Lotronex
Lotronex Information
Lotronex is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have:
- chronic IBS symptoms (generally lasting 6 months or longer),
- had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and
- failed to respond to conventional therapy.
Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following:
- frequent and severe abdominal pain/discomfort
- frequent bowel urgency or fecal incontinence
- disability or restriction of daily activities due to IBS
Less than 5 percent of IBS is considered severe.
In Simple Terms
Lotronex is a medicine that slows the movement of stools (bowel movements) through the bowels. Lotronex does not cure IBS and it will not help every person who takes it. For those who are helped, Lotronex reduces lower abdominal (stomach area) pain, abdominal discomfort, urgency (sudden need to have a bowel movement), and diarrhea of IBS. If you stop taking Lotronex, your IBS symptoms may return within 1 or 2 weeks.
Lotronex Ingredients and Composition
How Does Lotronex Work?
Mechanism of Action
Alosetron, the active ingredient in Lotronex, is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are nonselective cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HT3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of the enteric nervous system.
The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, IBS patients exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, Lotronex (alosetron) reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT3 receptors.
In healthy volunteers and IBS patients, Lotronex (alosetron) (2 mg orally, twice daily for 8 days) 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 twice daily for 6.5 days) significantly increased colonic compliance.
Single oral doses of Lotronex (alosetron) administered to healthy men produced a dose-dependant reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-?-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg orally twice daily. This decrease was not statistically significant. In another study utilizing Lotronex (alosetron) 1 mg orally twice daily for 4 days, there was a significant decrease in urinary 6-b-hydroxycortisol excretion. However, there was no change in the ratio of 6-b-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown.
How To Take Lotronex and Lotronex Dosage and Administration
Usual Dose in Adults
For safety reasons, Lotronex should be started at a dosage of 1 mg orally once a day for 4 weeks. This dosage may be less constipating than a regimen of 1 mg twice a day. If, after 4 weeks, the 1 mg once-a-day dosage of Lotronex is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to 1 mg twice a day, the dose used in controlled clinical trials. Although the efficacy of the 1 mg once-a-day dosage in treating diarrhea-predominant IBS has not been evaluated in clinical trials, for safety reasons consideration should be given to continuing this dosage if well tolerated and IBS symptoms in the individual patient are adequately controlled. Lotronex should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day.
Lotronex should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Lotronex should not be restarted in patients who develop ischemic colitis.
Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious Lotronex complications of constipation. Therefore, appropriate caution and follow-up should be exercised if Lotronex is prescribed for these patients.
Pediatric Patients
Lotronex safety and effectiveness have not been established in pediatric patients.
Geriatric Patients
Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if Lotronex is prescribed for these patients.
If you suspect a Lotronex Overdose
There is no specific antidote for overdose of Lotronex. Patients should be managed with appropriate supportive therapy. Individual oral doses as large as 16 mg have been administered in clinical studies without significant adverse events. This dose is 8 times higher than the recommended total daily dose. Inhibition of the metabolic elimination and reduced first pass of other drugs might occur with overdoses of alosetron. Single oral doses of Lotronex at 15 mg/kg in female mice and 60 mg/kg in female rats (30 and 240 times, respectively, the recommended human dose based on body surface area) were lethal.
Symptoms of acute toxicity were:
- labored respiration
- subdued behavior
- ataxia
- tremors
- convulsions
Lotronex Side Effects
Contraindications to Lotronex
Lotronex should not be initiated in patients with constipation. Lotronex is contraindicated in patients:
- With a history of chronic or severe constipation or with a history of sequelae from constipation.
- With a history of intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions.
- With a history of ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state.
- With current or a history of Crohn's disease or ulcerative colitis.
- With active diverticulitis or a history of diverticulitis.
- Who are unable to understand or comply with the Patient-Physician Agreement.
- With known hypersensitivity to any component of the product.
Lotronex Drug Interactions
In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that Lotronex (alosetron) did not inhibit CYP enzymes 2D6, 3A4, 2C9, or 2C19. In vitro, at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1-mg dosage, Lotronex (alosetron) inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, Lotronex (alosetron) did not inhibit CYP2E1 but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase. Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine. The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed. Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel (CYP3A4 substrates). A clinical interaction study was also conducted with Lotronex (alosetron) and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effect of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined. Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the major CYP enzyme 3A4, as well as the CYP enzymes 2D6, 2C9, 2C19, 2E1, or 1A2.
Lotronex (alosetron) does not appear to induce the major cytochrome P450 (CYP) drug metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes.
Because Lotronex (alosetron) is metabolized by a variety of hepatic CYP drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. The effect of induction or inhibition of these pathways on exposure to alosetron and its metabolites is not known.
Lotronex Precautions and Contraindications
Constipation: Serious complications of constipation, including obstruction, perforation, impaction, toxic megacolon, secondary colonic ischemia, and death have been reported with use of Lotronex. In some cases these complications have required intestinal surgery, including colectomy. In IBS clinical trials, the incidence of serious complications of constipation in women was approximately 1 per 1,000 patients, but approximately 10% of patients on Lotronex withdrew prematurely because of constipation. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation.
Lotronex should be discontinued immediately in patients who develop constipation.
Ischemic Colitis: Ischemic colitis has been reported in patients receiving Lotronex in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving Lotronex was 2 per 1,000 patients (95% confidence interval 1 to 3) over 3 months and was 3 per 1,000 patients (95% confidence interval 1 to 4) over 6 months. Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking Lotronex for longer than 6 months.
Lotronex Warnings
Lotronex Clinical Trials and Studies
Storing Lotronex
Store Lotronex at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
