Orlistat is a weight-loss drug that works inside the gut rather than in the brain or the bloodstream. It blocks the enzymes that digest dietary fat, so about 30% of the fat in a meal passes through undigested (at the 120 mg dose) instead of being absorbed. It is sold as the prescription capsule Xenical (120 mg) and as the over-the-counter capsule Alli (60 mg).
Orlistat is one of the oldest approved obesity drugs: FDA approved Xenical in 1999 and Alli in 2007 (Drugs@FDA: Xenical; Drugs@FDA: Alli). Its weight effect is modest, about 3 kg more than diet alone after one year in pooled trials. Its main drawbacks are oily, urgent bowel movements and reduced absorption of fat-soluble vitamins. Rare cases of severe liver injury have been reported after approval.
This page summarizes what the FDA labels, the clinical trials and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Gastrointestinal lipase inhibitor (acts in the gut, not systemically) |
| US brands and approval | Xenical 120 mg, prescription (NDA 020766, approved April 23, 1999); Alli 60 mg, over the counter (NDA 021887, approved February 7, 2007) |
| Route | Oral capsule |
| Labeled dose | Xenical: 120 mg three times daily with each main meal containing fat. Alli: 60 mg with each meal containing fat, no more than 3 capsules a day |
| Main effect | At 120 mg three times daily, blocks absorption of ≈30% of dietary fat |
| Systemic absorption | Minimal; intact orlistat in plasma near the detection limit (under 5 ng/mL) |
| Half-life | 1–2 h for the small absorbed fraction (label, based on limited data) |
| EU status | Xenical authorized 1998 (prescription); Alli authorized 2007 (non-prescription, BMI ≥28 kg/m²) |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Orlistat is a semi-synthetic molecule with the formula C₂₉H₅₃NO₅ and a molecular weight of 495.7 (Xenical label). It is also called tetrahydrolipstatin (PubChem). Its parent compound, lipstatin, was isolated at Roche from the soil bacterium Streptomyces toxytricini and described in 1987 as a very potent inhibitor of pancreatic lipase, the key enzyme of intestinal fat digestion (Weibel et al., J Antibiot 1987).
The working part of the molecule is a β-lactone ring (a strained four-atom ring). According to the label, orlistat forms a covalent bond with the active serine site of gastric and pancreatic lipases in the stomach and small intestine. The inactivated enzymes can no longer split dietary triglycerides into free fatty acids and monoglycerides, which are the forms the gut can absorb. Undigested triglycerides pass out in the stool, creating a calorie deficit.
The two US products contain the same drug at different strengths:
| Product | Strength | Status | Labeled use |
|---|---|---|---|
| Xenical | 120 mg capsule | Prescription | Obesity management (BMI ≥30 kg/m², or ≥27 kg/m² with risk factors such as hypertension, diabetes or dyslipidemia), plus reducing weight regain after prior loss; ages 12 and up |
| Alli | 60 mg capsule | Over the counter | Weight loss in overweight adults 18 and older, with a reduced-calorie, low-fat diet |
Sources: Xenical label; Alli Drug Facts.
How it works in the body
Because orlistat acts inside the gut, very little reaches the blood. From the Xenical label:
| Parameter | Label finding |
|---|---|
| Absorption | Minimal. After a 360 mg radiolabeled dose, intact orlistat in plasma was near the detection limit (under 5 ng/mL). In treatment studies, plasma levels were sporadic and low (under 10 ng/mL), with no accumulation |
| Protein binding | Over 99% in vitro (mainly lipoproteins and albumin) |
| Metabolites | M1 and M3, which have 1,000- and 2,500-fold weaker lipase inhibition and are considered pharmacologically inconsequential. Half-lives ≈3 h (M1) and ≈13.5 h (M3) |
| Elimination | ≈97% of the dose recovered in feces, 83% of that as unchanged orlistat; under 2% in urine; complete excretion in 3–5 days |
| Half-life of absorbed drug | 1–2 h (limited data) |
| Onset and offset | Effect on fecal fat seen within 24–48 h of dosing; fecal fat returns to pretreatment levels within 48–72 h after stopping |
| Dose–response | ≈30% of dietary fat blocked at 120 mg three times daily; doses above this showed no additional benefit |
The drug only works when fat is present in the gut. The label says a dose can be skipped if a meal is missed or contains no fat. In a 3-week study of 28 healthy men, Xenical 120 mg three times daily did not significantly change the balance of calcium, magnesium, phosphorus, zinc, copper or iron.
