Alosetron

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Brand names: Lotronex™

Chemical formula:

Drug Forms:
• Alosetron Hydrochloride Oral tablet (below)
• Alosetron tablets

Español:
• Clorhidrato de Alosetrón, Tableta oral
• Tabletas de alosetrón

Alosetron Hydrochloride Oral tablet

What is this medicine?

ALOSETRON is used to treat irritable bowel syndrome (IBS) in women. It is reserved for those women who have severe diarrhea as the main symptom and who have not had success with other treatments. This medicine has not been shown to work in men with IBS. It is available only from health care providers who participate in a special Prescribing Program because this drug may cause serious side effects. Your health care provider will discuss your condition and these side effects with you prior to prescribing this drug.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•constipation
•Crohn's disease
•diverticulitis
•history of ischemic colitis, impaired intestinal circulation, bleeding, or blood clots
•history of a stomach, bowel, or intestine problems
•kidney disease or liver disease
•toxic megacolon
•ulcerative colitis
•an unusual or allergic reaction to alosetron, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. You can take this medicine with or without food. Take your doses at regular intervals. Do not take your medicine more often than directed.

A special MedGuide will be given to you by the pharmacist with each prescription and refill. Be sure to read this information carefully each time.

Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed. This medicine is not for use in children.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

Do not take this medicine with any of the following medications:
•antidiarrheal medicines, like Imodium, Kaopectate, or Lomotil
•enoxacin
•fluvoxamine
•mexiletine
•zileuton

This medicine may also interact with the following medications:
•certain antibiotics like ciprofloxacin, clarithromycin, erythromycin or troleandomycin
•cimetidine
•hydralazine
•isoniazid, INH
•medicines for fungal infections like ketoconazole, itraconazole and voriconazole
•medicines for HIV or AIDS
•procainamide

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Constipation is a common and serious side effect of this medicine. Stop taking this medicine and call your health care provider immediately if you become constipated. Only restart this medicine if your constipation has resolved and you and your doctor have agreed to restart treatment. You should not start taking this medicine if you are already constipated or constipated most of the time.

Ischemic colitis is a serious and potentially life-threatening condition that has been rarely reported with this medicine. If you experience new or worsening abdominal pain, bloody diarrhea or blood in the stool, immediately stop taking this medicine and contact your doctor or health care professional.

This medicine may not work for all women who take it. For women who are helped by this medicine, relief may occur within the first week or within four weeks of starting the drug. If you stop taking this medicine, it is likely that your symptoms will return within one week.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this medicine affects you. Alcohol can increase drowsiness or dizziness. Avoid alcoholic drinks.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional immediately:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•blood in stool, bloody diarrhea or rectal bleeding
•constipation
•dark urine
•hemorrhoids
•fever
•irregular heart beat
•unusually weak or tired
•worsening of abdominal pain
•yellowing of the eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•anxiety
•difficulty sleeping
•dry mouth
•frequent urination
•gas
•headache
•nausea
•restlessness

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Protect from light and moisture. Throw away any unused medicine after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

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
Identifiers
CAS number	122852-42-0
ATC code	A03AE01
PubChem	2099
DrugBank	APRD00580
ChemSpider	2015
Chemical data
Formula	C17H18N4O
Mol. mass	294.351 g/mol
Pharmacokinetic data
Bioavailability	50–60%
Protein binding	82%
Metabolism	Hepatic (including CYP2C9, CYP3A4 and CYP1A2)
Half life	1.5–1.7 hours
Excretion	Renal 73%, faecal 24%
Therapeutic considerations
Pregnancy cat.	B (U.S.)
Legal status	℞-only (U.S.)
Routes	Oral

Alosetron (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.

Contents 1 History 2 Adverse effects 3 Pharmacodynamics and mechanism of action 4 References

History

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; it was the first drug ever returned to the U.S. market after withdrawal for safety concerns.^[1]

In 2001, the editor of the renown medical journal The Lancet, Richard Horton, critizised the FDA's handling of alosetron in an unusually sharp language.^[2] 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.

