Alosetron

Alosetron is a Selective 5-HT₃ Receptor Antagonist of drug belonging to Gastrointestinal Agent.

Alosetron is a 5-HT3 antagonist used to treat diarrhea-predominant irritable bowel syndrome (IBS).

Alosetron rapidly absorb with having mean bioavailability of 50% to 60%. The peak plasma concentration is approximately 1 hour. The volume of distribution is about 65 to 95 L. Alosetron having extensive hepatic metabolism via CYP2C9, 3A4, and 1A2. Thirteen metabolites have been detected in the urine. Biological activity of these metabolites in unknown. The elimination half-life is about 1.5 hours. It is excreted via urine (74%, 13% of total dose as unchanged drug); feces (11%, 1% of total dose as unchanged drug).

Alosetron shows side effects like Upset stomach, swelling in the stomach area, hemorrhoids.

Alosetron is available in the form of Oral Tablet.

Alosetron is available in India, Canada, US, China, Spain, Australia, France, Italy, and Germany.

Alosetron belongs to the Gastrointestinal Agent acts as a Selective 5-HT₃ Receptor Antagonist.

Alosetron 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 serotonin-sensitive GI motor and sensory processes.

The data of onset of action and duration of action is not clinically established.

The Tmax of Alosetron is approximately 1 hour.

Alosetron is available in the form of Oral Tablet.

Alosetron Tablet is taken orally, usually twice daily.

Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modulate serotonin-sensitive gastrointestinal (GI) processes.

Alosetron is a Selective 5-HT₃ Receptor Antagonist of drug belonging to Gastrointestinal Agent.

Alosetron is a potent and selective antagonist of a subtype of the serotonin 5-HT₃ receptor. 5-HT₃ receptors are ligand-gated ion channels extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations.

Alosetron is approved for use in the following clinical indications

• Irritable bowel syndrome with diarrhea, severe

Alosetron is a 5-HT3 antagonist used to treat diarrhea-predominant Irritable bowel syndrome (IBS).

• Irritable bowel syndrome with diarrhea, severe

Standard dose: Oral: Initial: 0.5 mg twice daily; if patient becomes constipated at 0.5 mg twice daily, discontinue therapy until constipation resolves. May restart at 0.5 mg once daily. If constipation recurs at 0.5 mg once daily, permanently discontinue.

Dosage titration: If 0.5 mg twice daily is tolerated but response is inadequate after 4 weeks, may increase to 1 mg twice daily (maximum dose: 2 mg/day). If response is inadequate after 4 weeks at 1 mg twice-daily dosing, discontinue treatment.

Low dose: Oral: Due to safety concerns with standard dosing, some experts recommend initiating at 0.5 mg once daily.

Dosage titration: After 4 weeks, increase dose only if needed to 0.5 mg twice daily; if response is inadequate after 4 weeks at 0.5 mg twice-daily dosing and patient is tolerating, may increase to 1 mg twice daily (maximum: 2 mg/day).

Alosetron is available in various strengths as 0.5 mg and 1 mg.

Alosetron is contraindicated in patients with

• Constipation
• Alosetron should not be initiated in patients with constipation.
• History of Severe Bowel or Hepatic Disorders Alosetron is contraindicated in patients with a history of the following:
• Chronic or severe constipation or sequelae from constipation
• Intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions
• Ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state
• Crohn’s disease or ulcerative colitis
• Diverticulitis
• Severe hepatic impairment
• Concomitant Use of Fluvoxamine Concomitant administration of Alosetron with fluvoxamine is contraindicated. Fluvoxamine, a known strong inhibitor of CYP1A2, has been shown to increase mean alosetron 4 plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold.

• Constipation

Discontinue immediately in patients who develop constipation; infrequent but serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, or death have been reported (obstruction, ileus, perforation [rare], impaction, toxic megacolon, secondary bowel ischemia). Constipation is a frequent, dose-related side effect; risk for complications from constipation may be increased in elderly, debilitated patients, or with concurrent use of other medications which decrease GI motility. Non severe constipation may be managed by temporarily interrupting therapy and decreasing the dose. Do not initiate in patients with constipation.

