Alosetron

Mechanism of Action

Irritable bowel syndrome is a complex condition with an unclear etiopathogenesis. Researchers have postulated that serotonin is involved in the mechanism of IBS because more than 90% of the body's serotonin is present in the enterochromaffin cells of the GI tract.[13] The enterochromaffin cells release serotonin in response to chemical and barometric stimuli, activating peristaltic and secretory reflexes.[14]

Alosetron is a 5-hydroxytryptamine 3 (5-HT3, or serotonin) receptor antagonist that blocks these receptors, inhibiting peristalsis and slowing colonic transit time, allowing increased water reabsorption and stool formation.[6][13] In patients with IBS-D, blockade of these receptors reduces pain, abdominal discomfort, urgency, and diarrhea. This blockade also decreases visceral hypersensitivity by reducing blood flow to the brain's emotional centers, which helps regulate the emotional component of visceral stimulation.[15][16][17] Alosetron prolongs colonic transit without affecting oro-cecal transit time and enhances basal water and sodium absorption in the jejunum, providing benefits for patients with IBS-D.[18]

Pharmacokinetics

Absorption: Alosetron demonstrates rapid oral absorption and has an absolute bioavailability of 50% to 60%. Peak plasma concentrations are typically attained within an hour. Alosetron absorption rates are reduced by approximately 25% if taken with food, causing a delay in the time to peak plasma concentration by approximately 15 minutes. Despite equal dosing, plasma concentrations are 27% lower in men than women. Population pharmacokinetic studies of patients with IBS have confirmed this difference.

Distribution: Alosetron's volume of distribution ranges from 65 to 95 L, with 82% plasma protein binding.

Metabolism: Alosetron is primarily metabolized by cytochrome P450 enzymes, including CYP2C9, CY3A4, and CYP1A2. Non-CYP-mediated Phase I mechanisms account for about 11% of alosetron metabolism. In vivo studies have shown that CYP1A2 plays a significant role in alosetron metabolism.[19] The coadministration of some drugs and lifestyle factors, such as smoking, can influence CYP1A2 activity and affect alosetron clearance.

Elimination: The terminal elimination half-life of alosetron is approximately 1.5 hours. Studies involving radiolabeled alosetron have demonstrated that 74% (±5%) is eliminated through urine, primarily as the 6-hydroxy glucuronide and oxygenated imidazole derivatives. Fecal excretion accounts for 11% (±4%), and less than 1% is excreted unchanged.

Administration

Available Dosage Forms and Strengths

Alosetron is available as a 0.5 or 1 mg oral tablet.

Adult Dosing

The recommended initial dose is 0.5 mg twice daily to minimize constipation risk. If constipation occurs, the medication is discontinued until symptoms resolve. Patients may be restarted on 0.5 mg once daily; alosetron should be discontinued if constipation recurs at this dose.[20][21] 

Patients can remain on 0.5 mg once or twice daily dosing if their symptoms are well-controlled. If symptoms remain uncontrolled after 4 weeks at this dose, alosetron can be increased to 1 mg twice daily. If symptoms persist after 4 weeks despite this increased dosing, alosetron should be discontinued.[20]

Dosage Adjustment for Toxicity

• Constipation: Patients experiencing constipation at 0.5 mg twice daily must discontinue the medication immediately until symptoms resolve. The drug may be restarted at 0.5 mg once daily. If constipation recurs at this lower dose, alosetron must be discontinued immediately. 

• Ischemic colitis: Alosetron should be discontinued immediately without restarting.

• Debilitated patients: Alosetron should be administered cautiously due to the increased risk of complications from constipation.

Specific Patient Populations

Hepatic impairment: No dosage adjustments are necessary for mild to moderate impairment (Child-Pugh class A or B). Caution is advised due to alosetron's extensive hepatic metabolism via CYP2C9, 3A4, and 1A2 enzymes. Alosetron is contraindicated for patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment: No dosage adjustments are necessary.

