The active ingredient in LOTRONEX Tablets is alosetron hydrochloride (HCl), a potent and selective antagonist of the serotonin 5-HT₃ 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: C₁₇H₁₈N₄O•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:

LOTRONEX 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.

Last updated on RxList: 5/16/2008

LOTRONEX is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have:

• chronic IBS symptoms (generally lasting 6 months or longer),
• had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and
• not responded adequately to conventional therapy.

Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following:

• frequent and severe abdominal pain/discomfort
• frequent bowel urgency or fecal incontinence
• disability or restriction of daily activities due to IBS

Because of infrequent but serious gastrointestinal adverse events associated with LOTRONEX, the indication is restricte to those patients for whom the benefit-to-risk balance is most favorable.

Clinical studies have not been performed to adequately confirm the benefits of LOTRONEX in men.

For safety reasons, only physicians who enroll in the Prometheus Prescribing Program for LOTRONEX should prescribe LOTRONEX (see PRECAUTIONS: Prescribing Program for LOTRONEX).

Usual Dosage in Adults: To lower the risk of constipation, LOTRONEX should be started at a dosage of 0.5 mg twice a day. Patients well controlled on 0.5 mg twice a day may be maintained on this regimen. If, after 4 weeks, the 0.5-mg twice-daily 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, the dose used in controlled clinical trials (see Clinical Trials). LOTRONEX 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.

LOTRONEX can be taken with or without food (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Food Effects).

LOTRONEX should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. LOTRONEX 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 LOTRONEX is prescribed for these patients (see also Geriatric Patients).

Pediatric Patients: Safety and effectiveness have not been established in pediatric patients.

Geriatric 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 LOTRONEX is prescribed for these patients (see WARNINGS).

Patients With Renal Impairment: There are insufficient data available on the biological activity of the metabolites of LOTRONEX. It is unknown if dosage adjustment is needed in patients with renal impairment (see CLINICAL PHARMACOLOGY: Population Subgroups: ReducedRenalFunction).

Patients With Hepatic Impairment: LOTRONEX is extensively metabolized by the liver and increased exposure to LOTRONEX is likely to occur in patients with hepatic impairment. Increased drug exposure may increase the risk of serious adverse events. LOTRONEX should be used with caution in patients with mild or moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY: Population Subgroups: Reduced Hepatic Function, CONTRAINDICATIONS, and PRECAUTIONS: Hepatic Insufficiency).

Information for Pharmacists: LOTRONEX may be dispensed only on presentation of a prescription for LOTRONEX with a sticker for the Prescribing Program for LOTRONEX attached. A Medication Guide for LOTRONEX must be given to the patient each time LOTRONEX is dispensed as required by law. No telephone, facsimile, or computerized prescriptions are permitted with this program. Refills are permitted to be written on prescriptions.

LOTRONEX 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 0173-0738-00) with child-resistant closures.

LOTRONEX 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 0173-0690-05) with child-resistant closures.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Protect from light and moisture.

Prometheus Laboratories Inc. January 2008. FDA revision date: 4/1/2008

Last updated on RxList: 5/16/2008

Table 1 summarizes adverse events from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of LOTRONEX twice daily for 8 to 24 weeks. The adverse events in Table 1 were reported in 1% or more of patients who received LOTRONEX and occurred more frequently on LOTRONEX than on placebo. A statistically significant difference was observed for constipation in patients treated with LOTRONEX compared to placebo (p < 0.0001).

Table 1. Adverse Events Reported in ≥ 1% of IBS Patients and More Frequently on LOTRONEX 1 mg B.I.D. Than Placebo

Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with LOTRONEX (see WARNINGS). In clinical studies constipation was reported in approximately 29% of IBS patients treated with LOTRONEX 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p < 0.0001). Eleven percent (11%) of patients treated with LOTRONEX 1 mg twice daily withdrew from the studies due to constipation. Although the number of IBS patients treated with LOTRONEX 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with LOTRONEX 1 mg twice daily who. reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in postmarketing experience (see BOXED WARNING and WARNINGS). In Studies 1 and 2, 9% of patients treated with LOTRONEX reported constipation and 4 consecutive days with no bowel movement (see Clinical Trials). Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with LOTRONEX.

Hepatic: A similar incidence in elevation of ALT ( > 2-fold) was seen in patients receiving LOTRONEX or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice was reported in a 12-week study. A causal association with LOTRONEX 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 LOTRONEX for longer than 6 months.

Other Events Observed During Clinical Evaluation of LOTRONEX: During its assessment in clinical trials, multiple and single doses of LOTRONEX were administered resulting in 11,874 subject-exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to LOTRONEX varied between trials, and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications.

