Alosetron

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 was approved by the FDA in February 2000 for the treatment of 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 The first use of alosetron was widespread; however, it was voluntarily withdrawn from the US market in November 2000 due to concerns of postmarketing adverse effects, including serious complications of constipation (CoC) and instances of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 for the treatment of 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 IC or CoC
• Have failed conventional therapy

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

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]

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.[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]

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.[13]

Other common side effects include [14][15]:

1. Abdominal discomfort and pain
2. Nausea
3. Intestinal discomfort and pain
4. Abdominal distention
5. Regurgitation and reflux
6. Hemorrhoids

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.[16] 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).[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.[17] This vasoconstriction in the presence of concomitant atherosclerotic disease in the blood vessels feeding the GI tract may predispose to developing IC.[18] 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.[19] These predictions are based on animal models and have not been the object of explicit study in humans. 

The contraindications to alosetron include [13][15]:

1. Chronic or severe constipation or any sequelae from constipation
2. Intestinal obstruction or stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions
3. Diverticulitis
4. Crohn disease or ulcerative colitis
5. Ischemic colitis, thrombophlebitis, impaired intestinal circulation, or hypercoagulable state
6. Severe hepatic impairment
7. History of blood clots
8. 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.