Severe Diarrhea-predominant Irritable Bowel Syndrome Research Articles

Alosetron versus traditional pharmacotherapy in clinical practice: effects on resource use, health-related quality of life, safety and symptom improvement in women with severe diarrhea-predominant irritable bowel syndrome

Objective: Severe diarrhea-predominant irritable bowel syndrome (IBS-D) is associated with decreased health-related quality of life (HRQOL) and increased health care costs. Treatment recommendations for IBS-D often start with traditional pharmacotherapy (TP), with escalation to alosetron, rifaximin or eluxadoline if there is no success. There has been no previous head-to-head clinical trial comparing IBS-D treatment outcome for alosetron versus TP. This study, GSK protocol S3B30020, evaluated resource use, work productivity, health-related quality of life and global symptom response in women with IBS-D who were treated with alosetron or TP.Methods: A total of 1956 patients who met criteria for severe IBS-D were randomized to treatment with alosetron 1 mg twice daily (BID) or only TP for up to 24 weeks. Work productivity and resource use were evaluated by standard questionnaires, HRQOL by the IBSQOL instrument and IBS symptoms by the Global Improvement Scale (GIS).Results: Compared to only TP, alosetron-treated patients reported: (1) fewer clinic/office visits for any health problem (p = .0181) or for IBS-D (p = .0004); (2) reduced use of over-the-counter medications for IBS-D (p < .0001); (3) fewer days of lost work productivity (p < .0001); (4) decreased restriction of social and outdoor activities (p < .0001); and (5) greater global improvement in IBS-D symptoms (p < .0001). Alosetron treatment improved HRQOL scores for all domains (p < .0001). Incidence of adverse events during alosetron use was not remarkable and was similar to that previously reported.Conclusions: Alosetron 1 mg BID significantly reduced health care utilization and lost productivity, and significantly improved global IBS symptoms, HRQOL, and participation in outdoor and social activities compared with treatment response to TP.

Evaluation of treatment continuation with alosetron by IBS-D severity criteria

Objectives:This article evaluates the characteristics and treatment patterns of female patients with severe diarrhea-predominant irritable bowel syndrome (IBS-D) who were treated with alosetron under a risk management program.Methods:Patients prescribed alosetron (2002–2009) and who voluntarily enrolled in the follow-up study were evaluated. Questionnaires were administered at baseline, Wk 5, Wk 10, and quarterly thereafter for ≤1 year. Subgroup analyses were conducted in female patients with IBS-D ≥6 months, stratified by IBS-D severity criteria met (1–3) from the alosetron prescribing information (treatment recommended in female patients meeting ≥1 severity criterion). The voluntary and observational nature of the study are potential limitations, such that eligible patients in the clinical practice setting may have had more severe IBS-D, possibly representing a more motivated and homogeneous subpopulation of patients than the broader IBS-D population.Results:A total of 7841 patients enrolled in the study; 92.4% were adult females; 79.4% (n = 6229) met label criteria. Mean follow-up time was ∼10.3 months; 50.3% completed 1 year. Of the 6229 female patients, 76.9% met 3/3 severity criteria; 21.5% met 2/3 severity criteria; 1.4% met 1/3 severity criteria. The most common complaint was restriction of daily activities, followed by accidents/fecal incontinence, and stomach cramps/bloating. One-year treatment continuation was ≥64% across IBS-D severity groups.Conclusions:One-year treatment continuation with alosetron was high, irrespective of the number of IBS-D severity criteria met. Restriction of daily activities was the primary indicator of disease severity. These findings demonstrate that alosetron continues to be safely and effectively used under the risk management program, and appears to provide long-term benefit in appropriate patients with IBS-D.

