Alosetron

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Alosetron
Alosetron.svg
Alosetron ball-and-stick model.png
Clinical data
Trade names Lotronex
AHFS/Drugs.com Monograph
MedlinePlus a601230
Routes of
administration 		Oral (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 50–60%
Protein binding 82%
Metabolism Hepatic (including CYP2C9, CYP3A4 and CYP1A2)
Elimination half-life 1.5–1.7 hours
Excretion Renal 73%, faecal 24%
Identifiers
  • 5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C17H18N4O
Molar mass 294.358 g·mol−1
3D model (JSmol)
  • Cc1nc[nH]c1CN2CCc4c(C2=O)c3ccccc3n4C
  • 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) Yes check.svgY
  • Key:JSWZEAMFRNKZNL-UHFFFAOYSA-N Yes check.svgY
   (verify)

Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only.

Contents

It was patented in 1987 and approved for medical use in 2002. [2] It is currently marketed by Prometheus Laboratories Inc. (San Diego). Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability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.

Medical uses

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

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

Efficacy

The phase III trial for approval was published in 2000 as an industry-funded randomized, 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 diarrhea-predominant patients. [4] The prescription of alosetron is currently approved in the U.S. at 0.5 and 1 mg. [5]

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". [6] 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. [5]

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. [3]

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. [3] A 1999 review performed by FDA medical officer John Senior, indicated that 27% of patients experienced constipation. [7] 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. [4]

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. [3]

History

Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000, [8] after a seven-month review. [9] 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. [10]

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. [7]

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. [9] 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. [9] 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. [11]

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. [12] [5]

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). [3] [13] [14] The strict prescribing guidelines initially introduced in 2002 were relaxed slightly in 2016, enabling electronic prescriptions among other benefits.

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. [15]

Since 2015, generic versions of alosetron have been available in the US, sold by a number of different companies including Actavis Pharma Company, Prometheus Laboratories and Sebela Pharmaceuticals Inc

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. [16] 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." [17] Others have argued that the approval process of Lotronex was an example of regulatory capture. [5]

Related Research Articles

<span class="mw-page-title-main">Irritable bowel syndrome</span> Functional gastrointestinal disorder

Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating and changes in the consistency of bowel movements. These symptoms may occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.

<span class="mw-page-title-main">Ondansetron</span> Medication to prevent nausea and vomiting

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<span class="mw-page-title-main">Tegaserod</span> Medication

Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation. Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.

<span class="mw-page-title-main">Renzapride</span> Chemical compound

Renzapride is a prokinetic agent and antiemetic which acts as a full 5-HT4 agonist and partial 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

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<span class="mw-page-title-main">Cilansetron</span> Chemical compound

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<span class="mw-page-title-main">Lubiprostone</span> Medication used for constipation

Lubiprostone, sold under the brand name Amitiza among others, is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company.

5-HT<sub>3</sub> antagonist Anti-nausea group of medications

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

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References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 448. ISBN   9783527607495.
  3. 1 2 3 4 5 "Lotronex (alosetron hydrochloride) Tablets. Full Prescribing Information" (PDF). Prometheus Laboratories Inc., 9410 Carroll Park Drive, San Diego, CA 92121. Archived from the original (PDF) on 22 February 2016. Retrieved 14 February 2016.
  4. 1 2 Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW (March 2000). "Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial". Lancet. 355 (9209): 1035–40. doi:10.1016/S0140-6736(00)02033-X. PMID   10744088. S2CID   31290668.
  5. 1 2 3 4 Moynihan R (September 2002). "Alosetron: a case study in regulatory capture, or a victory for patients' rights?". BMJ. 325 (7364): 592–5. doi:10.1136/bmj.325.7364.592. PMC   1124108 . PMID   12228140.
  6. ↑ Barbehenn E, Lurie P, Wolfe SM (December 2000). "Alosetron for irritable bowel syndrome". Lancet. 356 (9246): 2009–10. doi: 10.1016/S0140-6736(05)72978-0 . PMID   11130544. S2CID   30340322.
  7. 1 2 Willman D (2 November 2000). "FDA Minimized Issue of Lotronex's Safety". The Los Angeles Times. Retrieved 11 December 2012.
  8. ↑ U.S. Food and Drug Administration. "Drug Details" . Retrieved 11 December 2012.
  9. 1 2 3 Willman D (29 November 2000). "Drug Lotronex Pulled Over Safety Fears". The Los Angeles Times. Retrieved 11 December 2012.
  10. ↑ Willman D (20 December 2000). "Officer Foresaw Deadly Effects". The Los Angeles Times. Retrieved 11 December 2012.
  11. ↑ Center for Drug Evaluation and Research (23 April 2002). "Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science" (PDF). U.S. Food and Drug Administration. Retrieved 11 December 2012.
  12. ↑ Grady D (23 April 2002). "Appeals Prompt U.S. Agency to Consider Allowing Sales of Diarrhea Drug Linked to Deaths". The New York Times. Retrieved 11 December 2012.
  13. ↑ Pollack A (2006-03-09). "F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk". The New York Times . Retrieved 2008-03-13.
  14. ↑ Grady D (8 June 2002). "U.S. Lets Drug Tied to Deaths Back on Market". The New York Times. Retrieved 11 December 2012.
  15. ↑ "Prometheus to Acquire Lotronex® From GlaxoSmithKline". Press Release. Prometheus Laboratories Inc. 7 November 2007. Archived from the original on 14 July 2012. Retrieved 27 August 2008.
  16. ↑ Horton R (May 2001). "Lotronex and the FDA: a fatal erosion of integrity". Lancet. 357 (9268): 1544–5. doi:10.1016/S0140-6736(00)04776-0. PMID   11377636. S2CID   10886502.
  17. ↑ Lièvre M (September 2002). "Alosetron for irritable bowel syndrome". BMJ. 325 (7364): 555–6. doi:10.1136/bmj.325.7364.555. PMC   1124090 . PMID   12228116.
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