Orlistat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2] Bezalel Hakkeem, M.B.B.S[3]
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Overview
Orlistat is a reversible inhibitor of gastrointestinal lipases that is FDA approved for the treatment of Prescription obesity management, including weight loss, weight maintenance, and reduction of the risk for weight regain after prior weight loss; nonprescription weight loss in overweight adults aged 18 years and older when used with a reduced-calorie, low-fat diet[1][2]. Common adverse reactions include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence[1].
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Prescription orlistat (120 mg)
- Prescription orlistat is indicated for obesity management, including weight loss and weight maintenance, when used with a reduced-calorie diet.[1]
- It is also indicated to reduce the risk for weight regain after prior weight loss.
- It is indicated for patients 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 mellitus, or dyslipidemia.
- The following FDA-label figure illustrates BMI according to weight and height.
Nonprescription alli (60 mg)
- OTC alli is labeled as a weight-loss aid for overweight adults aged 18 years and older when used with a reduced-calorie, low-fat diet.[2]
- The OTC label does not use the prescription product's BMI thresholds and directs consumers to its height-and-weight eligibility chart.
FDA-labeled dosing and administration
| Formulation | Labeled population | Dose | Maximum |
|---|---|---|---|
| Prescription orlistat | Patients meeting the prescription obesity indication; safety and effectiveness are established for patients aged ≥12 years | 120 mg orally with each main meal containing fat, during the meal or up to 1 hour afterward | 120 mg three times daily; higher doses provide no additional benefit |
| Nonprescription alli | Overweight adults aged ≥18 years | 60 mg orally with each meal containing fat | Three 60 mg capsules daily |
- If a meal is missed or contains no fat, the dose may be omitted.[1][2]
- Prescription users should follow a nutritionally balanced, reduced-calorie diet containing approximately 30% of calories from fat, with fat, carbohydrate, and protein distributed across three main meals.
- Patients should take a daily multivitamin containing vitamins A, D, E, and K and beta-carotene at least 2 hours before or after prescription orlistat; the OTC label directs users to take a multivitamin at bedtime.
- Do not administer cyclosporine and prescription orlistat simultaneously. Cyclosporine should be taken at least 3 hours before or after orlistat; the Dosage and Administration section of the prescription label specifically directs administration of cyclosporine 3 hours after orlistat. Consider more frequent cyclosporine-level monitoring. Separate levothyroxine and prescription orlistat by at least 4 hours and monitor thyroid function.
- Fecal fat excretion increases within 24–48 hours after prescription dosing begins and usually returns to pretreatment levels within 48–72 hours after discontinuation.
Guideline context: polycystic ovary syndrome
- The 2023 International Evidence-Based Guideline for PCOS states that anti-obesity medications, including orlistat, could be considered with active lifestyle intervention for management of higher weight in adults with PCOS, according to general-population guidelines.[3]
- When a patient with PCOS independently meets an FDA-labeled obesity or OTC overweight indication, use for weight management is not a separate PCOS-specific off-label indication. Use intended specifically to treat reproductive or hormonal PCOS manifestations is not FDA-approved, and no PCOS-specific dose is established.
- In the evidence review informing the guideline, orlistat appeared superior to placebo for anthropometric outcomes in descriptive analyses; an orlistat-versus-placebo meta-analysis was not performed. The available meta-analysis of orlistat plus a combined oral contraceptive pill versus the oral contraceptive alone did not show improved metabolic outcomes, and the overall evidence was very limited.[4]
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding guideline-supported off-label use of orlistat in adults. The 2023 PCOS guideline recommends considering orlistat for higher-weight management according to general-population obesity guidelines and does not establish a separate PCOS-specific regimen.[3]
Non–Guideline-Supported Use
There is limited information regarding off-label non–guideline-supported use of orlistat in adults.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Prescription orlistat
- Safety and effectiveness have been established for pediatric patients aged ≥12 years; the labeled dose is 120 mg orally three times daily with each main meal containing fat.[1]
- Safety and effectiveness in patients aged <12 years have not been established.
Nonprescription alli
- OTC alli is labeled only for adults aged ≥18 years and is not labeled for pediatric use.[2]
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding off-label guideline-supported use of orlistat in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding off-label non–guideline-supported use of orlistat in pediatric patients.
Contraindications
Prescription orlistat (120 mg)[1]
- Pregnancy
- Chronic malabsorption syndrome
- Cholestasis
- Known hypersensitivity to orlistat or any component of the product
Nonprescription alli (60 mg)[2]
- Do not use after an organ transplant, while taking cyclosporine, with a diagnosed food-absorption disorder, when not overweight, or with allergy to any ingredient.
- Do not use during pregnancy or while breastfeeding.
Warnings
Prescription-label drug interactions
- Orlistat may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs.