Diagnosis and Management of Diarrhea-Predominant Irritable Bowel Syndrome: Clinical Overview of Alosetron

Background:Irritable bowel syndrome (IBS) is a functional bowel disorder associated with considerable impairment in quality of life and utilization of healthcare resources. Owing to the high incidence and chronicity of the disorder, nurse practitioners (NPs) and physician assistants (PAs) likely encounter IBS patients in their practices. Recent updates in the Risk Evaluation and Mitigation Strategy (REMS) for alosetronhave allowed NPs and PAs to enroll in the program to prescribe this selective 5-HT3 receptor antagonist used to treat IBSfor patients with severe diarrhea-predominant IBS (IBS-D).Aim: To provide an overview of the diagnostic process and current treatment options for IBS, with specific focus on the efficacy, safety, tolerability, and prescribing requirements for alosetron. Methods: The supporting evidence for the labeled efficacy and safety of alosetron in the management of IBS-D was assessed.Results:Whereas conventional therapies provide benefit for a specific symptom of IBS, alosetronhas been shown to provide multisymptom relief in IBS-D, including improvements in abdominal pain, stool consistency, stool frequency, bowel urgency, and IBS-related quality of life. Analysis of postmarketing safety data captured since the alosetronrisk management program was initiated in 2002 suggests that serious outcomes associated with ischemic colitis and serious complications of constipation have been mitigated.Conclusions:Alosetronprovides a favorable risk-to-benefit profile for women with severe IBS-D who have not responded to treatment with conventional agents. By acquiring evidence-based treatment knowledge related to IBS, NPs and PAs may ultimately improve the overall management of this complicated, and relatively common, condition.

Review: Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder that causes a range of symptoms. Currently, alosetron hydrochloride (Lotronex®), a selective serotonin type 3 receptor antagonist, is the only medication approved for the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS-D) in women who have inadequately responded to conventional therapy. Alosetron has demonstrated efficacy compared with placebo in clinical trials and has been shown to improve overall health-related quality of life (HRQoL). However, rare instances of ischemic colitis and severe complications of constipation have been reported. As a result, in 2000 alosetron was voluntarily withdrawn from the market but was reintroduced in 2002 with a more restricted indication and a requirement that clinicians and patients follow a prescribing program. Although the efficacy and benefit of alosetron has been clearly demonstrated, it has been used sparingly since its reintroduction. This brief review describes the history of alosetron, efficacy of alosetron in the treatment of IBS, the impact of severe IBS on HRQoL, safety considerations, the risk evaluation and mitigation strategy program under which alosetron is now prescribed, and an update on postmarketing surveillance data.

Ischemic Colitis and Complications of Constipation Associated With the Use of Alosetron Under a Risk Management Plan: Clinical Characteristics, Outcomes, and Incidences

Alosetron is a potent, selective 5-HT(3) receptor antagonist prescribed for women with severe diarrhea-predominant irritable bowel syndrome (IBS-D) under a risk management plan (RMP). The RMP was implemented following cases of ischemic colitis (IC) and complications of constipation (CoC) associated with the use of alosetron. The objectives of this study were to characterize IC and CoC clinical features, outcomes, and incidence rates in the new restricted patient population to evaluate the effectiveness of the RMP in the prevention of serious outcomes. Safety data from adverse event reporting from November 2002 through June 2008 were reviewed for probable and possible IC and CoC using the US Food and Drug Administration/sponsor-defined criteria and definitions. Evidence for IC included medical documentation, colonoscopy, and sigmoidoscopy+/-biopsy. Evidence for CoC included medical history and confirmation from health-care professionals. Within the inclusion dates, 29,072 patients received 203,939 alosetron prescriptions. Although the absolute numbers of IC and CoC cases have declined, the incidence rates for IC and CoC (0.95 and 0.36 cases per 1,000 patient-years, respectively) were similar to rates during the postmarketing cycle before alosetron withdrawal. In patients with severe IBS-D receiving alosetron (n=998) or placebo (n=411) in clinical trials since reintroduction, incidence rates for IC were 4 and 2 cases per 1,000 patients, respectively. Rates for CoC were 2 and 0 cases per 1,000 patients in the alosetron and placebo groups, respectively. No mesenteric ischemia, surgeries, transfusions, or deaths occurred in patients with IC and no cases of CoC were associated with toxic megacolon, perforation, surgeries, transfusions, or deaths. IC and CoC cases were typically of short duration and all improved on prompt withdrawal of alosetron. Serious outcomes associated with IC and CoC appear to be mitigated since introduction of alosetron under the RMP.

Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective

Irritable bowel syndrome affects 5–10% of North Americans, with an estimated one-third having a diarrhea-predominant form. Alosetron hydrochloride (Lotronex®) is a serotonin receptor type 3 antagonist approved in early 2000 for use in women with diarrhea-predominant irritable bowel syndrome (IBS-D). Initial use was widespread, but infrequent serious adverse events of ischemic colitis and severe constipation-related complications prompted alosetron’s voluntary withdrawal from the US market in November 2000. Unprecedented public request prompted its reintroduction in 2002 under a Risk Management Plan, including a more restricted indication and a Prescribing Program for Lotronex. Despite these measures, the use of alosetron has been very limited since its reintroduction. Possible deterrents to its use include concerns over safety and the possible medical–legal implications raised by the Risk Management Plan. It is also possible that changes in the natural history and/or diagnosis of IBS-D have reduced the target population. Given the unique regulatory history of alosetron, these issues continue to engender controversy. This article profiles these concerns and reviews the pharmacology, clinical efficacy and safety, and post-marketing experience with alosetron. Myths and misconceptions related to alosetron use, or lack thereof, are addressed to provide the reader with the evidence needed to make informed treatment decisions for their female patients with severe IBS-D.

A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT₃) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT₃ receptor antagonists has gender difference is uncertain. Methods: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT₃ receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 µg, 103 subjects: 5 µg, and 101 subjects: 10 µg) and administered the study drug once daily. Results: The monthly responder rates of ‘Patient-reported global assessment of relief of irritable bowel syndrome symptoms’ in the 5- and 10-µg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 µg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 µg. Conclusion: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

Alosetron: An Effective Treatment for Diarrhea-Predominant Irritable Bowel Syndrome

Serotonin (5-HT) is one of the key mediators of gut motility, secretion and sensation. Most 5-HT is localized in the gastrointestinal tract. Particularly important for gut function and regulation are the 5-HT(1P), 5-HT(3) and 5-HT(4) receptors. These receptors have been the focus of research evaluating the pathophysiologic mechanisms of irritable bowel syndrome (IBS) as well as targets for the development of novel agents to treat irritable bowel syndrome. Alosetron is one of three 5-HT(3) antagonists currently available. The other two, ondansetron and granisetron, are primarily used in the treatment of chemotherapy-induced nausea and vomiting. Alosetron, which slows gut transit, has been approved for the treatment of severe diarrhea-predominant IBS (IBS-D) in women. This review will examine the common, yet therapeutically challenging, disorder IBS, as well as the role of alosetron in the treatment of IBS-D.

Cilansetron: a novel, high-affinity 5-HT3receptor antagonist for irritable bowel syndrome with diarrhea predominance

Irritable bowel syndrome (IBS) is associated with significant morbidity, impaired quality of life, work absenteeism and high healthcare costs. Current drug treatments, with the exception of drugs targeting serotonin receptor subtypes, are of limited value. Tegaserod (Zelnorm™, Novartis Pharmaceuticals Corp., NJ, USA), a partial agonist, is useful in women with the constipation-predominant form of IBS. Alosetron (Lotronex™, GlaxoSmithKline plc, London, UK), a 5-HT3 receptor antagonist, is effective in women with severe diarrhea-predominant IBS; however, its use is limited and it is restricted to the USA. Cilansetron is a potent and selective 5-HT3 receptor antagonist that is being developed for IBS with diarrhea predominance (IBS-D). It delays colonic transit and reduces visceral hypersensitivity. In large, randomized controlled trials, cilansetron has been shown to improve global and specific IBS-D symptoms, including abdominal pain/discomfort, stool frequency, stool consistency, urgency and health-relate...