In the listing that follows, reported adverse events were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to alosetron, occurred in at least 2 patients, and occurred at a greater frequency during treatment with LOTRONEX than during placebo administration are presented. Serious adverse events occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to alosetron treatment and occurring at a greater frequency in LOTRONEX than placebo-treated patients are also presented.

In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency. The following definitions are used: Infrequent adverse events are those occurring on one or more occasion in 1/100 to 1/1,000 patients; Rare adverse events are those occurring on one or more occasion in fewer than 1/1,000 patients.

Although the events reported occurred during treatment with LOTRONEX, they were not necessarily caused by it.

Blood and Lymphatic: Rare: Quantitative red cell or hemoglobin defects, hemorrhage, and lymphatic signs and symptoms.

Cardiovascular: Infrequent: Tachyarrhythmias. Rare: Arrhythmias, increased blood pressure, and extrasystoles.

Drug Interaction, Overdose, and Trauma: Rare: Contusions and hematomas.

Ear, Nose, and Throat: Rare: Ear, nose, and throat infections; viral ear, nose, and throat infections; and laryngitis.

Endocrine and Metabolic: Rare: Disorders of calcium and phosphate metabolism, hyperglycemia, hypothalamus/pituitary hypofunction, hypoglycemia, and fluid disturbances.

Eye: Rare: Light sensitivity of eyes.

Gastrointestinal: Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis (see WARNINGS), and gastrointestinal lesions. Rare: Abnormal tenderness, colitis, gastrointestinal signs and symptoms, proctitis, diverticulitis, positive fecal occult blood, hyperacidity, decreased gastrointestinal motility and ileus, gastrointestinal obstructions, oral symptoms, gastrointestinal intussusception, gastritis, gastroduodenitis, gastroenteritis, and ulcerative colitis.

Hepatobiliary Tract and Pancreas: Rare: Abnormal bilirubin levels and cholecystitis.

Lower Respiratory: Infrequent: Breathing disorders. Rare: Viral respiratory infections.

Musculoskeletal: Rare: Muscle pain; muscle stiffness, tightness and rigidity; and bone and skeletal pain.

Neurological: Infrequent: Hypnagogic effects. Rare: Memory effects, tremors, dreams, cognitive function disorders, disturbances of sense of taste, disorders of equilibrium, confusion, sedation, and hypoesthesia.

Non-Site Specific: Infrequent: Malaise and fatigue, cramps, pain, temperature regulation disturbances. Rare: General signs and symptoms, non-specific conditions, burning sensations, hot and cold sensations, cold sensations, and fungal infections.

Psychiatry: Infrequent: Anxiety. Rare: Depressive moods.

Reproduction: Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections, and fungal reproductive infections.

Skin: Infrequent: Sweating and urticaria. Rare: Hair loss and alopecia; acne and folliculitis; disorders of sweat and sebum; allergic skin reaction; eczema; skin infections; dermatitis and dermatosis; and nail disorders.

Urology: Infrequent: Urinary frequency. Rare: Bladder inflammation; polyuria and diuresis; and urinary tract hemorrhage.

Postmarketing Experience: The following events have been identified during use of LOTRONEX 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 LOTRONEX.

Gastrointestinal: Constipation, ileus, impaction, obstruction, perforation, ulceration, ischemic colitis, small bowel mesen-teric ischemia (see WARNINGS).

Neurological: Headache.

Skin: Rash.

Drug Abuse And Dependence

LOTRONEX has no known potential for abuse or dependence.

Because alosetron is metabolized by a variety of hepatic CYP drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmaco-kinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg per 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).

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 2D6, 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 major CYP enzyme 3A4, as well as the CYP enzymes 2D6, 2C9, 2C19, 2E1, or 1A2.

Alosetron does not appear to induce the major cytochrome P450 (CYP) 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.

Hepatic Insufficiency: Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic insufficiency. 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 (see CLINICAL PHARMACOLOGY: Population Subgroups: Reduced Hepatic Function).

Last updated on RxList: 5/16/2008

(See BOXED WARNING and DOSAGE AND ADMINISTRATION.)

Some patients have experienced serious complications of constipation or ischemic colitis without warning.

Constipation: Serious complications of constipation including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia have been reported with use of LOTRONEX during clinical trials. 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. In IBS clinical trials, approximately 10% of patients on LOTRONEX withdrew prematurely because of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either LOTRONEX or placebo. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation.

LOTRONEX should be discontinued immediately in patients who develop constipation (see BOXED WARNING).

