Chemical formula: C₁₇H₁₈N₄O Molecular mass: 294.351 g/mol PubChem compound: 2099
The available data with alosetron use in pregnant women are insufficient to draw conclusions about any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of alosetron in rats and rabbits during organogenesis at doses 160 to 240 times, respectively, the recommended human dosage (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively.
No adverse developmental effects were observed with oral administration of alosetron during the period of organogenesis to pregnant rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) or to pregnant rabbits at doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area).
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 alosetron is administered to a nursing woman.
There are no data regarding the presence of alosetron in human milk, the effects on the breastfed infant, or the effects on milk production.
Alosetron and/or metabolites of alosetron are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for alosetron and any potential adverse effects on the breastfed infant from alosetron or from the underlying maternal condition.
Monitor infants exposed to alosetron through breast milk for severe constipation and blood in stools.
In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.
The following adverse reactions are described in more detail in other sections of the label:
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.
Patients with Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of alosetron twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron and occurred more frequently on alosetron than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron compared to placebo (p<0.0001).
Table 1. Adverse Reactions Reported in ≥1% of Patients with Irritable Bowel Syndrome and More Frequently on alosetron 1 mg Twice Daily Than Placebo:
| Alosetron | ||
|---|---|---|
| Body System Adverse Reaction | Placebo (n=2,363) | 1 mg twice daily (n=8,328) |
| Gastrointestinal | ||
| Constipation | 6% | 29% |
| Abdominal discomfort and pain | 4% | 7% |
| Nausea | 5% | 6% |
| Gastrointestinal discomfort and pain | 3% | 5% |
| Abdominal distention | 1% | 2% |
| Regurgitation and reflux | 2% | 2% |
| Hemorrhoids | 1% | 2% |
Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with alosetron. In clinical studies constipation was reported in approximately 29% of patients with IBS treated with alosetron 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 alosetron 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with alosetron 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 alosetron 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. In Studies 1 and 2, 9% of patients treated with alosetron reported constipation and 4 consecutive days with no bowel movement. 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.
Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving alosetron 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 was reported in a 12-week study. A causal association with alosetron 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 alosetron for longer than 6 months.
Women 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 and occurred more frequently with alosetron than with placebo. Other events reported in 3% or more of patients who received alosetron and occurring more frequently with alosetron than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches, and fatigue.
Table 2. Gastrointestinal Adverse Reactions Reported in ≥3% of Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome and More Frequently on alosetron Than Placebo:
| Adverse Reaction | Placebo (n = 176) | Alosetron 0.5 mg once daily (n = 175) | Alosetron 1 mg once daily (n = 172) | Alosetron 1 mg twice daily (n = 176) |
|---|---|---|---|---|
| Constipation | 5% | 9% | 16% | 19% |
| Abdominal pain | 3% | 5% | 6% | 7% |
| Diarrhea | 2% | 3% | 2% | 2% |
| Hemorrhoidal hemorrhage | 2% | 3% | 2% | 2% |
| Flatulance | 2% | 2% | 1% | 3% |
| Hemorrhoids | 2% | 1% | 1% | 3% |
| Abdominal pain upper | 1% | 3% | 1% | 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 and occurring more frequently with alosetron than with placebo included constipation (14% and 10% of patients taking alosetron 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 and occurring more frequently with alosetron 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 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 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: During its assessment in clinical trials, multiple and single doses of alosetron were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to alosetron 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, occurred in at least 2 patients, and occurred at a greater frequency during treatment with alosetron 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 and occurring at a greater frequency in patients treated with alosetron 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, they were not necessarily caused by it.
In addition to events reported in clinical trials, the following events have been identified during use of alosetron 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.
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