"The U.S. Food and Drug Administration today approved Viberzi (eluxadoline) and Xifaxan (rifaximin), two new treatments, manufactured by two different companies, for irritable bowel syndrome with diarrhea (IBS-D) in adult men and women.
Table 1 summarizes adverse events from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of LOTRONEX (alosetron hydrochloride) twice daily for 8 to 24 weeks. The adverse events in Table 1 were reported in 1% or more of patients who received LOTRONEX (alosetron hydrochloride) and occurred more frequently on LOTRONEX (alosetron hydrochloride) than on placebo. A statistically significant difference was observed for constipation in patients treated with LOTRONEX (alosetron hydrochloride) compared to placebo (p < 0.0001).
Table 1. Adverse Events Reported in ≥ 1% of IBS Patients
and More Frequently on LOTRONEX (alosetron hydrochloride) 1 mg B.I.D. Than Placebo
|LOTRONEX (alosetron hydrochloride)
1 mg B.I.D.
(n = 8,328)
(n = 2,363)
|Abdominal discomfort and pain||7%||4%|
|Gastrointestinal discomfort and pain||5%||3%|
|Regurgitation and reflux||2%||2%|
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 (alosetron hydrochloride) 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 (alosetron hydrochloride) 1 mg twice daily withdrew from the studies due to constipation. Although the number of IBS patients treated with LOTRONEX (alosetron hydrochloride) 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 (alosetron hydrochloride) 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 (alosetron hydrochloride) 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 (alosetron hydrochloride) .
Hepatic: A similar incidence in elevation of ALT ( > 2-fold) was seen in patients receiving LOTRONEX (alosetron hydrochloride) 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 (alosetron hydrochloride) has not been established.
Long-Term Safety: Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking LOTRONEX (alosetron hydrochloride) for longer than 6 months.
Other Events Observed During Clinical Evaluation of LOTRONEX (alosetron hydrochloride) : During its assessment in clinical trials, multiple and single doses of LOTRONEX (alosetron hydrochloride) were administered resulting in 11,874 subject-exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to LOTRONEX (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 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 (alosetron hydrochloride) 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 (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 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 (alosetron hydrochloride) , they were not necessarily caused by it.
Cardiovascular: Infrequent: Tachyarrhythmias. Rare: Arrhythmias, increased blood pressure, and extrasystoles.
Drug Interaction, Overdose, and Trauma: Rare: Contusions and hematomas.
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.
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.
Postmarketing Experience: The following events have been identified during use of LOTRONEX (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 LOTRONEX (alosetron hydrochloride) .
Drug Abuse And Dependence
LOTRONEX (alosetron hydrochloride) has no known potential for abuse or dependence.
Read the Lotronex (alosetron hydrochloride) Side Effects Center for a complete guide to possible side effects
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).
Read the Lotronex Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/16/2008
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