- Weight loss may affect glycemic control in patients with diabetes mellitus; a reduction in the dose of an oral hypoglycemic medication such as a sulfonylurea, or of insulin, may be required.[1]
Decreased Vitamin Absorption
- Orlistat reduces absorption of some fat-soluble vitamins and beta-carotene; patients should be strongly encouraged to take a daily multivitamin containing fat-soluble vitamins, taken once a day at least 2 hours before or after orlistat (e.g., at bedtime).
- Vitamin D and beta-carotene levels may be lower in obese patients compared with non-obese subjects, making supplementation particularly important.[1]
Liver Injury
- Rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure have occurred in patients treated with orlistat, with some cases resulting in liver transplant or death.
- Patients should be instructed to report any symptoms of hepatic dysfunction while taking orlistat, including anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain.
- If these symptoms occur, orlistat and other suspect medications should be discontinued immediately, and liver function tests (including ALT and AST levels) should be obtained.[1]
Oxalate Nephrolithiasis and Oxalate Nephropathy with Renal Failure
- Some patients may develop increased levels of urinary oxalate following treatment with orlistat.
- Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported.
- Monitor renal function when prescribing orlistat to patients at increased risk for oxalate nephropathy, including those with renal impairment and those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
- Discontinue orlistat in patients who develop oxalate nephropathy.[1]
Cholelithiasis
- Substantial weight loss can increase the risk of cholelithiasis.
- In a clinical trial of orlistat for the prevention of type 2 diabetes, cholelithiasis as an adverse event occurred in 2.9% (47/1649) of patients randomized to orlistat vs. 1.8% (30/1655) of patients randomized to placebo.[1]
Miscellaneous
- Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing orlistat.
- Patients should be advised to adhere to dietary guidelines.
- Gastrointestinal events may increase when orlistat is taken with a diet high in fat (>30% of total daily calories from fat).
- Daily fat intake should be distributed over three main meals; taking orlistat with any single meal very high in fat increases the possibility of gastrointestinal effects.[1]
Additional nonprescription alli warnings
- Before using OTC alli, patients should ask a physician if they have ever had gallbladder disease, kidney disease or kidney stones, or pancreatitis.[2]
- The March 2026 OTC label instructs users to stop taking alli and ask a doctor if they develop itching, yellow eyes or skin, dark urine, or loss of appetite; severe pain in the back or groin, painful urination, blood in the urine, swelling of the legs or feet, or urination less often than normal; severe or continuous abdominal pain; or worsening seizures.[2]
- FDA announced in June 2026 that the OTC label had been revised to warn about rare acute kidney injury, hyperoxaluria, calcium oxalate nephrolithiasis, and oxalate nephropathy and to make renal-risk warnings consistent across FDA-approved orlistat products.[5]
Adverse Reactions
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.[1]
Commonly observed adverse reactions[1]
- Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events and are primarily a manifestation of the mechanism of action.
- The most frequently reported events were oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence.
- The first occurrence of these events was generally within 3 months of starting therapy.
- Approximately 50% of all GI adverse event episodes lasted less than 1 week, and a majority lasted no more than 4 weeks; however, GI adverse events may occur in some individuals over a period of 6 months or longer.[1]
Discontinuation of treatment[1]
- The most common adverse events resulting in treatment discontinuation were gastrointestinal.
Other adverse events
- Other treatment-emergent adverse events occurring at ≥2% incidence and greater than placebo, across body systems, included abdominal pain/discomfort, nausea, infectious diarrhea, rectal pain/discomfort, tooth disorder, gingival disorder, and vomiting (gastrointestinal); influenza and upper/lower respiratory infection (respiratory); back pain, arthritis, myalgia, joint disorder, and lower-extremity pain (musculoskeletal); headache and dizziness (central nervous system); fatigue and sleep disorder (body as a whole); rash and dry skin (skin); menstrual irregularity and vaginitis (female reproductive); urinary tract infection (urinary); anxiety and depression (psychiatric); otitis (hearing/vestibular); and pedal edema (cardiovascular).
- In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies, with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.
- In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.[1]
Pediatric patients
- In clinical trials with orlistat in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.[1]
Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of orlistat. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to orlistat exposure.
- Rare cases of increased transaminases, increased alkaline phosphatase, and hepatitis that may be serious have been reported. There have been reports of hepatic failure in postmarketing surveillance, with some cases resulting in liver transplant or death.
- Rare cases of hypersensitivity have been reported, with signs and symptoms including pruritus, rash, urticaria, angioedema, bronchospasm, and anaphylaxis. Very rare cases of bullous eruption have been reported.
- Rare cases of leukocytoclastic vasculitis have been reported, with clinical signs including palpable purpura, maculopapular lesions, or bullous eruption.
- Acute oxalate nephropathy after treatment with orlistat has been reported in patients with or at risk for renal disease.
