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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(a LOE se tron)

Generic Available (U.S.)

No

Medication Guide

An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088624.pdf, must be dispensed with this medication.

REMS Components

Elements to Assure Safe Use; Implementation System; Medication Guide

Prescribing and Access Restrictions

As a requirement of the REMS program, access to the medication is restricted. Physicians must enroll in the Prometheus Prescribing Program for Lotronex® (www.lotronexppl.com or 1-888-423-5227) in order to prescribe this medication. Program stickers must be affixed to all prescriptions; no phone, fax, or computerized prescriptions are permitted with this program.

Brand Names: U.S.

• Lotronex®

Pharmacologic Category

• Selective 5-HT3 Receptor Antagonist

Pharmacologic Category Synonyms

• 5-HT₃ Receptor Antagonist

Use: Labeled Indications

Treatment of women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional therapy

Pregnancy Risk Factor

B

Pregnancy Considerations

There are no adequate and well-controlled studies in pregnant women. Alosetron should be used in pregnant women only if clearly needed.

Lactation

Excretion in breast milk unknown/use caution

Breast-Feeding Considerations

Animal studies indicate that alosetron and/or metabolites are excreted in breast milk. It is not known if alosetron in excreted in human milk. Caution should be used in administering alosetron to a nursing woman.

Contraindications

Do not start treatment in patients who are constipated. History of severe or chronic constipation or sequelae from constipation; history of ischemic colitis, intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, adhesions, diverticulitis, Crohn's disease, ulcerative colitis, severe hepatic impairment, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; patients unable to understand or comply with “Patient-Physician” agreement; concomitant administration with fluvoxamine

Warnings/Precautions

Boxed warnings:

• Appropriate use: See “Other warnings/precautions” below.

• Constipation: See “Concerns related to adverse effects” below.

• Ischemic colitis: See “Concerns related to adverse effects” below.

• REMS program: See “Other warnings/precautions” below.

Concerns related to adverse effects:

• Constipation: [U.S. Boxed Warning]: Discontinue immediately in patients who develop constipation; serious complications of constipation have been infrequently reported (obstruction, ileus, perforation, impaction, toxic megacolon, secondary ischemia). Constipation is a frequent, dose-related side effect; risk for complications from constipation may be increased in elderly, debilitated patients, or with concurrent use of other medications which decrease GI motility. Nonsevere constipation may be managed by temporarily interrupting therapy. Do not initiate in patients with constipation.

• Ischemic colitis: [U.S. Boxed Warning]: Acute ischemic colitis has been reported during treatment. Discontinue and evaluate immediately in patients who experience rectal bleeding, bloody diarrhea, or a sudden worsening of abdominal pain, and do not restart therapy if ischemic colitis is diagnosed.

Disease-related concerns:

• Hepatic impairment: Use caution in mild-to-moderate hepatic impairment (Child-Pugh score ≤9); contraindicated in severe impairment (Child-Pugh score ≥10).

Special populations:

• Elderly: Use with caution in the elderly due to increased risk of complications from constipation.

Other warnings/precautions:

• Appropriate use: [U.S. Boxed Warning]: Only indicated for women with severe diarrhea-predominant irritable bowel syndrome with inadequate response to conventional therapy who have chronic IBS symptoms (lasting ≥6 months) and are without anatomic or biochemical abnormalities of the GI tract. Severe diarrhea-predominant IBS includes at least one of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, and disability or restriction of daily activities due to IBS.

• REMS program: [U.S. Boxed Warning]: Should only be prescribed by physicians enrolled in the Prometheus Prescribing Program for Lotronex®. Patients must read and sign a “Patient-Physician” agreement before receiving the initial prescription.

Adverse Reactions

>10%: Gastrointestinal: Constipation (dose related; 9% to 29%)

1% to 10%:

Central nervous system: Fatigue (≥3%), headache (≥3%)

Gastrointestinal: Abdominal discomfort and pain (1% to 7%), nausea (6%), gastrointestinal discomfort and pain (5%), gastroenteritis (≥3%), vomiting (≥3%), diarrhea (2% to 3%), flatulence (1% to 3%), hemorrhoids (1% to 3%), abdominal distention (2%), regurgitation and reflux (2%)

Genitourinary: Urinary tract infection (≥3%)

Neuromuscular & skeletal: Muscle spasm (≥3%)

Respiratory: Cough (≥3%), nasopharyngitis (≥3%), upper respiratory tract infection (≥3%)