Ischemic Colitis: Ischemic colitis has been reported in patients receiving LOTRONEX 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 LOTRONEX 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 was not reported in women receiving placebo. The patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX for longer than 6 months.

LOTRONEX 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 LOTRONEX should not be resumed in patients who develop ischemic colitis.

Prescribing Program for LOTRONEX: To prescribe LOTRONEX, the physician must be enrolled in the Prescribing Program for LOTRONEX. To enroll, physicians must understand the benefits and risks of treatment with LOTRONEX for severe diarrhea-predominant IBS, including the information in the Prescribing Information, Medication Guide, and Patient-Physician Agreement for LOTRONEX. Physicians need to be able to:

• Diagnose and manage IBS, ischemic colitis, constipation and complications of constipation, or refer patients to specialists as needed.
• Educate patients on the benefits and risks of treatment with LOTRONEX, provide them with the Medication Guide, instruct them to read it, and encourage them to ask questions when first considering LOTRONEX. Patients may be educated by the enrolled physician or a healthcare provider under a
• Prior to the initial prescription of LOTRONEX, obtain the patient's sign it, place the original signed form in the patient's
• Affix program stickers to all prescriptions for LOTRONEX (i.e., the original and all subsequent prescriptions). Stickers will be provided as part of the Prometheus Prescribing Program for LOTRONEX. No telephone, facsimile, or computerized prescriptions are permitted with this program. Refills are permitted to be written on prescriptions.
• Report all serious adverse events with LOTRONEX to Prometheus at 1-888-423-5227 or to the Food and Drug Administration's MedWatch Program at 1-800-FDA-To enroll in the Prescribing Program for LOTRONEX call 1-888-423-5227 or visit www.lotronex.com to complete the Physician Enrollment Form.

Information for Patients: Patients should be fully counseled on and understand the risks and benefits of LOTRONEX before an initial prescription is written. The patient may be educated by the enrolled physician or a healthcare provider under a physician's direction.

PHYSICIANS MUST:

• Counsel patients for whom LOTRONEX is appropriate about the benefits and risks of LOTRONEX and discuss the impact of IBS symptoms on the patient's life.
• Give the patient a copy of the Medication Guide, which outlines the benefits and risks of LOTRONEX, and instruct the patient to read it carefully. Answer all questions the patient may have about LOTRONEX. The complete text of the Medication Guide is printed at the end of this document.
• Review the Patient-Physician Agreement for LOTRONEX with the patient, answer all questions, and give a copy of the signed agreement to the patient.
• Provide each patient with appropriate instructions for taking LOTRONEX.

Copies of the Patient-Physician Agreement for LOTRONEX and additional copies of the Medication Guide are available by contacting Prometheus at 1-888-423-5227 or visiting www. lotronex.com.

PATIENTS WHO ARE PRESCRIBED LOTRONEX SHOULD BE INSTRUCTED TO:

• Read the Medication Guide before starting LOTRONEX and each time they refill their prescription.
• Not start taking LOTRONEX if they are constipated.
• Immediately discontinue LOTRONEX and contact their physician 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 physician again if their constipation does not resolve after discontinuation of LOTRONEX. Resume LOTRONEX only if their constipation has resolved and after discussion with and the agreement of their treating physician.
• Stop taking LOTRONEX and contact their physician if LOTRONEX does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.

Carcinogenesis, Mutagenesis, Impairment of Fertility: 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, respectively, about 60 to 160 times 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.

Pregnancy:Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, LOTRONEX should be used during pregnancy only if clearly needed.

Nursing Mothers: Alosetron and/or metabolites of alosetron are excreted in the breast milk of lactating rats. It is not known whether alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRONEX is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation (see WARNINGS).

Last updated on RxList: 5/16/2008

There is no specific antidote for overdose of LOTRONEX. 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 events. 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 (see PRECAUTIONS: DRUG INTERACTIONS). Single oral doses of LOTRONEX at 15 mg/kg in female mice and 60 mg/kg in female rats (30 and 240 times, respectively, the recommended human dose based on body surface area) were lethal. Symptoms of acute toxicity were labored respiration, subdued behavior, ataxia, tremors, and convulsions.

LOTRONEX should not be initiated in patients with constipation (see WARNINGS).

LOTRONEX 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
• hypersensitivity to any component of the product

LOTRONEX should not be used by patients who are unable to understand or comply with the Patient-Physician Agreement for LOTRONEX.

Concomitant administration of alosetron 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 PRECAUTIONS: DRUG INTERACTIONS).

Last updated on RxList: 5/16/2008

Pharmacodynamics: Mechanism of Action: Alosetron is a potent and selective 5-HT₃ receptor antagonist. 5-HT₃ 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 irritable bowel syndrome (IBS). 5-HT₃ 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, IBS patients 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-HT₃ receptors.