- Pancreatitis has been reported in postmarketing surveillance; no causal relationship or physiopathologic mechanism between pancreatitis and obesity therapy has been definitively established.
- Lower gastrointestinal bleeding has been reported in patients treated with orlistat; most reports are nonserious, but severe or persistent cases should be investigated further.[1]
Drug Interactions
Prescription-label interactions[1]
| Drug/Class | Interaction | Recommendation |
|---|---|---|
| Cyclosporine | Reduces cyclosporine plasma levels | Prescription: do not administer simultaneously; separate cyclosporine and orlistat by at least 3 hours (the Dosage and Administration section specifically directs cyclosporine 3 hours after orlistat) and consider more frequent cyclosporine-level monitoring. OTC: do not use alli while taking cyclosporine. |
| Fat-soluble vitamin supplements (beta-carotene, vitamin E) | Reduces absorption of beta-carotene and vitamin E acetate supplements; effect on vitamin D, vitamin A, and vitamin K not known | Prescription: separate by ≥2 hours. OTC: take a multivitamin once daily at bedtime. |
| Levothyroxine | Hypothyroidism reported postmarketing | Administer ≥4 hours apart; monitor thyroid function |
| Warfarin and other anticoagulants | Decreased vitamin K absorption; decreased prothrombin, increased INR, altered hemostatic parameters reported | Monitor coagulation parameters closely in patients on chronic stable anticoagulant doses |
| Amiodarone | Reduced systemic exposure to amiodarone and desethylamiodarone | Reduced therapeutic effect possible; not studied in patients on stable amiodarone therapy |
| Antiepileptic drugs | Convulsions reported | Monitor for changes in seizure frequency/severity |
| Antiretroviral drugs (e.g., atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir/ritonavir, efavirenz combinations) | Loss of virological control reported in HIV-infected patients | Monitor HIV RNA levels frequently; discontinue orlistat if viral load increase is confirmed |
Nonprescription-label interaction precautions[2]
- OTC users should ask a physician or pharmacist before use if taking an anticoagulant, amiodarone, diabetes medication, thyroid medication, seizure medication, an antiretroviral drug, or another weight-loss product.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): Contraindicated
- Orlistat is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm.
- A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.
- No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.[1]
Animal Data
- Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day; neither study showed embryotoxicity or teratogenicity.
- This dose is 23 and 47 times the daily human dose, calculated on a body surface area (mg/m²) basis, for rats and rabbits, respectively.[1]
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Orlistat in women who are pregnant.
Labor and Delivery
Orlistat is contraindicated during pregnancy and has no established role during labor or delivery.[1]
Nursing Mothers
- It is not known whether prescription orlistat is present in human milk; the prescription label advises caution when it is administered to a nursing woman.[1]
- The OTC alli label states that the product should not be used while breastfeeding.[2]
Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
- Safety and efficacy have been evaluated in obese adolescent patients aged 12 to 16 years, supported by evidence from adequate and well-controlled adult studies plus a 54-week efficacy and safety study and a 21-day mineral balance study in this age group.
- In the 54-week study (64.8% female, 75% Caucasian, 18.8% Black, 6.3% Other), orlistat-treated patients had a mean BMI reduction of 0.55 kg/m² compared with an average increase of 0.31 kg/m² in placebo-treated patients (p=0.001).
- Adverse effects in both adolescent studies were generally similar to those seen in adults, including fatty/oily stool, oily spotting, and oily evacuation.
- In a DEXA substudy (152 orlistat, 77 placebo patients from the 54-week study), body composition changes were similar between groups except for fat mass, which was significantly reduced with orlistat compared with placebo (-2.5 kg vs. -0.6 kg, p=0.033).
- Because orlistat can interfere with absorption of fat-soluble vitamins, all patients should take a daily multivitamin containing vitamins A, D, E, K, and beta-carotene, taken at least 2 hours before or after orlistat.
- Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level.
- Daily fecal fat excretion was 27% of dietary intake in the orlistat group versus 7% in the placebo group.[1]
- OTC alli is labeled only for adults aged ≥18 years.[2]
Geriatic Use
Clinical studies of orlistat did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.[1]
Gender
There is no FDA guidance on the use of orlistat with respect to specific gender.
Race
There is no FDA guidance on the use of orlistat with respect to specific racial populations.
Renal Impairment
- No pharmacokinetic study of orlistat has been conducted specifically in patients with renal impairment.
- Patients with renal impairment are at increased risk for oxalate nephropathy; monitor renal function when prescribing orlistat to these patients, as well as to those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
- Discontinue orlistat if oxalate nephropathy develops.
- Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported with orlistat use. [1]
Hepatic Impairment
- No pharmacokinetic study of orlistat has been conducted specifically in patients with hepatic impairment.
