Alosetron hydrochloride (Lotronex) for irritable bowel syndrome

INTRODUCTION — Alosetron hydrochloride is a selective 5-HT3 antagonist that has been approved for the treatment of patients with severe diarrhea-predominant irritable bowel syndrome (IBS) who failed to respond to conventional treatment. The drug has been reintroduced to the market after being withdrawn due to adverse effects including severe constipation and ischemic colitis. Communications from the US Food and Drug Administration (FDA) suggest that fewer than 5 percent of patients with IBS are considered to have severe disease, have symptoms that last more than six months and curtail daily activities, and that only a fraction of these have diarrhea-predominant symptoms. Thus, the proportion of IBS patients who will be eligible for alosetron is small [1].

We begin treatment with a low starting dose of 0.5 mg once daily, which can be increased to 0.5 mg twice daily after four weeks if the lower dose is well tolerated but does not adequately control symptoms. If the response is inadequate after four weeks of 0.5 mg twice daily and the patient is tolerating alosetron, the dose can be increased to 1 mg twice daily (maximum 2 mg/day). This topic review will summarize the major clinical trials of alosetron in IBS. A general approach to IBS is presented separately. (See "Treatment of irritable bowel syndrome in adults".)

CLINICAL PHARMACOLOGY — Alosetron selectively blocks 5-HT3 receptors, which are extensively distributed on enteric motor neurons and in peripheral afferents and central locations such as the vomiting center. The receptors are cation channels that modulate visceral pain, colonic transit, and gastrointestinal secretion.

In nonconstipated patients with irritable bowel syndrome (IBS), alosetron decreases brain activity of central autonomic networks (mostly in the amygdala, ventral striatum, and dorsal pons) that mediate emotional expression in response to aversive rectal stimuli [2,3]. It is unclear whether this reduction in activation of central structures results from a central effect of the medication or is simply the downstream effect of a reduction in the ability of peripheral visceral afferent nerves that convey sensations of pain and discomfort to the spinal cord and central nervous system [4]. Brain imaging studies suggest that greater symptom improvement on alosetron in IBS patients was predicted by less activity in bilateral orbitofrontal cortex and medial temporal gyrus during pre-treatment scans, which may be partially predicted by psychological factors [5]. An explanation for the greater efficacy demonstrated in human clinical trials in females with IBS-diarrhea was provided by studies in serotonin-transporter (SERT) knock-out rats, in which there is visceral hypersensitivity in response to colorectal balloon distention. In this model, increased 5-HT signaling at dorsal spine 5-HT₃ receptors was responsible for visceral hypersensitivity in female but not male SERT-KO rats [6].

Although effects on peripheral afferents have not been conclusively demonstrated in humans, there are ample experimental animal data to suggest that alosetron reduces nociception by blocking peripheral sensory pathways. It increases the number and propagation length of high-amplitude contractions in the left colon, leading to a paradoxical decrease in stool frequency and a firming of stool consistency [7]. It also significantly retards small intestinal and colonic transit in females to a much larger degree than in males [8]. The degree of response to alosetron may be due to genetic polymorphism in the promoter region of the serotonin gene [9].

There is also evidence from animal studies that 5-HT3 antagonists affect intestinal secretion, which may benefit patients with IBS and diarrhea [10].

Alosetron is extensively metabolized by cytochrome P450 (CYP) enzymes 2C9 (30 percent), 3A4 (18 percent), and 1A2 (10 percent). It is likely that increased exposure to alosetron occurs in patients with hepatic insufficiency, although no pharmacokinetic data are available. Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination. However, the effect of renal impairment on the excretion of alosetron metabolites has not been assessed.

Drug interaction studies have not demonstrated any clinically significant effect of alosetron on the pharmacokinetics of fluoxetine or its major metabolite or alprazolam, which are metabolized by CYP2D6, CYP2C9, and CYP3A4 [11,12]. Alosetron does not alter the pharmacokinetics or efficacy for a low-dose combination oral contraceptive, and thromboembolic risk is not increased when alosetron is coadministered with an oral contraceptive [13]. The latter is important given the risk of ischemic colitis identified with alosetron (approximately 1 per 1000 patient-years).