In healthy volunteers and IBS patients, 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 IBS patients, 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 orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1 mg 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.

Pharmacokinetics: 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.

Absorption: Alosetron is rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range 30% to > 90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1-mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurs at 1 hour. In young women, the mean peak plasma concentration is approximately 9 ng/mL, with a similar time to peak.

Food Effects: Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes (see DOSAGE AND ADMINISTRATION: Usual Dosage in Adults).

Distribution: Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL.

Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in IBS patients confirmed that alosetron clearance is minimally influenced by doses up to 8 mg.

Renal elimination of unchanged alosetron accounts for only 6% of the dose. Renal clearance is approximately 94 mL/min.

Alosetron is extensively metabolized in humans. The biological activity of the metabolites is unknown. A mass balance study was performed utilizing an orally administered dose of unlabeled and ¹⁴C-labeled alosetron. On a molar basis, alos-etron metabolites reached additive peak plasma concentrations 9-fold greater than alosetron, and the additive metabolite AUCs were 13-fold greater than the alosetron AUC. Plasma radioactivity declined with a half-life 2-fold longer than that of alosetron, indicating the presence of circulating metabolites. Approximately 73% of the radiolabeled dose was recovered in urine with another 24% of the dose recovered in feces. Only 7% of the dose was recovered as unchanged drug. At least 13 metabolites have been detected in urine. The predominant product in urine was a 6-hydroxy metabolite (15% of the dose). This metabolite was secondarily metabolized to a glucuronide that was also present in urine (14% of the dose). Smaller amounts of the 6-hydroxy metabolite and the 6-O-glucuronide also appear to be present in feces. A bis-oxidized dicarbonyl accounted for 14% of the dose, and its monocarbonyl precursor accounted for another 4% in urine and 6% in feces. No other urinary metabolite accounted for more than 4% of the dose. Glucuronide or sulfate conjugates of unchanged alosetron were not detected in urine.

In studies of Japanese men, an N-desmethyl metabolite was found circulating in plasma in all subjects and accounted for up to 30% of the dose in 1 subject when alosetron was administered with food. The clinical significance of this finding is unknown.

Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non-CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism, based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine (see CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS).

Population Subgroups: Age: 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). However, this effect was not consistently observed in men.

Gender: Plasma concentrations are 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men).

Reduced Hepatic Function: 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 pharma-cokinetic 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 CONTRAINDICATIONS, PRECAUTIONS: Hepatic Insufficiency, and DOSAGE AND ADMINISTRATION: Patients With Hepatic Impairment).

Reduced Renal Function: 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 kinetics and the effect of end-stage renal disease have not been assessed (see DOSAGE AND ADMINISTRATION: Patients With Renal Impairment).

Drug Interactions: See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS.

Clinical Trials

LOTRONEX 1 mg twice daily was studied in two 12-week U.S. multicenter, randomized, double-blind, placebo-controlled trials of identical design (Studies 1 and 2) in non-constipated women with IBS meeting the Rome Criteria¹ for at least 6 months. Women with severe pain or a history of severe constipation were excluded. A 2-week run-in period established baseline IBS symptoms.

Of the 633 women on LOTRONEX and 640 on placebo, about two thirds had diarrhea-predominant IBS. Compared with placebo, 10% to 19% more women with diarrhea-predominant IBS who received LOTRONEX had adequate relief of IBS abdominal pain and discomfort during each month of the study.

Clinical studies have not been performed to adequately confirm the benefits of LOTRONEX in men or patients under the age of 18.

Starting Dosage: Data from a dose-ranging study of women (n = 85) who received 0.5 mg BID of alosetron, indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1 mg BID (29%). Therefore, to lower the risk of constipation, LOTRONEX 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.

Women With Severe Diarrhea-Predominant IBS: LOTRONEX is indicated only for women with severe diarrhea-predominant IBS (see INDICATIONS AND USAGE). The efficacy of LOTRONEX in this subset of the women studied in clinical trials is supported by prospective and retrospective analyses.

Prospective Analyses: : In two 12-week, randomized, double-blind, placebo-controlled clinical trials of women with diarrhea-predominant IBS and bowel urgency on at least 50% of days at entry (Studies 3 and 4), a total of 778 women received LOTRONEX and 515 received placebo. Women receiving LOTRONEX had significant increases over placebo (13% to 16%) in the median percentage of days with urgency control.

