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WARNING: Infrequent but serious gastrointestinal adverse events have been reported with the use of LOTRONEX. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death.
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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: C 17 H 18 N 4 O·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.
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.
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 doses 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-(beta)-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-(beta)-hydroxycortisol excretion. However, there was no change in the ratio of 6-(beta)-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 mg 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 doses 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 ).
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 14 C-labeled alosetron. On a molar basis, alosetron 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 one 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: No pharmacokinetic data are available in this patient group (see 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 .
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 Criteria 1 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 Dose: 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 evaluated on a scale of 1 to 5 (1 = very hard, 2 = hard, 3 = formed, 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 two 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.
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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.
LOTRONEX is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have:
Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following:
Because of infrequent but serious gastrointestinal adverse events associated with LOTRONEX, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable.
Clinical studies have not been performed to adequately confirm the benefits of LOTRONEX in men.
LOTRONEX should not be initiated in patients with constipation (see WARNINGS ).
LOTRONEX is contraindicated in patients with a history of the following:
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 ).
WARNINGS
(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:
To enroll in the Prescribing Program for LOTRONEX call 1-888-825-5249 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:
Copies of the Patient-Physician Agreement for LOTRONEX and additional copies of the Medication Guide are available by contacting GlaxoSmithKline at 1-888-825-5249 or visiting www.lotronex.com.
PATIENTS WHO ARE PRESCRIBED LOTRONEX SHOULD BE INSTRUCTED TO:
Drug Interactions: 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 pharmacokinetic 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 dosage, 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.
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 ).
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).
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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 mesenteric ischemia (see WARNINGS ).
Neurological: Headache.
LOTRONEX has no known potential for abuse or dependence.
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.
For safety reasons, only physicians who enroll in the GlaxoSmithKline Prescribing Program for LOTRONEX should prescribe LOTRONEX (see PRECAUTIONS : Prescribing Program for LOTRONEX ).
Usual Dose 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 : Reduced Renal Function ).
Patients with Hepatic Impairment: No studies have been conducted in 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 hepatic impairment (see PRECAUTIONS: Hepatic Insufficiency and CLINICAL PHARMACOLOGY : Population Subgroups : Reduced Hepatic Function ).
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.
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LOTRONEX® (LOW-trah-nex) Tablets
(alosetron hydrochloride)
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Before using LOTRONEX for the first time, you should:
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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.
LOTRONEX is a medicine only for some women with severe chronic IBS whose:
A. Some patients have developed serious bowel side effects while taking LOTRONEX.
Serious bowel (intestine) side effects can happen suddenly, including the following two:
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:
B. Is LOTRONEX right for you?
LOTRONEX may be right for you if all of these things are true about you:
You can tell if your IBS is severe if at least 1 of the following is true for 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 doctor's direction. Your doctor will ask 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.
LOTRONEX is a medicine only for some women with severe chronic IBS whose:
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.
LOTRONEX is not right for everyone. Do not take LOTRONEX if any of the following apply to you:
If you are constipated now, do not start taking LOTRONEX .
Talk with your doctor:
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.
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 1-888-825-5249 or at www.lotronex.com.
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.
February 2005 MG-030
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 LOTRONEX should be prescribed only by doctors who have signed up with the company that makes the drug. Doctors in the program must:
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)
______________________________________________________
SignatureDate
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, have given the patient named above:
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)
______________________________________________________
SignatureDate
After the patient and the physician sign thisPatient-Physician Agreement, give a copy to the patient and put the original signed form in the patient's medical record.
PRESCRIBING PROGRAM FOR LOTRONEX™:
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.
__________________________
Name of Physician (print)
______________________________________________________
SignatureDate
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.
If you have any questions, please call the Prescribing Program for LOTRONEX at 1-888-825-5249 or visit www.lotronex.com.
TO ENROLL, VISIT WWW.LOTRONEX.COM OR PHONE 1-888-825-5249 OR COMPLETE THIS FORM IN ITS ENTIRETY AND MAIL OR FAX TO THE FOLLOWING ADDRESS:
Prescribing Program for Lotronex
PO Box 13398
Research Triangle Park, NC 27709-3398
Fax Number: 1-866-698-7582
GlaxoSmithKline, Research Triangle Park, NC 27709
©2005, GlaxoSmithKline. All rights reserved.
February 2005/RL-2174