Rationale for using serotonergic agents to treat irritable bowel syndrome

The role of serotonin in gastrointestinal (GI)-tract functioning, the pharmacologic rationale for using serotonergic agents in the treatment of irritable bowel syndrome (IBS), and clinical experience with novel serotonergic agents are described. IBS is a common multisymptom disorder that is associated with a high socioeconomic burden. The goal of treatment is to provide rapid and sustained global relief of the multiple symptoms of IBS with a single, effective, well-tolerated agent. Traditional treatment options target single symptoms, and many patients are dissatisfied with the level of relief achieved and adverse effects. Research has revealed that serotonin is involved in three major actions in the gut: (1) mediating intestinal motility, (2) mediating intestinal secretion in the GI tract, and (3) modulating perception in the bowels. Serotonin is also a vital link in the brain-gut axis. Alterations in key elements of serotonin signaling have been demonstrated in patients with IBS. Tegaserod, a selective serotonin type 4 (5-HT(4))-receptor partial agonist, is indicated for use in women with IBS whose primary bowel symptom is constipation. Alosetron, a 5-HT(3)-receptor antagonist, is indicated for use in women with severe diarrhea-predominant IBS in whom traditional therapies have failed. The clinical usefulness of several other serotonergic agents for IBS is being investigated. The use of serotonergic agents in patients with IBS is based on the critical role that serotonin plays in the maintenance of normal gut function and brain-gut communication. Pharmacologic therapies targeting specific serotonin receptors represent an important step in the management of IBS.

Long-Term Safety and Efficacy of Alosetron in Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome

To assess long-term safety and efficacy of alosetron in women with severe, chronic diarrhea-predominant IBS and in a subset having more frequent urgency (i.e., bowel urgency at least 10 of 14 days during screening). Randomized patients received either alosetron 1 mg (n = 351) or placebo (n = 363) twice daily during a 48-wk, double-blind study. The primary endpoint was the 48-wk average rate of adequate relief of IBS pain and discomfort. Secondary endpoints included 48-wk average satisfactory control rates of urgency, stool frequency, stool consistency, and bloating. Other efficacy endpoints were average monthly adequate relief and urgency control rates and impact of provided rescue medication. Alosetron-treated patients had significantly greater 48-wk average adequate relief (p= 0.01) and urgency control (p < 0.001) rates, regardless of rescue medication use, compared with placebo. Results in subjects with more frequent urgency were more robust than those in the overall population (p= 0.005). In weeks without rescue medication use, satisfactory control rates for stool frequency and stool consistency were significantly greater in alosetron-treated patients than placebo. Alosetron-treated patients had significantly greater adequate relief than placebo-treated patients (p < 0.05) in 9 of 12 months and significantly greater urgency control (p < 0.001) in all months. Adequate relief and urgency control were maintained throughout the treatment. Adverse events and serious adverse events were similar between treatment groups, except for constipation. Neither ischemic colitis nor serious events related to bowel motor dysfunction was reported. Long-term use of alosetron is effective and well-tolerated in women with chronic, diarrhea-predominant IBS, including those with more frequent urgency.

Pharmacologic therapy for the irritable bowel syndrome.

The management of the irritable bowel syndrome (IBS) remains unsatisfactory. For abdominal pain, antispasmodics are, at best, of only modest efficacy. Tricyclic antidepressants in low dose are useful (with the number needed to treat being three), but side effects and patient concerns regarding use of a centrally acting agent for depression remain limitations. Selective serotonin reuptake inhibitors are of uncertain efficacy in IBS. Opioid agonists, especially loperamide, are useful for diarrhea but not for pain in IBS; rebound constipation also remains a problem. Bile salt sequestering agents are not of established value in IBS but seem to be useful clinically in a small group of IBS patients with diarrhea. Aloestron, a 5HT(3) antagonist, should be reserved, if available, for women with severe diarrhea predominant IBS who have failed to respond to conventional therapy, and started at a low dose. Fiber and bulking agents may help constipation in some trials, but the evidence that they are efficacious in IBS is equivocal; they are frequently prescribed as first-line drugs for IBS regardless of the primary bowel disturbance but often increase bloating, gas, and pain. Laxatives are not of established value in IBS but are often taken by patients with constipation predominant IBS. Tegaserod, a partial 5HT(4) agonist, is now available in the United States and other countries for use in women with IBS whose primary bowel symptom is constipation; its efficacy in men and in those with alternating bowel habits is unknown. Probiotics are of uncertain efficacy. Chinese herbal medicine data are insufficient. Other new drugs in development include the cholecystokinin antagonists and novel visceral analgesics. Both current and potential therapies for IBS are reviewed in this article.