Skip to Content

Alosetron Hydrochloride

Class: Anti-inflammatory Agents
VA Class: GA900
Chemical Name: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]- 1H-pyrido[4,3-b]indol-1-one monohydrochloride
Molecular Formula: C17H18N4O•HCl
CAS Number: 122852-69-1
Brands: Lotronex

Warning(s)

  • Serious GI Effects
  • Infrequent but serious adverse GI effects reported, including ischemic colitis and serious complications of constipation; in some cases, resulted in hospitalization, blood transfusion, surgery (e.g., colectomy) and/or death.1 (See Warnings under Cautions.)

  • Discontinue immediately and contact clinician if manifestations of constipation or ischemic colitis develop.1

  • Do not resume alosetron in patients who develop ischemic colitis.1

  • Contact clinician if constipation does not resolve after discontinuance of alosetron; if constipation resolves after discontinuance, resume therapy only on advice of clinician.1

  • Restricted Distribution
  • Voluntarily withdrawn from US market by manufacturer in November 2000 because of numerous reports of severe adverse effects, including ischemic colitis, severely obstructed or ruptured bowel, and death; FDA approved a supplemental New Drug Application (sNDA) for alosetron in June 2002, permitting remarketing under restricted conditions of use.7 8 9 11

  • Approved only for severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms who have not responded adequately to conventional therapy.1 (See Uses.)

  • May be prescribed only by clinicians who have enrolled in the Prescribing Program for Lotronex or Alosetron REMS Program.1 8 11 13 (See Restricted Distribution Programs under Dosage and Administration.)

REMS:

FDA approved a REMS for alosetron to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of alosetron and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page (http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm) or the ASHP REMS Resource Center ().

Introduction

Selective serotonergic type 3 (5-HT3) receptor inhibitor; may modulate serotonin-sensitive GI processes.1 2 5 6 11 12

Uses for Alosetron Hydrochloride

Severe Diarrhea-predominant Irritable Bowel Syndrome in Women

Only for management of severe diarrhea-predominant IBS in women with chronic symptoms (generally lasting ≥6 months) who have had anatomic or biochemical GI abnormalities excluded and have not responded to conventional therapy.1 11 17 20 Diarrhea-predominant IBS is considered severe if accompanied by at least one of the following symptoms: frequent and severe abdominal pain and/or discomfort; frequent bowel urgency or fecal incontinence; or disability or restriction of daily activities.1 11

Use restricted to patients for whom benefit-to-risk balance is considered to be most favorable.1 (See Boxed Warning.)

Efficacy in men not adequately demonstrated in clinical studies.1 11 18 19

Alosetron Hydrochloride Dosage and Administration

General

Restricted Distribution Programs

  • Prescribed and distributed under the Prescribing Program for Lotronex or Alosetron REMS Program to help mitigate risk of serious GI events.1 8 11 13 (See REMS and also see Cautions.)

  • May be prescribed only by clinicians who have enrolled in these programs.1 13

  • Additional information on the Prescribing Program for Lotronex available at 888-423-5227 or .1 Additional information on the Alosetron REMS Program available at 844-267-8675 or .13

Administration

Oral Administration

Administer orally without regard to meals.1

Dosage

Available as alosetron hydrochloride; dosage expressed in terms of alosetron.1

Adults

Severe Diarrhea-predominant IBS in Women
Oral

Initially, 0.5 mg twice daily is recommended to minimize risk of constipation (although efficacy of this dosage has not been established in clinical studies).1

If constipation occurs at a dosage of 0.5 mg twice daily, interrupt therapy until constipation resolves; may then reinitiate at a reduced dosage of 0.5 mg once daily.1 If constipation recurs, immediately discontinue therapy.1

May continue on a dosage of 0.5 mg once or twice daily as maintenance therapy if dosage is well tolerated and IBS symptoms are adequately controlled.1 If patient tolerates, but does not respond adequately to the dosage after 4 weeks, may increase up to 1 mg twice daily.1 If adequate control of symptoms not achieved after 4 weeks on a dosage of 1 mg twice daily, discontinue therapy.1

Discontinue immediately and permanently in patients who develop ischemic colitis.1 (See Ischemic Colitis under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Alosetron Hydrochloride

Contraindications

  • Current constipation, history of chronic or severe constipation, or history of complications related to constipation.1 11

  • History of intestinal obstruction, stricture, toxic megacolon, GI perforation, and/or adhesions.1

  • History of ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state.1

  • History of Crohn’s disease, ulcerative colitis, or diverticulitis.1 11

  • History of severe hepatic impairment.1

  • Inability to understand or comply with the Patient Acknowledgment Form.1

  • Concomitant use of fluvoxamine.1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Serious Complications of Constipation

Serious complications of constipation (e.g., obstruction, perforation, ileus, impaction, toxic megacolon, secondary bowel ischemia, death) reported infrequently.1 16 17 (See Boxed Warning.)

