These Highlights Do Not Include All The Information Needed To Use Alosetron Hydrochloride Tablets Safely And Effectively. See Full Prescribing Information For Alosetron Hydrochloride Tablets.

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<0.0001).

MEDICATION GUIDEALOSETRON HYDROCHLORIDE (a-LOE-se-tron HYE-droe-KLOR-ide)

TABLETS

Read the Medication Guide you get with each refill for alosetron hydrochloride tablets. There may be new information. This Medication Guide does not take the place of talking with your doctor.

What is the most important information I should know about alosetron hydrochloride tablets?

Alosetron hydrochloride is a medicine only for some women with severe chronic irritable bowel syndrome (IBS) whose:

main problem is diarrhea and

IBS symptoms have not been helped enough by other treatments.

Some people have developed serious bowel side effects while taking alosetron hydrochloride tablets. Serious bowel (intestine) side effects can happen suddenly, including the following:

Serious complications of constipation: These complications may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death. People who are older, who are weak from illness, or who take other constipating medicines may be more likely to have serious complications of constipation with alosetron hydrochloride tablets.

To lower your chances of getting serious complications of constipation, do the following:

If you are constipated, do not start taking alosetron hydrochloride tablets.

If you get constipated while taking alosetron hydrochloride tablets, stop taking it right away and call your doctor.

If your constipation does not get better after stopping alosetron hydrochloride tablets, call your doctor again.

If you stopped taking alosetron hydrochloride, do not start taking alosetron hydrochloride again unless your doctor tells you to do so.

Inflammation and injury of the intestines caused by reduced blood flow (ischemic colitis): Ischemic colitis is caused by reduced blood flow to parts of the large bowel. The chance of getting ischemic colitis when you take alosetron hydrochloride tablets for more than 6 months is not known. Ischemic colitis may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death.

Stop taking alosetron hydrochloride and call your doctor or get medical help if you have symptoms of ischemic colitis such as new or worsening stomach-area (abdominal) pain, bloody diarrhea or blood in the stool.

What are alosetron hydrochloride tablets?

Alosetron hydrochloride tablets are a prescription medicine usedonly for some women with severe chronic IBS whose:

main problem is diarrhea and

IBS symptoms have not been helped enough by other treatments.

Alosetron hydrochloride does not cure IBS, and it may not help every person who takes it. For those who are helped, alosetron hydrochloride reduces lower stomach area (abdominal) pain and discomfort, the sudden need to have a bowel movement (bowel urgency), and diarrhea from IBS. If you stop taking alosetron hydrochloride tablets, your IBS symptoms may return within 1 or 2 weeks to what they were before you started taking alosetron hydrochloride tablets.

It is not known if alosetron hydrochloride tablets are safe and effective in men with IBS.

It is not known if alosetron hydrochloride tablets are safe and effective in children.

Who should not take alosetron hydrochloride?

Do not take Alosetron hydrochloride tablets if you:

have constipation or you are constipated most of the time.

have had a serious problem from constipation. If you are constipated now, do not start taking alosetron hydrochloride tablets.

have had serious bowel blockages.

have had blood flow problems to your bowels, such as ischemic colitis.

have had blood clots.

have had Crohn's disease, ulcerative colitis, diverticulitis, or severe liver disease.

You are taking fluvoxamine (LUVOX).

What should I talk about with my doctor before taking alosetron hydrochloride?

Talk with your doctor:

about the possible benefits and risks of alosetron hydrochloride tablets.

about how much of a problem IBS is in your life and what treatments you have tried.

about any other illnesses you have and medicines you take or plan to take. These include prescription and non-prescription medicines, supplements, and herbal remedies. Certain illnesses and medicines can increase your chance of getting serious side effects while taking alosetron hydrochloride tablets. Other medicines may interact with how the body handles alosetron hydrochloride tablets.

about any allergies that you have. See the end of the Medication Guide for a complete list of ingredients in alosetron hydrochloride tablets.

if you have liver problems

if you are pregnant or planning to become pregnant. It is not known if alosetron hydrochloride tablets can harm your unborn baby.

if you are breastfeeding or plan to breastfeed. It is not known if alosetron hydrochloride tablets can harm your baby. Talk to your doctor about the best way to feed your baby if you take alosetron hydrochloride tablets.

How should I take alosetron hydrochloride tablets?

Take alosetron hydrochloride tablets exactly as your doctor prescribes them. You can take alosetron hydrochloride with or without food.

