Alosetron Hydrochloride

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 a 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)

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 post-marketing 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. Post-marketing 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 are 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) ] .

3 DOSAGE FORMS AND STRENGTHS 0.5 mg and 1 mg tablets Alosetron tablets USP, 0.5 mg (0.562 mg alosetron hydrochloride, USP equivalent to 0.5 mg alosetron), are white, oval shaped, film coated tablets debossed with “AN248” on one side and plain on the other side. Alosetron tablets USP, 1 mg (1.124 mg alosetron hydrochloride, USP equivalent to 1 mg alosetron), are light blue, oval shaped, film coated tablets debossed with “AN249” on one side and plain on the other side. Tablets: 0.5 and 1 mg (3)

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 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) ] .

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 AvKARE at 1-855-361-3993 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 hydrochloride twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron hydrochloride and occurred more frequently on alosetron hydrochloride than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron hydrochloride compared to placebo (p 2-fold) was seen in patients receiving alosetron hydrochloride 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 hydrochloride was reported in a 12-week study. A causal association with alosetron hydrochloride has not been established. Long-Term Safety: 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. Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome: Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received alosetron hydrochloride and occurred more frequently with alosetron hydrochloride than with placebo. Other events reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches and fatigue. Table 2: Gastrointestinal Adverse Reactions Reported in ≥ 3% of Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome and More Frequently on Alosetron Hydrochloride Than Placebo Adverse Reaction Placebo (n = 176) Alosetron Hydrochloride 0.5 mg once daily (n = 175) Alosetron Hydrochloride 1 mg once daily (n = 172) Alosetron Hydrochloride 1 mg twice daily (n = 176) Constipation 5% 9% 16% 19% Abdominal pain 3% 5% 6% 7% Diarrhea 2% 3% 2% 2% Hemorrhoidal hemorrhage 2% 3% 2% 2% Flatulence 2% 2% 1% 3% Hemorrhoids 2% 1% 1% 3% Abdominal pain upper 1% 3% 1% 1% Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included constipation (14% and 10% of patients taking alosetron hydrochloride 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting and flatulence. Other events reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral …

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 mg/day to 200 mg/day for 16 days, with co-administration 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 co-administration 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. Co-administration 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 ethinyl estradiol and levonorgestrel (CYP3A4 substrates). A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effects of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined. Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the CYP enzymes 2C9, 2C19, or 2E1. Alosetron does not appear to induce the major cytochrome P450 drug-metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes.

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Contraindicated in severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment. (4.2, 8.6) Geriatric use: Elderly patients may be at greater risk for complications of constipation. (8.5) 8.1 Pregnancy Risk Summary The available data with alosetron hydrochloride 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). 8.2 Lactation Risk Summary There are no data regarding the presence of alosetron in human milk, the effects on the breastfed infant, or the effects on milk production. Alosetron and/or metabolites of alosetron are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for alosetron hydrochloride and any potential adverse effects on the breastfed infant from alosetron hydrochloride or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to alosetron through breast milk for severe constipation and blood in stools. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use of alosetron hydrochloride is not recommended in the pediatric population, based upon the risk of serious complications of constipation and ischemic colitis in adults. 8.5 Geriatric Use In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults [see Warnings and Precautions (5.1) ] . However, this effect was not consistently observed in men. Post-marketing 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 is prescribed for these patients [see Warnings and Precautions (5.1) ] . 8.6 Hepatic Impairment Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic impairment. Alosetron should not be used in patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment. A single 1 mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of > 9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed appro …

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. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, patients with IBS exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT 3 receptors.

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 molecular formula C 17 H 18 N 4 O•HCl, representing a molecular weight of 330.81 g/mol. Alosetron is a white to pale brown color powder that has a solubility of 70.5 mg/mL in DI Water, 45.7 mg/mL in 0.1 N HCl, 79.4 mg/mL in pH 4.5 Acetate Buffer, 3.2 mg/mL in pH 6.8 Phosphate Buffer and 0.1 mg/mL in pH 7.5 Phosphate Buffer. The chemical structure of alosetron is: Alosetron tablets, USP are supplied for oral administration as 0.5 mg (white) and 1 mg (light blue) tablets. The 0.5 mg tablet contains 0.562 mg alosetron hydrochloride, USP equivalent to 0.5 mg alosetron and the 1 mg tablet contains 1.124 mg alosetron hydrochloride, USP equivalent to 1 mg of alosetron. Each tablet also contains the inactive ingredients lactose anhydrous, magnesium stearate, microcrystalline cellulose and pregelatinized starch (maize). The white film coat for the 0.5 mg tablet contains hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide. The light blue film coat for the 1 mg tablet contains FD&C blue #2, hypromellose, macrogol, polysorbate 80 and titanium dioxide. 1

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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Alosetron tablets USP, 0.5 mg (0.562 mg alosetron hydrochloride, USP equivalent to 0.5 mg alosetron), are supplied as white, oval shaped, film-coated tablets debossed with “AN248” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-248-03 with child-resistant closures. Bottles of 500: NDC 65162-248-50 with child-resistant closures. Alosetron tablets USP, 1 mg (1.124 mg alosetron hydrochloride, USP equivalent to 1 mg alosetron), are supplied as light blue, oval shaped, film-coated tablets debossed with “AN249” on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-249-03 with child-resistant closures. Bottles of 500: NDC 65162-249-50 with child-resistant closures. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture.