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Lotronex (Alosetron Hydrochloride) - Description and Clinical Pharmacology


(alosetron hydrochloride)


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.



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.


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.


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).


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, 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 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


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.


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 pharmacokinetic 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



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 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 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

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.

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