Begin with 0.5 mg two times a day for 4 weeks to see how alosetron hydrochloride tablets affect you. You and your doctor may decide that you should keep taking this dose if you are doing well.

Check with your doctor 4 weeks after starting alosetron hydrochloride tablets:

If you try 0.5 mg two times a day for 4 weeks, it may not control your symptoms. If you do not get constipation or other side effects from alosetron hydrochloride tablets, your doctor may increase your dose up to 1 mg two times a day.

If 1 mg two times a day does not work after 4 weeks, alosetron hydrochloride tablets are not likely to help you. You should stop taking it and call your doctor.

Follow the instructions in the section “What is the most important information I should know about alosetron hydrochloride tablets?” about when you must stop taking the medicine and when you should call your doctor.

What are the possible side effects of alosetron hydrochloride tablets?

Alosetron hydrochloride tables may cause serious side effects, including:

See“What is the most important information I should know about Alosetron hydrochloride tablets?”The most common side effects of alosetron hydrochloride talets include:

constipation

stomach (abdominal) discomfort and pain

nausea

intestinal discomfort and pain

These are not all the possible side effects of alosetron hydrochloride tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store alosetron hydrochloride tablets?

Store alosetron hydrochloride between 68ºF to 77ºF (20ºC to 25ºC).

Protect alosetron hydrochloride from light and moisture.

Keep alosetron hydrochloride and all medicines out of the reach of children.

General information about the safe and effective use of alosetron hydrochloride tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use alosetron hydrochloride tablets for a condition for which it was not prescribed. Do not give alosetron hydrochloride tablets to oter people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about alosetron hydrochloride tablets that is written for healthcare professionals.

What are the ingredients of alosetron hydrochloride tablets?

Active Ingredient: alosetron hydrochloride.

Inactive Ingredients: lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The white film-coat for the 0.5 mg tablet contains hypromellose, titanium dioxide, and triacetin. The blue film-coat for the 1 mg tablet contains hypromellose, titanium dioxide, triacetin, and indigo carmine.

Brands listed are the trademarks of their respective owners.

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054

Made in CANADA

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised April 2019

Principal Display Panel - Bottle Label

actavis

NDC 45963- 479-03 Rx Only 30 tablets

Alosetron Hydrochloride







Tablets 0.5 mg

Each film-coated tablet contains alosetron







hydrochloride equivalent to 0.5 mg alosetron.

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)].

• Thompson WG, Creed F, Drossman DA, et al. Functional bowel disease and functional abdominal pain. Gastroenterol Int. 1992;5:75-91.

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).

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 hydrochloride through breast milk for severe constipation and blood in stools.

The active ingredient in alosetron hydrochloride tablets is alosetron hydrochloride (HCl), 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 ₁₇H ₁₈N ₄O•HCl, representing a molecular weight of 330.8. Alosetron is a white to beige solid that has a solubility of 61 mg/mL in water, 42  mg/mL in 0.1M hydrochloric acid, 0.3  mg/mL in pH 6 phosphate buffer, and <0.1  mg/mL in pH 8 phosphate buffer. The chemical structure of alosetron is:

Alosetron hydrochloride tablets are supplied for oral administration as 0.5 mg (white) and 1 mg (blue) tablets. The 0.5 mg tablet contains 0.562 mg alosetron HCl equivalent to 0.5  mg alosetron, and the 1 mg tablet contains 1.124 mg alosetron HCl equivalent to 1  mg of alosetron. Each tablet also contains the inactive ingredients lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The white film coat for the 0.5 mg tablet contains hypromellose, titanium dioxide, and triacetin. The blue film coat for the 1 mg tablet contains hypromellose, titanium dioxide, triacetin, and indigo carmine.

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

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.

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.

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 is prescribed for these patients [see Warnings and Precautions ( 5.1)] .

In a 48-week multinational, double-blind, placebo-controlled study, alosetron hydrochloride 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial.

Alosetron hydrochloride (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis.

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

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

• 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)

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)]

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.

Some 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 hydrochloride was 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.

Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite pharmacokinetics and the effect of end-stage renal disease have not been assessed.

In healthy volunteers and patients with IBS, alosetron (2  mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4  mg dose. In patients with IBS, multiple oral dosages of alosetron (4 mg twice daily for 6.5  days) significantly increased colonic compliance.

Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2  mg administered orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1  mg administered orally twice daily for 4  days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion. However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown.

The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8  mg twice daily.

Alosetron hydrochloride has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies.