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.^[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.^[4]

Pharmacodynamics and 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.^[4]

References

1. ^ Pollack, A (2006-03-09). "F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk". The New York Times. http://www.nytimes.com/2006/03/09/business/09drug.html?_r=1&scp=2&sq=natalizumab&st=nyt&oref=slogin. Retrieved on 2008-03-13. 
2. ^ Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet. 2001;357:1544-5. PMID 11377636
3. ^ Prometheus Laboratories Inc. Press Release of 7 November 2007. Retrieved on 27 August 2008.
4. ^ ^{a b} Prometheus Laboratories Inc. Lotronex (U.S. Prescribing Information) 2008 [1].

v • d • e Drugs for functional gastrointestinal disorders (A03) Drugs for functional bowel disorders Antimuscarinics Tertiary amino group Oxyphencyclimine · Camylofin · Mebeverine · Trimebutine · Rociverine · Dicycloverine · Dihexyverine · Difemerine · Piperidolate Quaternary ammonium compounds Benzilone · Glycopyrronium · Oxyphenonium · Penthienate · Propantheline · Otilonium bromide · Methantheline · Tridihexethyl · Isopropamide · Hexocyclium · Poldine · Mepenzolate · Bevonium · Pipenzolate · Diphemanil · Tiemonium iodide · Prifinium bromide · Timepidium bromide · Fenpiverinium Phosphodiesterase inhibitors Papaverine · Drotaverine · Moxaverine Acting on serotonin receptors 5-HT3 antagonists (Alosetron, Cilansetron) · 5-HT4 agonists (Mosapride, Prucalopride, Tegaserod) Other Fenpiprane · Diisopromine · Chlorbenzoxamine · Pinaverium · Fenoverine · Idanpramine · Proxazole · Alverine · Trepibutone · Isometheptene · Caroverine · Phloroglucinol · Silicones · Trimethyldiphenylpropylamine Belladonna and derivatives (antimuscarinics) tertiary amines: Atropine · Hyoscyamine quaternary ammonium compounds: Scopolamine (Butylscopolamine, Methylscopolamine) · Methylatropine · Fentonium · Cimetropium bromide Propulsives primarily dopamine antagonists (Metoclopramide/Bromopride, Clebopride, Domperidone, Alizapride) · 5-HT4 agonists (Cisapride)