• Ischemic colitis

Ischemic colitis has been reported during treatment without warning. Discontinue and evaluate immediately in patients who experience rectal bleeding, bloody diarrhea, or a sudden worsening of abdominal pain, and do not restart therapy if ischemic colitis is diagnosed.

• Debilitated patients

Use with caution in debilitated patients due to increased risk of complications from constipation.

Alosetron and/or metabolites of Alosetron are excreted in the breast milk of lactating rats. It is not known whether Alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Alosetron is administered to a nursing woman.

Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to Alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Alosetron should be used during pregnancy only if clearly needed.

• Common

Tachyarrhythmia, Diaphoresis, urticaria, Abdominal distention, abdominal distress, abdominal pain, active gastrointestinal lesion, dyspepsia, flatulence, gastrointestinal distress, gastrointestinal pain, gastrointestinal spasm, hemorrhoidal bleeding, hemorrhoids, ischemic colitis, nausea, viral gastroenteritis, vomiting, xerostomia, Urinary frequency, urinary tract infection, Anxiety, disruption of body temperature regulation, drowsiness, fatigue, headache, malaise, pain, Muscle cramps, muscle spasm, Cough, nasopharyngitis, sinusitis, upper respiratory tract infection.

• Rare

Skin rash, Fecal impaction, gastrointestinal perforation, gastrointestinal ulcer, mesenteric ischemia (small bowel).

• CYP1A2 Inhibitors

Fluvoxamine is a known strong inhibitor of CYP1A2 and inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/ day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Concomitant administration of alosetron and fluvoxamine is contraindicated. Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions.

• CYP3A4 Inhibitors

Ketoconazole is a known strong inhibitor of CYP3A4. In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day. Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%. Caution should be used when alosetron and ketoconazole are administered concomitantly. Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions. The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known.

• Other CYP Enzymes

In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 3A4, 2C9, or 2C19. In vitro at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1 mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, 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 alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effects 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 CYP enzymes 2C9, 2C19, or 2E1. Alosetron does not appear to induce the major cytochrome P450 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.

The common side effects of Alosetron include the following

Common side effects

• Upset stomach, swelling in the stomach area, hemorrhoids.

• Pregnancy

Pregnancy Category B

Teratogenic Effects

Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to Alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Alosetron should be used during pregnancy only if clearly needed.

• Nursing Mothers

Alosetron and/or metabolites of Alosetron are excreted in the breast milk of lactating rats. It is not known whether Alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Alosetron is administered to a nursing woman.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Use of Alosetron is not recommended in the pediatric population, based upon the risk of serious complications of constipation and ischemic colitis in adults.

• Geriatric Use

In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults. However, this effect was not consistently observed in men. Post marketing experience suggests that elderly patients may be at greater risk for complications of constipation therefore, appropriate caution and follow-up should be exercised if Alosetron is prescribed for these patients.

There is no specific antidote for overdose of Alosetron. 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 reactions. 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.

Pharmacodynamic

Alosetron is a potent and selective antagonist of the serotonin 5-HT₃ receptor type. Activation of these receptors and the resulting neuronal depolarization affects the regulation of visceral pain, colonic transit, and GI secretions processes that are related to IBS. By blocking these receptors, alosetron is able to effectively control IBS.

Pharmacokinetics

• Absorption

Alosetron rapidly absorb with having mean bioavailability of 50% to 60%. The peak plasma concentration is approximately 1 hour.

• Distribution

The volume of distribution is about 65 to 95 L.

• Metabolism and Excretion

Alosetron having extensive hepatic metabolism via CYP2C9, 3A4, and 1A2. Thirteen metabolites have been detected in the urine. Biological activity of these metabolites in unknown. The elimination half-life is about 1.5 hours. It is excreted via urine (74%, 13% of total dose as unchanged drug); feces (11%, 1% of total dose as unchanged drug).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021107s013lbl.pdf
• https://www.drugs.com/pregnancy/alosetron.html
• https://go.drugbank.com/drugs/DB00969
• https://www.rxlist.com/lotronex-drug.htm#warnings
• https://medlineplus.gov/druginfo/meds/a601230.html#:~:text=Alosetron is used to treat,been helped by other treatments.
• https://reference.medscape.com/drug/lotronex-alosetron-342042