The lower gastrointestinal functions of stool consistency, stool frequency, and sense of incomplete evacuation were also evaluated by patients' daily reports. Stool consistency was 4 = loose, and 5 = watery). At baseline, average stool consistency was approximately 4 (loose) for both treatment groups. During the 12 weeks of treatment, the average stool consistency decreased to approximately 3.0 (formed) for patients who received LOTRONEX and 3.5 for the patients who received placebo in the two studies.

At baseline, average stool frequency was approximately 3.2 per day for both treatment groups. During the 12 weeks of treatment, the average daily stool frequency decreased to approximately 2.1 and 2.2 for patients receiving LOTRONEX and 2.7 and 2.8 for patients receiving placebo in the 2 studies.

There was no consistent effect upon the sense of incomplete evacuation during the 12 weeks of treatment for patients receiving LOTRONEX as compared to patients receiving placebo in either study.

Retrospective Analyses: In analyses of patients from Studies 1 and 2 who had diarrhea-predominant IBS and indicated their baseline run-in IBS symptoms were severe at the start of the trial, LOTRONEX provided greater adequate relief of IBS pain and discomfort than placebo. In further analyses of Studies 1 and 2, 57% of patients had urgency at baseline on 5 or more days per week. In this subset, 32% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared to 19% of patients on placebo.

Patient-reported subjective outcomes related to IBS were assessed by questionnaires obtained at baseline and week 12. Patients in the more severe subset who received LOTRONEX reported less difficulty sleeping, less tiredness, fewer eating problems, and less interference with social activities and work/main activities due to IBS symptoms or problems compared to those who received placebo. Change in the impact of IBS symptoms and problems on emotional and mental distress, and on physical and sexual activity in women who received LOTRONEX were not statistically different from those reported by women who received placebo.

In Studies 3 and 4, 66% of patients had urgency at baseline on 5 or more days per week. In this subset, 50% of patients on LOTRONEX had urgency no more than 1 day in the last week of the trial, compared to 29% of patients on placebo. Moreover, in the same subset, 12% on LOTRONEX had urgency no more than 2 days per week in any of the 12 weeks on treatment compared to 1% of placebo patients.

Figure 1. Percent of Patients With Urgency on > 5 Days/Week at Baseline Who Improved to No More Than 1 Day in the Final Week

Long-Term Use: In a 48-week multinational, double-blind, placebo-controlled study, LOTRONEX 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 d-IBS enrolled, 62% completed the trial.

LOTRONEX (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.

REFERENCES

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

Last updated on RxList: 5/16/2008

MEDICATION GUIDE

LOTRONEX®
(LOW-trah-nex)
(alosetron hydrochloride) Tablets

Read this Medication Guide carefully before you sign the Patient-Physician Agreement. You must sign the Patient-Physician Agreement before you start LOTRONEX. Read the Medication Guide you get with each refill for LOTRONEX. There may be new information. This Medication Guide does not take the place of talking with your doctor.

1. What is the most important information I should know about LOTRONEX?

LOTRONEX is a medicine only for some women with severe chronic IBS whose:

• main problem is diarrhea and
• IBS symptoms have not been helped enough by other treatments.

A. Some patients have developed serious bowel side effects while taking LOTRONEX. Serious bowel (intestine) side effects can happen suddenly, including the following two:

1. Serious complications of constipation: About 1 out of every 1,000 women who take LOTRONEX may get 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 constipation problems with LOTRONEX.

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

• If you are constipated, do not start taking LOTRONEX.
• If you get constipated while taking LOTRONEX, stop taking it right away and call your doctor.
• If your constipation does not get better after stopping LOTRONEX, call your doctor again.
• If you stopped taking LOTRONEX, do not start taking LOTRONEX again unless your doctor tells you to do so.

2. Ischemic colitis (reduced blood flow to the bowel): About 3 out of every 1,000 women who take LOTRONEX over a 6-month period may get a serious problem where blood flow to parts of the large bowel is reduced. This is called ischemic colitis. The chance of getting ischemic colitis when you take LOTRONEX 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.

To lower your chances of getting serious complications of ischemic colitis, stop taking LOTRONEX and call your doctor right away if you get:

• new or worse pain in your stomach area (abdomen) or
• blood in your bowel movements.

B. Is LOTRONEX right for you?

LOTRONEX may be right for you if all of these things are true about you:

• Your doctor has told you that your symptoms are due to IBS.
• Your IBS bowel problem is diarrhea.
• Your IBS has lasted for 6 months or longer.
• You tried other IBS treatments and they didn't give you the relief you need.
• Your IBS is severe.

You can tell if your IBS is severe if at least 1 of the following is true for you:

• You have lots of painful stomach cramps or bloating.
• You often can't control the need to have a bowel movement, from diarrhea or bowel movements.
• You can't lead a normal home or work life because you

Enough testing has not been done to confirm LOTRONEX works in men or children under age 18.

