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)

  • Ischemic Colitis and Constipation
  • Serious adverse GI effects reported, including ischemic colitis and serious complications of constipation, that have resulted in serious injury or death. (See Warnings under Cautions.)1

  • 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 Program
  • Voluntarily withdrawn from US market by manufacturer in November 2000 because of numerous reports of severe adverse effects, including ischemic colitis, severely obstructed or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.1 8 11 Before therapy is initiated, clinician must provide and patient must read the Medication Guide for Lotronex and Patient-Physician Agreement for Lotronex and both must sign the Agreement.1 8 11 (See Restricted Distribution Program 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: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () 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 Use restricted to patients with most favorable risk-benefit profile.a (See Cautions.)

Slideshow: Doctor Avoidance: 5 Reasons Why It's Not a Good Idea

Diarrhea-predominant IBS is considered severe if accompanied by at least one of these symptoms: frequent and severe abdominal pain and/or discomfort; frequent bowel urgency or fecal incontinence; or disability or restriction of daily activities.1 11

Alosetron Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Restricted Distribution Program

Prescribed only by clinicians who have enrolled in the Prescribing Program for Lotronex.1 8 11 (See REMS.)

Before therapy is initiated, clinician must provide and patient must read the Medication Guide for Lotronex and Patient-Physician Agreement for Lotronex, and both must sign the Agreement.1 8 11

Pharmacists may fill only those prescriptions with the sticker signifying enrollment in the Prescribing Program for Lotronex and must dispense a Medication Guide for Lotronex with each filled prescription.1 8 10 11 a Telephone, facsimile, or computerized prescription transmissions are not permitted.a

For details on program requirements, contact GlaxoSmithKline’s Prescribing Program for Lotronex at 888-825-5249 or at the special website ().1 11

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 for 4 weeks is recommended to minimize incidence of constipation (although efficacy of this dosage has not been established in clinical trials).a Consider continuation of this dosage if well tolerated and symptoms adequately controlled.a

Increase to 1 mg twice daily after 4 weeks if initial dosage is well tolerated but IBS symptoms are not adequately controlled.1 11 a

Prescribing Limits

Adults

Severe Diarrhea-predominant IBS in Women
Oral

Discontinue after 4 weeks of therapy with 1 mg twice daily if symptoms are not adequately controlled.1 11 a

Safety of long-term use not established; insufficient data to estimate incidence of ischemic colitis after >6 months therapy.1

Special Populations

Hepatic Impairment

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

Renal Impairment

Not known whether dosage adjustment is required in patients with renal impairment.1

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

  • Current Crohn’s disease or ulcerative colitis, active diverticulitis, or a history of these disorders.1 11

  • Severe hepatic impairment.a

  • Inability to understand or comply with the Patient-Physician Agreement for Lotronex.1

  • Known hypersensitivity to alosetron or any ingredient in the formulation.1

  • Concomitant administration with fluvoxamine.a (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Constipation

Frequent, dose-related constipation occurs.a Serious complications (e.g., obstruction, perforation, impaction, toxic megacolon, secondary intestinal ischemia, death) reported.a

Discontinue immediately if constipation occurs.1

If constipation resolves, resume therapy only on the advice of clinician.1 11 (See Contraindications under Cautions and see Boxed Warning.)

Elderly or debilitated patients or those taking drugs that decrease GI motility may be at increased risk for complications of constipation.1

Ischemic Colitis

Ischemic colitis reported; may be life-threatening.a

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 and see Boxed Warning.)

Specific Populations

Pregnancy

Category B.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

Geriatric Use

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

Men

Clinical studies have not been performed to adequately confirm benefits in men.a 11

Hepatic Impairment

Extensively metabolized in liver; increased exposure to alosetron and/or its metabolites is probable in patients with hepatic impairment.1 11 Use with caution in patients with mild or moderate hepatic impairment; contraindicated in patients with severe hepatic impairment.a (See Contraindications under Cautions and see Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Constipation, abdominal discomfort or pain, nausea, GI discomfort or pain.1

Interactions for Alosetron Hydrochloride

Metabolized by CYP isoenzymes; in vitro, 2C9 (30%), 3A4 (18%), and 1A2 (10%) isoenzymes are involved.a In vivo, metabolized by CYP1A2 to a greater extent.a

Inhibits CYP1A2 (60%) and CYP2E1 (50%) in vitro at very high concentrations (27-fold higher than peak plasma concentrations observed with 1 mg dose); in vivo, inhibits CYP1A2 (30%), but no effect on CYP2E1.a Inhibits N-acetyltransferase in vivo (30%).a Does not inhibit CYP2C9, CYP2C19, CYP2D6, or CYP3A4.a

Does not induce CYP2E1, CYP2C19, or CYP3A.a

Drugs Affecting Hepatic Microsomal Enzymes

Inducers or inhibitors of CYP2C9, 3A4, or 1A2: potential altered alosetron clearance.a

Drugs Metabolized by Hepatic Microsomal Enzymes

Alosetron is unlikely to inhibit clearance of drugs metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.a

Substrates of 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 concentrationsa

Use concomitantly with cautiona

Cimetidine

Possible increased plasma alosetron concentrationsa

Concomitant use not recommended unless clinically requireda

Cisapride

No substantial effect on cisapride metabolism or QT interval a

Fluvoxamine

Increased plasma alosetron concentrations and prolonged alosetron half-lifea

Concomitant use contraindicateda

Hormonal contraceptives, oral (ethinyl estradiol, levonorgestrel)

No clinically important effect on plasma contraceptive concentrationa

Macrolides (clarithromycin, telithromycin)

Possible increased plasma alosetron concentrationsa

Use concomitantly with cautiona

Quinolone antibiotics

Potential increased plasma alosetron concentrationsa

Concomitant use not recommended unless clinically requireda

Theophylline

Potential inhibition of theophylline metabolism; no clinically important effect in one studya

Alosetron Hydrochloride Pharmacokinetics

Absorption

Bioavailability

About 50–60%.a

Food

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

Special Populations

In healthy adult males, 30–50% decrease in plasma concentrations; in males with IBS, 27% decrease.a

In geriatric adults, about 40% increase in plasma concentrations, but was inconsistent in males.a

In one female with severe hepatic impairment, exposure to alosetron was approximately 14-fold higher than that reported in healthy individuals.a

Distribution

Plasma Protein Binding

82%.a

Elimination

Metabolism

Extensively metabolized in liver; biological activity of metabolites is unknown.a

Elimination Route

Excreted principally in urine (73%), mainly as metabolites, and in feces (24%).a Also excreted as unchanged drug (7%) in urine (6%) and feces.1 2 a

Half-life

About 1.5 hours.a

Special Populations

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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C); protect from light and moisture.a

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 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).a

  • Importance of patient reading and understanding Lotronex Medication Guide before starting alosetron and rereading it each time prescription is refilled.1 (See REMS.)

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

Preparations

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

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

Alosetron Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.5 mg (of alosetron)

Lotronex

GlaxoSmithKline

1 mg (of alosetron)

Lotronex

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Lotronex 0.5MG Tablets (PROMETHEUS): 30/$472.03 or 90/$1,374.18

Lotronex 1MG Tablets (PROMETHEUS): 30/$700.89 or 90/$2,040.67

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Lotronex (alosetron hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2002 Jun.

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. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.

a. GlaxoSmithKline. Lotronex (alosetron hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2006 Mar

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