ALOSETRON HYDROCHLORIDE

ALOSETRON HYDROCHLORIDE- alosetron hydrochloride tablet
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

Alosetron hydrochloride 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 hydrochloride 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 hydrochloride tablets in men.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Patients

To lower the risk of constipation, alosetron hydrochloride 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 hydrochloride tablets until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, alosetron hydrochloride 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 hydrochloride tabletsshould 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 hydrochloride tablets can be taken with or without food [ see Clinical Pharmacology (12.3) ].

Alosetron hydrochloride tablets should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron hydrochloride 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 hydrochloride 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 hydrochloride tablets are prescribed for these patients [see Warnings and Precautions (5.1)].

2.2 Patients with Hepatic Impairment

Alosetron hydrochloride tablets are extensively metabolized by the liver, and increased exposure to alosetron hydrochloride tablets are likely to occur in patients with hepatic impairment. Increased drug exposure may increase the risk of serious adverse reactions. Alosetron hydrochloride 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)].

3 DOSAGE FORMS AND STRENGTHS

0.5 mg and 1 mg tablets

Alosetron hydrochloride tablets, 0.5 mg (0.562 mg alosetron HCl equivalent to 0.5 mg alosetron), are white, oval, film-coated tablets debossed with “P” on one side and 819 on the other side.

Alosetron hydrochloride tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with “P” on one side and 820 on the other side.

4 CONTRAINDICATIONS

4.1 Constipation

Alosetron hydrochloride should not be initiated in patients with constipation [see Warnings and Precautions (5.1)].

4.2 History of Severe Bowel or Hepatic Disorders

Alosetron hydrochloride is 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 hydrochloride 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)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Complications of Constipation

S ome patients have experienced serious complications of constipation without warning.

Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported with use of alosetron hydrochloride during clinical trials. Complications of constipation have been reported with use of 1 mg twice daily and with lower doses. A dose response relationship has not been established for serious complications of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either alosetron hydrochloride tabletsor placebo.In addition, rare cases of perforation and death have been reported from postmarketing clinical practice. In some cases, complications of constipation required intestinal surgery, including colectomy. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation.

Alosetron hydrochloride should be discontinued immediately in patients who develop constipation [see Boxed Warning].

5.2 Ischemic Colitis

S ome patients have experienced ischemic colitis without warning.

Ischemic colitis has been reported in patients receiving alosetron hydrochloride in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving alosetron hydrochloridewas 0.2% (2 per 1,000 patients, 95% confidence interval 1 to 3) through 3 months and was 0.3% (3 per 1,000 patients, 95% confidence interval 1 to 4) through 6 months.Ischemic colitis has been reported with use of 1 mg twice daily and with lower doses. A dose-response relationship has not been established. Ischemic colitis was reported in one patient receiving placebo. The patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking alosetron hydrochloride for longer than 6 months.

Alosetron hydrochloride should be discontinued immediately in patients with signs of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Because ischemic colitis can be life-threatening, patients with signs or symptoms of ischemic colitis should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with alosetron hydrochloride should not be resumed in patients who develop ischemic colitis.