Orlistat, sold under the brand name Xenical among others, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

used to treat

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

. Its primary function is preventing the absorption of fats from the human diet by acting as a lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet. Orlistat is the saturated derivative of lipstatin, a potent

natural Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans ar ...

inhibitor of pancreatic lipases isolated from the

bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

'' Streptomyces toxytricini''. However, due to its relative simplicity and stability, orlistat was chosen over lipstatin for development as an anti-obesity drug. The effectiveness of orlistat in promoting weight loss is definite but modest. Pooled data from

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about more than those not taking the drug over the course of a year. Orlistat also modestly reduces

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...

and appears to prevent the onset of type 2 diabetes, whether from the weight loss itself or other effects. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do. Benefits aside, however, orlistat is noted for its gastrointestinal

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequenc ...

(sometimes referred to as ''treatment effects''), which can include

steatorrhea Steatorrhea (or steatorrhoea) is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may o ...

(oily, loose stools). They decrease with time, however, and are the most frequently reported adverse effects of the drug. In Australia, the United States and the European Union, orlistat is available for sale without a prescription. Over-the-counter approval was controversial in the United States, with consumer advocacy group

Public Citizen Public Citizen is a non-profit, progressive consumer rights advocacy group and think tank based in Washington, D.C., United States, with a branch in Austin, Texas. Lobbying efforts Public Citizen advocates before all three branches of the Unit ...

repeatedly opposing it on safety and efficacy grounds.

Generic Generic or generics may refer to: In business * Generic term, a common name used for a range or class of similar things not protected by trademark * Generic brand, a brand for a product that does not have an associated brand or trademark, other ...

formulations of orlistat are available in some countries. In Australia it has been listed as an S3 medication, available from a pharmacist without a prescription, since 2000.

Medical uses

Orlistat is used for the treatment of

. The amount of weight loss achieved with orlistat varies. In one-year

s, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body fat. After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do. Long-term use of orlistat also leads to a very modest reduction in

(mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively).

Contraindications

Orlistat is contraindicated in: * Malabsorption * Hypersensitivity to orlistat * Reduced gallbladder function (e.g. after cholecystectomy) *

Pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

and

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

* Anorexia and Bulimia * Use caution with: obstructed

bile duct A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. ...

, impaired liver function, and

pancreatic disease Pancreatic diseases are diseases that affect the pancreas, an organ in most vertebrates and in humans and other mammals located in the abdomen. The pancreas plays a role in the digestive and endocrine system, producing enzymes which aid the digesti ...

Side effects

The primary

of the drug are gastrointestinal-related, and include

(oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements. To minimize these effects, foods with high fat content should be avoided; the manufacturer advises consumers to follow a low-fat, reduced-calorie diet. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 grams per meal. The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects. Side effects are most severe when beginning therapy and may decrease in frequency with time; It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with a low-fat diet. On 26 May 2010, the U.S. Food and Drug Administration (FDA) approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication. An analysis of over 900 orlistat users in Ontario showed that their rate of acute kidney injury was more than triple that of non-users. A study from 2013 looked at 94,695 participants receiving orlistat in the UK between 1999 and 2011. The study showed no evidence of an increased risk of liver injury during treatment. They concluded:

Long-term

Despite a higher incidence of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat—a two-year study published in 1999 found similar rates between orlistat and placebo (0.54% versus 0.51%), and evidence that tumors predated treatment in 3 of the 4 participants who had them. There is evidence from an ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...

'' study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and the monoclonal antibody

trastuzumab Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wi ...

, can induce cell death in breast cancer cells and block their growth. Fecal fat excretion promotes colon carcinogenesis. In 2006 the results of 30-day study were published indicating that orlistat at a dosage of 200 mg/kg chow administered to rats consuming a high-fat chow and receiving two 25 mg/kg doses of the potent carcinogen 1,2-dimethylhydrazine produced significantly higher numbers of aberrant crypt foci (ACF) colon lesions than did the carcinogen plus high-fat chow without orlistat. ACF lesions are believed to be one of the earliest precursors of

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowe ...