- Orlistat has been associated with rare postmarketing reports of severe liver injury, including hepatocellular necrosis and acute hepatic failure, some resulting in liver transplant or death, in patients without pre-existing hepatic impairment.
- Patients should be instructed to report symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain); orlistat should be discontinued immediately if these occur, with liver function tests and ALT/AST levels obtained.
- The FDA prescribing information provides no specific dose adjustment for hepatic impairment.[1]
Females of Reproductive Potential and Males
- Orlistat is contraindicated during pregnancy. Patients who become pregnant should discontinue orlistat and contact their clinician.[1]
- The FDA labels do not specify a contraception requirement for orlistat.
Immunocompromised Patients
- The prescription label provides no separate dosing recommendation for immunocompromised patients.
- Because orlistat can reduce cyclosporine exposure, transplant recipients and other patients receiving cyclosporine require careful interaction management. The OTC label states not to use alli after an organ transplant or while taking cyclosporine.[1][2]
Organ Transplant Recipients
- The OTC alli label states not to use the product after an organ transplant because orlistat can interfere with medicines used to prevent transplant rejection.[2]
- For prescription orlistat, do not administer cyclosporine and orlistat simultaneously. Separate them by at least 3 hours; the Dosage and Administration section specifically directs cyclosporine 3 hours after orlistat. Consider more frequent cyclosporine-level monitoring.[1]
Administration and Monitoring
Administration
- Orlistat is administered orally as prescription 120 mg capsules or nonprescription 60 mg capsules.
- Prescription: take one 120 mg capsule three times daily with each main meal containing fat, during the meal or up to 1 hour afterward.[1]
- Nonprescription: adults aged ≥18 years should take one 60 mg capsule with each meal containing fat, not to exceed three capsules daily.[2]
- If a meal is occasionally missed, or a meal contains no fat, the dose of orlistat can be omitted.
- Distribute daily intake of fat, carbohydrate, and protein over three main meals; taking orlistat with any single meal very high in fat increases the likelihood of gastrointestinal effects.
- Prescription doses above 120 mg three times daily have not been shown to provide additional benefit.
- Administer with a nutritionally balanced, reduced-calorie diet containing approximately 30% of calories from fat.
- Prescription users should take a daily multivitamin containing fat-soluble vitamins at least 2 hours before or after orlistat; the OTC label directs users to take a multivitamin at bedtime.[1][2]
Monitoring
Note: The FDA labels do not mandate a universal laboratory-testing schedule for orlistat. The following table distinguishes label-directed risk- and interaction-based monitoring from the 2025 American Association of Clinical Endocrinology (AACE) consensus recommendation to monitor kidney and liver function during orlistat therapy.[1][2][6]
| Parameter | Trigger / Population | Monitoring Guidance |
|---|---|---|
| Renal function | All patients during therapy (AACE); especially patients at increased risk for oxalate nephropathy (FDA label: renal impairment, history of hyperoxaluria, or calcium oxalate nephrolithiasis) | AACE recommends monitoring kidney function during therapy. The FDA label specifically directs renal-function monitoring in patients at increased risk; discontinue orlistat if oxalate nephropathy develops. |
| Hepatic function | All patients during therapy (AACE); any patient with symptoms of hepatic dysfunction (FDA label) | AACE recommends monitoring liver function during therapy. Instruct patients to report anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain; if these occur, discontinue orlistat immediately and obtain liver function tests, including ALT and AST. |
| Glycemic control | Patients with diabetes mellitus | Monitor for need to reduce dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin as weight loss occurs |
| Thyroid function | Concomitant levothyroxine use | Monitor for changes in thyroid function |
| Coagulation parameters | Concomitant warfarin or other anticoagulants (chronic stable dose) | Monitor closely for changes in coagulation parameters |
| Seizure frequency/severity | Concomitant antiepileptic drug use | Monitor for possible changes in frequency or severity of convulsions |
| HIV RNA levels | Concomitant antiretroviral therapy in HIV-infected patients | Monitor frequently; discontinue orlistat if a confirmed increase in HIV viral load occurs |
| Cyclosporine levels | Concomitant cyclosporine use | Consider more frequent monitoring, given reduced cyclosporine plasma levels observed with concomitant orlistat |
IV Compatibility
Not applicable; orlistat is administered orally.
Overdosage
- Single doses of orlistat up to 800 mg, and multiple doses of up to 400 mg three times a day for 15 days, have been studied in normal-weight and obese subjects without significant adverse findings.
- Should a significant orlistat overdose occur, it is recommended that the patient be observed for 24 hours.
- Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible, consistent with orlistat's minimal systemic absorption and local mechanism of action in the gastrointestinal tract.[1]
- The OTC label instructs patients to obtain medical help or contact a Poison Control Center immediately in the event of overdose.[2]
Pharmacology
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.
Structure
- Orlistat is a gastrointestinal lipase inhibitor for weight management that acts by reducing the absorption of dietary fat.