No dose-response relationship has been established; reported with dosages of 1 mg twice daily or less.1

Geriatric or debilitated patients or those taking drugs that decrease GI motility may be at increased risk.1

Discontinue immediately if constipation occurs.1 If constipation resolves, resume therapy only on the advice of clinician.1 11 (See Dosage under Dosage and Administration.)

Ischemic Colitis

Ischemic colitis reported infrequently; may be life-threatening.1 16 17 (See Boxed Warning.)

No dose-response relationship has been established; reported with dosages of 1 mg twice daily or less.1

Discontinue immediately if symptoms of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new/worsening abdominal pain) occur.1 11 Promptly evaluate and perform appropriate diagnostic tests.1

Do not resume therapy in patients who develop ischemic colitis.1 (See Contraindications under Cautions.)

Specific Populations

Pregnancy

Category B.1

No adequate and well-controlled studies in pregnant women; no evidence of fetal harm demonstrated in animal studies.1 Use during pregnancy only if clearly needed.1

Lactation

Distributed into milk in rats; not known whether distributed into milk in humans.1 Caution advised.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 6

Not recommended in pediatric population because of risk of serious GI complications.1

Geriatric Use

Geriatric patients may be at greater risk for complications of constipation.1 Exercise appropriate caution and follow-up.1

Hepatic Impairment

Extensively metabolized in liver; increased exposure to alosetron and/or its metabolites likely in patients with hepatic impairment, which can increase risk of serious adverse effects.1 11

Use with caution in patients with mild or moderate hepatic impairment; contraindicated in patients with severe hepatic impairment.1 (See Contraindications under Cautions and see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Renal impairment not expected to affect clearance of alosetron.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Not evaluated in patients with end-stage renal disease.1

Common Adverse Effects

Constipation, abdominal discomfort or pain, nausea, GI discomfort or pain, abdominal distention, regurgitation and reflux, hemorrhoids.1

In women with severe diarrhea-predominant IBS, diarrhea and flatulence also reported.1

Interactions for Alosetron Hydrochloride

Metabolized by CYP isoenzymes, principally by CYP1A2, and to a lesser extent by CYP3A4 and 2C9.1

Inhibits CYP1A2 and CYP2E1 in vitro at very high concentrations (27-fold higher than peak plasma concentrations observed with 1-mg dose); in vivo, inhibits CYP1A2, but no effect on CYP2E1.1 Inhibits N-acetyltransferase in vivo.1 Does not inhibit CYP2C9, C19, 2E1, or 3A4.1

Does not appear to induce CYP3A, 2E1, or 2C19.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered alosetron clearance) when used concomitantly with drugs that inhibit or induce CYP1A2, 3A4, or 2C9.1

CYP1A2 inhibitors: Avoid concomitant use.1

CYP3A4 inhibitors: Caution advised when used concomitantly.1

Potential to inhibit clearance of drugs metabolized by CYP1A2.1 Unlikely to inhibit clearance of drugs metabolized by CYP2C9, 2C19, 2E1, or 3A4.1

Drugs Metabolized by N-Acetyltransferase

Potential pharmacokinetic interaction (decreased metabolism of drugs metabolized via N-acetyltransferase).1

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (itraconazole, ketoconazole, voriconazole)

Possible increased plasma alosetron concentrations1

Ketoconazole: Increased systemic exposure of alosetron by 29%1

Use concomitantly with caution1

Cimetidine

Possible increased plasma alosetron concentrations1

Concomitant use not recommended unless clinically required1

Cisapride

No substantial effect on cisapride metabolism or QT interval 1

Fluvoxamine

Increased plasma concentrations and half-life of alosetron by approximately sixfold and threefold, respectively1

Concomitant use contraindicated1

Hormonal contraceptives, oral (ethinyl estradiol, levonorgestrel)

No clinically important effect on plasma contraceptive concentration1

Hydralazine

Possible increased concentrations of hydralazine via N-acetyltransferase inhibition1

Isoniazid

Possible increased concentrations of isoniazid via N-acetyltransferase inhibition1

Macrolides (clarithromycin, telithromycin)

Possible increased plasma alosetron concentrations1

Use concomitantly with caution1

Procainamide

Possible increased concentrations of procainamide via N-acetyltransferase inhibition1

Protease inhibitors

Possible increased plasma alosetron concentrations1

Use concomitantly with caution1

Quinolone anti-infectives

Possible increased plasma alosetron concentrations1

Concomitant use not recommended unless clinically required1

Theophylline

Potential inhibition of theophylline metabolism; however, no clinically important effect observed in one study1

Alosetron Hydrochloride Pharmacokinetics

Absorption

Bioavailability

About 50–60%.1

Food

25% decrease in absorption; 15 minute delay in reaching peak plasma concentration.1

Special Populations

In some studies in geriatric adults, about 40% increase in plasma concentrations observed.1

In one female with severe hepatic impairment, exposure to alosetron following administration of a single 1-mg dose was approximately 14-fold higher than that reported in healthy individuals.1 In another female with moderate hepatic impairment, exposure to alosetron was increased by 1.6-fold.1