Approved medical use
Xenical (prescription). FDA approved it for obesity management, including weight loss and weight maintenance, together with a reduced-calorie diet, and to reduce the risk of weight regain after prior weight loss. The labeled dose is one 120 mg capsule three times a day with each main meal containing fat, taken during or up to 1 hour after the meal. The label calls for a nutritionally balanced, reduced-calorie diet with about 30% of calories from fat, spread across three main meals (Xenical label).
Alli (over the counter). The Drug Facts label allows one 60 mg capsule with each meal containing fat, up to 3 capsules daily, for overweight adults 18 and older on a reduced-calorie, low-fat diet. It states that most weight loss occurs in the first 6 months (Alli Drug Facts).
European Union. Xenical has been authorized as a prescription medicine since July 29, 1998 (EMA, Xenical). Alli has been authorized without prescription since July 22, 2007, for overweight adults with a BMI of 28 kg/m² or more. In the EU it is also available as a 27 mg chewable tablet, and EMA states it should not be taken for more than six months (EMA, Alli).
Both labels advise a daily multivitamin taken at bedtime or at least 2 hours apart from orlistat (see vitamin absorption below).
Anti-doping. Orlistat is not named on the current list of substances banned in sport (WADA 2026 Prohibited List).
What the research shows
One- and two-year weight loss with 120 mg
The Xenical label pools seven double-blind, placebo-controlled trials of 1–2 years with over 2,800 patients on Xenical and 1,400 on placebo, all on a reduced-calorie diet. In five trials, mean weight loss after 1 year was 13.4 lb (≈6.1 kg) on Xenical versus 5.8 lb (≈2.6 kg) on placebo, a difference of about 3% of body weight. Among patients who completed the year, 57% on Xenical and 31% on placebo lost at least 5% of their starting weight (Xenical label).
In three trials that tested weight regain after an initial weight loss, Xenical reduced the share of lost weight that came back:
| Study | Weight regained on placebo | Weight regained on Xenical |
|---|---|---|
| 14119C | 52% | 26% |
| 14185 | 63% | 35% |
| 14302 | 53% | 32% |
All three differences had p under 0.001. Pooled one-year data also showed small relative improvements in LDL cholesterol (−4.0% vs +5.0% on placebo) and waist circumference (−6.45 cm vs −4.04 cm).
XENDOS: four years and diabetes prevention
XENDOS (XENical in the prevention of Diabetes in Obese Subjects) is the longest orlistat trial. It randomized 3,305 adults with a BMI of 30 kg/m² or more to lifestyle changes plus orlistat 120 mg or placebo three times daily for 4 years (Torgerson et al., Diabetes Care 2004). Only 52% of the orlistat group and 34% of the placebo group completed treatment.
| Outcome at 4 years | Orlistat | Placebo |
|---|---|---|
| Mean weight loss (published paper) | 5.8 kg | 3.0 kg |
| Mean weight change (label, ITT LOCF) | −5.17% | −2.75% |
| Lost ≥5% of body weight (label) | 45% | 28% |
| Lost ≥10% of body weight (label) | 21% | 10% |
| Cumulative diabetes incidence (published paper) | 6.2% | 9.0% |
| Cholelithiasis (gallstones) as an adverse event (label) | 2.9% | 1.8% |
The paper reported a 37.3% relative reduction in diabetes risk (p = 0.0032). The label’s analysis of the same trial, limited to patients with follow-up glucose tests, gives 5.5% vs 8.3% (34% relative reduction, p = 0.01). Both sources say the benefit was confined to people who started with impaired glucose tolerance (a prediabetic state): in that subgroup the label’s life-table rates were 18.7% vs 27.2%. Orlistat did not reduce diabetes risk in people with normal glucose tolerance. The label attributes the effect to weight loss rather than any direct action of the drug on glucose or insulin.
