Alosetron

Alosetron

Systematic (IUPAC) name
5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one
Clinical data
Trade names	Lotronex
AHFS/Drugs.com	monograph
MedlinePlus	a601230
Pregnancy category	B (U.S.)
Legal status	℞-only (U.S.)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	50–60%
Protein binding	82%
Metabolism	Hepatic (including CYP2C9, CYP3A4 and CYP1A2)
Biological half-life	1.5–1.7 hours
Excretion	Renal 73%, faecal 24%
Identifiers
CAS Number	122852-42-0 Y
ATC code	A03AE01 (WHO)
PubChem	CID: 2099
IUPHAR/BPS	2296
DrugBank	DB00969 Y
ChemSpider	2015 Y
UNII	13Z9HTH115 Y
KEGG	D07129 Y
ChEBI	CHEBI:253342 Y
ChEMBL	CHEMBL1110 Y
Chemical data
Formula	C17H18N4O
Molecular mass	294.351 g/mol
SMILES O=C1N(CCc3c1c2ccccc2n3C)Cc4ncnc4C
InChI InChI=1S/C17H18N4O/c1-11-13(19-10-18-11)9-21-8-7-15-16(17(21)22)12-5-3-4-6-14(12)20(15)2/h3-6,10H,7-9H2,1-2H3,(H,18,19) Y Key:JSWZEAMFRNKZNL-UHFFFAOYSA-N Y
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Alosetron hydrochloride (initial brand name: Lotronex; originator: GSK) is a 5-HT₃ antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name Lotronex. Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted.

Approval history

Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000, after a seven month review. At the time of the initial approval U.S. Food and Drug Administration (FDA) reviewers found that alosetron improved symptoms in 10% to 20% of patients.

Shipment to pharmacies started in March, 2000. On July 17, a health professional filed a report with the FDA on the death of a 50-year-old woman who suffered mesenteric ischemia. The report identified alosetron as the "primary suspect" in the death.

Alosetron was withdrawn from the market voluntarily by GlaxoWellcome on November 28, 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, including 5 deaths and additional bowel surgeries. The FDA said it had reports of 49 cases of ischemic colitis and 21 cases of "severe constipation" and that ten of the 70 patients underwent surgeries and 34 others were examined at hospitals and released without surgery. Through November 17, 2000, pharmacists had filled 474,115 prescriptions for Alosetron. Severe adverse events continued to be reported, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths.

Patient advocacy groups, most notably the Lotronex Action Group and the International Foundation for Functional Gastrointestinal Disorders (IFFGD) lobbied for the drug's return. Public Citizen Health Research Group, another patient advocacy group, opposed the reintroduction.

On June 7, 2002, the FDA announced the approval of a supplemental New Drug Application (sNDA) that allows restricted marketing of Lotronex (alosetron hydrochloride), to treat only women with severe diarrhea-predominant irritable bowel syndrome (IBS). It was the first drug ever returned to the U.S. market after withdrawal for safety concerns.

It is not known whether alosetron has been filed for registration in the EU.

GSK sold Lotronex to the Californian corporation Prometheus in late 2007.

Criticism of the FDA

In 2001, the editor of the renowned medical journal The Lancet, Richard Horton, criticized the FDA's handling of alosetron in an unusually sharp language. Horton argued that the treatment of a non-fatal condition did not justify the use of a drug with potentially lethal side effects, and that the FDA should have revoked the approval for alosetron sooner when postmarketing surveillance revealed that many patients had suffered constipation necessitating surgical intervention and ischaemic colitis. He asserted that FDA officials were improperly motivated to maintain and reinstate the approval for alosetron because of the extent to which the FDA's Center for Drug Evaluation and Research is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives of GlaxoSmithKline.

An article published in the British Medical Journal (BMJ) noted: "By allowing the marketing of alosetron, a drug that poses a serious and significant public health concern according to its own terms, the FDA failed in its mission." Others have argued that the approval process of Lotronex was an example of regulatory capture.

Indications

Alosetron is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS-D) who have:

• chronic IBS symptoms (generally lasting 6 months or longer),
• had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and
• not responded adequately to conventional therapy.

Severe IBS-D includes: diarrhea and 1 or more of the following:

• frequent and severe abdominal pain/discomfort,
• frequent bowel urgency or fecal incontinence,
• disability or restriction of daily activities due to IBS.

Contraindications

Lotronex's prescribing information brochure states that alosetron should not be initiated in patients with constipation. Other contraindications are: history of chronic or severe constipation or sequelae from constipation; intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions, ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; Crohn's disease or ulcerative colitis; diverticulitis; severe hepatic impairment. Concomitant use of fluvoxamine is also contraindicated.

Efficacy

The phase III trial for approval was published in 2000 as an industry-funded randomised, placebo-controlled trial (PCT). Its authors found 1 mg alosetron, taken orally twice daily for 12 weeks, was associated with a 12% (CI 4.7-19.2) improvement in relief from abdominal pain and discomfort associated with diarrhoea-predominant patients. The prescription of alosetron is currently approved in the U.S. at 0.5 and 1 mg.

The FDA Medical Officer's Review, dated November 4, 1999, noted: “Patients considered by investigators to fit the diarrhea-predominant subtype had at baseline… stool consistency values that were neither loose nor watery”. The FDA's Gastrointestinal Drugs Advisory Committee referred to the drug's efficacy as "modest", highlighting that the placebo brought relief on the primary outcome measure to 40–50% of women.

Adverse effects

Alosetron was withdrawn in 2000 following the association of alosetron with serious life-threatening gastrointestinal adverse effects. The cumulative incidence of ischaemic colitis was 2 in 1000, while serious complications arising from constipation (obstruction, perforation, impaction, toxic megacolon, secondary colonic ischaemia, death) was 1 in 1000. A 1999 review performed by FDA medical officer John Senior, indicated that 27% of patients experienced constipation. The phase III trial reported constipation occurred in 30% and 3% of patients in the alosetron and placebo groups, respectively. It was cited as the most important reason for patients dropping out of the study.

Mechanism of action

Alosetron has an antagonist action on the 5-HT₃ receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT₃ antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT₃ receptors is positively correlated with gastrointestinal motility, alosetron's 5-HT₃ antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.