Distribution

Plasma Protein Binding

82%.1

Elimination

Metabolism

Extensively metabolized in liver to several metabolites.1 Circulating metabolites are present in low concentrations (≤15% of unchanged alosetron), and therefore not likely to contribute to pharmacologic activity of the drug.1

Elimination Route

Excreted principally in urine (74%), mainly as metabolites, and in feces (11%).1 Also excreted as unchanged drug in urine (13%) and feces (1%).1

Half-life

About 1.5 hours.1

Special Populations

Renal impairment (Clcr 4–56 mL/minute) has no effect on renal elimination of alosetron.1 Effects on metabolite pharmacokinetics not studied in patients with renal impairment.1

Stability

Storage

Oral

Tablets

20–25°C; protect from light and moisture.1

Actions

  • Inhibition of enteric neuronal, peripheral, and CNS serotonergic type 3 (5-HT3) receptors may modulate serotonin-sensitive GI processes (visceral pain, colonic transit, and GI secretion) related to the pathophysiology of IBS.1 2 4 5 6 11 12

Advice to Patients

  • Importance of patients reading the manufacturer’s patient information (medication guide) prior to starting therapy and each time the prescription is refilled.1

  • Importance of not starting alosetron if constipated.1

  • Importance of immediately discontinuing alosetron and informing clinician if constipation occurs or does not resolve after discontinuance.1

  • Importance of resuming alosetron only if constipation is resolved and clinician treating IBS agrees.1

  • Importance of immediately discontinuing alosetron and informing clinician if signs or symptoms of acute ischemic colitis (e.g., blood in stools, sudden worsening of abdominal pain) occur.1

  • Importance of not resuming alosetron if ischemic colitis has occurred.1

  • Discontinue and consult clinician if IBS symptoms are not adequately controlled after 4 weeks of taking 1 mg twice daily.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs,1 as well as any concomitant illnesses (e.g., hepatic disease).

  • Importance of informing patients of other precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of alosetron hydrochloride is restricted.1 7 8 10 (See Restricted Distribution Programs under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Alosetron Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.5 mg (of alosetron)*

Alosetron Hydrochloride Tablets

Lotronex

Prometheus

1 mg (of alosetron)*

Alosetron Hydrochloride Tablets

Lotronex

Prometheus

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Prometheus Labs. Lotronex (alosetron hydrochloride) tablets prescribing information. San Diego, CA; 2014 Mar.

2. Balfour JAB, Goa KL, Perry CM. Alosetron. Drugs. 2000; 59:511-8. [PubMed 10776833]

3. Camilleri M, Northcutt AR, Kong S et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial. Lancet. 2000; 355:1035-40. [IDIS 444751] [PubMed 10744088]

4. Lembo T. Neurotransmitter antagonism in management of irritable bowel syndrome. Lancet. 2000; 355:1030-1. [IDIS 444749] [PubMed 10744083]

5. Anon. FDA approves irritable bowel syndrome treatment for women. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2000 Feb 9.

6. Glaxo Wellcome, Research Triangle Park, NC: Personal Communication.

7. Woodcock J. Letter regarding Lotronex from Dr. Janet Woodcock, Director, Center for Drug Evaluation and Research. Rockville, MD: US Food and Drug Administration; 2001 Mar 8.

8. GlaxoSmithKline. Lotronex tablets to be re-introduced for women with severe diarrhea-predominant IBS. Research Triangle Park, NC; 2002 Jun 7. Press release.

9. Anon. FDA Dear IBS patient letter: Lotronex information. Rockville, MD: US Food and Drug Administration; 2002 Jan 24.

10. Young D. Lotronex returns to market. Bethesda, MD; 2002 Jun 12. News article from web site.

11. Anon. Alosetron (Lotronex) revisited. Med Lett Drugs Ther. 2002; 44:67-8. [PubMed 12163838]

12. Lembo T, Wright RA, Lotronex Investigator Team et al. Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. . 2001; 96:2662-70. [IDIS 470043] [PubMed 11569692]

13. Roxane Labs. Alosetron hydrochloride tablets prescribing information. Columbus, OH; 2015 Feb.

14. Prometheus Labs. Lotronex (alosetron hydrochloride) tablets medication guide. San Diego, CA; 2014 Mar.

15. Roxane Labs. Alosetron hydrochloride tablets medication guide. Columbus, OH; 2015 Feb.

16. US Food and Drug Administration. Medical Review: NDA# 21-107/S005. From FDA website.

17. Krause R, Ameen V, Gordon SH et al. A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS. Am J Gastroenterol. 2007; 102:1709-19. [PubMed 17509028]

18. Camilleri M, Mayer EA, Drossman DA et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther. 1999; 13:1149-59. [PubMed 10468696]

19. Bardhan KD, Bodemar G, Geldof H et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2000; 14:23-34. [PubMed 10632642]

20. Chey WD, Chey WY, Heath AT et al. Long-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2004; 99:2195-203. [PubMed 15555002]

Hide