The 60 mg dose (Alli strength)
Two placebo-controlled trials tested 60 mg three times daily:
| Trial | Design | Result |
|---|---|---|
| Hauptman et al., Arch Fam Med 2000 | 2 years, 17 US primary care centers, n = 796 obese adults (BMI 30–44); placebo vs 60 mg vs 120 mg | Year 1 weight loss: 4.14 kg (placebo), 7.08 kg (60 mg), 7.94 kg (120 mg). Lost ≥5%: 30.7%, 48.8%, 50.5% |
| Anderson et al., Ann Pharmacother 2006 | 16 weeks, 20 US centers, n = 391 mildly to moderately overweight adults | Weight loss 3.05 kg vs 1.90 kg on placebo (p under 0.001); completers lost 4.8% vs 3.1% of baseline weight |
In the 2-year trial, the 60 mg dose gave most of the effect of 120 mg. The Alli label summarizes this as 2–3 extra pounds lost for every 5 pounds lost by diet alone.
How it compares with other obesity drugs
Meta-analyses consistently place orlistat at the low end for weight loss:
- 2007 meta-analysis of 16 orlistat trials (n = 10,631) lasting 1–4 years: 2.9 kg more weight loss than placebo (95% CI 2.5–3.2 kg). Orlistat lowered diabetes incidence and total and LDL cholesterol, but increased GI side effects and slightly lowered HDL (Rucker et al., BMJ 2007).
- 2016 network meta-analysis of 28 trials (n = 29,018) at 1 year: 2.6 kg excess weight loss with orlistat (95% credible interval 2.16–3.04 kg) versus 5.3 kg with liraglutide and 8.8 kg with phentermine-topiramate. At least 5% weight loss was reached by 44% on orlistat versus a median 23% on placebo. Attrition was 30–45% across trials (Khera et al., JAMA 2016).
- 2024 network meta-analysis (republished after a 2022 retraction) of 132 trials (n = 48,209): orlistat raised the odds of stopping treatment because of adverse events (OR 1.71, 95% CI 1.42–2.05). In a post-hoc analysis, semaglutide produced an 11.40-point larger percentage weight loss than lifestyle change alone (Shi et al., Lancet 2024).
Tirzepatide was approved after the search period of these analyses, so it is not included in them. The Xenical label states that the long-term effects of orlistat on obesity-related morbidity and mortality have not been established.
Side effects and risks
Gastrointestinal effects
GI effects are the most common adverse reactions and follow directly from the mechanism: unabsorbed fat ends up in the stool. Rates from the seven placebo-controlled trials in the Xenical label:
| Adverse event | Xenical, year 1 (n = 1,913) | Placebo, year 1 (n = 1,466) | Xenical, year 2 (n = 613) | Placebo, year 2 (n = 524) |
|---|---|---|---|---|
| Oily spotting | 26.6% | 1.3% | 4.4% | 0.2% |
| Flatus with discharge | 23.9% | 1.4% | 2.1% | 0.2% |
| Fecal urgency | 22.1% | 6.7% | 2.8% | 1.7% |
| Fatty/oily stool | 20.0% | 2.9% | 5.5% | 0.6% |
| Oily evacuation | 11.9% | 0.8% | 2.3% | 0.2% |
| Increased defecation | 10.8% | 4.1% | 2.6% | 0.8% |
| Fecal incontinence | 7.7% | 0.9% | 1.8% | 0.2% |
These effects usually started in the first 3 months. About half of episodes lasted less than a week, and most lasted no more than 4 weeks, though some people had them for 6 months or longer. The label says GI events increase when orlistat is taken with a diet over 30% fat or with a single very high-fat meal. In controlled trials, 8.8% of Xenical patients stopped treatment because of adverse events versus 5.0% on placebo, mostly for GI reasons.