- 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 C29H53NO5, and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm. The structure is:
- Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pKa within the physiological pH range.
- Prescription orlistat is supplied as a turquoise hard-gelatin capsule containing 120 mg. OTC alli is supplied as a turquoise capsule with a dark-blue band containing 60 mg. Inactive ingredients and package presentations are product-specific.[1][2]
Pharmacodynamics
Dose-response relationship[1]
The dose-response relationship for orlistat in human volunteers is shown in FIGURE 1. The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in FIGURE 1.
At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Ethanol does not affect orlistat's effect on preventing the absorption of fat.
Other short-term studies
- Adults
In several studies of up to 6-weeks duration, the effects of therapeutic doses of orlistat on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of orlistat in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of orlistat in these studies. In a 3-week study of 28 healthy male volunteers, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.
- Pediatrics
In a 3-week study of 32 obese adolescents aged 12 to 16 years, orlistat (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in orlistat and placebo treatment groups, respectively.
Pharmacokinetics
Absorption [1]
Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.
Distribution
In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.
Metabolism
Based on an oral 14C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 eliminated at a slower rate (half-life approximately 13.5 hours).
Elimination
Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 83% of that was found to be unchanged orlistat. The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg 14C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.
Specific Populations
No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility [1]
- Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material.
- Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.
- When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/m2) basis.
Clinical Studies
The long-term effects of orlistat on morbidity and mortality associated with obesity have not been established. Efficacy was assessed in seven long-term (1- to 2-year) multicenter, double-blind, placebo-controlled trials and in the 4-year XENDOS study, with orlistat and placebo both given alongside a reduced-calorie diet.[1]
Guideline context
- The 2022 American Gastroenterological Association (AGA) guideline suggests against orlistat for most adults with obesity or overweight and weight-related complications because its average additional weight loss is modest (approximately 3% of total body weight versus control) and gastrointestinal adverse effects limit tolerability. Across 12 randomized trials, discontinuation due to gastrointestinal adverse effects was more frequent with orlistat than control (RR 2.86, 95% CI 1.91–4.30).[8]
- This position is not universal: the 2025 AACE consensus statement continues to include orlistat among available anti-obesity medications and recommends kidney- and liver-function monitoring during therapy.[6] Treatment selection should account for expected efficacy, gastrointestinal tolerability, contraindications, interactions, cost and access, and patient preference.
One-Year Weight Management (Pooled Analysis, 5 Studies)
Summary: Across five 1-year, placebo-controlled trials, orlistat produced significantly higher rates of clinically meaningful weight loss than placebo in most individual studies.
| Study No. | Orlistat n | Placebo n | ≥5% Weight Loss (Orlistat) | ≥5% Weight Loss (Placebo) | p-value | ≥10% Weight Loss (Orlistat) | ≥10% Weight Loss (Placebo) | p-value |
|---|---|---|---|---|---|---|---|---|
| 14119B | 110 | 108 | 35.5% | 21.3% | 0.021 | 16.4% | 6.5% | 0.022 |
| 14119C | 343 | 340 | 54.8% | 27.4% | <0.001 | 24.8% | 8.2% | <0.001 |
| 14149 | 241 | 236 | 50.6% | 26.3% | <0.001 | 22.8% | 11.9% | 0.02 |
| 14161 | 210 | 212 | 37.1% | 16.0% | <0.001 | 19.5% | 3.8% | <0.001 |
| 14185 | 657 | 223 | 42.6% | 22.4% | <0.001 | 17.7% | 9.9% | 0.006 |
Additional detail: Pooled mean weight loss at 1 year was 13.4 lb with orlistat vs. 5.8 lb with placebo. 69% of orlistat-treated and 63% of placebo-treated patients completed 1 year of treatment. Improvements in LDL cholesterol, waist circumference, and other risk factors were generally greater with orlistat, particularly among patients with abnormal baseline values.
Weight Regain (3 Studies)
Summary: In patients who had already lost weight, continued orlistat treatment significantly reduced the amount of weight regained compared with placebo.
| Study No. | Prior Weight Loss Achieved Via | Weight Regained (Orlistat) | Weight Regained (Placebo) | p-value |
|---|---|---|---|---|
| 14119C | 1 year of prior orlistat + diet | 26% | 52% | <0.001 |
| 14185 | 1 year of prior orlistat + diet | 35% | 63% | <0.001 |
| 14302 | Diet alone (≥8% weight loss in prior 6 months) | 32% | 53% | <0.001 |
Two-Year Weight Management (Pooled Analysis, 4 Studies)
Summary: Weight-loss benefit with orlistat was generally sustained through year 2, though statistical significance for continued benefit varied by individual study.
