Orlistat

Packaging of orlistat (Xenical) 120 mg capsules, as sold in Canada.
Systematic (IUPAC) name
(S)-((S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate
Clinical data
Trade names	Xenical, Alli
AHFS/Drugs.com	monograph
MedlinePlus	a601244
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B1 (AU) B (US)
Legal status	Pharmacist Only (S3) (AU) P (UK) OTC (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	Negligible[1]
Protein binding	>99%
Metabolism	In the GI tract
Half-life	1 to 2 hours
Excretion	Fecal
Identifiers
CAS number	96829-58-2 Y
ATC code	A08AB01
PubChem	CID 3034010
DrugBank	DB01083
ChemSpider	2298564 Y
UNII	95M8R751W8 N
KEGG	D04028 Y
ChEMBL	CHEMBL175247 Y
Chemical data
Formula	C29H53NO5
Mol. mass	495.735 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C29H53NO5/c1-5-7-9-11-12-13-14-15-16-18-24(34-29(33)26(30-22-31)20-23(3)4)21-27-25(28(32)35-27)19-17-10-8-6-2/h22-27H,5-21H2,1-4H3,(H,30,31)/t24-,25-,26-,27-/m0/s1 Y Key:AHLBNYSZXLDEJQ-FWEHEUNISA-N Y
N (what is this?)  (verify)

Orlistat (marketed as a prescription under the trade name Xenical by Roche in most countries, or over-the-counter as Alli^[2] by GlaxoSmithKline in the United Kingdom and the United States), also known as tetrahydrolipstatin, is a drug designed to treat obesity.^[3] Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physician-supervised reduced-calorie diet. Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini.^[4] However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.^[5]

The effectiveness of orlistat in promoting weight loss is definite, though modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 2–3 kilograms (4.4–6.6 lb) more than those not taking the drug over the course of a year.^[6] Orlistat also modestly reduces blood pressure, and appears to prevent the onset of type 2 diabetes, whether due to weight loss itself or to other effects; in a large randomized controlled trial, orlistat was found to reduce the incidence of diabetes by nearly 40% in obese people.^[7]

Orlistat is notorious for its gastrointestinal side effects (sometimes referred to as treatment effects), which can include steatorrhea (oily, loose stools). These decrease with time, however, and are the most frequently reported adverse effects of the drug^{[citation needed]}.^[8] In the United States, the European Union, and Australia, orlistat is available for sale without a prescription. Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds.^[9] Generics of orlistat are available in India and Russia.

At times, such as in spring 2012, Orlistat has come into short supply, with consequent price changes, because of nonavailability of one of the drug's components.^[10]

Medical uses[link]

Orlistat is used for the treatment of obesity.^[11] The amount of weight loss achieved with orlistat varies. In one-year clinical trials, 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 mass.^[12] After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost.^[12]

The incidence of type 2 diabetes in an obese population over four years is decreased with orlistat (6.2%) compared to placebo (9.0%).^[7] Long-term use of orlistat also leads to a modest reduction in blood pressure (mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively).^[13]

Contraindications[link]

Orlistat is contraindicated in:^[14]

• Malabsorption
• Hypersensitivity to orlistat
• Reduced gallbladder function (e.g. after cholecystectomy)
• Pregnancy and breastfeeding
• Use caution with: obstructed bile duct, impaired liver function, and pancreatic disease

Side effects[link]

The primary side effects of the drug are gastrointestinal-related, and include steatorrhea (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements. GlaxoSmithKline recommends that all users be cautious of the possible side effects until they "have a sense of any treatment effects".^[15][16] 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.^[17] The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.^[18]

According to Roche, side effects are most severe when beginning therapy and may decrease in frequency with time;^[14] this is supported by the results of the XENDOS study, which found that only 36% of people had gastrointestinal adverse effects during their fourth year of taking orlistat, whereas 91% of study subjects had experienced at least one GI-related side effect during the first year of treatment.^[7] 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.^[19]

The side effect profile of orlistat led US consumer group Prescription Access Litigation (PAL) to award its first 2007 "Bitter Pill Award" to GlaxoSmithKline—the 'With Allies Like This, Who Needs Enemas?' Award.^[20][21]

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.^[22]

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.^[23] The putative mechanism for this effect is postulated to be excessive oxalate absorption from the gut and its subsequent deposition in the kidney, with excessive oxalate absorption being a known consequence of fat malabsorption.