C. There is a special prescribing program for LOTRONEX.

Only doctors who have signed up with the company that makes LOTRONEX should write prescriptions for LOTRONEX. As part of signing up, these doctors have said that they understand about IBS and the possible side effects of LOTRONEX. They have agreed to use a special sticker on all prescriptions for LOTRONEX, so the pharmacist will know that the doctors have signed up with the company.

You may be taught about LOTRONEX by your doctor or healthcare provider under a you to sign a Patient-Physician Agreement after you read this Medication Guide for the first time. Signing the Agreement means that you understand the benefits and risks of LOTRONEX and that you have read and understand this Medication Guide.

2. What is LOTRONEX?

LOTRONEX is a medicine only for some women with severe chronic IBS whose:

• main problem is diarrhea and
• IBS symptoms have not been helped enough by other treatments.

LOTRONEX does not cure IBS, and it may not help every person who takes it. For those who are helped, LOTRONEX 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 LOTRONEX, your IBS symptoms may return within 1 or 2 weeks.

3. Who should not take LOTRONEX?

LOTRONEX is not right for everyone. Do not take LOTRONEX if any of the following apply to you:

• Your main IBS problem is constipation or you are constipated most of the time.
• You have had a serious problem from constipation.
• You have had serious bowel blockages.
• You have had blood flow problems to your bowels, such as ischemic colitis.
• You have had blood clots.
• You have had Crohn's disease, ulcerative colitis, diverticulitis,
• You do not understand this Medication Guide or the Patient-Physician Agreement, or you are not willing to follow them.
• You are allergic to LOTRONEX or any of its ingredients. (See the list of ingredients at the end of this Medication Guide.)
• You are taking fluvoxamine (LUVOX®)

If you are constipated now, do not start taking LOTRONEX.

4. What should I talk about with my doctor before taking LOTRONEX?

Talk with your doctor:

• about the possible benefits and risks of LOTRONEX.
• 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 LOTRONEX. Other medicines may interact with how the body handles LOTRONEX. excursions permitted to 15-30°C
• if you are pregnant, planning to get pregnant, or breastfeeding.

5. How should I take LOTRONEX?

• Take LOTRONEX exactly as your doctor prescribes it. You can take LOTRONEX with or without food.
• Begin with 0.5 mg two times a day for 4 weeks to see how LOTRONEX affects 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 LOTRONEX:
  • 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 LOTRONEX, 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, LOTRONEX is not likely to help you. You should stop taking it and call your doctor.
• If you miss a dose of LOTRONEX, just skip that dose. Do not take 2 doses the next time. Wait until the next time you are supposed to take it and then take your normal dose.
• Follow the important instructions in the section “What is the most important information I should know about LOTRONEX?” about when you must stop taking the drug and when you should call your doctor.
• If you see other doctors about your IBS or side effects from LOTRONEX, let the doctor who prescribed LOTRONEX know.

6. What are the possible side effects of LOTRONEX?

Constipation is the most common side effect among women with IBS who take LOTRONEX. Some patients have developed serious bowel side effects while taking LOTRONEX. Read the section “What is the most important information I should know about LOTRONEX?” at the beginning of this Medication Guide for information about the serious side effects you may get with LOTRONEX.

This Medication Guide does not tell you about all the possible side effects of LOTRONEX. Your doctor or pharmacist can give you a more complete list.

7. General information about the safe and effective use of LOTRONEX

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any questions or concerns about LOTRONEX, ask your doctor. Do not use LOTRONEX for a condition for which it was not prescribed. Do not share your medicine with other people. It may harm them.

Your doctor or pharmacist can give you more information about LOTRONEX that was written for healthcare professionals. You can also contact the company that makes LOTRONEX (toll free) at 1-888-423-5227 or at www.lotronex.com.

8. What are the ingredients of LOTRONEX?

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.

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

PATIENT-PHYSICIAN AGREEMENT FOR LOTRONEX

LOTRONEX® (alosetron hydrochloride) is only for women with severe irritable bowel syndrome (IBS) whose main problem is diarrhea and who did not get the relief needed from other treatments. LOTRONEX has not been shown to help men with IBS or patients under age 18.