CLINICAL TRIALS — Alosetron was approved initially by the US Food and Drug Administration based upon the results of four placebo-controlled trials. The first two were 12-week dose-ranging studies (phase II trials) with a total of 832 patients [14,15]. The second two (phase III studies) were multicenter trials conducted in the United States that determined the efficacy and safety of a dose of 1 mg twice daily for 12 weeks in a total of 1273 nonconstipated females with irritable bowel syndrome (IBS) [16,17]. IBS was diagnosed based upon the Rome criteria. The mean age of the females was 46, and the majority (approximately 90 percent) were White Americans. The first of these phase III trials was published in final form [16]. A third phase III study compared alosetron (1 mg twice daily) with mebeverine, an antispasmodic approved in Europe for the treatment of IBS [18].

Primary endpoints — The primary endpoints of the placebo-controlled trials were adequate relief of pain and discomfort, which was assessed weekly. Secondary endpoints were the percentage of days with urgency and daily assessment of stool frequency and consistency.

In both of the phase III placebo-controlled studies, alosetron was associated with a significant improvement in the proportion of females with pain relief during treatment (41 versus 29 percent and 41 versus 26 percent in the two studies, respectively) [16,17]. The beneficial response for the primary endpoints (pain and discomfort) was observed within one to four weeks after beginning therapy, and was sustained throughout the duration of the trial (figure 1). Bloating was not improved. Within one week after discontinuing the drug, symptoms were comparable to those in females receiving placebo. Secondary endpoints relating to bowel movements were typically improved within one week of starting therapy. Subgroup analysis in one of the two studies revealed that the benefit appeared to be confined to patients with diarrhea-predominant symptoms.

Secondary endpoints — Alosetron was associated with a significant decrease in the percentage of days with urgency compared with placebo throughout the study. Treatment was associated with firmer stools and a significant decrease in stool frequency. These symptoms improved within one week of beginning therapy, and returned to baseline (pretreatment) levels similar to those of the placebo-treated group within one week of discontinuing therapy.

Several issues need to be considered when interpreting the efficacy data discussed above:

First, the studies discussed above used a 1 mg twice-daily dose in contrast to the 1 mg once-daily dose recommended for initiating therapy only in females with severe diarrhea-predominant IBS (IBS-D). Randomized trials have also demonstrated that alosetron 0.5 mg every day results in statistically significant and clinically relevant improvements in health-related quality of life (QOL), restriction of daily activities, and treatment satisfaction over placebo [19]. (See 'Postmarketing studies' below.)

Second, although the females included in the trials were permitted to take fiber, other agents commonly used to treat IBS-D (such as antidiarrheal, antispasmodic, and anticholinergic) were not permitted. Thus, whether alosetron would have an added benefit compared to standard approaches is uncertain.

Third, although the absolute proportion of females who benefited from therapy is clinically significant, nearly 30 percent of females in the placebo arm also achieved the primary endpoint. The placebo response rate of these trials approximated the mean placebo response rate described in the literature [20]. While many previous trials in IBS had flawed experimental designs [21], other trials show enhanced trial methodology. This opens the question as to how effective comparable agents or approved antispasmodics might be if evaluated by the same methods. Alosetron was significantly superior in the only study in which it was directly compared with an active agent (mebeverine) [18].

A fourth issue is that the trials described above have not necessarily identified the optimal method of administration (eg, intermittent, during exacerbation, or continuous). Thus, further phase IV studies will be needed to evaluate optimal dosing regimens, safety, and effectiveness.

Finally, the cost-effectiveness of alosetron has been defined; its cost per quality-adjusted life-year (QALY) gained is substantial [22,23].