Fat-soluble vitamins
Orlistat reduces absorption of some fat-soluble vitamins and beta-carotene. In a pharmacokinetic study, it cut absorption of a beta-carotene supplement by 30% and of a vitamin E acetate supplement by about 60%. Its effect on supplemental vitamins A and D and on dietary vitamin K is not known (Xenical label).
In adults who were not taking vitamin supplements and had normal baseline levels, low values on two or more consecutive visits over 1–2 years were more common on Xenical:
| Vitamin | Placebo | Xenical |
|---|---|---|
| Vitamin A | 1.0% | 2.2% |
| Vitamin D | 6.6% | 12.0% |
| Vitamin E | 1.0% | 5.8% |
| Beta-carotene | 1.7% | 6.1% |
The label therefore advises a daily multivitamin containing vitamins A, D, E and K and beta-carotene, taken at least 2 hours before or after orlistat, for example at bedtime. In the adolescent trial, where all patients took supplements, low values were rare (vitamin D 1.4% vs 0.7%).
Liver injury
The Xenical label warns of rare postmarketing reports of severe liver injury with hepatocellular necrosis (liver cell death) or acute liver failure, some ending in liver transplant or death. It tells patients to report signs of liver trouble (loss of appetite, itching, jaundice, dark urine, pale stools, or pain in the upper right abdomen). If these occur, the label says orlistat and other suspect drugs should be stopped and liver tests (ALT and AST) checked. The Alli Drug Facts label carries a similar warning.
Whether orlistat causes liver injury is uncertain. A UK self-controlled case series of 94,695 orlistat users found 988 cases of acute liver injury (Douglas et al., BMJ 2013). The rate was higher in the 90 days before starting orlistat (incidence rate ratio 1.50) and the first 30 days of treatment (2.21) than at other times. However, the first 90 days on the drug did not differ from the 90 days just before it (1.02, 95% CI 0.67–1.56). The authors concluded that the raised risk around the start of treatment probably reflects the patients’ health at that time rather than a causal effect of the drug.
Kidney stones and kidney injury
Orlistat can increase urinary oxalate. Cases of oxalate kidney stones and oxalate nephropathy (kidney damage from oxalate crystals) with renal failure have been reported. The label calls for kidney monitoring in people with kidney impairment, a history of high urinary oxalate or calcium oxalate stones, and for stopping the drug if oxalate nephropathy develops. The Alli label lists kidney disease or kidney stones as a reason to ask a doctor before use.
Other risks
- Gallstones. Substantial weight loss can raise the risk of gallstones (2.9% vs 1.8% in XENDOS).
- Hypersensitivity. Rare reports of itching, rash, hives, angioedema, bronchospasm and anaphylaxis; very rare blistering rashes and leukocytoclastic vasculitis (inflammation of small blood vessels).
- Pancreatitis and lower GI bleeding have been reported after approval. The label notes no causal link to pancreatitis has been established, and most bleeding reports were not serious.
- Low blood sugar in diabetes. Weight loss may improve glucose control, so doses of sulfonylureas or insulin may need to be reduced.
