Alosetron

Irritable bowel syndrome (IBS) is a common functional bowel disorder that is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal (GI) tract. IBS symptoms include lower abdominal pain, discomfort, bloating, and altered bowel function. Functional abnormalities vary but may include a sense of bowel urgency, diarrhea, constipation, or alternating diarrhea and constipation.

About 20% of Americans report symptoms consistent with IBS. IBS is the most common diagnosis in gastroenterology practices and one of the top 10 reasons for primary care visits. Approximately 70% of IBS patients are women, but less than 50% seek treatment. 1-4

Etiology

The cause of IBS is unknown and cannot be explained by identifiable structural or biochemical abnormalities. Some patients have abnormalities of intestinal motility or enhanced visceral sensitivity. Patients with IBS have been shown to have increased motility and abnormal contractions in response to stimuli, including psychological stress and physiologic factors. Those with diarrhea-predominant IBS have accelerated whole-gut transit times, while those with constipation-predominant symptoms have delays in colonic transit.5

The central nervous system, an important component of the brain-gut axis, plays an important role in symptom production both in response to stress and when there is an underlying affective disorder. The enteric nervous system controls motility and secretory functions of the intestine. Many neurotransmitters play a role in its function, including 5-hydroxytryptamine (5-HT), substance P, vasoactive intestinal peptide, and calcitonin gene-related peptide. Both the parasympathetic and sympathetic nervous system modify its actions. Defects in the enteric nervous system produce an increased visceral afferent response to normal and noxious stimuli. Identification and characterization of 5HT receptors in the GI tract, particularly 5-HT3 and 5-HT4 receptors, are involved not only in modulating gut motility but also in visceral sensory pathways.6,7

The 5-HT3 receptors are nonselective cation channels that are extensively distributed on enteric neurons in the GI tract and in other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit, and GI secretions.

Diagnosis

The hallmark of IBS is abdominal pain relieved with defecation; the stool is changed in its consistency or frequency. Associated symptoms include bloating, mucus in the stool, urgency, or a feeling of incomplete evacuation. Symptoms may be either diarrhea- or constipation-dominant, or an alternating combination. The Rome II diagnostic criteria provide guidelines for diagnosis based on symptoms (see Table 1). Symptoms that suggest an alternative or coexisting diagnosis include anemia; fever; rectal bleeding; severe constipation; weight loss; nocturnal symptoms of pain or abnormal bowel function; new onset of symptoms after age 50; and a family history of GI cancer, inflammatory bowel disease, or celiac disease. The physical examination is usually normal except for possible tenderness to abdominal palpation, especially in the lower left quadrant. Differential diagnoses are outlined in Table 2.

For patients younger than age 50, diagnostic tests to confirm the diagnosis of IBS include a complete blood count; sedimentation rate; electrolytes; liver enzymes; stool for occult blood, ova, and parasites; and possible sigmoidoscopy. For those over age 50, a colonoscopy or air-contrast barium enema with sigmoidoscopy is indicated.

Nonpharmacologic Treatment

Treatment is based on symptom severity. Patients with mild symptoms may require only reassurance, education, and dietary modification. Identification and elimination of irritating dietary substances including caffeine, beans, fatty foods, lactose, alcohol, or drugs can significantly decrease symptoms. A high-fiber, low-fat diet is recommended. A fiber supplement, such as psyllium or dietary bran, up to 12 grams daily, may be effective for patients with diarrhea or constipation symptoms. Milk should be avoided only in those patients with lactose intolerance.

If psychological factors play a role, patients may respond to counseling or stress management techniques. The clinician should explain to the patient that these methods are a means to cope with a chronic, uncomfortable illness; the patient should understand that the disorder is not considered psychiatric in origin.8

Traditional Pharmacologic Approaches

Drug options should be targeted to specific symptoms. For abdominal pain, anticholinergic drugs, such as dicyclomine or hyoscyamine, which are taken prior to meals, can decrease postprandial pain. Diarrhea may respond to loperamide, which decreases intestinal transit and increases water absorption in some patients. Cholestyramine, which sequesters bile acids, may also decrease diarrhea) symptoms. In patients with constipation, osmotic laxatives such as lactulose or sorbitol may be beneficial. Chronic use of stimulant laxatives should be avoided.8

A small percentage of patients report severe symptoms, usually constant pain that may be only partially related to physiologic factors; these patients may have significantly impaired daily functioning. Treatment with tricyclic antidepressants or selective serotonin reuptake inhibitors may be instituted for central analgesia and to improve psychological well-being.8

