57. Kim DH, Lee EH, Hwang JC et al. [A case of acute cholestatic hepatitis associated with Orlistat]. Taehan Kan Hakhoe Chi . 2002; 8:317-20. [PubMed 12499790]
58. Montero JL, Muntané J, Fraga E et al. Orlistat associated subacute hepatic failure. J Hepatol . 2001; 34:173. [PubMed 11211898]
59. Roche Laboratories Inc. Xenical® (orlistat) capsules patient information. Nutley, NJ; 2009 Jan.
60. Madhava K, Hartley A. Hypothyroidism in thyroid carcinoma follow-up: orlistat may inhibit the absorption of thyroxine. Clin Oncol ® Coll Radiol) . 2005; 17:492.
61. Filippatos TD, Derdemezis CS, Gazi IF et al. Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf . 2008; 31:53-65. [PubMed 18095746]
62. Thurairajah PH, Syn WK, Neil DA et al. Orlistat (Xenical)-induced subacute liver failure. Eur J Gastroenterol Hepatol . 2005; 17:1437-8. [PubMed 16292105]
63. Alli Educational Resources. From Alli Healthcare Professionals web site. Accessed 2009 Sep 10. [Web]
64. Zhi J, Moore R, Kanitra L et al. Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers. J Clin Pharmacol . 2003; 43:428-35. [PubMed 12723464]
65. US Food and Drug Administration. FDA drug safety communication: completed safety review of Xenical/Alli (orlistat) and severe liver injury. Rockville, MD; 2010 May 26. From FDA website [Web]/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213038.htm. Accessed 2010 Nov 9.
66. US Food and Drug Administration. Questions and answers: orlistat and severe liver injury. Rockville, MD; 2010 May 26. From FDA website [Web]/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213040.htm. Accessed 2010 Nov 9.
67. Humayun Y, Ball KC, Lewin JR et al. Acute oxalate nephropathy associated with orlistat. J Nephropathol . 2016; 5:79-83. [PubMedCentral][PubMed 27152294]
68. Gonzalez-Gay MA, Garcia-Porrua C, Lueiro M et al. Orlistat-induced cutaneous leukocytoclastic vasculitis. Arthritis Rheum . 2002; 47:567. [PubMed 12382312]
69. Lazic T, Fonder M, Robinson-Bostom L et al. Orlistat-induced bullous leukocytoclastic vasculitis. Cutis . 2013; 91:148-9. [PubMed 23617088]
70. Roche Registration Limited,. Xenical® (orlistat) 120-mg hard capsules summary of product characteristics. Welwyn Garden City, UK; 2008 Jul 29.