Alosetron

U.S. BRAND NAMES — Lotronex®
PHARMACOLOGIC CATEGORY Selective 5-HT3 Receptor Antagonist
DOSING: ADULTS — IBS: Female: Oral: 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.
DOSING: PEDIATRIC — Safety and efficacy have not been established.
DOSING: ELDERLY — Refer to adult dosing. Dosage adjustment is not required; however, postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation.
DOSING: RENAL IMPAIRMENT — The need for dosage adjustment has not been defined (due to limited information on activity of metabolites).
DOSING: HEPATIC IMPAIRMENT — In mild-to-moderate dysfunction (Child-Pugh score 9), use caution. Avoid use in severe hepatic dysfunction (Child-Pugh score >9).
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 0.5 mg, 1 mg
DOSAGE FORMS: CONCISE Tablet: Lotronex®: 0.5 mg, 1 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — May be administered with or with food; however, absorption may be reduced by approximately 25%.
USE — Treatment of women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional therapy
ADVERSE REACTIONS SIGNIFICANT >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, headache, hemorrhage, hepatitis, hyperacidity, hyper-/hypoglycemia, hypertension, hypnagogic effects, hypoesthesia, hypothalamus/pituitary dysfunction, ileus, impaction, ischemic colitis, memory effects, muscle pain/stiffness, obstruction, occult stools, pain, perforation, rash, RBC/hemoglobin defects, sedation, sexual dysfunction, skeletal pain, small bowel mesenteric ischemia, tachyarrhythmia, temperature regulation impairment, tremor, ulceration, ulcerative colitis, urinary frequency, urticaria
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, severe hepatic dysfunction, 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 Box warnings: Constipation: See "Concerns related to adverse effects" below. Ischemic colitis: See "Concerns related to adverse effects" below. Patient-Physician agreement: See "Other warnings/precautions" below.
Concerns related to adverse effects: Constipation: [U.S. Boxed Warning]: Discontinue immediately in patients with constipation. 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 with concurrent use of other medications which decrease GI motility. Nonsevere constipation may be managed by temporarily interrupting therapy. Ischemic colitis: [U.S. Boxed Warning]: Acute ischemic colitis has been reported during 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.
Disease-related concerns: Hepatic impairment: Use caution in mild-to-moderate hepatic impairment (Child-Pugh score 9); do not use in severe impairment (Child-Pugh score 10).
Special populations: Males: Safety and efficacy have not been established in males. Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions: Patient-Physician agreement: [U.S. Boxed Warning]: Patients must read and sign a "Patient-Physician" agreement before receiving the initial prescription.
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.
An FDA-approved medication guide must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.
DRUG INTERACTIONS — Substrate of CYP1A2 (major), 2C9 (minor), 3A4 (minor); Inhibits CYP1A2 (weak), 2E1 (weak)
CYP1A2 inhibitors: May increase the levels/effects of alosetron. Example inhibitors include ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.
Fluvoxamine: Concomitant use is contraindicated.
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: When administered with food, absorption may be reduced by ~25%.
PREGNANCY RISK FACTOR — B (show table)
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
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.
DIETARY CONSIDERATIONS — May be taken with or without food.
PRICING — (data from drugstore.com)Tablets (Lotronex) 0.5 mg (30): $252.47
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)
PATIENT INFORMATION — 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; if after stopping the medication, constipation does not resolve, call your prescriber again. Notify your prescriber if you are pregnant, plan on becoming pregnant, or if you are breast-feeding.