View source for Alosetron

{{Short description|Medication}}
{{Infobox drug
| verifiedrevid      = 477318612
| drug_name          = 
| type               = 
| IUPAC_name         = 5-methyl-2-[(4-methyl-1''H''-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1''H''-pyrido[4,3-''b'']indol-1-one
| image              = Alosetron.svg
| width              = 222
| alt                = 
| caption            = 
| image2             = Alosetron ball-and-stick model.png

<!--Clinical data-->| tradename          = Lotronex
| Drugs.com          = {{drugs.com|monograph|alosetron-hydrochloride}}
| MedlinePlus        = a601230
| licence_EU         = 
| licence_US         = 
| pregnancy_AU       = 
| pregnancy_US       = B
| pregnancy_category = 
| legal_US           = Rx-only
| legal_status       = 
| routes_of_administration = Oral ([[Tablet (pharmacy)|tablets]])

<!--Pharmacokinetic data-->| bioavailability    = 50–60%
| protein_bound      = 82%
| metabolism         = Hepatic (including [[CYP2C9]], [[CYP3A4]] and [[CYP1A2]])
| elimination_half-life = 1.5–1.7 hours
| excretion          = Renal 73%, faecal 24%

<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 122852-42-0
| ATC_prefix         = A03
| ATC_suffix         = AE01
| PubChem            = 2099
| IUPHAR_ligand      = 2296
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00969
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 2015
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 13Z9HTH115
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D07129
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 253342
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 1110

<!--Chemical data-->| C                  = 17
| H                  = 18
| N                  = 4
| O                  = 1
| smiles             = Cc1nc[nH]c1CN2CCc4c(C2=O)c3ccccc3n4C
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 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)
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = JSWZEAMFRNKZNL-UHFFFAOYSA-N
}}

'''Alosetron''', sold under the brand name '''Lotronex''' among others, is a [[5-HT3 antagonist|5-HT<sub>3</sub> antagonist]] used for the management of severe diarrhea-predominant [[irritable bowel syndrome]] (IBS) in females only.

<!-- Society and culture -->
It was patented in 1987 and approved for medical use in 2002.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=448 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA448 |language=en}}</ref> It is currently marketed by Prometheus Laboratories Inc. ([[San Diego, California|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: 
* 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.<ref name = "PI" />

===Efficacy===
The phase III trial for approval was published in 2000 as an industry-funded randomized, placebo-controlled trial (PCT). Its authors found 1&nbsp;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.<ref name=Camilleri>{{cite journal |vauthors=Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW | title = Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial | journal = Lancet | volume = 355 | issue = 9209 | pages = 1035–40 | date = March 2000 | pmid = 10744088 | doi = 10.1016/S0140-6736(00)02033-X | s2cid = 31290668 }}<!--|access-date=11 December 2012--></ref> The prescription of alosetron is currently approved in the U.S. at 0.5 and 1&nbsp;mg.<ref name=Moynihan />

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".<ref name=Barbehenn>{{cite journal | vauthors = Barbehenn E, Lurie P, Wolfe SM | title = Alosetron for irritable bowel syndrome | journal = Lancet | volume = 356 | issue = 9246 | pages = 2009–10 | date = December 2000 | pmid = 11130544 | doi = 10.1016/S0140-6736(05)72978-0 | s2cid = 30340322 | doi-access = free }}</ref> 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.<ref name=Moynihan />

==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, [[Stenosis|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.<ref name="PI" />

==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, [[Fecal impaction|impaction]], [[toxic megacolon]], secondary colonic [[ischaemia]], [[death]]) was 1 in 1000.<ref name="PI" /> A 1999 review performed by FDA medical officer John Senior, indicated that 27% of patients experienced constipation.<ref name=Willman2>{{cite news| vauthors = Willman D |title=FDA Minimized Issue of Lotronex's Safety|url=http://www.pulitzer.org/archives/6488|access-date=11 December 2012|newspaper=The Los Angeles Times|date=2 November 2000}}</ref> 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.<ref name=Camilleri />
<!-- == Overdose (including toxicity) == --> 
<!-- == Physical and Chemical Properties == -->
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==Mechanism of action==
Alosetron has an antagonist action on the 5-HT<sub>3</sub> receptors of the [[enteric nervous system]] of the gastrointestinal tract. While being a 5-HT<sub>3</sub> antagonist like [[ondansetron]], it is not classified or approved as an antiemetic. Since stimulation of 5-HT<sub>3</sub> receptors is positively correlated with gastrointestinal motility, alosetron's 5-HT<sub>3</sub> 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.<ref name="PI" />
<!-- == Interactions == -->
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==History==
Alosetron was originally approved by the [[U.S. Food and Drug Administration]] (FDA) on February 9, 2000,<ref name=FDAFact>{{cite web|last=U.S. Food and Drug Administration|title=Drug Details|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|archive-url=https://web.archive.org/web/20071213104224/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|url-status=dead|archive-date=December 13, 2007|access-date=11 December 2012}}</ref> after a seven-month review.<ref name=Willman /> 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.<ref name=Willman3>{{cite news| vauthors = Willman D |title=Officer Foresaw Deadly Effects|url=http://www.pulitzer.org/archives/6479|access-date=11 December 2012|newspaper=The Los Angeles Times|date=20 December 2000}}</ref>