Long-term[link]

Despite a higher incidence of breast cancer amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat^[24]—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.^[25] There is evidence from an in vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and the monoclonal antibody trastuzumab, can induce cell death in breast cancer cells and block their growth.^[26]

A 2006 animal study linked orlistat with aberrant crypt foci (ACF), lesions found in the colon which are believed to be one of the earliest precursors of colon cancer.^[27][28]

Precautions[link]

Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitamins A,^[29] D, E, K, and beta-carotene should be taken once a day, at bedtime, when using orlistat.^[14]

On 4 June 2009, the U.S. Food and Drug Administration released its quarterly list of drugs that are under investigation for potential safety issues or new safety information. Orlistat was included in the list as having a "Potential Signal of Serious Risk" of liver toxicity, meaning that a potential risk of liver toxicity was identified based on reports to the FDA Adverse Event Reporting System between October and December 2008.^[30] Isolated cases of orlistat-associated liver problems have been reported before.^[31] On 24 August, the FDA reported that it would investigate 30 cases of liver damage reported between 1999 and October 2008 in patients taking orlistat, including six cases of liver failure.^[32]

Interactions[link]

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; the two drugs should therefore not be administered concomitantly.^[14] Orlistat can also impair absorption of the antiarrhythmic amiodarone.^[33]

Mechanism of action[link]

Crystallographic structure of human fatty acid synthase (rainbow color, N-terminus = blue, C-terminus = red) inhibited by orlistat (space-filling model; carbon = grey, oxygen = red, nitrogen = blue).^[34]

Orlistat works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and are excreted undigested instead. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.

At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed,^[35] and about 25% at the standard over-the-counter dose of 60 mg.^[36][37] Higher doses do not produce more potent effects.^[12]

Legal status[link]

Orlistat has historically been available by prescription only, and this situation continues in Canada. In Australia, the European Union,^[38] and the United States, certain formulations of orlistat have been approved for sale without a prescription.

In 2009, Roche began recruiting in Russia for a clinical trial of Xenical in obese teenagers between the ages of 12 and 14.^[39]

Australia and New Zealand[link]

In Australia and New Zealand, orlistat is currently^[update] available over-the-counter in 120 mg size (84 capsules to the pack). Initially available only with a prescription, it was reclassified as a "Pharmacist Only Medicine" in October 2003. In late 2006, the Australian Consumers' Association complained that Roche was inappropriately advertising the drug to teenagers, and Roche was forced to withdraw its ads.^[40] The Association filed further complaints^[40] with the Therapeutic Goods Administration—TGA, Australia's regulatory authority for healthcare products—and the TGA's Scheduling Committee agreed to convene on 20 February 2007, to discuss possible revoking of orlistat's over-the-counter status.^[41] The Committee ultimately 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".^[42] Xenical has recently^[when?] began being advertised direct-to-customers again.

United States[link]

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 marketed under the name alli ( /ˈælaɪ/) by GlaxoSmithKline.^[43] Approval was granted on 7 February 2007,^[44] and alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.^[45] Consumer advocacy organization Public Citizen, through its Health Research Group, opposed over-the-counter approval for orlistat, calling it "the height of recklessness" and "a dangerous mistake" due to questionable benefits and possible adverse effects.^[9] Public Citizen had already called for a ban of orlistat in April 2006.^[46]

Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.^[9][45]

European Union[link]

On 21 January 2009, the European Medicines Agency granted approval for the sale of orlistat without a prescription.^[38][47]

Generic formulations[link]

As of September 2009^[update], no generic formulations of orlistat are legally available in the United States. 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,^[48] and expired on 18 June 2009.^[49]

Generic orlistat is available in India, under the brands Olistat, Obelit, Orlica and Reeshape.^[50]

In Russia orlistat is available under the brand Orsoten.

Counterfeit products[link]

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.^[51]

References[link]

Further reading[link]

• Boehm, Marcus F.; McClurg, Michael R.; Pathirana, Charles; Mangelsdorf, David; White, Steven K.; Hebert, Jonathan; Winn, David; Goldman, Mark E. et al. (1994). "Synthesis of high specific activity tritium-labeled [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties". Journal of Medicinal Chemistry 37 (3): 408–14. DOI:10.1021/jm00029a013. PMID 8308867. 
• Hanessian, Stephen; Tehim, Ashok; Chen, Ping (1993). "Total synthesis of (-)-tetrahydrolipstatin". The Journal of Organic Chemistry 58 (27): 7768. DOI:10.1021/jo00079a022. 

External links[link]

Pharmacy and Pharmacology portal

• Official US alli site from GlaxoSmithKline
• Official UK alli site from GlaxoSmithKline
• Official Xenical site from Roche
• FDA Consumer Info