Alosetron

LOTRONEX is 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 LOTRONEX, 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 LOTRONEX in men.

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. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity.

Starting dose is 0.5 mg twice a day. 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. Discontinue LOTRONEX in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day.

Do not initiate in patients with constipation. 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. Concomitant use of fluvoxamine

Boxed warning (serious gastrointestinal adverse reactions): Infrequent but serious gastrointestinal adverse reactions have been reported with the use of LOTRONEX. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death. Serious Complications of Constipation: May occur in some patients without warning. Includes obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia and in rare cases perforation and death have been reported. Risk is increased in patients who are elderly, debilitated, or taking medications that decrease bowel motility. Discontinue LOTRONEX immediately if constipation occurs. Ischemic colitis: May occur in some patients without warning.

The following adverse reactions are described in more detail in other sections of the label: Complications of constipation Ischemic colitis Most common adverse reactions (incidence >2% and >placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea, and gastrointestinal discomfort and pain.

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. CYP3A4 inhibitors: Use with caution in combination due to increased exposure of alosetron.

Store at 20-25°C (68-77°F) (USP Controlled Room Temperature). Protect from light and moisture.