Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional disorder of the gastrointestinal tract (GI), which manifests with chronic abdominal pain and diarrhea. It is a condition that negatively impacts the quality of life of individuals affected and contributes to increased healthcare costs. First-line therapy for the management of IBS-D is usually diet and lifestyle modifications. Alosetron is a medication that was approved by the FDA in February 2000 for the treatment of IBS-D in females . The first use of alosetron was widespread; however, it was voluntarily withdrawn from the US market in November 2000 due to concerns of postmarketing adverse effects, including serious complications of constipation (CoC) and instances of ischemic colitis (IC).
Alosetron was eventually reintroduced in 2002 with more restricted indications, with its use limited for the treatment of severe IBS-D symptoms in women that are refractory to other therapies.
The definition of severe IBS-D is diarrhea with one or more of the following :
To meet the criteria to be started on alosetron, women with severe IBS-D had to have:
The starting dose was also lowered to minimize the incidence of constipation.
Irritable bowel syndrome is a complex condition with an unclear etiopathogenesis. Researchers postulated that serotonin might be involved in one of the mechanisms of IBS because greater than 90% of the body's serotonin is present in the enterochromaffin cells of the gut. The enterochromaffin cells are responsible for releasing serotonin in response to chemical stimuli and increased intraluminal pressure, thereby activating peristaltic and secretory reflexes. Alosetron is a 5-hydroxytryptamine 3 (5-HT3, serotonin) receptor antagonist that blocks these receptors, thus inhibiting peristalsis and slowing colonic transit time to allow for more water reabsorption to allow for more formed stool. In patients with IBS-D, blockade of these receptors reduces pain, abdominal discomfort, urgency, and diarrhea. It also decreases visceral hypersensitivity by regulating the emotional component of visceral stimulation via diminished blood flow to emotional centers in the brain.
Alosetron is taken orally. There are 0.5 mg and 1 mg tablets. The initial dose is 0.5 mg twice a day to minimize the risk of constipation. If constipation occurs, patients must stop taking the medication until symptoms resolve. They may be restarted on 0.5 mg once a day; however, if constipation recurs at a lower dose, alosetron should be discontinued.
Patients can maintain 0.5 mg once or twice a day dosing if they are well-controlled on this regimen. If symptoms are not controlled on this dose after four weeks, the dosage can be increased to 1 mg twice a day. If symptoms persist after four weeks despite increasing the dosage to 1 mg twice a day, alosetron should be discontinued.
The most common adverse effect of alosetron is constipation. A randomized, double-blind placebo-controlled study was done to assess the efficacy and safety of 0.5 mg and 1 mg of alosetron in women with severe IBS-D. The study revealed that constipation occurred in 9%, 16%, and 19% patients in the 0.5 mg, 1 mg once daily, and 1 mg twice daily groups, respectively.
Although rare, there have been a few reported cases of IC in patients taking alosetron for the treatment of IBS. Clinical trials comparing patients receiving alosetron 1 mg twice daily to patients receiving placebo showed that the cumulative incidence of IC was 0.2% within the first three months and 0.3% within the first six months. Overall, a statistically significant increase in the incidence of IC was observed from pooled data of clinical trials in alosetron-treated patients when compared with placebo (0.15% versus 0.00%, p = 0.03). No clear mechanism is known, but multiple mechanisms have been hypothesized. One of the mechanisms postulated is that blockade of 5HT3 receptors causes serotonin to attach and stimulate other serotonin receptors in excess (i.e., 5HT1 and 5HT2) that may be involved in vasoconstriction. This vasoconstriction in the presence of concomitant atherosclerotic disease in the blood vessels feeding the GI tract may predispose to developing IC. Another hypothesis predicts that IC may result from the effect of alosetron on colonic motility and intestinal blood flow. Because alosetron is associated with severe constipation, patients with existing vascular disease may be predisposed to developing concomitant intestinal ischemia. These predictions are based on animal models and have not been the object of explicit study in humans.
Although serious gastrointestinal adverse events are infrequent, patients should receive instruction to look for alarming signs and symptoms to avoid complications. Alosetron therapy should be discontinued immediately in any patient who develops constipation, or there is a concern of ischemic colitis. If a patient develops ischemic colitis, the medication should not be resumed. Patients who develop constipation, which does not resolve after discontinuation of alosetron, need to notify their provider immediately.
There is no specific antidote for overdose of alosetron .
No dosage adjustments are necessary.
Adjustment for toxicity in adults:
Breastfeeding considerations :
Although studies have shown that the treatment of IBS-D with alosetron improves IBS symptoms, reduces pain and discomfort, and improves the quality of life of the patients, healthcare providers need to be mindful of the serious adverse effects that can accompany the use of this medication. An interprofessional team of primary care providers, gastroenterologists, specialty trained nurses, and pharmacists improve patient care. GI nurses educate patients, monitor status, and report issues to the team. Pharmacists review the use of the medication, the dose, drug-drug interactions, and inform patients about potentially dangerous side effects. Ischemic colitis and complications of constipation as a result of alosetron use have resulted in hospitalization, surgery, and death. It is of utmost importance that patients taking this medication are monitored closely and are advised of the symptoms to monitor to prevent a serious complication. Nursing can be a valuable resource in this regard, verifying patient compliance, watching for adverse events, and noting and charting therapeutic progress and informing the clinician of any concerns. These interprofessional collaborations will lead to better patient outcomes when using alosetron. [Level 5]
Before receiving the initial prescription for alosetron, the patient must read and sign the patient-physician agreement for alosetron, which helps ensure the patients understand their role and responsibilities regarding their treatment, the conditions under which their treatment may be terminated, and the responsibilities of their physician. The prescribing program for alosetron was put in place to reduce gastrointestinal adverse events. This program restricts the prescribing of alosetron to providers enrolled in the program based on their understanding of the risks versus benefits of the medication.
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