Alosetron
FDA Drug Information • Also known as: Alosetron
- Brand Names
- Alosetron
- Route
- ORAL
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: SERIOUS GASTROINTESTINAL ADVERSE REACTIONS Infrequent but serious gastrointestinal adverse reactions have been reported with the use of alosetron tablets. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death. Alosetron tablets are indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy [see Indications and Usage (1)] . Alosetron tablets should be discontinued immediately in patients who develop constipation or symptoms of ischemic colitis. Patients should immediately report constipation or symptoms of ischemic colitis to their prescriber. Alosetron tablets should not be resumed in patients who develop ischemic colitis. Patients who have constipation should immediately contact their prescriber if the constipation does not resolve after alosetron tablets is discontinued. Patients with resolved constipation should resume alosetron tablets only on the advice of their treating prescriber [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) , (5.2)]. WARNING: SERIOUS GASTROINTESTINAL ADVERSE REACTIONS See full prescribing information for complete boxed warning. Infrequent but serious gastrointestinal adverse reactions have been reported with the use of alosetron tablets. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization and, rarely, blood transfusion, surgery, and death. Alosetron tablets are indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy. ( 1 ) Discontinue alosetron tablets immediately in patients who develop constipation or symptoms of ischemic colitis. Do not resume alosetron tablets in patients who develop ischemic colitis. ( 2.1 , 5.1 , 5.2 )
Description
11 DESCRIPTION The active ingredient in alosetron tablets USP, is alosetron hydrochloride (HCl) USP, a potent and selective antagonist of the serotonin 5-HT 3 receptor type. Chemically, alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, monohydrochloride. Alosetron is achiral and has the empirical formula C 17 H 18 N 4 O
What Is Alosetron Used For?
1 INDICATIONS AND USAGE Alosetron tablets are indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and not responded adequately to conventional therapy. Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. Because of infrequent but serious gastrointestinal adverse reactions associated with alosetron tablets, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable. Clinical studies have not been performed to adequately confirm the benefits of alosetron tablets in men. Alosetron tablets are selective serotonin 5-HT 3 antagonist indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal tract excluded and not responded adequately to conventional therapy. ( 1 ) Severe IBS includes diarrhea and 1 or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Starting dose is 0.5 mg twice a day ( 2.1 ) May increase dose to 1 mg twice a day after 4 weeks if starting dosage is well tolerated but does not adequately control IBS symptoms ( 2.1 ) Discontinue alosetron tablets in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. ( 2.1 ) 2.1 Adult Patients To lower the risk of constipation, alosetron tablets should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking alosetron tablets until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, Alosetron tablets should be discontinued immediately. Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. Alosetron tablets should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. Alosetron tablets can be taken with or without food [see Clinical Pharmacology (12.3) ] . Alosetron tablets should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron tablets should not be restarted in patients who develop ischemic colitis. Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if alosetron tablets are prescribed for these patients. Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if alosetron tablets are prescribed for these patients [see Warnings and Precautions (5.1) ] . 2.2 Patients with Hepatic Impairment Alosetron tablets are extensively metabolized by the liver, and increased exposure to alosetron tablets is likely to occur in patients with hepatic impairment. Increased drug exposure may increase the risk of serious adverse reactions. Alosetron tablets should be used with caution in patients with mild or moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment [see Contraindications (4) , Use in Specific Populations (8.6) ].