| Study No. | Orlistat n | Placebo n | ≥5% Weight Loss (Orlistat) | ≥5% Weight Loss (Placebo) | p-value | ≥10% Weight Loss (Orlistat) | ≥10% Weight Loss (Placebo) | p-value |
|---|---|---|---|---|---|---|---|---|
| 14119C | 133 | 123 | 45.1% | 23.6% | <0.001 | 24.8% | 6.5% | <0.001 |
| 14149 | 178 | 158 | 43.3% | 27.2% | 0.002 | 18.0% | 9.5% | 0.025 |
| 14161 | 148 | 113 | 25.0% | 15.0% | 0.049 | 16.9% | 3.5% | 0.001 |
| 14185 | 147 | 122 | 34.0% | 27.9% | 0.279 (ns) | 17.7% | 11.5% | 0.154 (ns) |
Additional detail: 74% of orlistat-treated and 76% of placebo-treated patients completed 2 years of therapy across the pooled studies; the mean weight-loss difference between groups at year 2 was 3%.
Four-Year Results and Diabetes Prevention (XENDOS)
Summary: In the 4-year, 3,304-patient XENDOS study, orlistat produced greater sustained weight loss than placebo and delayed onset of type 2 diabetes, an effect concentrated in patients with impaired glucose tolerance at baseline.
| Baseline OGTT Status | Placebo n | Orlistat n | Diabetes Incidence (Placebo) | Diabetes Incidence (Orlistat) | p-value |
|---|---|---|---|---|---|
| Normal | 1148 | 1235 | 2.1% | 1.7% | 0.79 |
| Impaired | 324 | 337 | 27.2% | 18.7% | <0.01 |
| All patients | 1472 | 1572 | 8.3% | 5.5% | 0.01 |
Additional detail: The current prescription label reports mean percentage weight change at 4 years of -5.17% with orlistat versus -2.75% with placebo (p<0.001), and cumulative diabetes incidence of 5.5% versus 8.3%, respectively. In the published XENDOS report, the corresponding results were presented as mean weight loss of 5.8 kg versus 3.0 kg (p<0.001) and cumulative diabetes incidence of 6.2% versus 9.0% (37.3% relative risk reduction; p=0.0032).[9] These source-specific presentations should not be treated as contradictory. In the label analysis, 52% of orlistat-treated and 34% of placebo-treated patients completed the 4-year study. The diabetes-delaying effect was concentrated in patients with impaired glucose tolerance at baseline and was not demonstrated in those with normal baseline glucose tolerance.
Type 2 Diabetes Study (N=321)
Summary: In diabetic patients stabilized on sulfonylureas, orlistat improved weight loss and glycemic control compared with placebo over 1 year.
| Parameter | Orlistat 120 mg (n=162) | Placebo (n=159) | Statistical Significance |
|---|---|---|---|
| % discontinued sulfonylurea | 11.7% | 7.5% | Significant |
| % decreased sulfonylurea dose | 31.5% | 21.4% | — |
| Average reduction in sulfonylurea dose | -22.8% | -9.1% | Significant |
| Body weight change (lbs) | -8.9 | -4.2 | Significant |
| HbA1c | -0.18% | +0.28% | Significant |
| Fasting glucose (mmol/L) | -0.02 | +0.54 | Significant |
| Fasting insulin (pmol/L) | -19.68 | -18.02 | Not significant |
Additional detail: 30% of orlistat-treated patients achieved ≥5% weight loss vs. 13% on placebo (p<0.001). Orlistat was also associated with significant improvements in total cholesterol, LDL cholesterol, LDL/HDL ratio, and triglycerides compared with placebo.
Glucose Tolerance Studies
Summary: In patients stratified by baseline oral glucose tolerance test (OGTT) status, orlistat reduced progression to impaired/diabetic glucose tolerance and increased normalization rates among patients with baseline impaired glucose tolerance.
| Baseline OGTT Status | Outcome | Orlistat | Placebo |
|---|---|---|---|
| Normal (2-year) | Progressed to diabetic | 0.0% | 1.9% |
| Normal (2-year) | Progressed to impaired | 7.2% | 12.6% |
| Impaired (1-year) | Normalized | 73% | 45.8% |
| Impaired (1-year) | Progressed to diabetic | 2.6% | 10.4% |
| Impaired (2-year) | Normalized | 71.7% | 50% |
| Impaired (2-year) | Progressed to diabetic | 1.7% | 7.5% |
Pediatric Study (54-Week, N=539, Ages 12–16)
Summary: In obese adolescents, orlistat produced a significantly greater reduction in BMI and body weight than placebo.
| Endpoint | Orlistat n | Placebo n | Orlistat (%) | Placebo (%) |
|---|---|---|---|---|
| ≥5% decrease in BMI | 347 | 178 | 26.5% | 15.7% |
| ≥10% decrease in BMI | 347 | 178 | 13.3% | 4.5% |
| ≥5% decrease in body weight | 348 | 180 | 19.0% | 11.7% |
| ≥10% decrease in body weight | 348 | 180 | 9.5% | 3.3% |
Additional detail: Mean BMI change was -0.55 kg/m² with orlistat vs. +0.31 kg/m² with placebo (p=0.001). In a DEXA substudy, fat mass was reduced by -2.5 kg with orlistat vs. -0.6 kg with placebo (p=0.033), while other body composition measures were similar between groups.