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.

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.

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.

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 approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment [see Dosage and Administration ( 2.2), Contraindications ( 4)] .

Alosetron hydrochloride 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 alosetron hydrochloride, 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 in men.

Data from a dose-ranging study of women (n = 85) who received alosetron hydrochloride 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1  mg twice daily (29%). Therefore, to lower the risk of constipation, Alosetron hydrochloride should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials. [See Dosage and Administration ( 2.1)]

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.

• Serious Complications of Constipation: May occur in some patients without warning. Include 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. ( 5.1)
• Discontinue alosetron hydrochloride immediately if constipation occurs. ( 5.1)
• Ischemic colitis: May occur in some patients without warning. Promptly evaluate patients with signs of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain). ( 5.2)
• Discontinue alosetron hydrochloride immediately if signs of ischemic colitis occur, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. ( 5.2)

• 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 hydrochloride in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1  mg twice a day. ( 2.1)

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 GX EX1 on one face.

Alosetron hydrochloride Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face.

In addition to events reported in clinical trials, the following events have been identified during use of alosetron hydrochloride in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to alosetron hydrochloride.

Gastrointestinal: Impaction, perforation, ulceration, small bowel mesenteric ischemia.

Neurological: Headache.

Skin: Rash.

• 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)

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.

Advise the patient to read the FDA-approved patient labeling.

Medication Guide

Prescriber and Patient Responsibilities

Patients should be fully counseled on and understand the risks and benefits of alosetron hydrochloride before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber's direction. Patients should be fully counseled on and understand the risks and benefits of alosetron hydrochloride before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber's direction.

Prescribers must:

• counsel patients for whom alosetron hydrochloride is appropriate about the benefits and risks of alosetron hydrochloride and discuss the impact of IBS symptoms on the patient's life. counsel patients for whom alosetron hydrochloride is appropriate about the benefits and risks of alosetron hydrochloride and discuss the impact of IBS symptoms on the patient's life.
• review the Medication Guide, which outlines the benefits and risks of alosetron hydrochloride, and instruct the patient to read it carefully. Answer all questions the patient may have about alosetron hydrochloride. The complete text of the Medication Guide is printed at the end of this document. review the Medication Guide, which outlines the benefits and risks of alosetron hydrochloride, and instruct the patient to read it carefully. Answer all questions the patient may have about alosetron hydrochloride. The complete text of the Medication Guide is printed at the end of this document.
• provide each patient with appropriate instructions for taking alosetron hydrochloride. provide each patient with appropriate instructions for taking alosetron hydrochloride.

Additional copies of the Medication Guide are available by contacting the company that makes alosetron hydrochloride tablets at 1-888-423-5227 or visiting www.lotronex.com. Additional copies of the Medication Guide are available by contacting the company that makes alosetron hydrochloride tablets at 1-888-423-5227 or visiting www.lotronex.com.

Patients who are prescribed alosetron hydrochloride should be instructed to:

• read the Medication Guide before starting alosetron hydrochloride and each time they refill their prescription. read the Medication Guide before starting alosetron hydrochloride and each time they refill their prescription.
• not start taking alosetron hydrochloride if they are constipated. not start taking alosetron hydrochloride if they are constipated.
• immediately discontinue alosetron hydrochloride and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of alosetron hydrochloride. Resume alosetron hydrochloride only if their constipation has resolved and after discussion with and the agreement of their treating prescriber. immediately discontinue alosetron hydrochloride and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of alosetron hydrochloride. Resume alosetron hydrochloride only if their constipation has resolved and after discussion with and the agreement of their treating prescriber.
• stop taking alosetron hydrochloride and contact their prescriber if alosetron hydrochloride does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day. stop taking alosetron hydrochloride and contact their prescriber if alosetron hydrochloride does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.

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)] .

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 GX EX1 on one face. Bottles of 30 (NDC 45963-479-03) with child-resistant closures.

Alosetron hydrochloride Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face. Bottles of 30 (NDC 45963-480-03) with child-resistant closures.

Store at 20-25˚C (USP Controlled Room Temperature). Protect from light and moisture.

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

Some 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 or 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].

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

Infrequent but serious gastrointestinal adverse reactions have been reported with the use of alosetron hydrochloride. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death.

• Alosetron hydrochloride is 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 hydrochloride 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 hydrochloride 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 hydrochloride is discontinued. Patients with resolved constipation should resume alosetron hydrochloride only on the advice of their treating prescriber [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.1), ( 5.2)].