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.<ref name=Willman2 />

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.<ref name=Willman>{{cite news| vauthors = Willman D |title=Drug Lotronex Pulled Over Safety Fears|url=http://www.pulitzer.org/archives/6489|access-date=11 December 2012|newspaper=The Los Angeles Times|date=29 November 2000}}</ref> 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.<ref name=Willman /> 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.<ref name=FDApanel>{{cite web|last=Center for Drug Evaluation and Research|title=Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science|url=https://www.fda.gov/ohrms/dockets/ac/02/transcripts/3848T1.pdf|archive-url=https://web.archive.org/web/20060927230527/http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3848T1.pdf|url-status=dead|archive-date=September 27, 2006|publisher=U.S. Food and Drug Administration|access-date=11 December 2012|date=23 April 2002}}</ref>

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.<ref name=Denise>{{cite news| vauthors = Grady D  |title=Appeals Prompt U.S. Agency to Consider Allowing Sales of Diarrhea Drug Linked to Deaths|url=https://www.nytimes.com/2002/04/23/us/appeals-prompt-us-agency-consider-allowing-sales-diarrhea-drug-linked-deaths.html|access-date=11 December 2012|newspaper=The New York Times|date=23 April 2002}}</ref><ref name=Moynihan>{{cite journal | vauthors = Moynihan R | title = Alosetron: a case study in regulatory capture, or a victory for patients' rights? | journal = BMJ | volume = 325 | issue = 7364 | pages = 592–5 | date = September 2002 | pmid = 12228140 | pmc = 1124108 | doi = 10.1136/bmj.325.7364.592 }}</ref>

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).<ref name = "PI">{{cite web|title=Lotronex (alosetron hydrochloride) Tablets. Full Prescribing Information|url=https://www.lotronex.com/hcp/_docs/Lotronex_PI.pdf|publisher=Prometheus Laboratories Inc., 9410 Carroll Park Drive, San Diego, CA 92121|access-date=14 February 2016|archive-date=22 February 2016|archive-url=https://web.archive.org/web/20160222142743/https://www.lotronex.com/hcp/_docs/Lotronex_PI.pdf}}</ref><ref name = NYT>{{cite news | url = https://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin | title = F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk | vauthors = Pollack A | work = [[The New York Times]] | date = 2006-03-09 | access-date = 2008-03-13 }}</ref><ref name=Grady>{{cite news| vauthors = Grady D |title=U.S. Lets Drug Tied to Deaths Back on Market|url=https://www.nytimes.com/2002/06/08/us/us-lets-drug-tied-to-deaths-back-on-market.html|access-date=11 December 2012|newspaper=The New York Times|date=8 June 2002}}</ref> 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 [[European Union|EU]].

GSK sold ''Lotronex'' to the [[California]]n corporation Prometheus in late 2007.<ref>{{cite web | title = Prometheus to Acquire Lotronex® From GlaxoSmithKline | publisher = Prometheus Laboratories Inc. | url = http://phx.corporate-ir.net/phoenix.zhtml?c=130685&p=irol-newsArticle_print&ID=1074178&highlight= | work = Press Release | date = 7 November 2007 | archive-url = https://archive.today/20120714004951/http://phx.corporate-ir.net/phoenix.zhtml?c=130685&p=irol-newsArticle_print&ID=1074178&highlight= | archive-date= 14 July 2012 | access-date = 27 August 2008 }}</ref>

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 in chief|editor]] of the medical journal ''[[The Lancet]]'', [[Richard Horton (editor)|Richard Horton]], criticized the FDA's handling of alosetron in an unusually sharp language.<ref>{{cite journal | vauthors = Horton R | title = Lotronex and the FDA: a fatal erosion of integrity | journal = Lancet | volume = 357 | issue = 9268 | pages = 1544–5 | date = May 2001 | pmid = 11377636 | doi = 10.1016/S0140-6736(00)04776-0 | s2cid = 10886502 }}</ref> 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."<ref name=Michel>{{cite journal | vauthors = Lièvre M | title = Alosetron for irritable bowel syndrome | journal = BMJ | volume = 325 | issue = 7364 | pages = 555–6 | date = September 2002 | pmid = 12228116 | pmc = 1124090 | doi = 10.1136/bmj.325.7364.555 }}</ref> Others have argued that the approval process of Lotronex was an example of [[regulatory capture]].<ref name=Moynihan />

== References ==
{{reflist|30em}}

{{Drugs for functional gastrointestinal disorders}}
{{Serotonergics}}

[[Category:5-HT3 antagonists]]
[[Category:Drugs developed by GSK plc]]
[[Category:Imidazoles]]
[[Category:Lactams]]
[[Category:Tetrahydropyridoindoles]]