Alosetron versus mebeverine — The study comparing alosetron to mebeverine included 623 nonconstipated females with IBS who were randomly assigned to alosetron (1 mg twice daily) or mebeverine (135 mg three times daily) for 12 weeks [18]. Similar to the placebo-controlled trials, the primary endpoint was adequate relief of abdominal pain and discomfort, while secondary endpoints included assessments of bowel function. At the end of the study, significantly more patients in the alosetron group achieved the primary outcome. Alosetron was also associated with a significant increase in stool firmness and a decrease in the proportion of days with urgency and mean stool frequency.

Postmarketing studies — Several postmarketing studies have been performed since the initial controlled trials [24-30]:

●A 2008 meta-analysis summarized the efficacy and safety of the 5-HT3 receptor antagonist class of drugs in IBS [29]. The study included 14 randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). The 5-HT3 antagonists were significantly more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk [RR] 1.60; 95% CI 1.49-1.72) and relief of abdominal pain and discomfort (pooled RR 1.30; 95% CI 1.22-1.39). Benefits were apparent for both agents in both females and males. These results were confirmed in a meta-analysis [31], and another meta-analysis indicated significant differences between alosetron and placebo in both females and males (female: RR 1.34 [95% CI 1.21-1.48]; male: RR 1.23 [95% CI 1.02-1.47]) [32].

These agents were more likely to cause constipation (pooled RR 4.28; 95% CI 3.28-5.60); there was less constipation with 5-HT3 antagonists in IBS-D patients than in mixed populations (nonconstipated IBS and IBS-D; RR ratio 0.65; 95% CI 0.41-0.99). Nine patients (0.2 percent) using 5-HT3 antagonists had possible ischemic colitis versus none in control groups. Similar conclusions were reached in a later meta-analysis [31].

●One study provided follow-up information for up to 12 months in females who had participated in one of the multicenter phase III trials [25]. Overall, 59 percent of the subjects completed the study. Adverse events were reported in a significantly higher proportion of patients who received alosetron (83 versus 76 percent), with the difference mostly attributed to a higher rate of constipation in the alosetron group (32 versus 5 percent). Constipation was mild or moderate in most patients, occurring within a median of 13 days after initiating treatment.

●Another study also involving previously reported patients, suggested that alosetron was associated with improvement in health-related QOL [26].

●A third trial included 492 females who were randomly assigned to alosetron (1 mg twice daily) or placebo for 12 weeks [27]. Alosetron was associated with a significantly greater percentage of days with satisfactory control of urgency (69 versus 56 percent). Furthermore, a greater percentage of patients had improvement on a global improvement scale at 4, 8, and 12 weeks. Constipation occurred significantly more often in the alosetron group (28 versus 9 percent). Of patients with constipation in the alosetron group, 11, 75, and 14 percent were rated as mild, moderate, and severe, respectively. No cases of ischemic colitis were observed.

●Other randomized trials have addressed the efficacy of lower doses of alosetron than the original dose evaluated in the registration trials [19,28]. In one randomized trial, alosetron 0.5 mg and 1 mg once daily as well as 1 mg twice daily were effective in providing global improvement in IBS symptoms, adequate relief of IBS pain and discomfort, and improvement in bowel symptoms in females with severe IBS-D [28]. These data are important since the prevalence of constipation was 19 percent with the highest dose, 9 percent with the lowest dose of 0.5 mg/day, and 5 percent with placebo. This suggests that it is prudent to start with 0.5 mg alosetron dose and to titrate the dose up if needed. This is a clinically appealing strategy that has been used by the author as a precaution to reduce the risk of constipation and potential for associated adverse events. This strategy is particularly relevant given evidence that genetic variation in the serotonin reuptake transporter influences the response to therapy [9]. Nevertheless, it should be noted that one patient on the lowest dose 0.5 mg alosetron (out of 175 patients) developed ischemic colitis. Hence, caution is always necessary when using this medication in patients with IBS.