How Supplied
Prescription orlistat (120 mg)
- The current H2-Pharma product is an NDA-authorized generic (NDA 020766). DailyMed specifically lists it as a turquoise, hard-gelatin, two-piece, No. 1 opaque capsule imprinted with "XENICAL 120" in black ink.
- Each capsule contains a pellet formulation of 120 mg orlistat, with inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc.
- The capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2, with black printing ink containing pharmaceutical grade shellac, propylene glycol, strong ammonium solution, potassium hydroxide, and black iron oxide.
- Available as bottles of 90 capsules: NDC 61269-565-90. The XENICAL imprint and this H2-Pharma NDC appear together in the current authorized-generic labeling and are not a labeler mismatch.[1]
Nonprescription alli (60 mg)
- OTC alli is supplied as a turquoise capsule with a dark-blue band and an imprint identifying orlistat 60 mg.
- Current DailyMed-listed bottle presentations include 60, 120, and 170 capsules; package availability can vary.[2]
Storage
Prescription orlistat
- Store at 25°C (77°F); excursions are permitted to 15°C–30°C (59°F–86°F).
- Keep bottle tightly closed.
- Do not use orlistat after the expiration date printed on the bottle.[1]
Nonprescription alli
- Store at 20°C–25°C (68°F–77°F) and protect from excessive light, humidity, and temperatures above 30°C (86°F).[2]
Images
Drug Images
Package and Label Display Panel
- Prescription orlistat 120 mg labeling and package information
- OTC alli 60 mg Drug Facts and package information
Patient Counseling Information
What is orlistat?
- Prescription orlistat 120 mg is used with a reduced-calorie diet for obesity management, including weight loss, weight maintenance, and reduction of the risk for weight regain after prior weight loss. Safety and effectiveness in children under 12 years old have not been established.[1]
- OTC alli 60 mg is a weight-loss aid for overweight adults aged ≥18 years when used with a reduced-calorie, low-fat diet.[2]
Who should not take orlistat?
- Prescription orlistat is contraindicated in pregnancy, chronic malabsorption syndrome, cholestasis, or hypersensitivity to orlistat or any product component.
- OTC alli should not be used after an organ transplant, while taking cyclosporine, with a diagnosed food-absorption disorder, when not overweight, during pregnancy or breastfeeding, or with allergy to any ingredient.
What should patients tell their doctor before taking orlistat?
- Tell your doctor about all medical conditions, including liver problems, kidney problems, thyroid problems, eating disorders (anorexia or bulimia), diabetes, seizure disorder (epilepsy), abnormal heart rhythm (arrhythmia), HIV, and whether you are breastfeeding, pregnant, or planning to become pregnant.
- Tell your doctor about all medicines, vitamins, and herbal supplements you take, especially cyclosporine (Gengraf, Neoral, Sandimmune, Restasis, Sangcya), beta-carotene or vitamin E supplements, levothyroxine (Levo-T, Levolet, Levothyroid, Levoxyl, Novothyrox, Synthroid, Tirosint, Unithroid), warfarin (Coumadin, Jantoven, Panwarfin), amiodarone (Cordarone, Pacerone), antiepileptic drugs, and antiretroviral drugs, due to potential interactions.
How should patients take orlistat?
- Prescription: take 120 mg with each main meal containing fat, during the meal or up to 1 hour afterward, up to three times daily.
- Nonprescription: adults aged ≥18 years should take one 60 mg capsule with each meal containing fat, not to exceed three capsules daily.
- Skip the dose if a meal is missed or contains no fat.
- Prescription users should not take cyclosporine simultaneously with orlistat. Separate them by at least 3 hours; the Dosage and Administration section specifically directs cyclosporine 3 hours after orlistat. Separate multivitamins by at least 2 hours and levothyroxine by at least 4 hours. OTC users should not use alli while taking cyclosporine and should take a multivitamin at bedtime.
- Follow a nutritionally balanced, low-calorie diet with no more than about 30% of calories from fat; a high-fat meal may worsen common side effects.
- If too much orlistat is taken, call a doctor or go to the nearest emergency room right away.
What are the possible risks and benefits of orlistat?
- Lowered absorption of fat-soluble vitamins — take a daily multivitamin (A, D, E, K, beta-carotene) at least 2 hours before or after orlistat.
- Severe liver injury — stop orlistat and call a doctor right away for loss of appetite, itchy skin, yellowing of skin/eyes, amber-colored urine, light-colored stools, or upper right stomach pain.