In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK ^±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.

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<0.0001).

MEDICATION GUIDEALOSETRON HYDROCHLORIDE (a-LOE-se-tron HYE-droe-KLOR-ide)

TABLETS

Read the Medication Guide you get with each refill for alosetron hydrochloride tablets. There may be new information. This Medication Guide does not take the place of talking with your doctor.

What is the most important information I should know about alosetron hydrochloride tablets?

Alosetron hydrochloride is a medicine only for some women with severe chronic irritable bowel syndrome (IBS) whose:

main problem is diarrhea and

IBS symptoms have not been helped enough by other treatments.

Some people have developed serious bowel side effects while taking alosetron hydrochloride tablets. Serious bowel (intestine) side effects can happen suddenly, including the following:

Serious complications of constipation: These complications may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death. People who are older, who are weak from illness, or who take other constipating medicines may be more likely to have serious complications of constipation with alosetron hydrochloride tablets.

To lower your chances of getting serious complications of constipation, do the following:

If you are constipated, do not start taking alosetron hydrochloride tablets.

If you get constipated while taking alosetron hydrochloride tablets, stop taking it right away and call your doctor.

If your constipation does not get better after stopping alosetron hydrochloride tablets, call your doctor again.

If you stopped taking alosetron hydrochloride, do not start taking alosetron hydrochloride again unless your doctor tells you to do so.

Inflammation and injury of the intestines caused by reduced blood flow (ischemic colitis): Ischemic colitis is caused by reduced blood flow to parts of the large bowel. The chance of getting ischemic colitis when you take alosetron hydrochloride tablets for more than 6 months is not known. Ischemic colitis may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death.

Stop taking alosetron hydrochloride and call your doctor or get medical help if you have symptoms of ischemic colitis such as new or worsening stomach-area (abdominal) pain, bloody diarrhea or blood in the stool.

What are alosetron hydrochloride tablets?

Alosetron hydrochloride tablets are a prescription medicine usedonly for some women with severe chronic IBS whose:

main problem is diarrhea and

IBS symptoms have not been helped enough by other treatments.

Alosetron hydrochloride does not cure IBS, and it may not help every person who takes it. For those who are helped, alosetron hydrochloride reduces lower stomach area (abdominal) pain and discomfort, the sudden need to have a bowel movement (bowel urgency), and diarrhea from IBS. If you stop taking alosetron hydrochloride tablets, your IBS symptoms may return within 1 or 2 weeks to what they were before you started taking alosetron hydrochloride tablets.

It is not known if alosetron hydrochloride tablets are safe and effective in men with IBS.

It is not known if alosetron hydrochloride tablets are safe and effective in children.

Who should not take alosetron hydrochloride?

Do not take Alosetron hydrochloride tablets if you:

have constipation or you are constipated most of the time.

have had a serious problem from constipation. If you are constipated now, do not start taking alosetron hydrochloride tablets.

have had serious bowel blockages.

have had blood flow problems to your bowels, such as ischemic colitis.

have had blood clots.

have had Crohn's disease, ulcerative colitis, diverticulitis, or severe liver disease.

You are taking fluvoxamine (LUVOX).

What should I talk about with my doctor before taking alosetron hydrochloride?

Talk with your doctor:

about the possible benefits and risks of alosetron hydrochloride tablets.

about how much of a problem IBS is in your life and what treatments you have tried.

about any other illnesses you have and medicines you take or plan to take. These include prescription and non-prescription medicines, supplements, and herbal remedies. Certain illnesses and medicines can increase your chance of getting serious side effects while taking alosetron hydrochloride tablets. Other medicines may interact with how the body handles alosetron hydrochloride tablets.

about any allergies that you have. See the end of the Medication Guide for a complete list of ingredients in alosetron hydrochloride tablets.

if you have liver problems

if you are pregnant or planning to become pregnant. It is not known if alosetron hydrochloride tablets can harm your unborn baby.

if you are breastfeeding or plan to breastfeed. It is not known if alosetron hydrochloride tablets can harm your baby. Talk to your doctor about the best way to feed your baby if you take alosetron hydrochloride tablets.

How should I take alosetron hydrochloride tablets?

Take alosetron hydrochloride tablets exactly as your doctor prescribes them. You can take alosetron hydrochloride with or without food.

Begin with 0.5 mg two times a day for 4 weeks to see how alosetron hydrochloride tablets affect you. You and your doctor may decide that you should keep taking this dose if you are doing well.