My doctor, or a healthcare provider under a doctor's direction answered my questions about treatment with LOTRONEX. I have read and I understand the Medication Guide for LOTRONEX, and

• I understand that some patients using LOTRONEX have had serious bowel conditions (ischemic colitis and complications of constipation). I understand that these serious conditions can happen suddenly, and that they may lead to a hospital stay, and in rare cases, blood transfusions, surgery, and death. I also understand that certain patients may be more likely to develop a serious bowel condition while taking LOTRONEX. These include older patients, those who have other health problems and those who take other medicines that may cause constipation.
• My doctor and I agree that my IBS is severe and that other treatments have not given me the relief that I need. I also agree that I meet all of the requirements described in the section of the Medication Guide “What is the most important information I should know about LOTRONEX?” I understand that these requirements help to make sure that LOTRONEX is used only by patients who are likely to have more benefit from treatment than risk.
• I don't have any problems listed in the section of the me from taking LOTRONEX.
• I will follow instructions in the Medication Guide about:
  • telling my doctor, before taking LOTRONEX, about any illnesses I have, or other medicines I am taking or planning to take.
  • taking LOTRONEX exactly as my doctor prescribes it.
  • stopping LOTRONEX and calling my doctor right away if I get constipated, if I have new or worse pain in my abdomen, or if I see blood in my bowel movements.
  • calling my doctor again if the constipation I called about before has not gotten better.
  • not starting LOTRONEX again unless my doctor tells me to do so, if I stopped taking it because I got constipated.
  • talking with my doctor 4 weeks after starting LOTRONEX to recheck my IBS symptoms.
  • stopping LOTRONEX and calling my doctor if my IBS symptoms have not improved after 4 weeks of taking 1 mg 2 times a day.

I understand that LOTRONEX should be prescribed only by doctors who have signed up with the company that makes the drug. Doctors in the program must:

• fully discuss the drug's benefits and risks with each
• sign this agreement with each patient before giving the initial prescription. It is not necessary to sign an agreement more than once.
• use a special sticker on all LOTRONEX prescriptions so that pharmacists know the doctor has signed up.

If I see other doctors about my IBS or possible side effects from LOTRONEX, I will let the doctor who prescribed LOTRONEX know.

My signature below indicates I have read, understood, and agree with all the statements made above. I would like to begin treatment with LOTRONEX.

________________________
Name of Patient (print)

_______________________                   _____________________
         Signature                                                        Date

SECTION FOR THE PHYSICIAN

I am enrolled in the Prescribing Program for LOTRONEX, and I will continue to follow the requirements of the Program.

I, or a healthcare provider under a physician's direction,

• a copy of the Medication Guide for LOTRONEX, and instructed the patient to read it carefully before signing this Agreement, and to take it home.
• counseling about the benefits and risks of LOTRONEX.
• appropriate instructions for taking LOTRONEX.
• answers to all of the patient's questions about treatment
• a prescription for LOTRONEX that has the program sticker affixed on it to alert pharmacists I am enrolled in the Prescribing Program for LOTRONEX.

The patient signed the Patient-Physician Agreement in my presence after I counseled the patient, asked if the patient had any questions about treatment with LOTRONEX, and answered all questions to the best of my ability.

_______________________
Name of Physician (print)

_______________________                    _____________________
           Signature                                                                     Date

After the patient and the physician sign this Patient-Physician Agreement, give a copy to the patient and put the original signed form in the patient's medical record.

PRESCRIBING PROGRAM FOR LOTRONEX™: PHYSICIAN ENROLLMENT FORM

The Prescribing Program for LOTRONEX was implemented to help reduce risks of serious gastrointestinal adverse events, some fatal, associated with this medicine. The program is intended to help physicians and their patients understand the benefits and risks of treatment with LOTRONEX in order to make fully informed decisions.

I wish to participate in the Prescribing Program for LOTRONEX (PPL) and acknowledge that I have read the complete Prescribing Information for LOTRONEX and understand and will follow the requirements of the PPL described below.

• For safety reasons, LOTRONEX is approved only for women with severe, diarrhea-predominant irritable bowel syndrome (D-IBS) who have:
  • Chronic IBS symptoms (generally lasting for 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
• Physicians who enroll in the PPL should be able to diagnose and manage IBS, ischemic colitis, constipation, and complications of constipation, or refer patients to a specialist as needed.
• Patients considering treatment with LOTRONEX must be educated on the benefits and risks of the drug, given a copy of the Medication Guide, instructed to read it, and encouraged to ask questions. The patient may be educated by the enrolled physician or a healthcare provider under a physician's direction
• After reviewing the Medication Guide prior to the initial prescription, the physician and the patient must both sign the Patient-Physician Agreement form. The original signed form must be placed in the given to the patient.
• Program stickers must be affixed to all prescriptions for LOTRONEX (i.e., the original and all subsequent prescriptions). Stickers will be provided as part of the Prometheus Prescribing Program for LOTRONEX. Refills are permitted to be written on prescriptions.
• All prescriptions for LOTRONEX must be written and not transmitted by telephone, facsimile, or computer.
• Prescribers must report all serious adverse events with LOTRONEX to Prometheus at 1-888-423-5227 or to the Food and Drug Administration at 1-800-FDA-1088.