v • d • e Serotonergics Receptor Ligands 5-HT1 5-HT1A Agonists: Azapirones: Alnespirone • Binospirone • Buspirone • Gepirone • Ipsapirone • Perospirone • Tandospirone • Tiospirone • Zalospirone; Lysergamides: Dihydroergotamine • Ergotamine • Methysergide • LSD; Phenethylamines: MDA • MDMA; Piperazines: Eltoprazine • Flesinoxan • Flibanserin; Tryptamines: 5-CT • 5-MeO-DMT • 5-MT • DMT • Psilocin • Psilocybin • Rauwolscine • Yohimbine; Atypical Antipsychotics: Aripiprazole • Asenapine • Clozapine • Quetiapine • Ziprasidone; Others: 8-OH-DPAT • F 11440 • F 13640 • Lesopitron • Lu AA21004 • LY293284 • LY301317 • MKC-242 • Osemozotan • Piclozotan • PRX-00023 • Repinotan • RU-24969 • S-15535 • Sarizotan • SSR-181,507 • Sunepitron • U-92016A • Urapidil • Vilazodone • Xaliproden Antagonists: Beta Blockers: Alprenolol • Cyanopindolol • Iodocyanopindolol • Oxprenolol • Pindobind • Pindolol • Propranolol; Piperazines: Nefazodone • Trazodone • WAY-100,135 • WAY-100,635; Others: AV965 • BMY-7378 • Dotarizine • GR-46611 • Isamoltane • Lecozotan • Methiothepin • MPPF • NAN-190 • Robalzotan • S-15535 • SB-649915 • SDZ 216-525 • Spiperone • Spiroxatrine • UH-301 • Xylamidine 5-HT1B Agonists: Lysergamides: Dihydroergotamine • Ergotamine • Methysergide; Piperazines: Eltoprazine • TFMPP; Triptans: Eletriptan • Sumatriptan • Zolmitriptan; Tryptamines: 5-CT • 5-MT; Others: CP-93,129 • CP-94,253 • CP-135,807 • RU-24969 Antagonists: Lysergamides: Metergoline • Methiothepin; Tryptamines: Yohimbine; Others: AR-A000002 • GR-127,935 • Isamoltane • SB-216,641 • SB-224,289 • SB-236,057 5-HT1D Agonists: Lysergamides: Dihydroergotamine • Methysergide; Triptans: Almotriptan • Eletriptan • Frovatriptan • Naratriptan • Rizatriptan • Sumatriptan • Zolmitriptan; Tryptamines: 5-CT • 5-MT; Others: CP-135,807 • CP-286,601 • GR-46611 • L-694,247 • L-772,405 • PNU-109,291 • PNU-142,633 Antagonists: Lysergamides: Metergoline • Methiothepin; Tryptamines: Yohimbine; Others: BRL-15572 • GR-127,935 • Ketanserin • LY-310,762 • LY-367,642 • LY-456,219 • LY-456,220 • Rauwolscine • Ritanserin • Ziprasidone 5-HT1E Agonists: Lysergamides: Methysergide; Triptans: Eletriptan; Tryptamines: Tryptamine Antagonists: Methiothepin 5-HT1F Agonists: Triptans: Eletriptan • Naratriptan • Sumatriptan; Tryptamines: 5-MT; Others: LY-334,370 Antagonists: Methiothepin 5-HT2 5-HT2A Agonists: Lysergamides: ALD-52 • Ergonovine • Lisuride • LA-SS-Az • LSD • Lysergic acid 2-butyl amide • Methysergide; Phenethylamines: 25I-NBMD • 25I-NBOH • 25I-NBOMe • 2C-B • 2C-B-FLY • 2C-E • 2C-I • 2C-T-2 • 2C-T-7 • 2C-T-21 • 2CBCB-NBOMe • 2CBFly-NBOMe • Bromo-DragonFLY • DOB • DOC • DOI • DOM • DOTFM • MDA • MDMA • Mescaline • Myristicin • TCB-2 • TFMFly; Piperazines: BZP • Quipazine • TFMPP; Tryptamines: 5-CT • 5-MeO-α-ET • 5-MeO-α-MT • 5-MeO-DET • 5-MeO-DiPT • 5-MeO-DMT • 5-MeO-DPT • 5-MT • α-ET • α-Methyl-5-HT • α-MT • Bufotenin • DET • DiPT • DMT • DPT • Psilocin • Psilocybin; Others: AL-34662 • AL-37350A • PNU-22394 Antagonists: Atypical Antipsychotics: Amperozide • Aripiprazole • Clozapine • Iloperidone • Melperone • Olanzapine • Paliperidone • Pimozide • Quetiapine • Risperidone • Sertindole • Ziprasidone • Zotepine; Typical Antipsychotics: Loxapine • Pipamperone; Antidepressants: Amitriptyline • Amoxapine • Etoperidone • Mianserin • Mirtazapine • Nefazodone • Trazodone; Others: 5-I-R91150 • AC-90179 • Altanserin • AMDA • APD-215 • Blonanserin • Cinanserin • Cyproheptadine • Deramciclane • Dotarizine • Eplivanserin • Fananserin • Flibanserin • Ketanserin • Lubazodone • MDL-100,907 • Methiothepin • Nantenine • Pimavanserin • Pizotifen • Ritanserin • Sarpogrelate • Setoperone • SR-46349B • Xylamidine • Yohimbine 5-HT2B Agonists: Oxazolines: 4-Methylaminorex • Aminorex; Phenethylamines: Chlorphentermine • Fenfluramine • MDA • MDMA • Norfenfluramine; Tryptamines: 5-CT • 5-MT • α-Methyl-5-HT; Others: BW-723C86 • Cabergoline • mCPP • Pergolide • PNU-22394 • Ro60-0175 Antagonists: Agomelatine • Asenapine • EGIS-7625 • Ketanserin • Lisuride • LY-272,015 • Rauwolscine • Ritanserin • RS-127,445 • Sarpogrelate • SB-200,646 • SB-204,741 • SB-206,553 • SB-215,505 • SB-221,284 • SB-228,357 • SDZ SER-082 • Tegaserod • Yohimbine 5-HT2C Agonists: Piperazines: Aripiprazole • mCPP • TFMPP; Tryptamines: 5-CT • 5-MT • α-Methyl-5-HT; Others: A-372,159 • AL-38022A • CP-809,101 • Lorcaserin • MK-212 • PNU-22394 • Ro60-0175 • Vabicaserin • WAY-629 • WAY-161,503 • YM-348 Antagonists: Atypical Antipsychotics: Clozapine • Iloperidone • Melperone • Olanzapine • Paliperidone • Pimozide • Quetiapine • Risperidone • Sertindole • Ziprasidone • Zotepine; Typical Antipsychotics: Loxapine • Pipamperone; Antidepressants: Agomelatine • Amitriptyline • Amoxapine • Etoperidone • Fluoxetine • Mianserin • Mirtazapine • Nefazodone • Trazodone; Others: Cinanserin • Deramciclane • Dimebolin • Dotarizine • Eltoprazine • FR-260,010 • Ketanserin • Pizotifen • Ritanserin • RS-102,221 • SB-200,646 • SB-206,553 • SB-221,284 • SB-228,357 • SB-242,084 • SB-243,213 • SDZ SER-082 • Xylamidine 5-HT3 Agonists: Piperazines: BZP • Quipazine; Tryptamines: 2-Methyl-5-HT • 5-CT; Others: Chlorophenylbiguanide • RS-56812 • SR-57,227 • SR-57,227-A • YM-31636 Antagonists: Antiemetics: Alosetron • Azasetron • Batanopride • Bemesetron • Cilansetron • Dolasetron • Granisetron • Lerisetron • Ondansetron • Palonosetron • Ramosetron • Renzapride • Tropisetron • Zacopride • Zatosetron; Atypical Antipsychotics: Clozapine • Olanzapine • Quetiapine; Tetracyclic Antidepressants: Amoxapine • Mianserin • Mirtazapine; Others: BRL-46,470 • ICS-205,930 • Lu AA21004 • MDL-72,222 • Memantine 5-HT4 Agonists: Gastroprokinetic Agents: Cisapride • CJ-033,466 • Metoclopramide • Mosapride • Prucalopride • PRX-03140 • Renzapride • RS-67506 • TD-5108 • Tegaserod • Zacopride; Others: 5-MT • BIMU-8 • RS-67333 Antagonists: GR-113,808 • GR-125,487 • L-Lysine • Piboserod • RS-39604 • RS-67532 • SB-203,186 5-HT5 5-HT5A Agonists: Lysergamides: Ergotamine • LSD; Tryptamines: 5-CT; Others: Valerenic Acid Antagonists: Asenapine • Dimebolin • Methiothepin • Ritanserin • SB-699,551 • SB-699,551-A 5-HT5B Agonists: Lysergamides: Ergotamine • LSD Antagonists: Methiothepin 5-HT6 Agonists: Lysergamides: Lisuride • LSD • Metergoline; Tryptamines: 5-CT • 5-MT • E-6801 • E-6837 • EMD-386,088 • EMDT • LY-586,713 • WAY-181,187 • WAY-208,466 Antagonists: Antidepressants: Amitriptyline • Amoxapine • Clomipramine • Doxepin • Mianserin • Nortriptyline; Atypical Antipsychotics: Aripiprazole • Asenapine • Clozapine • Fluperlapine • Iloperidone • Olanzapine • Tiospirone; Typical Antipsychotics: Chlorpromazine • Loxapine; Others: BGC20-760 • BVT-5182 • BVT-74316 • Dimebolin • EGIS-12233 • GW-742,457 • Ketanserin • Methiothepin • MS-245 • PRX-07034 • Ritanserin • Ro 04-6790 • Ro 63-0563 • SB-258,585 • SB-271,046 • SB-357,134 • SB-399,885 5-HT7 Agonists: Lysergamides: LSD; Tryptamines: 