Pregnancy considerations: Alosetron is a former US FDA pregnancy category B medication. Studies involving alosetron hydrochloride administration during organogenesis in rat and rabbit models showed no adverse developmental effects at 160 and 240 times the recommended human dosage. However, due to insufficient data on pregnant women receiving alosetron, the risk of potential adverse maternal or fetal outcomes cannot be adequately assessed. Therefore, the potential benefits should weighed against these unknown risks before administering alosetron to women who are pregnant.[11]

Breastfeeding considerations: No information is currently available regarding alosetron administration to women who are breastfeeding. Due to its high protein binding and moderate bioavailability, infant exposure through breast milk is considered minimal. Until more data is available, alosetron should be administered cautiously to women who are breastfeeding. The infant should be monitored for constipation or blood in the stool.[22]

Pediatric patients: Alosetron is not recommended in pediatric patients due to the increased risk of serious complications such as constipation and ischemic colitis observed in adults.

Older patients: Older patients may be at an increased risk of constipation-related complications; caution and regular monitoring are advised when prescribing alosetron to these patients.

Adverse Effects

The most common adverse effect associated with alosetron administration is constipation. A randomized, double-blind, placebo-controlled study assessed the efficacy and safety of alosetron 0.5 mg and 1 mg in women with severe IBS-D. The study data revealed that constipation occurred in patients receiving 0.5 mg (9%), 1 mg once daily (16%), and 1 mg twice daily (19%).[21]

Other common adverse effects associated with alosetron therapy include:[23][24][25]

• Abdominal discomfort and pain
• Nausea
• Abdominal distension
• Regurgitation and reflux
• Hemorrhoids
• Headache
• Fatigue

Although rare, ischemic colitis has been reported in patients taking alosetron to treat IBS. 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 3 months and 0.3% within the first 6 months.[26] A statistically significant increase in the incidence of ischemic colitis was observed in the pooled data of clinical trials involving patients receiving alosetron compared with placebo (0.15% vs 0.00%, p=0.03).[4] No precise mechanism for this observation is known, but many have been hypothesized. One possible mechanism involves the blockade of 5-HT3 receptors, increasing free serotonin available to stimulate other serotonin receptors (ie, 5-HT1 and 5-HT2) that may be involved in vasoconstriction.[27] This vasoconstriction may increase the risk of developing ischemic colitis in patients with concomitant atherosclerotic disease in vessels feeding the GI tract.[28] Another hypothesis postulates that ischemic colitis may result from alosetron's effects on colonic motility and intestinal blood flow. Because alosetron is associated with severe constipation, patients with existing vascular disease may be at increased risk of developing intestinal ischemia.[29] These predictions are based on observations of animal models and have not been studied in humans.

Gastrointestinal adverse reactions are common in postmarketing surveillance studies. GI perforation, impaction, ulceration, small bowel mesenteric ischemia, headache, and skin rash have been reported in patients receiving alosetron.

Drug-Drug Interactions

• CYP1A2 inhibitors: Fluvoxamine, a potent CYP1A2 inhibitor, can inhibit the metabolism of alosetron if coadministered, leading to alosetron toxicity. Fluvoxamine can increase the mean plasma concentration of alosetron by 6-fold and prolong the half-life by 3-fold.[24] Moderate CYP1A2 inhibitors (eg, cimetidine, quinolone antibiotics) should be avoided unless clinically indicated. 

• CYP3A4 inhibitors: Ketoconazole, clarithromycin, telithromycin, voriconazole, itraconazole, and protease inhibitors are strong CYP3A4 inhibitors and may increase alosetron toxicity. Due to potential drug interactions, clinicians should exercise caution when administering alosetron and CYP3A4 inhibitors concomitantly.

