Drug Criteria & Outcomes-Alosetron (Lotronex) for irritable bowel syndrome
August 1, 2000
Drug Criteria & Outcomes-Alosetron (Lotronex) for irritable bowel syndrome
By Leta Miles, PharmD candidate
Medical University of South Carolina
Charleston, SC
Indications:
Alosetron hydrochloride, manufactured by Glaxo Wellcome, is indicated for the treatment of irritable bowel syndrome (IBS) in women whose predominant symptom is diarrhea.1
Pharmacology:
The cause of IBS is unknown. However, it is thought that the release of serotonin and substance P causes visceral hypersensitivity and hyperactivity of the gastrointestinal tract. This leads to symptoms of IBS such as abdominal pain, diarrhea, and/or constipation.1-2 The mechanism of action of alosetron is attributed to its antagonistic effect on serotonin (5HT3) receptors distributed on the enteric neurons of the gastrointestinal tract.1,3 5HT3 receptor antagonists relieve the symptoms of IBS by increasing thresholds for sensation and discomfort during rectal distension, increasing rectal compliance, slowing gastrointestinal transit, and decreasing gastric secretions.4
Pharmacokinetics:
Alosetron is rapidly absorbed after oral administration, with a mean bioavailability between 50% and 60%. Concomitant administration of alosetron with food decreases the bioavailability by approximately 25% and delays mean time to peak concentrations by 15 minutes.1,5 Following oral administration without food, the mean time to peak plasma concentrations is approximately one hour.1 The volume of distribution is between 65 to 95 liters.
About 82% of alosetron is protein-bound. The terminal half-life of alosetron is 1.5 hours.1,5 Alosetron is extensively metabolized by cytochrome P450 isoenzymes. Cytochrome P450 2C9, 3A4, and 1A2 isoenzymes account for the majority of the metabolism of alosetron. Approximately 13 metabolites of alosetron have been detected in the urine. Seven percent of the parent compound was recovered unchanged.1 The actual biological activity of these metabolites is unknown. Renal clearance of alosetron is approximately 94 mL/ min.1
Selected clinical trials:
A trial conducted by Bardhan and colleagues evaluated the efficacy of alosetron in the treatment of IBS.6 Four hundred sixty-two patients (335 of them female) met the inclusion criteria and entered into a two-week screening period before beginning the 12-week trial. During the screening period, patients assessed the severity of their IBS symptoms (such as abdominal pain, number of bowel movements, and stool consistency).
After the screening period, patients were randomized to receive either alosetron 0.1 mg, 0.5 mg, 2 mg, or matching placebo, administered orally, twice daily. The primary endpoints assessed in this trial were the number of pain-free days and the proportion of patients with an improvement in abdominal pain and discomfort scores of greater than 10%. Other endpoints evaluated included stool consistency (hardening of the stool), stool frequency, and improvement in diarrhea. Patient demographics were well-matched in both study populations. Approximately 73% of patients were female.
Sixty-three percent of female patients receiving alosetron 2 mg administered orally twice daily exhibited a statistically significant improvement in abdominal pain and discomfort scores after 12 weeks of treatment, compared with 51% of patients in the placebo group (p < 0.05). Patients with diarrhea-predominant IBS received the most benefit when compared with patients with alternating or constipation-predominant IBS.
Both male and female patients receiving alosetron 0.5 mg or 2 mg twice daily reported hardening of stool consistency and a reduction in frequency. In females, 51% receiving alosetron 2 mg twice daily reported a statistically significant decrease in diarrhea, compared with 34% in the placebo group. No significant difference was found in males receiving 2 mg twice daily when compared with the placebo group in the incidence of diarrhea. Constipation was the most commonly reported adverse event in alosetron-treated patients. The predominance of constipation increased as the dose of alosetron increased. Four percent of patients receiving 0.1 mg, 15% of patients receiving 0.5 mg, and 19% of patients receiving 2 mg twice daily exhibited constipation.
Benefits to men
This trial demonstrated that female patients improved in pain/discomfort, stool consistency, and diarrhea, whereas male patients did not exhibit convincing improvement in these symptoms during treatment with alosetron. Male patients did exhibit improvement in stool hardening with the highest dose of alosetron used in the trial. The lack of efficacy in male patients may be due to the small number of men studied. Patients with normal to loose/watery stool consistency received benefit from alosetron. The authors concluded that female patients with diarrhea-predominant IBS exhibit significant improvement during treatment with alosetron.
Camilleri and colleagues conducted a study to assess the efficacy and safety of alosetron in women with IBS.4 Six hundred forty-seven women met the inclusion criteria and were randomized to receive either alosetron 1 mg or placebo administered orally, twice daily, for a 12-week period followed by a four-week post-treatment period. Demographics were similar for both study groups. Patients were assessed monthly by the enrolling physician for drug compliance and occurrence of adverse events. The primary endpoint was relief of pain and discomfort associated with IBS for at least two weeks per month. A touch-tone telephone system was used to collect patient data (such as pain, severity, urgency, stool consistency, and stool frequency) on a daily basis.
Test group results
Approximately 41% of the patients in the alosetron group and 29% in the placebo group reported adequate relief for all three months of treatments. Alosetron was statistically superior to placebo in relieving the symptoms of IBS at months one and three. However, during the second month, there was no statistically significant difference between the two groups. Patients who were classified as having diarrhea-predominant IBS received significant improvement compared with the placebo group, whereas patients with alternating IBS received no benefit with alosetron.
