Continuing Education Activity

Alosetron is a medication used to manage and treat severe diarrhea-predominant irritable bowel syndrome (IBS-D). It is in the class of 5-HT receptor antagonist medications. This activity outlines the indications, action, and contraindications for alosetron as a valuable agent in IBS-D management. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with IBS-D.

Objectives:

• Identify the mechanism of action of alosetron.
• Describe the adverse effects of alosetron.
• Review the appropriate monitoring when treating patients with alosetron.
• Outline interprofessional team strategies for improving care coordination and communication to advance and improve outcomes for patients affected by IBS-D.

Indications

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.[1] First-line therapy for the management of IBS-D is usually diet and lifestyle modifications. Alosetron is a medication that the FDA approved in February 2000 to treat IBS-D in females.[2] The first use of alosetron was widespread; however, it was voluntarily withdrawn from the US market in November 2000 due to concerns of postmarketing adverse effects, including serious complications of constipation (CoC) and instances of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).[3][4][5]

Alosetron was eventually reintroduced in 2002 with more restricted indications, with its use limited to treating severe IBS-D symptoms in women that are refractory to other therapies.[6]

The definition of severe IBS-D is diarrhea with one or more of the following[7]:

• Frequent and severe abdominal pain and discomfort 
• Frequent bowel urgency and fecal incontinence
• Disability or restrictions in activities of daily living as a result of IBS 

To meet the criteria to be started on alosetron, women with severe IBS-D had to have:

• Chronic symptoms lasting six months or longer
• Must not have any anatomic or biochemical abnormalities of the GI tract, placing them at risk for ischemic colitis or complications of constipation
• Have failed conventional therapy

The starting dose was also lowered to minimize the incidence of constipation.[5]

Mechanism of Action

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.[8] The enterochromaffin cells are responsible for releasing serotonin in response to chemical stimuli and increased intraluminal pressure, thereby activating peristaltic and secretory reflexes.[9] 

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.[5][8] 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.[10][11]

Administration

Alosetron is taken orally. It is available in 0.5 mg tablet and 1 mg tablet strength. 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.[12][13] 

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.[12]

Specific Population

Renal Impairment

• No dosage adjustments are necessary.

Hepatic Impairment

• Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustments necessary. Use with caution due to extensive hepatic metabolism via CYP2C9, 3A4, and 1A2.
• Severe impairment (Child-Pugh class C): usage is contraindicated

Adjustment for Toxicity in Adults

• Constipation: Patients experiencing constipation with an initial dose of 0.5 mg twice a day must discontinue the medication immediately until symptoms resolve. The drug may be restarted at 0.5 mg once daily. If constipation recurs at a lower dose, discontinue immediately. 
• Ischemic Colitis: discontinue the medication immediately and do not restart.
• Geriatric Patients: use caution due to the increased risk of complications from constipation.
• Debilitated Patients: use caution due to increased risk of complications from constipation.

Pregnant Patients: It is US FDA pregnancy category B medicine. Adverse events have not been observed in animal studies.

Breastfeeding Considerations[14]

• It is unclear if alosetron will transfer to breast milk.
• Consider risks versus benefits of breastfeeding the infant while the mother is on therapy with alosetron, risk of infant exposure, and treatment benefits to mother.
• Monitor the infant for constipation or blood in the stool.

Adverse Effects

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% of patients in the 0.5 mg, 1 mg once daily, and 1 mg twice daily groups, respectively.[13]

Other common side effects include [15][16][17]:

• Abdominal discomfort and pain
• Nausea
• Intestinal discomfort and pain
• Abdominal distention
• Regurgitation and reflux
• Hemorrhoids
• Headache
• Tiredness

Although rare, there have been a few reported ischemic colitis cases in patients taking alosetron for IBS treatment. Clinical trials comparing patients receiving alosetron 1 mg twice daily to patients receiving placebo showed that the cumulative incidence of ischemic colitis was 0.2% within the first three months and 0.3% within the first six months.[18] Overall, a statistically significant increase in the incidence of ischemic colitis was observed from pooled data of clinical trials in alosetron-treated patients when compared with placebo (0.15% versus 0.00%, p = 0.03).[3] 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.[19] This vasoconstriction in the presence of concomitant atherosclerotic disease in the blood vessels feeding the GI tract may predispose to developing ischemic colitis.[20] Another hypothesis predicts that ischemic colitis 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.[21] These predictions are based on animal models and have not been the object of explicit study in humans. 

In postmarketing surveillance studies, gastrointestinal adverse reactions were common. Patients using alosetron tablets reported GI perforation, impaction, ulceration, small bowel mesenteric ischemia, headache, and skin rash.

Drug Interactions

CYP1A2 Inhibitors: Fluvoxamine, a strong CYP1A2 inhibitor, if coadministered with alosetron, can inhibit the metabolism of alosetron which can lead to alosetron toxicity. Moderate CYP1A2 inhibitors, including cimetidine and quinolone antibiotics, should be avoided unless clinically needed. 

CYP3A4 Inhibitors: Ketoconazole, clarithromycin, telithromycin, voriconazole, itraconazole, and protease inhibitors are strong inhibitors of CYP3A4 and may increase alosetron toxicity.  Exercise caution when alosetron and CYP3A4 inhibitors are administered concomitantly because of potential drug interactions.

Contraindications

The contraindications to alosetron include [13][16]:

• Chronic or severe constipation or any sequelae from constipation
• Intestinal obstruction or stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions
• Diverticulitis
• Crohn disease or ulcerative colitis
• Ischemic colitis, thrombophlebitis, impaired intestinal circulation, or hypercoagulable state
• Severe hepatic impairment
• History of blood clots
• Concomitant use of fluvoxamine as fluvoxamine is a strong inhibitor of CYP1A2. Research has shown it to increase the mean plasma concentration of alosetron by approximately 6-fold and prolong the half-life by 3-fold.

Monitoring

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.[16]

Toxicity

There is no specific antidote for overdose of alosetron [22]. It is recommended to manage patients with appropriate supportive therapy. Individual doses up to 16 mg (8 times the recommended total daily dose) are administered in clinical studies without major adverse reactions. Overdose with alosetron might reduce the first-pass metabolism of other drugs coadministered. The poison control center should be contacted for overdose treatment protocol.

Enhancing Healthcare Team Outcomes

Although studies have shown that the treatment of IBS-D with alosetron improves IBS symptoms, reduces pain and discomfort, and improves patients' quality of life, healthcare providers need to be mindful of the serious adverse effects that can accompany the use of this medication.[23] An interprofessional team of primary care providers, gastroenterologists, specialty trained nurses, and pharmacists improves 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 resulting from alosetron use have resulted in hospitalization, surgery, and death. It is of utmost importance that patients taking this medication to be monitored closely and 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, 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 implemented 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.[11]