Precautions

Absorption of

fat-soluble Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves li ...

vitamins and other fat-soluble nutrients is inhibited by the use of orlistat.

Interactions

Orlistat may reduce plasma levels of ciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), an immunosuppressive drug frequently used to prevent

transplant rejection Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient ...

; the two drugs should therefore not be administered concomitantly. Orlistat can also impair absorption of the antiarrhythmic amiodarone. The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested the possibility that orlistat could reduce the absorption of antiretroviral HIV medications.

Mechanism of action

Orlistat works by inhibiting gastric and pancreatic lipases, the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s that break down triglycerides in the

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...

. When lipase activity is blocked, triglycerides from the diet are not

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

into absorbable free

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

s, and instead are excreted unchanged. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the

GI tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...

after an oral dose. The primary route of elimination is through the

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...

. Orlistat was also found to inhibit the thioesterase domain of fatty acid synthase (FAS), an enzyme involved in the proliferation of cancer cells but not normal cells. However, potential side effects of orlistat, such as inhibition of other cellular off-targets or poor bioavailability, might hamper its application as an effective antitumor agent. One profiling study undertook a chemical proteomics approach to look for new cellular targets of orlistat, including its off-targets. Orlistat also shows potential activity against the '' Trypanosoma brucei'' parasite. Orlistat prevents approximately 30% of dietary fat from being absorbed.

Legal status

Orlistat is available both with and without a prescription.

Australia and New Zealand

In Australia and New Zealand, orlistat is available as a " Pharmacist Only Medicine. In 2007, the Committee decided to keep orlistat as a Schedule 3 drug, but withdrew its authorization of direct-to-consumer Xenical advertising, stating this "increased pressure on pharmacists to provide orlistat to consumers...this in turn had the potential to result in inappropriate patterns of use".

United States

On 23 January 2006, a U.S. Food and Drug Administration advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be sold under the brand name Alli by GlaxoSmithKline. Approval was granted on 7 February 2007, and Alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use. Consumer advocacy organization

opposed over-the-counter approval for orlistat. Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.

European Union and Switzerland

On 21 January 2009, the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

granted approval for the sale of orlistat without a prescription. At least since September 2017, tablets with 60 mg orlistat can be freely sold in Swiss drugstores. Formulations with 120 mg per tablet require a prescription, but can be sold without one in pharmacies under an exemption rule, which is based on a list of easily diagnosable diseases.

Generic formulations

U.S. patent protection for Xenical, originally to end on 18 June 2004, was extended by five years (until 2009) by the U.S. Patent and Trademark Office. The extension was granted on 20 July 2002, and expired on 18 June 2009. Generic orlistat is available in Iran under the brand Venustat manufactured by Aburaihan Pharmaceutical co., in India, under the brands Orlean (Eris), Vyfat, Olistat, Obelit, Orlica and Reeshape. In Russia, orlistat is available under the brand names Xenical (

Hoffmann–La Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

), Orsoten/Orsoten Slim ( KRKA d. d.) and Xenalten (OBL-Pharm). In Austria, orlistat is available under the brand name Slimox. In Malaysia, orlistat is available under the brand name Cuvarlix and is marketed by Pharmaniaga. In the Philippines orlistat is available under the brand name RedoXfat Plus manufactured by ATC Healthcare

Society and culture

Cost

At times, such as in spring 2012, orlistat has come into short supply, with consequent price increases because of nonavailability of one of the drug's components.

Counterfeit products

In January 2010, the U.S. Food and Drug Administration issued an alert stating that some counterfeit versions of Alli sold over the Internet contain no orlistat, and instead contain the weight-loss drug sibutramine. The concentration of sibutramine in these counterfeit products is at least twice the amount recommended for weight loss.

References

External links

* {{Portal bar , Medicine Aldehydes Antiobesity drugs Carboxylate esters Lipase inhibitors Hoffmann-La Roche brands GSK plc brands Lactones Formamides