Check with your doctor 4 weeks after starting alosetron hydrochloride tablets:

If you try 0.5 mg two times a day for 4 weeks, it may not control your symptoms. If you do not get constipation or other side effects from alosetron hydrochloride tablets, your doctor may increase your dose up to 1 mg two times a day.

If 1 mg two times a day does not work after 4 weeks, alosetron hydrochloride tablets are not likely to help you. You should stop taking it and call your doctor.

Follow the instructions in the section “What is the most important information I should know about alosetron hydrochloride tablets?” about when you must stop taking the medicine and when you should call your doctor.

What are the possible side effects of alosetron hydrochloride tablets?

Alosetron hydrochloride tables may cause serious side effects, including:

See“What is the most important information I should know about Alosetron hydrochloride tablets?”The most common side effects of alosetron hydrochloride talets include:

constipation

stomach (abdominal) discomfort and pain

nausea

intestinal discomfort and pain

These are not all the possible side effects of alosetron hydrochloride tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store alosetron hydrochloride tablets?

Store alosetron hydrochloride between 68ºF to 77ºF (20ºC to 25ºC).

Protect alosetron hydrochloride from light and moisture.

Keep alosetron hydrochloride and all medicines out of the reach of children.

General information about the safe and effective use of alosetron hydrochloride tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use alosetron hydrochloride tablets for a condition for which it was not prescribed. Do not give alosetron hydrochloride tablets to oter people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about alosetron hydrochloride tablets that is written for healthcare professionals.

What are the ingredients of alosetron hydrochloride tablets?

Active Ingredient: alosetron hydrochloride.

Inactive Ingredients: lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The white film-coat for the 0.5 mg tablet contains hypromellose, titanium dioxide, and triacetin. The blue film-coat for the 1 mg tablet contains hypromellose, titanium dioxide, triacetin, and indigo carmine.

Brands listed are the trademarks of their respective owners.

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054

Made in CANADA

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised April 2019

Principal Display Panel - Bottle Label

actavis

NDC 45963- 479-03 Rx Only 30 tablets

Alosetron Hydrochloride







Tablets 0.5 mg

Each film-coated tablet contains alosetron







hydrochloride equivalent to 0.5 mg alosetron.

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)].

• Thompson WG, Creed F, Drossman DA, et al. Functional bowel disease and functional abdominal pain. Gastroenterol Int. 1992;5:75-91.

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).

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 hydrochloride through breast milk for severe constipation and blood in stools.

The active ingredient in alosetron hydrochloride tablets is alosetron hydrochloride (HCl), 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 ₁₇H ₁₈N ₄O•HCl, representing a molecular weight of 330.8. Alosetron is a white to beige solid that has a solubility of 61 mg/mL in water, 42  mg/mL in 0.1M hydrochloric acid, 0.3  mg/mL in pH 6 phosphate buffer, and <0.1  mg/mL in pH 8 phosphate buffer. The chemical structure of alosetron is:

Alosetron hydrochloride tablets are supplied for oral administration as 0.5 mg (white) and 1 mg (blue) tablets. The 0.5 mg tablet contains 0.562 mg alosetron HCl equivalent to 0.5  mg alosetron, and the 1 mg tablet contains 1.124 mg alosetron HCl equivalent to 1  mg of alosetron. Each tablet also contains the inactive ingredients lactose (anhydrous), magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The white film coat for the 0.5 mg tablet contains hypromellose, titanium dioxide, and triacetin. The blue film coat for the 1 mg tablet contains hypromellose, titanium dioxide, triacetin, and indigo carmine.

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

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.

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.

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 is prescribed for these patients [see Warnings and Precautions ( 5.1)] .

In a 48-week multinational, double-blind, placebo-controlled study, alosetron hydrochloride 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial.

Alosetron hydrochloride (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis.

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

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

• 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)

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)]

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.

Some 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 hydrochloride was 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.

Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite pharmacokinetics and the effect of end-stage renal disease have not been assessed.

In healthy volunteers and patients with IBS, alosetron (2  mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4  mg dose. In patients with IBS, multiple oral dosages of alosetron (4 mg twice daily for 6.5  days) significantly increased colonic compliance.

Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2  mg administered orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1  mg administered orally twice daily for 4  days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion. However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown.

The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8  mg twice daily.

Alosetron hydrochloride has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies.

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.

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.

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.

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 approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment [see Dosage and Administration ( 2.2), Contraindications ( 4)] .

