Alosetron

Alosetron is a potent and selective 5-HT 3 receptor antagonist. 5-HT 3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations.

• Alosetron tablets are 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 not responded adequately 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.ICD-10: K58.9

• Do not initiate in patients with constipation ( 4.1 ) History of 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 ( 4.2 ) Concomitant use of fluvoxamine ( 4.3 ) 4.1 Constipation Alosetron tablets should not be initiated in patients with constipation [see Warnings and Precautions (5.1) ] . 4.2 History of Severe Bowel or Hepatic Disorders Alosetron tablets are 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 4.3 Concomitant Use of Fluvoxamine Concomitant administration of alosetron tablets with fluvoxamine is contraindicated.contraindicated

Starting dose is 0.5 mg twice a day ( 2.1 ) May increase dose to 1 mg twice a day after 4 weeks if starting dosage is well tolerated but does not adequately control IBS symptoms ( 2.1 ) Discontinue alosetron tablets in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. ( 2.1 ) 2.1 Adult Patients To lower the risk of constipation, alosetron tablets should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking alosetron tablets until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, Alosetron tablets should be discontinued immediately. Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. Alosetron tablets 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. Alosetron tablets can be taken with or without food [see Clinical Pharmacology (12.3) ] . Alosetron tablets should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron tablets should not be restarted in patients who develop ischemic colitis.

Serious Complications of Constipation: May occur in some patients without warning. Includes obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia and in rare cases perforation and death have been reported. Risk is increased in patients who are elderly, debilitated, or taking medications that decrease bowel motility. ( 5.1 ) Discontinue alosetron tablets immediately if constipation occurs. ( 5.1 ) Ischemic colitis: May occur in some patients without warning. Promptly evaluate patients with signs of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain). ( 5.2 ) Discontinue alosetron tablets immediately if signs of ischemic colitis occur, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. ( 5.2 ) 5.1 Serious Complications of Constipation Some patients have experienced serious complications of constipation without warning. Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported with use of alosetron tablets during clinical trials. Complications of constipation have been reported with use of 1 mg twice daily and with lower doses. A dose response relationship has not been established for serious complications of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either alosetron tablets or placebo. In addition, rare cases of perforation and death have been reported from postmarketing clinical practice.

The following adverse reactions are described in more detail in other sections of the label: Complications of constipation [see Boxed Warning , Warnings and Precautions ( 5.1 )] Ischemic colitis [see Boxed Warning , Warnings and Precautions ( 5.2 )] Most common adverse reactions (incidence >2% and >placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea and gastrointestinal discomfort and pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lifestar Pharma LLC at 1-888-995-4337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of alosetron tablets twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron tablets and occurred more frequently on alosetron tablets than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron tablets compared to placebo (p<0.0001). Table 1.

Hepatic impairment: Contraindicated in severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment. ( 4.2 , 8.6 ) Geriatric use: Elderly patients may be at greater risk for complications of constipation. ( 8.5 ) 8.1 Pregnancy Risk Summary The available data with alosetron tablets use in pregnant women are insufficient to draw conclusions about any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of alosetron in rats and rabbits during organogenesis at doses 160 to 240 times, respectively, the recommended human dosage (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively.

Metabolism

The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily.

There is no specific antidote for overdose of alosetron tablets. 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 hydrochloride [see Drug Interactions (7) ].

• Feb 9, 2000NDANDA021107Legacy Pharma
• Dec 22, 2016ANDAANDA206647Amneal Pharms
• Sep 16, 2019ANDAANDA211621Hibrow Hlthcare
• Sep 9, 2020ANDAANDA213614Mankind Pharma

1. 1Drug Ineffective13615%
2. 2Constipation13315%
3. 3Diarrhoea11613%
4. 4Abdominal Pain11312%
5. 5Colitis Ischaemic687.5%
6. 6Nausea626.8%
7. 7Vomiting606.6%
8. 8Adverse Event434.7%
9. 9Abdominal Pain Upper394.3%
10. 10Rectal Haemorrhage374.1%
11. 11Gastrointestinal Injury353.9%
12. 12Pain323.5%
13. 13Off Label Use303.3%
14. 14Death273.0%
15. 15Weight Decreased273.0%

The 5 most recently updated of 5 ClinicalTrials.gov registrations naming Alosetron as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Safety and Efficacy Study of GR68755 (Alosetron Hydrochloride) to Treat Severe Diarrhea-Predominant Irritable Bowel Syndrome (IBS)
  Completed · Phase 2 · Interventional · 32 enrolled · GlaxoSmithKline
  NCT01855711updated 2017-05-01
• Study to Assess the Effect Of Alosetron On Mucosal Blood Flow
  Completed · Phase 4 · Interventional · 49 enrolled · GlaxoSmithKline
  NCT00370032updated 2015-05-18
• Study In Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome Having Failed Conventional Therapy
  Completed · Phase 3 · Interventional · 700 enrolled · GlaxoSmithKline
  NCT00067457updated 2015-04-16
• Study Of Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome Having Failed Conventional Therapy
  Completed · Phase 3 · Interventional · 702 enrolled · GlaxoSmithKline
  NCT00067561updated 2015-04-16
• LOTRONEX® in Severe Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D)
  Completed · Observational · 400 enrolled · Prometheus Laboratories
  NCT01257477updated 2013-04-04

Frequently asked questions

How does Alosetron work?

Alosetron is a potent and selective 5-HT 3 receptor antagonist. 5-HT 3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations.

What is Alosetron used for?

According to FDA labeling, Alosetron carries indications including: Alosetron tablets are 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 not responded adequately 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.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Alosetron?

Alosetron is classified as Serotonin receptor antagonists, Serotonin-3 Receptor Antagonist, Cytochrome P450 1A2 Inhibitors, Serotonin 3 Receptor Antagonists, Decreased Enteric Nervous System Serotonin Activity, Increased Coagulation Factor Activity.

What are the brand names for Alosetron?

Alosetron is marketed under brand names including Lotronex.

What are the contraindications for Alosetron?

Alosetron labeling lists contraindications including: Do not initiate in patients with constipation ( 4.1 ) History of 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 ( 4.2 ) Concomitant use of fluvoxamine ( 4.3 ) 4.1 Constipation Alosetron tablets should not be initiated in patients with constipation [see Warnings and Precautions (5.1) ] . 4.2 History of Severe Bowel or Hepatic Disorders Alosetron tablets are 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 4.3 Concomitant Use of Fluvoxamine Concomitant administration of alosetron tablets with fluvoxamine is contraindicated.. Always consult the full prescribing information and a clinician.