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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the label: Complications of constipation [see Boxed Warning, Warnings and Precautions (5.1)] Ischemic colitis [see Boxed Warning, Warnings and Precautions (5.2) ] Most common adverse reactions (incidence >2% and >placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea, and gastrointestinal discomfort and pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pa tients with Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of alosetron hydrochloride twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron hydrochloride and occurred more frequently on alosetron hydrochloride tablets than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron hydrochloride tablets compared to placebo (p<0.0001). T able 1. Adverse Reactions Reported in ≥1% of Patients with Irritable Bowel Syndrome and More Frequently on alosetron hydrochloride 1 mg Twice Daily Than Placebo B ody System Adverse Reaction P lacebo ( n = 2,363) Alosetron Hydrochloride 1 mg twice daily ( n = 8,328) Gastrointestinal Constipation Abdominal discomfort and pain Nausea Gastrointestinal discomfort and pain Abdominal distention Regurgitation and reflux Hemorrhoids 6% 4% 5% 3% 1% 2% 1% 29% 7% 6% 5% 2% 2% 2% Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with alosetron hydrochloride [see Warnings and Precautions (5.1)] . In clinical studies constipation was reported in approximately 29% of patients with IBS treated with alosetron hydrochloride1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<0.0001). Eleven percent (11%) of patients treated with alosetron hydrochloride1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with alosetron hydrochloride0.5 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 alosetron hydrochloride1 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 and Precautions (5.1)] . In Studies 1 and 2, 9% of patients treated with alosetron hydrochloridereported constipation and 4 consecutive days with no bowel movement [see Clinical Studies (14.2)] . 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 alosetron hydrochloride. Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving alosetron hydrochloride or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving alosetron hydrochloride was reported in a 12-week study. A causal association with alosetron hydrochloride has not been established. Lo n g - Term Safety: Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking alosetron hydrochloride for longer than 6 months. W o m e n With Severe Diarrhea-Predominant Irritable Bowel Syndrome: Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received alosetron hydrochloride and occurred more frequently with alosetron hydrochloride than with placebo. Other events reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches and fatigue. T able 2. Gastrointestinal Adverse Reactions Reported in ≥ 3 % of Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome and More Frequently on Alosetron Hydrochloride Th a n Placebo. Adverse R eac tion P lacebo ( n = 176) Alosetron hydrochloride 0.5 mg once daily ( n = 175) Alosetron hydrochloride 1 mg once daily ( n = 172) Alosetron hydrochloride 1 mg twice daily ( n = 176) Constipation Abdominal pain Diarrhea Hemorrhoidal hemorrhage Flatulence Hemorrhoids Abdominal pain upper 5% 3% 2% 2% 2% 2% 1% 9% 5% 3% 3% 2% 1% 3% 16% 6% 2% 2% 1% 1% 1% 19% 7% 2% 2% 3% 3% 1% Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included constipation (14% and 10% of patients taking alosetron hydrochloride 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting, and flatulence. Other events reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis, and cough. Constipation: Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2. There was a dose response in the groups treated with alosetron hydrochloride in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily, and 11% on 1 mg twice daily). Among these patients with severe diarrhea-predominant IBS treated with alosetron hydrochloride who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days. Other Events Observed During Clinical Evaluation of Alosetron Hydrochloride: During its assessment in clinical trials, multiple and single doses of alosetron hydrochloride were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to alosetron hydrochloride 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 reactions were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to alosetron hydrochloride, occurred in at least 2 patients, and occurred at a greater frequency during treatment with alosetron hydrochloride than during placebo administration are presented. Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with alosetron hydrochloride and occurring at a greater frequency in patients treated with alosetron hydrochloride 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 reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients. Although the events reported occurred during treatment with alosetron hydrochloride, they were not necessarily caused by it. B lood and Lymphatic: Rare: Quantitative red cell or hemoglobin defects, and hemorrhage. Cardiovascular: I n frequent: Tachyarrhythmias. Rare : Arrhythmias, increased blood pressure, and extrasystoles. Drug Interaction, Overdose, and Trauma: Rare: Contusions and hematomas. Ea r , Nose, and Throat: Rare: Ear, nose, and throat infections; viral ear, nose, and throat infections; and laryngitis. Endo crine and Metabolic: Rare: Disorders of calcium and phosphate metabolism, hyperglycemia, hypothalamus/pituitary hypofunction, hypoglycemia, and fluid disturbances. E ye: Rare: Light sensitivity of eyes. Gastrointestinal: Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis [see Warnings and Precautions (5.2)] , 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. L o w e r Respiratory: Infrequent: Breathing disorders. M u sculoskeletal: 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: Burning sensations, hot and cold sensations, cold sensations, and fungal infections. P sychiatry: Infrequent: Anxiety. Rare : Depressive moods. Reproduction: Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections, and fungal reproductive infections. S kin: 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. 6.2 Postmarketing Experience In addition to events reported in clinical trials, the following events have been identified during use of alosetron hydrochloride in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to alosetron hydrochloride. Gastrointestinal: Impaction, perforation, ulceration, small bowel mesenteric ischemia. Neurological: Headache. S kin: Rash.