Alosetron hydrochloride 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 alosetron hydrochloride, 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 in men.

Data from a dose-ranging study of women (n = 85) who received alosetron hydrochloride 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1  mg twice daily (29%). Therefore, to lower the risk of constipation, Alosetron hydrochloride should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials. [See Dosage and Administration ( 2.1)]

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.

• Serious Complications of Constipation: May occur in some patients without warning. Include 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. ( 5.1)
• Discontinue alosetron hydrochloride immediately if constipation occurs. ( 5.1)
• Ischemic colitis: May occur in some patients without warning. Promptly evaluate patients with signs of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain). ( 5.2)
• Discontinue alosetron hydrochloride immediately if signs of ischemic colitis occur, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. ( 5.2)

• 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 hydrochloride in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1  mg twice a day. ( 2.1)

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 GX EX1 on one face.

Alosetron hydrochloride Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face.

In addition to events reported in clinical trials, the following events have been identified during use of alosetron hydrochloride in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to alosetron hydrochloride.

Gastrointestinal: Impaction, perforation, ulceration, small bowel mesenteric ischemia.

Neurological: Headache.

Skin: Rash.

• 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)

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.

Advise the patient to read the FDA-approved patient labeling.

Medication Guide

Prescriber and Patient Responsibilities

Patients should be fully counseled on and understand the risks and benefits of alosetron hydrochloride before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber's direction. Patients should be fully counseled on and understand the risks and benefits of alosetron hydrochloride before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber's direction.

Prescribers must:

• counsel patients for whom alosetron hydrochloride is appropriate about the benefits and risks of alosetron hydrochloride and discuss the impact of IBS symptoms on the patient's life. counsel patients for whom alosetron hydrochloride is appropriate about the benefits and risks of alosetron hydrochloride and discuss the impact of IBS symptoms on the patient's life.
• review the Medication Guide, which outlines the benefits and risks of alosetron hydrochloride, and instruct the patient to read it carefully. Answer all questions the patient may have about alosetron hydrochloride. The complete text of the Medication Guide is printed at the end of this document. review the Medication Guide, which outlines the benefits and risks of alosetron hydrochloride, and instruct the patient to read it carefully. Answer all questions the patient may have about alosetron hydrochloride. The complete text of the Medication Guide is printed at the end of this document.
• provide each patient with appropriate instructions for taking alosetron hydrochloride. provide each patient with appropriate instructions for taking alosetron hydrochloride.

Additional copies of the Medication Guide are available by contacting the company that makes alosetron hydrochloride tablets at 1-888-423-5227 or visiting www.lotronex.com. Additional copies of the Medication Guide are available by contacting the company that makes alosetron hydrochloride tablets at 1-888-423-5227 or visiting www.lotronex.com.

Patients who are prescribed alosetron hydrochloride should be instructed to:

• read the Medication Guide before starting alosetron hydrochloride and each time they refill their prescription. read the Medication Guide before starting alosetron hydrochloride and each time they refill their prescription.
• not start taking alosetron hydrochloride if they are constipated. not start taking alosetron hydrochloride if they are constipated.
• immediately discontinue alosetron hydrochloride and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of alosetron hydrochloride. Resume alosetron hydrochloride only if their constipation has resolved and after discussion with and the agreement of their treating prescriber. immediately discontinue alosetron hydrochloride and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of alosetron hydrochloride. Resume alosetron hydrochloride only if their constipation has resolved and after discussion with and the agreement of their treating prescriber.
• stop taking alosetron hydrochloride and contact their prescriber if alosetron hydrochloride does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day. stop taking alosetron hydrochloride and contact their prescriber if alosetron hydrochloride does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.

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)] .

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 GX EX1 on one face. Bottles of 30 (NDC 45963-479-03) with child-resistant closures.

Alosetron hydrochloride Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are blue, oval, film-coated tablets debossed with GX CT1 on one face. Bottles of 30 (NDC 45963-480-03) with child-resistant closures.

Store at 20-25˚C (USP Controlled Room Temperature). Protect from light and moisture.

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

Some 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 or 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].

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

Infrequent but serious gastrointestinal adverse reactions have been reported with the use of alosetron hydrochloride. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death.

• Alosetron hydrochloride is 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 hydrochloride 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 hydrochloride 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 hydrochloride is discontinued. Patients with resolved constipation should resume alosetron hydrochloride only on the advice of their treating prescriber [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.1), ( 5.2)].

In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK ^±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.