Alosetron

Pronunciation

(a LOE se tron)

U.S. Brand Names

Lotronex®

Generic Available

No

Use

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

Restrictions

Only physicians enrolled in GlaxoSmithKline's Prescribing Program for Lotronex® may prescribe this medication. Program stickers must be affixed to all prescriptions; no phone, fax or computerized prescriptions are permitted with this program.

Pregnancy Risk Factor

B

Pregnancy Implications

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

Contraindications

Do not start treatment in patients who are constipated. Hypersensitivity to alosetron or any component of the formulation; history of severe or chronic constipation; history of ischemic colitis, intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation and/or adhesions; active diverticulitis, current or history of Crohn's disease or ulcerative colitis; history of impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; patients unable to understand or comply with "Patient-Physician" agreement; concomitant administration with fluvoxamine

Warnings/Precautions

Patients must read and sign a "Patient-Physician" agreement before receiving the initial prescription. Constipation is a frequent, dose-related side effect. Serious complications of constipation have been infrequently reported (obstruction, perforation, impaction, toxic megacolon, secondary ischemia); risk may be increased in elderly, debilitated patients, or concurrent use of other medications which decrease GI motility. Discontinue immediately in patients with constipation. Nonsevere constipation may be managed by temporarily interrupting therapy. Acute ischemic colitis has been reported during alosetron treatment. Discontinue immediately in patients who experience rectal bleeding or a sudden worsening of abdominal pain, and do not restart therapy if ischemic colitis is diagnosed. Use caution in hepatic or renal impairment. Safety and efficacy have not been established in pediatric or male patients.

Adverse Reactions

>10%: Gastrointestinal: Constipation (dose related) (29%)

1% to 10%: Gastrointestinal: Abdominal discomfort and pain (7%), nausea (6%), gastrointestinal discomfort and pain (6%), abdominal distention (2%), hemorrhoids (2%), regurgitation and reflux (2%)

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

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

Overdosage/Toxicology

There is not a specific antidote for overdose; manage with appropriate supportive therapy.

Drug Interactions

Substrate of CYP1A2 (major), 2C8/9 (minor), 3A4 (minor); Inhibits CYP1A2 (weak), 2E1 (weak)

CYP1A2 inhibitors: May increase the levels/effects of alosetron. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

CYP2C8/9 inhibitors: May increase the levels/effects of alosetron. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

Fluvoxamine: Concomitant use is contraindicated.

Ethanol/Nutrition/Herb Interactions

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

Stability

Store at 15°C to 30°C (59°F to 86°F).

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: Vd: 65-95 L

Protein binding: 82%

Metabolism: Extensive hepatic metabolism. Alosetron is metabolized by 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 for alosetron

Time to peak: 1 hour after oral administration

Excretion: Urine (73%) and feces (24%); 7% as unchanged drug (1% feces, 6% urine)

Dosage

Oral:

Children: Safety and efficacy have not been established.

Adults: Female: 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.

Note: Discontinue immediately if constipation or signs/symptoms of ischemic colitis occur. Do not reinitiate in patients who develop ischemic colitis.

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

Dosage adjustment in renal impairment: The need for dosage adjustment has not been defined (due to limited information on activity of metabolites).

Dosage adjustment in hepatic impairment: Specific guidelines are not available. May increase risk of adverse events.

Administration

May be administered with or with food; however, absorption may be reduced by approximately 25%.

Dietary Considerations

May be taken with or without food.

Patient Education

Take with or without food. Do not take if you are frequently constipated; constipation is a side effect associated with this medication and can lead to serious complications. Stop taking this medication and call your prescriber if you become constipated, or if you have sudden worsening of abdominal pain, severe constipation, or blood in your stool. Do not continue taking the medication until you have spoken with your prescriber; call immediately. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Nursing Implications

Monitor for improvement in cramping abdominal pain, abdominal discomfort, urgency and diarrhea; notify prescriber immediately for sudden worsening of abdominal pain, blood in stool, or if constipation develops. Serious complications of constipation have been reported (obstruction, perforation, impaction, toxic megacolon, secondary ischemia). Discontinue immediately if constipation is severe.

Anesthesia and Critical Care Concerns/Other Considerations

Alosetron has been linked to reports of ischemic colitis, which prompted a call for withdrawal by a prominent U.S. consumer group. The manufacturer initially withdrew this drug voluntarily in response to this concern. It has been reintroduced with restrictions on prescribing.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Throat and tonsil discomfort and pain.

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

Tablet: 0.5 mg, 1 mg

International Brand Names

Lotronex® (BR, KR, MX, NO, PR)