●In a randomized controlled trial of 705 females with severe IBS-D, alosetron 0.5 mg once daily, 1 mg once daily, 1 mg twice daily, or placebo for 12 weeks were compared. Alosetron treatment, including 0.5 mg once daily, resulted in statistically significant and clinically relevant improvements in health-related QOL, restriction of daily activities, and treatment satisfaction over placebo. IBS symptom improvement was associated with positive changes in IBS QOL, lost workplace productivity, and treatment satisfaction. The incidence of adverse events with alosetron was low, with constipation being the most commonly reported event. A single case of ischemic colitis occurred in a patient receiving alosetron 0.5 mg once daily [19]. Satisfaction of treatment with alosetron has been assessed by estimating the number of 7841 patients treated with alosetron under a risk management program who continued the medication after follow-up of one year: ≥64 percent continued the drug across IBS-D severity groups. The most common reasons for taking the medication were restriction of daily activities, followed by accidents/fecal incontinence, and stomach cramps/bloating [33].

●In a prospective, open-label, multicenter, observational 12-week study that evaluated 192 females with severe IBS-D enrolled in the alosetron prescribing program, 152 females completed the program, and out of 105 fully evaluable patients, 45 percent met the FDA composite endpoint responder criteria (both changes from baseline in stool consistency and abdominal pain severity) for ≥50 percent of the study period. Moreover, improvements in all individual symptoms (IBS pain severity, stool consistency, stool frequency per day, percent days with fecal urgency or incontinence) were statistically significant compared with baseline. There were no serious adverse events, cases of colonic ischemia, or complications of constipation [34].

Males — As noted above, alosetron has been approved only for females. However, it has also been studied in males. A placebo-controlled trial involving 662 males with IBS-D found that alosetron was significantly more effective in relieving urgency and abdominal pain (53 versus 40 percent) [35]. Side effects were similar to the clinical trials in females. As noted in the meta-analysis described above, benefits of the 5-HT3 class of drugs were observed in males and females [29]. The original and subsequent guidance for use of alosetron in females was based upon the original phase III program, which was conducted exclusively in females.

SAFETY — The most common adverse event in the above studies was constipation, which was significantly more common among females receiving alosetron compared with placebo (28 to 32 versus 5 percent). The majority of patients reporting constipation had mild to moderate symptoms; only approximately 10 percent of those patients withdrew from the study due to constipation. In the phase III trials, treatment was interrupted per the protocol in 9 percent of patients who had four consecutive days without a bowel movement. The majority of these patients (88 percent) resumed therapy. The rate of other adverse events was comparable to placebo. Safety beyond 12 months has not been established.

Ischemic colitis and severe constipation — As noted above, the risk of ischemic colitis led to establishment of a risk management strategy for alosetron and restricted its use. However, the magnitude of the risk and its pathogenesis are unclear.

A systematic review of the published literature and cases reported through the US Food and Drug Administration Adverse Events Reporting System estimated that the risk of ischemic colitis associated with alosetron was significantly higher than with placebo (0.15 versus 0.0 percent), but there was no significant difference in the rate of serious complications of constipation [36]. Based upon postmarketing surveillance, the rate of ischemic colitis and serious complications of constipation were estimated to be 1.1 and 0.66 per 1000 patient-years of alosetron, respectively. A nine-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program showed that cumulative incidence rate of ischemic colitis (1.03 cases/1000 patient-years) is low and stable, while that of complications of constipation (0.25 cases/1000 patient-years) is low and has been decreasing over time [37].

The pathogenesis of ischemic colitis in patients with irritable bowel syndrome (IBS) taking alosetron is uncertain. It may be due to a drug class effect given that a related drug (cilansetron) has also been associated with ischemic colitis [38]. However, IBS itself has also been associated with ischemic colitis in epidemiologic studies [39]. Further complicating matters is the observation that focal active colitis may be seen in asymptomatic patients undergoing screening colonoscopy, and such a finding may be misclassified as being caused by ischemia [40].