______________________
Name of Physician (print)

____________________                               _____________________
 Signature                                                          Date

DEA Number ________________________________

Office Address:              ________________________________

                                       ________________________________

                                       ________________________________

Office Phone Number: ________________________________

Office Fax Number: ________________________________

Upon enrollment, you will receive a prescribing kit for LOTRONEX with the complete Prescribing Information, Prescribing Program for LOTRONEX stickers, multiple copies of the Medication Guide and Patient-Physician Agreement for LOTRONEX, and instructions for ordering additional supplies of Program materials.

You only need to enroll once, and you are under no obligation to prescribe LOTRONEX. have given the patient named above:

If you have any questions, please call the Prescribing Program for LOTRONEX at 1-888-423-5227 or visit www.lotronex. com.

TO ENROLL, VISIT WWW.LOTRONEX.COM OR PHONE 1-888-423-5227 OR COMPLETE THIS FORM IN ITS ENTIRETY AND MAIL OR FAX TO THE FOLLOWING ADDRESS: with LOTRONEX.

Prescribing Program for Lotronex, 9410 Carroll Park Drive San Diego, CA 92121 1-888-423-5227. Fax Number: 1-858-824-0896. January 2008

Last updated on RxList: 5/16/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ALOSETRON - ORAL

(a-LOE-se-tron)

COMMON BRAND NAME(S): Lotronex

WARNING: Alosetron has rarely caused serious, sometimes fatal intestinal side effects including constipation and ischemic colitis. You should not use this medication if you have ever had problems from blocked blood flow to the bowel (ischemic colitis).

This medication should only be used in women with severe cases of irritable bowel syndrome (IBS) where the major symptom is diarrhea. If you experience constipation, new or worsening bowel pains, or blood in your diarrhea or stool, stop taking this drug and seek immediate medical attention.

Before your doctor can prescribe this medication for you, your doctor must have completed the Prescribing Program for Lotronex (PPL).

Only carefully selected patients may use this medication. Consult your doctor or pharmacist for more information about the risks and benefits of using this medication.

USES: This medication is used to treat severe cases of irritable bowel syndrome (IBS) in women who have diarrhea as a major symptom.

Alosetron is not effective in men with IBS.

This medication is not recommended for use in children because of the serious side effects that have been seen in adults.

HOW TO USE: Read and complete the Patient-Physician Agreement form provided by your doctor. Read the Medication Guide provided by your pharmacist before you start using alosetron and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist. Your prescription must have a sticker affixed to it in order for your pharmacy to dispense you a supply of this medicine.

Take this medication by mouth with or without food as directed by your doctor. Do not begin this medication if you are currently constipated. Contact your doctor for further instructions.

SIDE EFFECTS: Headache, stomach upset, or hemorrhoids may occur. If these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if you have any of these unlikely but serious side effects: bloating, depression.

Stop taking this medication and seek immediate medical attention if any of these unlikely but serious side effects occur: constipation, bloody stools, unexplained fever, unusually fast pulse, new or sudden worsening of stomach/abdominal/bowel pain.

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking alosetron, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain intestinal disorders (e.g., ileus, ischemic colitis, impaired intestinal circulation, constipation or its complications, obstruction, megacolon, stricture/adhesions, or perforation), Crohn's disease, ulcerative colitis, diverticulitis, severe liver disease, blood disorders (e.g., history of blood clots).

Before using this medication, tell your doctor your medical history, including: liver disease.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of constipation if it occurs.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: apomorphine, fluvoxamine.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting alosetron.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anticholinergics/antispasmodics (e.g., atropine, dicyclomine), antidiarrheals (e.g., kaolin-pectin, loperamide), hydralazine, isoniazid, narcotics (e.g., codeine, diphenoxylate), procainamide.

Other medications can affect the removal of alosetron from your body, which may affect how alosetron works. Examples include cimetidine, quinolone antibiotics such as ciprofloxacin, among others.

Constipation can be a serious side effect of this medication. Discuss with your doctor or pharmacist before using any medications that may slow down the gut. Check the labels on all your medicines (e.g., allergy, cough-and-cold, sleep products) because they may contain ingredients that can cause constipation. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include difficulty breathing, loss of coordination, tremors, and seizures.

NOTES: Do not share this medication with others.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature, 77 degrees F (25 degrees C), away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.