5-CT • 5-MT; Others: 8-OH-DPAT • AS-19 • Bifeprunox • LP-12 • LP-44 • Sarizotan Antagonists: Antidepressants: Amitriptyline • Amoxapine • Clomipramine • Imipramine • Maprotiline • Mianserin; Atypical Antipsychotics: Amisulpride • Aripiprazole • Clozapine • Olanzapine • Risperidone • Sertindole • Tiospirone • Ziprasidone • Zotepine; Typical Antipsychotics: Chlorpromazine • Loxapine; Others: EGIS-12233 • LY-215,840 • Mesulergine • Metergoline • Methiothepin • Pimozide • Ritanserin • SB-258,719 • SB-258,741 • SB-269,970 • SB-656,104 • SB-656,104-A • SB-691,673 • SLV-313 • SLV-314 • Spiperone • SSR-181,507 Reuptake Inhibitors Plasmalemmal SERT Inhibitors Selective Serotonin Reuptake Inhibitors (SSRIs): Citalopram • Dapoxetine • Escitalopram • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline • Vilazodone • Zimelidine; Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Bicifadine • Desvenlafaxine • Duloxetine • Milnacipran • Venlafaxine; Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs): Brasofensine • Diclofensine • DOV 102,677 • DOV 21,947 • DOV 216,303 • NS2359 • SEP-225289 • SEP-227162 • Tesofensine; Tricyclic Antidepressants (TCAs): Amitriptyline • Butriptyline • Cianopramine • Clomipramine • Desipramine • Dosulepin • Doxepin • Imipramine • Lofepramine • Nortriptyline • Protriptyline • Trimipramine; Tetracyclic Antidepressants (TeCAs): Amoxapine; Piperazines: Lubazodone • Nefazodone • Trazodone • Vilazodone; Tropanes: Cocaine; Antihistamines: Brompheniramine • Chlorpheniramine • Diphenhydramine • Pheniramine; Opioids: Meperidine/Pethidine • Methadone • Propoxyphene • Tramadol; Others: Cyclobenzaprine • Dextromethorphan • Mesembrine • SB-649915 • Sibutramine • Ziprasidone TRPC6 Activators Adhyperforin • Hyperforin Vesicular VMAT Inhibitors Ibogaine • Reserpine • Tetrabenazine Releasing Agents Aminoindanes: ETAI • MDAI • MDMAI • MMAI • TAI; Aminopropanes: Indanylaminopropane • Naphthylaminopropane; Benzofurans: 5-APDB; Oxazolines: 4-Methylaminorex • Aminorex; Phenethylamines: 2-Methyl-MDA • 3-Methoxy-4-methylamphetamine • 4-Bromomethcathinone • 4-Fluoroamphetamine • 4-Fluoromethamphetamine • 4-Methylamphetamine • 4-Methylmethamphetamine • 4-Methylthioamphetamine • 5-Methyl-MDA • BDB • BOH • Butylone • Chlorphentermine • Diethylcathinone • Dimethylcathinone • EBDB • Ethylone • Fenfluramine • Flephedrone • MBDB • MDA • MDEA • MDMA (Ecstasy) • MDOH • MDPEA • Mephedrone • Methylone • MMDA • MMDMA • Norfenfluramine • para-Bromoamphetamine • para-Chloroamphetamine • para-Chloromethamphetamine • para-Iodoamphetamine • para-Methoxyamphetamine • para-Methoxymethamphetamine • para-Methoxyethylamphetamine; Tryptamines: α-ET • α-MT Enzyme Inhibitors Anabolism TPH Inhibitors AGN-2979 • Fenclonine AAAD Inhibitors Benserazide • Carbidopa Catabolism MAO Inhibitors Nonselective: Iproclozide • Iproniazid • Isocarboxazid • Nialamide • Phenelzine • Pheniprazine • Tranylcypromine; MAO-A Selective: Befloxatone • Brofaromine • Cimoxatone • Clorgiline • Harmala Alkaloids • Minaprine • Moclobemide • Pirlindole • Toloxatone • Tyrima Others Precursors L-Tryptophan • 5-HTP Cofactors Iron • Tetrahydrobiopterin • Vitamin B3 (Niacin/Nicotinamide/NADPH) • Vitamin B6 (Pyridoxine/Pyridoxamine/Pyridoxal 5-Phosphate) • Vitamin B9 (Folic Acid/Tetrahydrofolic Acid) • Vitamin C (Ascorbic Acid) • Zinc Others Activity Enhancers: BPAP • PPAP; Reuptake Enhancers: Tianeptine

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