Alosetron, a New Neumenteric Modulator

Pharmacodynamics

Alosetron hydrochloride (Lotronex) is a selective antagonist of the serotonin 5-HT3 receptor type. The blockade of 5-HT3 receptors potentially reduces visceral pain and exaggerated motor responses, but the site of action has not been fully established. In healthy volunteers and IBS patients, alosetron increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4-mg dose. In IBS patients, multiple oral doses of alosetron (4 mg b.i.d. for 6.4 days) significantly increased colonic compliance.9

Pharmacokinetics

Alosetron is rapidly absorbed after oral administration with a mean absolute bioavailability of 50% to 60%. After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Peak plasma concentration of approximately 5 ng/ml occurs at 1 hour in young, healthy men and at approximately 9 ng/ml in young women. Absorption is decreased by approximately 25% when administered with food, with a mean delay in time to peak concentration of 15 minutes.

Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg; the plasma concentrations increase more than proportionately at a single oral dose of 16 mg. Twice-daily dosing does not result in accumulation. The elimination half-life is approximately 1.5 hours. Renal elimination of unchanged alosetron accounts for 6% of the dose. Renal clearance is approximately 94 ml/minute.

Alosetron is extensively metabolized in humans, although the biologic activity of these metabolites is unknown. One study indicated that alosetron metabolites reach additive peak plasma concentrations ninefold greater than alosetron and that the additive metabolite areas under the curve (AUC) are thirteenfold greater than alosetron's areas under the curve. Plasma radioactivity declined with a half-life twofold longer than that of alosetron, which indicates the presence of circulating metabolites. Approximately 73% of the radiolabeled dose was recovered in urine and another 24% in feces. Only 7% of the drug was recovered as unchanged drug. At least 13 metabolites have been detected in urine.

Alosetron is metabolized by,cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non-CYP-mediated Phase 1 metabolic conversion contributes to an extent of about 11%.

Clinical Trials

To compare the efficacy and tolerability of alosetron to the smooth muscle relaxant mebeverine, 623 nonconstipated women were randomized to receive alosetron 1 mg b.i.d. (n = 319) or mebeverine 135 mg t.i.d. for 12 weeks, followed by a 4-week posttreatment period. The primary efficacy end point was responders who reported adequate relief of IBS-related abdominal pain and discomfort for at least 2 weeks monthly. Secondary end points included assessments of bowel function including urgency, stool frequency, and stool consistency. Significantly more responders were in the alosetron group at months 2 and 3 (P

A total of 462 patients (335 female) enrolled in a placebo-controlled, parallel-group study with a 2-week screening and a 12-week treatment period. Severity of abdominal pain and bowel function was recorded in a daily diary. At monthly clinic visits, patients recorded the severity of abdominal pain or discomfort and diarrhea on a visual analogue scale. In the total population and in the female subpopulation, alosetron 2 mg b.i.d. significantly increased the proportion of pain-free days and decreased the visual analogue scale score for diarrhea compared with placebo. Doses of 0.5 mg b.i.d. and 2 mg b.i.d. led to a significant hardening of stools and a reduction in stool frequency in the total population.11

Two multicenter, double-blind, placebo-controlled dose-ranging studies were conducted over 12 weeks to determine alosetron's dose. The identically designed studies enrolled women with IBS who met the Rome criteria for at. least 6 months. An average pain score of at least mild pain, collected during a 2-week screening period, was required. Women with severe pain were excluded. An entry stool consistency requirement was also used to target women whose predominant symptom was diarrhea or in which diarrhea was prominent in an alternating pattern.

Women with a history of severe constipation were excluded, and men were excluded. The primary efficacy measure was a weekly assessment of adequate relief of IBS pain and discomfort. Key secondary measures included percentage of days with urgency and daily assessment of stool frequency and consistency.

One study enrolled 647 women (71% diarrhea-predominant, 28% alternating diarrhea and constipation, and 1% constipation-predominant). The second study enrolled 626 women with similar bowel patterns. In both trials, alosetron 1 mg b.i.d. was significantly more effective in relieving IBS pain and discomfort only in women with diarrhea-predominant IBS. In the first study, significantly more women reported pain relief within I week of starting therapy compared with placebo. In the second study, the treatment effect was observed within 4 weeks. In both studies, women who received alosetron reported a significant decrease in percentage of days with urgency and stool frequency and firmer stools. Significant treatment effect persisted throughout the remainder of the treatment period. Within 1 week of discontinuing therapy, there was no difference between placebo- and alosetron-treated patients.12

Clinical Guidelines Indications and Usage

Alosetron is indicated for the treatment of IBS in women whose predominant bowel symptom is diarrhea. Safety and effectiveness in men have not been established.