During the second and third months of treatment, patients receiving alosetron experienced a statistically significant decrease in pain severity compared with the placebo group. Those receiving alosetron exhibited a significant decrease in urgency, stool frequency, and stool consistency (p < 0.05). These changes were significant in diarrhea-predominant and alternating IBS.
The most commonly reported adverse event in the alosetron study population was constipation. Thirty percent of patients receiving alosetron and 3% of patients in the placebo group reported constipation. Women receiving alosetron had significant improvement in pain, urgency, stool frequency, and stool consistency after only one to two weeks of therapy. Symptoms of IBS did not occur during the 12-week treatment period but did return after treatment was stopped.
| Adverse Reactions Occurring in > 5% of Alosetron-Treated Patients | ||
| Adverse Event | Alosetron (n = 632) | Placebo (n = 637) |
| Constipation | 28% (174) | 5% (32) |
| Nausea | 7% (44) | 6% (38) |
| Abdominal discomfort/pain | 5% (32) | 3% (19) |
Adverse reactions:
Constipation is the most common adverse event associated with the use of alosetron.1,4,6 The incidence of constipation and other adverse events reported in clinical trials can be found in the table on p. 2.1
Pregnancy/lactation:
Alosetron is ranked as a pregnancy category B. Studies performed in rats and rabbits given 160 times and 240 times the recommended human daily dose, respectively, showed no evidence of impaired fertility in the mother or harm to the fetus. Because this may not correlate with human models, alosetron should only be used in pregnant women when the benefit to the mother clearly outweighs the risks to the fetus. Due to the excretion of alosetron in the breast milk of rats, breast-feeding is not recommended while taking alosetron.1
Contraindications:
Alosetron is contraindicated in patients with known hypersensitivity to the active ingredient or any other component of the tablet.1
Warnings:
Acute ischemic colitis may occur with the use of alosetron. There have been only a few cases reported in clinical trials.1,4 If signs and symptoms of acute colitis such as rectal bleeding and increasing abdominal pain occur, alosetron should be discontinued.
A patient experiencing these signs and symptoms should see her physician immediately for appropriate diagnostic tests. Another manifestation that may be problematic with the use of alosetron is constipation. If a patient is currently constipated or her predominant symptom of IBS is constipation, alosetron should not be administered.1
Dosage and administration:
The recommended adult dosage of alosetron is 1 mg taken twice daily orally. If a patient experiences constipation with her current dose, a decrease in the dose should be considered. No initial dosage adjustments are recommended in geriatric patients (65 years and older). Alosetron is not recommended in pediatric patients (under 18 years of age); no studies have been conducted in this patient population. Currently, no dosage adjustments are required in patients with renal or hepatic insufficiency.1
Drug interactions:
Alosetron has not been shown to inhibit cytochrome P450 enzymes (examples are 3A4, 2D6, 2C9, 2C19, 2E1, and 1A2). Therefore, alosetron does not inhibit the hepatic clearance of drugs metabolized by these isoenzymes, nor does alosetron appear to induce cytochrome P450 enzymes such as 3A, 2E1, or 2C19. Concentrations of drugs metabolized by these enzymes should not be decreased by alosetron. However, since alosetron is extensively metabolized by the cytochrome P450 enzymes, and because there is no information available on specific drug-drug interactions, caution should be exhibited when using alosetron concomitantly with drugs that induce or inhibit those enzymes.1
Dosage forms available:
Alosetron is supplied as a blue, oval, film-coated tablet. Each tablet contains 1.124 mg of alosetron HCl that is equivalent to alosetron 1 mg. Alosetron is available in bottles of 60 tablets.1,7
Potential for medication errors:
Lotronex sounds like and is spelled similarly to Lovenox. Health care professionals may mistake these agents for one another. Another potential for medication error is between ondansetron (Zofran) and the generic name for Lotronex, alosetron.
Discussion:
Alosetron is the newest agent for the treatment of diarrhea-predominant IBS in females. The use of alosetron, a selective 5HT3 antagonist, was recently discovered because of the increased understanding of the pathophysiology of IBS. It is thought that there are serotonin receptors on the enteric neurons lining the gastrointestinal tract. Blocking these receptors leads to a decrease in visceral hypersensitivity and motility associated with IBS.
Alosetron costs more than other agents used to treat IBS (examples are loperamide, cholestyramine resin, and dicyclomine), but it has shown significant improvement in pain/discomfort, stool urgency, stool frequency, and stool consistency in female patients with diarrhea-predominant IBS when compared with placebo. Current regimens used to treat diarrhea-predominant IBS only treat the symptoms associated with the disorder and do not block the pathophysiological process. Therefore, the advent of alosetron may change the way IBS is treated.
References
1. Lotronex package insert. Research Triangle Park, NC: Glaxo Wellcome Inc; February 2000.
2. Saslow SB, Scolapio JS, Camilleri M, et al. Medium term effects of a new 5HT3 antagonist, alosetron, in patients with carcinoid diarrhoea. Gut 1998; 42:628-634.
3. Farthing MJ. Irritable bowel syndrome: New pharmaceutical approaches to treatment. Bailliere's Clinical Gastroenterology 1999; 13:461-471.
4. Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: A randomized, placebo-controlled trial. Lancet 2000; 355: 1,035-1,040.
5. Gunput MD. Review article: Clinical pharmacology of alosetron. Aliment Pharmacol Ther 1999; 13:70-76.
6. Bardhan KD, Bodemar G, Geldof H, et al. Double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2000; 14:23-34.
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