≤1% (Limited to important or life-threatening): Allergic skin reactions, alopecia, anxiety, arrhythmia, bilirubin level changes, bladder inflammation, bone pain, breathing disorder, cholecystitis, cognitive function disorders, confusion, cramps, colitis, depression, dermatitis, diaphoresis, diverticulitis, dyspepsia, extrasystoles, fluid disturbances, GI intussusception, GI lesions, GI motility decreased, GI obstructions, GI spasms, hematoma, hemorrhage, hyperacidity, hyper-/hypoglycemia, hypertension, hypnagogic effects, hypoesthesia, hypothalamus/pituitary dysfunction, ileus, ischemic colitis, memory effects, muscle pain/stiffness, occult stools, pain, proctitis, RBC/hemoglobin defects, sedation, sexual dysfunction, skeletal pain, tachyarrhythmia, temperature regulation impairment, tremor, ulcerative colitis, urinary frequency, urticaria

Postmarketing and/or case reports: GI impaction, GI perforation, GI ulceration, hepatitis, rash, small bowel mesenteric ischemia

Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Risk X: Avoid combination

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Alosetron. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

FluvoxaMINE: May decrease the metabolism of Alosetron. Risk X: Avoid combination

Rifamycin Derivatives: May increase the metabolism of Antiemetics (5HT3 Antagonists). Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Food: When administered with food, absorption may be reduced by ~25%.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Mechanism of Action

Alosetron is a potent and selective antagonist of a subtype of the serotonin 5-HT₃ receptor. 5-HT₃ receptors are ligand-gated ion channels extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels affect the regulation of visceral pain, colonic transit, and gastrointestinal secretions. In patients with irritable bowel syndrome, blockade of these channels may reduce pain, abdominal discomfort, urgency, and diarrhea.

Pharmacodynamics/Kinetics

Distribution: V_d: 65-95 L

Protein binding: 82%

Metabolism: Extensive hepatic metabolism via CYP2C9, 3A4, and 1A2. Thirteen metabolites have been detected in the urine. Biological activity of these metabolites in unknown.

Bioavailability: Mean: 50% to 60% (range: 30% to >90%); decreased with food (25%)

Half-life elimination: 1.5 hours

Time to peak: 1 hour

Excretion: Urine (74%, 13% of total dose as unchanged drug); feces (11%, 1% of total dose as unchanged drug)

Dosage

Oral:

Adults: Females: Initial: 0.5 mg twice daily for 4 weeks, with or without food; if tolerated, but response is inadequate, may be increased after 4 weeks to 1 mg twice daily. If response is inadequate after 4 weeks of 1 mg twice-daily dosing, discontinue treatment.

Elderly: Dosage adjustment is not required; however, postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation.

Dosage adjustment for toxicity:

Constipation: Patients experiencing constipation with 0.5 mg twice daily should discontinue therapy until constipation resolves. Therapy may be reinitiated at 0.5 mg once daily. Discontinue immediately if constipation recurs at lower dose.

Ischemic colitis: Discontinue therapy immediately; do not restart

Dosage adjustment in renal impairment: There are no dosage adjustments recommended in the manufacturer's labeling.

Dosage adjustment in hepatic impairment:

Mild-to-moderate dysfunction (Child-Pugh score ≤9): Use caution

Severe dysfunction (Child-Pugh score ≥10): Use is contraindicated

Administration: Oral

May be administered with or without food.

Dietary Considerations

May be taken with or without food.

Geriatric Considerations

Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause depression or sleep abnormalities; may rarely cause anxiety or sedation

Mental Health: Effects on Psychiatric Treatment

Constipation is common; use caution with concurrent psychotropics possessing anticholinergic activity (eg, benztropine, clozapine, TCAs); may cause nausea; concurrent use with SSRIs, lithium, or valproate may produce additive effects

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral:

Lotronex®: 0.5 mg, 1 mg

Pricing: U.S. (www.drugstore.com)

Tablets (Lotronex)

0.5 mg (30): $472.03

1 mg (30): $700.89

References

Koch KM, Corrigan BW, Manzo J, et al, “Alosetron Repeat Dose Pharmacokinetics, Effects on Enzyme Activities, and Influence of Demographic Factors,” Aliment Pharmacol Ther, 2004, 20(2):223-30.

Lexi-Comp.com

Last full review/revision December 2011

Content last modified December 2011