In experimental settings, preconstricted arterioles exhibited normal dilatory responses to balloon distension in the presence or absence of 5-HT3 or 5-HT4 antagonists, suggesting that these classes of receptors do not change the ability of normal vessels to induce reflex vasodilatation [41]. Intravenously administered alosetron (0.03 to 0.3 mg per kg) and cilansetron caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered; oral administration of alosetron had no effects at any site [42].

Some authors have speculated that ischemia results from constipation that may result from the slow transit induced by 5-HT3 antagonists. Subtle changes in Doppler mucosal blood flow have been observed in patients with normal or slow transit constipation [43]. However, it is unclear whether these subtle differences can overcome the pressure-flow autoregulation intrinsic to colonic blood flow; thus, even with perfusion pressures of 60 mmHg, increased oxygen extraction will maintain normal colonic oxygen uptake [44].

Finally, although rise in intraluminal pressure or straining may temporarily reduce mucosal blood flow [45], such changes are not sustained over time, and it is typical for contractile amplitudes and frequency of high-amplitude contractions to be reduced rather than increased in patients with constipation [46,47]. A critical appraisal could not find an experimental basis for the development of ischemic colitis with 5-HT3 antagonists [48], and a study in rats [49] showed that alosetron did not significantly alter baseline colonic blood flow in the anesthetized rat; nor did it interfere with vascular control mechanisms activated during occlusion and reactive hyperemia.

ALTERNATIVE TREATMENTS — Alternative treatments have been approved by the US Food and Drug Administration (FDA) and are marketed for the treatment of diarrhea-predominant IBS (IBS-D). These are eluxadoline (a mu-and kappa-opiate receptor agonist and delta-opiate receptor antagonist) and the unabsorbed antibiotic, rifaximin. A 5-HT3 receptor antagonist, ramosetron, has shown efficacy in treatment of IBS-D [50,51], as has the marketed drug in the same class, ondansetron [52]; neither of these two medications is approved for treatment of IBS-D in the United States. (See "Treatment of irritable bowel syndrome in adults", section on '5-hydroxytryptamine (serotonin) 3 receptor antagonists'.)

In a systematic review and network meta-analysis of pharmacologic therapies licensed for patients with IBS-D or mixed stool pattern (alosetron, eluxadoline, ramosetron and rifaximin), alosetron 1 mg twice daily had the highest efficacy based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS, and effect on stool consistency [51]. The overall benefits of alosetron were also addressed in a comparison of treatment with alosetron and traditional pharmacotherapies. Alosetron 1 mg twice daily significantly reduced health care utilization and lost productivity, and significantly improved global IBS symptoms, health-related quality of life, and participation in outdoor and social activities [53]. Based on a separate network meta-analysis of randomized control trials in patients with non-constipated IBS [54], 5-HT3 receptor antagonists performed better in comparison to control drugs, and in addition, alosetron had the best performance evaluated as cumulative ranking probability for global symptom improvement.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Irritable bowel syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Irritable bowel syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Irritable bowel syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Alosetron hydrochloride is a selective 5-HT3 antagonist that has been approved for the treatment of females with severe diarrhea-predominant irritable bowel syndrome (IBS) who failed to respond to conventional treatment. (See 'Introduction' above.)

●Alosetron selectively blocks 5-HT3 receptors, which are extensively distributed on enteric motor neurons and in peripheral afferents and central locations such as the vomiting center. The receptors are cation channels that modulate visceral pain, colonic transit, and gastrointestinal secretion. (See 'Clinical pharmacology' above.)

●Alosetron is more effective than placebo and mebeverine in the treatment of females who have diarrhea-predominant IBS. However, the lingering safety concerns and the restrictions have limited the role of alosetron in the treatment of IBS. (See 'Clinical trials' above.)

●Adverse effects of alosetron include constipation and ischemic colitis. A systematic review of the published literature and cases reported through the US Food and Drug Administration Adverse Events Reporting System estimated that the risk of ischemic colitis associated with alosetron was significantly higher than with placebo (0.15 versus 0.0 percent), but there was no significant difference in the rate of serious complications of constipation. (See 'Safety' above.)