Overview
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.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alosetron is a potent and selective 5-HT 3 receptor antagonist. 5-HT 3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit, and gastrointestinal secretions, processes that relate to the pathophysiology of IBS. 5-HT 3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels, which results in the modulation of the enteric nervous system. The cause of IBS is unknown.
Indications
- 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.
Common Doses
- 0.5 mg
- 1 mg
Dosage
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.
Black Box Warning
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)] .
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) ] .
Side Effects
- 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.
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.