Drug interactions
Orlistat can reduce the absorption of other drugs taken with it. From the Xenical label:
| Drug | Interaction | Label instruction |
|---|---|---|
| Cyclosporine | Taken together: cyclosporine AUC −31%, peak −25%. Taken 3 h after orlistat: AUC −17% | Do not take at the same time; give cyclosporine at least 3 h after orlistat and consider more frequent level checks |
| Levothyroxine | Hypothyroidism reported after approval | Separate doses by at least 4 h; monitor thyroid function |
| Warfarin and other anticoagulants | Vitamin K absorption may fall; reports of changed INR | Monitor coagulation closely |
| Amiodarone | Exposure to amiodarone and its metabolite fell 23–27% | Reduced effect possible |
| Antiepileptic drugs | Convulsions reported | Monitor seizure frequency and severity |
| Antiretrovirals (e.g., atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, efavirenz combinations) | Loss of HIV viral control reported | Monitor HIV RNA; stop orlistat if viral load rises |
Label studies found no clinically relevant interaction with alcohol, digoxin, glyburide, extended-release nifedipine, phenytoin, pravastatin or oral contraceptives (no change in ovulation suppression in 20 women). The Alli label tells people who have had an organ transplant or take cyclosporine not to use it.
Who should not use it
Xenical is contraindicated in pregnancy, chronic malabsorption syndrome, cholestasis (reduced bile flow) and known hypersensitivity to the product. The label also says organic causes of obesity, such as hypothyroidism, should be ruled out first. Alli should not be used by people who are not overweight, are pregnant or breastfeeding, or have problems absorbing food. Safety and effectiveness below age 12 have not been established.
Key takeaways
- A fat blocker, not an appetite drug. Orlistat inactivates gut lipases so ≈30% of dietary fat is not absorbed; almost none of the drug reaches the bloodstream.
- Two strengths of the same drug. Xenical 120 mg is prescription only; Alli 60 mg is sold over the counter in the US and EU.
- Modest weight loss. Pooled trials show about 3 kg more than placebo at 1 year. In the 4-year XENDOS trial, the difference was 5.8 vs 3.0 kg, and diabetes risk fell only in people with prediabetes.
- GI effects are common and diet dependent. Oily spotting, urgency and fecal incontinence affected up to about a quarter of users in year 1 and rise with high-fat meals.
- Vitamins and drug absorption. Orlistat lowers absorption of vitamins A, D, E and beta-carotene and can interfere with cyclosporine, levothyroxine, warfarin, antiepileptics and HIV drugs.
- Rare serious events. Labels warn of rare severe liver injury and oxalate kidney damage, although a large UK study did not find clear evidence that orlistat causes liver injury.
Sources
- H2-Pharma LLC. Xenical (orlistat) capsules prescribing information. Revised 11/2022; DailyMed version January 2026. DailyMed.
- Haleon US Holdings LLC. Alli (orlistat 60 mg) capsules Drug Facts label. DailyMed version March 2026. DailyMed.
- U.S. Food and Drug Administration. Drugs@FDA: Xenical, NDA 020766. FDA.
- U.S. Food and Drug Administration. Drugs@FDA: Alli, NDA 021887. FDA.
- European Medicines Agency. Xenical: EPAR. EMA.
- European Medicines Agency. Alli (previously Orlistat GSK): EPAR. EMA.
- National Center for Biotechnology Information. PubChem Compound Summary for CID 3034010, Orlistat. PubChem.
- Weibel EK, Hadvary P, Hochuli E, et al. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J Antibiot (Tokyo). 1987;40(8):1081–1085. PubMed.
- Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. 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. 2004;27(1):155–161. PubMed.
- 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(2):160–167. PubMed.
- 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(10):1717–1723. PubMed.
- Rucker D, Padwal R, Li SK, et al. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ. 2007;335(7631):1194–1199. PubMed.
- Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315(22):2424–2434. PubMed.
- Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet. 2024;403(10434):e21–e31. PubMed.
- Douglas IJ, Langham J, Bhaskaran K, et al. Orlistat and the risk of acute liver injury: self controlled case series study in UK Clinical Practice Research Datalink. BMJ. 2013;346:f1936. PubMed.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.