Contraindications

Contraindications to alosetron administration include:[21][24]

• Chronic or severe constipation or any sequelae from constipation
• Intestinal obstruction or stricture
• Toxic megacolon
• Gastrointestinal perforation or adhesions
• Diverticulitis
• Crohn disease or ulcerative colitis
• Ischemic colitis
• Thrombophlebitis
• Impaired intestinal circulation
• Severe hepatic impairment
• Hypercoagulable state
• Patients receiving fluvoxamine

Box Warnings

Severe gastrointestinal adverse reactions: Alosetron hydrochloride is indicated only for severe diarrhea-predominant irritable bowel syndrome (IBS) in women who have not responded adequately to standard therapy. Severe gastrointestinal adverse reactions, including ischemic colitis and complications of constipation, have been reported. These events have led to hospitalization and, in rare cases, require blood transfusion or surgery or have resulted in death.

Complications of constipation (CoC): Intestinal obstruction, ileus, fecal impaction, and toxic megacolon have been reported with alosetron use.[26] Alosetron should be discontinued immediately if constipation develops. Intestinal surgery, including colectomy, may be indicated. Patients who are older, debilitated, or taking medications that reduce gastrointestinal motility may be at greater risk of developing these adverse reactions.

Ischemic colitis: Alosetron should discontinued immediately if signs of ischemic colitis are observed, including rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Prompt evaluation and appropriate diagnostic testing are essential as ischemic colitis is a life-threatening condition. Advanced age is associated with fatal outcomes.[30]

Monitoring

Although severe gastrointestinal adverse events are uncommon, patients should be advised to look for alarming signs and symptoms. Alosetron therapy should be discontinued immediately for any patient who develops constipation or ischemic colitis. Alosetron should not be resumed for any patient who develops ischemic colitis. Patients who develop constipation that does not resolve after discontinuing alosetron must notify their provider immediately.[24] Treatment response should be monitored using validated tools such as the IBS global improvement scale (IBS-GIS) and health-related QOL.[31][32]

Toxicity

Signs and Symptoms of Overdose

During clinical studies, doses up to 16 mg (8 times the recommended daily dose) have been administered without significant adverse reactions. 

Management of Overdose

There is no specific antidote for alosetron.[33] Patients should be managed with appropriate supportive therapy. Overdose with alosetron may reduce the first-pass metabolism of other drugs. A poison control center should be contacted for overdose treatment protocol.

Enhancing Healthcare Team Outcomes

Although studies have shown that alosetron improves IBS-D symptoms, reduces pain and discomfort, and improves patients' quality of life, healthcare providers need to be mindful of the severe adverse effects associated with this medication.[34] Physicians should rule out other GI conditions before prescribing alosetron. Specially trained nurses educate patients, monitor their status, and report issues to the team. Pharmacists review the medication dose and drug-drug interactions and inform patients about potentially dangerous adverse drug reactions. Ischemic colitis and complications of constipation resulting from alosetron use have resulted in hospitalization, surgery, and death. Patients receiving this medication must be monitored closely and advised of the possible symptoms to monitor and prevent severe complications. Nurses can verify patient compliance, monitor for adverse events, document therapeutic responses, and inform clinicians of concerns. Gastroenterologists should be consulted for patients with ischemic colitis or ileus.

An umbrella systematic review evaluating pharmacologic treatments for irritable bowel syndrome (IBS) assessed patient outcomes associated with 5-HT-3 antagonists, 5-HT4 agonists, guanylate cyclase-C agonists, antispasmodics, and alosetron. According to the review's findings, alosetron exhibited beneficial effects, including relief of global IBS symptoms.[35]

The REMS program for alosetron was implemented to reduce gastrointestinal adverse events. This program restricted the prescribing of alosetron to providers enrolled in the program based on their understanding of the risks versus benefits of the medication.[16] The FDA eliminated the Alosetron REMS program in 2023 based on stable adverse event reporting from its reintroduction in 2002 to 2016, consistent ischemic colitis rates in new patients, and a trend in prescriptions without increased utilization. The prescribing information includes warnings regarding ischemic colitis and complications of constipation. Collaboration between an interprofessional team of clinicians (MDs, DOs, NPs, PAs), specialty-trained nurses, and pharmacists leads to improved patient outcomes.