- Kidney problems (increased urinary oxalate) — call a doctor right away for swelling, little or no urine output, frequent or painful urination, blood in urine, loss of appetite, nausea/vomiting, or severe back/belly/groin pain.
- Gallbladder problems (cholelithiasis) — call a doctor right away for upper right stomach pain, nausea, or vomiting.
- Treatment with orlistat may result in weight loss and improvement in obesity-related risk factors due to weight loss.
What are the most common side effects?
- Oily rectal discharge, passing gas with oily discharge, urgent need for a bowel movement, oily/fatty stools, increased bowel movements, and inability to control bowel movements.
- These are not all possible side effects; report side effects to a doctor or to FDA at 1-800-FDA-1088.
How should orlistat be stored?
- Store prescription orlistat at 59°F to 86°F (15°C to 30°C) in a tightly closed container.
- Store OTC alli at 68°F to 77°F (20°C to 25°C) and protect it from excessive light, humidity, and temperatures above 86°F (30°C).
- Keep all medicines out of reach of children and do not use them after the expiration date.
General information
- Do not use orlistat for a condition for which it is not indicated, and do not give it to others even if they have similar symptoms.
- This summary covers the most important information; consult a doctor or pharmacist for information written for health professionals.
Ingredients
- Active ingredient: orlistat.
- Inactive ingredients and capsule markings are product-specific; patients should consult the current package label for their formulation.[1][2]
Precautions with Alcohol
In a multiple-dose study in 30 normal-weight subjects, coadministration of orlistat and 40 grams of alcohol (approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.[1]
Brand Names
- Xenical
- alli
Look-Alike Drug Names
- Xenical (orlistat) / Xeloda (capecitabine)
- Orlistat (Xenical) is an oral anti-obesity agent, whereas capecitabine (Xeloda) is an oral antineoplastic agent.[10]
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 1.39 1.40 1.41 1.42 1.43 1.44 H2-Pharma LLC (January 9, 2026). "ORLISTAT capsules for oral use: U.S. prescribing information". DailyMed, U.S. National Library of Medicine. Retrieved July 30, 2026.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 Haleon US Holdings LLC (March 18, 2026). "ALLI (orlistat 60 mg) Drug Facts label". DailyMed, U.S. National Library of Medicine. Retrieved July 30, 2026.
- ↑ 3.0 3.1 Teede HJ, Tay CT, Laven J, Dokras A, Moran LJ, Piltonen TT, et al. (October 2023). "Recommendations From the 2023 International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome". The Journal of Clinical Endocrinology & Metabolism. 108 (10): 2447–2469. doi:10.1210/clinem/dgad463. PMID 37580314 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ Goldberg A, Graca S, Liu J, Rao V, Witchel SF, Pena A, et al. (May 2024). "Anti-obesity pharmacological agents for polycystic ovary syndrome: a systematic review and meta-analysis to inform the 2023 international evidence-based guideline". Obesity Reviews. 25 (5): e13704. doi:10.1111/obr.13704. PMID 38355887 Check
|pmid=value (help). - ↑ "FDA Approves Labeling Changes for Over-the-Counter (OTC) Weight Loss Drug alli (Orlistat) to Warn of Risk of Kidney Stones and Kidney Injury". U.S. Food and Drug Administration. June 10, 2026. Retrieved July 30, 2026.
- ↑ 6.0 6.1 Nadolsky K, Garvey WT, Agarwal M, Bonnecaze A, Burguera B, Chaplin M, et al. (November 2025). "American Association of Clinical Endocrinology Consensus Statement: Algorithm for the Evaluation and Treatment of Adults With Obesity/Adiposity-Based Chronic Disease—2025 Update". Endocrine Practice. 31 (11): 1351–1394. doi:10.1016/j.eprac.2025.07.017. PMID 40956256 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ Zhi J, Melia AT, Eggers H, Joly R, Patel IH (November 1995). "Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers". Journal of Clinical Pharmacology. 35 (11): 1103–1108. doi:10.1002/j.1552-4604.1995.tb04034.x. PMID 8626884.
- ↑ Grunvald E, Shah R, Hernaez R, Chandar AK, Pickett-Blakely O, Teigen LM, et al. (November 2022). "AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity". Gastroenterology. 163 (5): 1198–1225. doi:10.1053/j.gastro.2022.08.045. PMID 36273831 Check
|pmid=value (help). - ↑ Torgerson JS, Hauptman J, Boldrin MN, Sjöström L (January 2004). "XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients". Diabetes Care. 27 (1): 155–161. doi:10.2337/diacare.27.1.155. PMID 14693982.
- ↑ "ISMP List of Confused Drug Names" (PDF). Institute for Safe Medication Practices. 2023. Retrieved July 30, 2026.