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the label: Complications of constipation [see Boxed Warning , Warnings and Precautions ( 5.1 )] Ischemic colitis [see Boxed Warning , Warnings and Precautions ( 5.2 )] Most common adverse reactions (incidence >2% and >placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea and gastrointestinal discomfort and pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lifestar Pharma LLC at 1-888-995-4337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of alosetron tablets twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron tablets and occurred more frequently on alosetron tablets than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron tablets compared to placebo (p<0.0001). Table 1. Adverse Reactions Reported in ≥1% of Patients with Irritable Bowel Syndrome and More Frequently on Alosetron Tablets 1 mg Twice Daily Than Placebo Body System Adverse Reaction Placebo (n = 2,363) Alosetron Tablets 1 mg twice daily (n = 8,328) Gastrointestinal Constipation 6% 29% Abdominal discomfort and pain 4% 7% Nausea 5% 6% Gastrointestinal discomfort and pain 3% 5% Abdominal distention 1% 2% Regurgitation and reflux 2% 2% Hemorrhoids 1% 2% Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with alosetron tablets [see Warnings and Precautions ( 5.1 )] . In clinical studies constipation was reported in approximately 29% of patients with IBS treated with alosetron tablets 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<0.0001). Eleven percent (11%) of patients treated with alosetron tablets 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with alosetron tablets 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with alosetron tablets 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in postmarketing experience [see Boxed Warning and Warnings and Precautions (5.1) ] . In Studies 1 and 2, 9% of patients treated with alosetron tablets reported constipation and 4 consecutive days with no bowel movement [see Clinical Studies (14.2) ] . Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with alosetron tablets. Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving alosetron tablets or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving alosetron tablets was reported in a 12-week study. A causal association with alosetron tablets has not been established. Long-Term...
Drug Interactions
7 DRUG INTERACTIONS In vivo data suggest that alosetron is primarily metabolized by cytochrome P450 (CYP) 1A2, with minor contributions from CYP3A4 and CYP2C9. Therefore, inducers or inhibitors of these enzymes may change the clearance of alosetron. CYP1A2 inhibitors: Avoid concomitant uses because of increased exposure and half-life of alosetron. Use with fluvoxamine is contraindicated. ( 4.3 , 7.1) CYP3A4 inhibitors: Use with caution in combination due to increased exposure of alosetron. ( 7.2 ) 7.1 CYP1A2 Inhibitors Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Concomitant administration of alosetron and fluvoxamine is contraindicated [see Contraindications (4.3) ] . Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions. 7.2 CYP3A4 Inhibitors Ketoconazole is a known strong inhibitor of CYP3A4. In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day. Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%. Caution should be used when alosetron and ketoconazole are administered concomitantly. Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions. The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known. 7.3 Other CYP Enzymes In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 3A4, 2C9, or 2C19. In vitro at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1 mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, alosetron did not inhibit CYP2E1 but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase. Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine. The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed. Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents...
Contraindications
4 CONTRAINDICATIONS Do not initiate in patients with constipation ( 4.1 ) History of chronic or severe constipation or sequelae from constipation; intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions; ischemic colitis; impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; Crohn's disease or ulcerative colitis; diverticulitis; severe hepatic impairment ( 4.2 ) Concomitant use of fluvoxamine ( 4.3 ) 4.1 Constipation Alosetron tablets should not be initiated in patients with constipation [see Warnings and Precautions (5.1) ] . 4.2 History of Severe Bowel or Hepatic Disorders Alosetron tablets are contraindicated in patients with a history of the following: chronic or severe constipation or sequelae from constipation intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation and/or adhesions ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state Crohn's disease or ulcerative colitis diverticulitis severe hepatic impairment 4.3 Concomitant Use of Fluvoxamine Concomitant administration of alosetron tablets with fluvoxamine is contraindicated. Fluvoxamine, a known strong inhibitor of CYP1A2, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold [see Drug Interactions (7.1) ] .
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary The available data with alosetron tablets use in pregnant women are insufficient to draw conclusions about any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of alosetron in rats and rabbits during organogenesis at doses 160 to 240 times, respectively, the recommended human dosage (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively. Data Animal Data No adverse developmental effects were observed with oral administration of alosetron during the period of organogenesis to pregnant rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) or to pregnant rabbits at doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area).
Overdosage
10 OVERDOSAGE There is no specific antidote for overdose of alosetron hydrochloride. Patients should be managed with appropriate supportive therapy. Individual oral doses as large as 16 mg have been administered in clinical studies without significant adverse reactions. This dose is 8 times higher than the recommended total daily dose. Inhibition of the metabolic elimination and reduced first pass of other drugs might occur with overdoses of alosetron hydrochloride [see Drug Interactions (7) ].
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Alosetron Tablets USP, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are round, film coated, blue colored biconvex tablets debossed with "LS 701" on one side and plain on other side. Bottles of 30 (NDC 63629-2518-1) with child-resistant closures. Store at 20-25°C (68-77°F) (See USP Controlled Room Temperature). Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.