Contraindications

Alosetron should not be used in patients who are currently constipated or whose predominant bowel symptom is constipation. Acute ischemic colitis was reported infrequently in patients in controlled trials; however, a causal correlation between alosetron and acute colitis has not been established. Alosetron should be discontinued in patients experiencing rectal bleeding or sudden worsening of abdominal pain.

Because of extensive hepatic metabolism and first-pass metabolism, this drug should not be used in patients with hepatic insufficiency. Renal impairment, creatinine clearance of 4 to 56 ml/minute, has no effect on renal elimination. Individuals age 65 and older exhibited plasma concentrations elevated 40% compared with younger adults. However, patients over age 65 showed no evidence of differential treatment effects compared with other age groups. Alosetron should not be used during pregnancy, lactation, or in pediatric patients.

Drug Interactions

Alosetron does not appear to induce the major cytochrome P450 drug metabolizing enzyme 3A. It did inhibit CYP enzymes 1A2 and 2E1 in vitro at total drug concentrations 27 times higher than peak plasma concentrations observed with the 1-mg dose. Although not studied, alosetron may have a significant interaction with drugs using the CYP 1A2 pathway, including isoniazid, procainamide, and hydralazine. Clinical interaction studies showed no deleterious effects when alosetron was used in combination with theophylline, ethinyl estradiol, and levonorgestrel. The interactions with monoamine oxidases and intestinal first pass secondary to high intraluminal concentrations have not been examined.

Adverse Reactions

Constipation is a frequent and doserelated adverse effect. In clinical studies, 25% to 30% of patients experienced constipation (n = 702). For most patients, constipation was mild to moderate in intensity and selflimited. Approximately 9% of patients required interruption of treatment for a few days, and about 10% could not tolerate b.i.d. dosing on a continuous basis and discontinued therapy. Of the patients reporting constipation, 75% reported a single episode with mean time to constipation onset of about 3 weeks. Most constipation events resolved spontaneously with continued treatment.12 Management of constipation with usual care, including laxatives, fiber, or a brief discontinuation of therapy, should be considered.

Infrequent adverse events (those occurring on one or more occasions in 1 / 100 to 1/1,000 patients) include cardiac arrhythmias, throat and tonsil discomfort, allergic rhinitis symptoms, ischemic colitis, breathing disorders, anxiety, menstrual disorders, and abnormal bilirubin levels. Rare adverse events (those occurring on one or more occasions in fewer than 1/1,000 patients) include photophobia, proctitis, cough, sedation, abnormal dreams, unusual odors and taste, sexual dysfunction, acne, folliculitis, urinary infections, polyuria, diuresis and contusions, and hematomas.

Dosage and Administration

The recommended adult dose of alosetron is 1 mg b.i.d. orally with or without food. Patients who experience constipation may need to interrupt treatment. A dosage adjustment is not necessary in geriatric patients or in those with renal impairment.

Average wholesale cost is $1.98 per tablet. Patient cost can vary from $150 to $180 for a 1-month supply of the recommended daily dose.

Conclusion

Irritable bowel syndrome is a common GI disorder characterized by abdominal pain and discomfort and altered bowel function. Defects in the enteric nervous system may contribute to these symptoms. A treatment program should be based on the dominant symptoms and their severity. Management options include a thorough diagnostic evaluation, lifestyle modifications, and pharmacologic therapy. A novel neuroenteric modulating agent, alosetron, may prove beneficial to female patients whose predominant bowel symptom is diarrhea.

REFERENCES

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4. Drossman DA, Thompson WG: The irritable bowel syndrome: Review and a graduated multicomponent treatment approach. Ann Intern Med 1992;116:1009-16.

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8. Dalton CB, Drossman DA: Diagnosis and treatment of irritable bowel syndrome. Am Fam Physician 1997;55(3):875-80.

9. Gunput MD: Clinical pharmacology of alosetron. Aliment Pharmacol Ther 1999;13(suppl 2):70-76.

10. Jones RH, Holtmann G, Rodrigo L, et al.: Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients. Aliment Pharmacol Ther 1999; 13(11):1419-27.

11. Bardhan KD, Bodemar G, Geldof H, et al.: A double-blind, randomized, placebo-controlled dose-- ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Ailment Pharmacol Ther 2000;14(1):23-34.

12. Camilleri M, Northcutt AR, Kong S, et al.: Efficacy and safety of alosetron in women with irritable bowel syndrome: A randomized, placebocontrolled trial. Lancet 2000;355:1035-39.

ABOUT THE AUTHOR

Deborah Kupecz, RN, ANP, MSN, a nurse practitioner in Denver, Colo., is on the faculty at the University of Phoenix, is a doctoral student at the University of Northern Colorado, and is the editor of The Nurse Practitioners Drug News column.

Copyright Springhouse Corporation Jul 2000
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