Brands, Medical Use, Clinical Data
- Serotonin Antagonists
- Gastrointestinal Agents
Brands / Synonyms
Alosetron HCl; Lotronex; Lotronex
For the treatment of symptoms of irritable bowel syndrome in women whose primary symptom is diarrhea
Alosetron is a potent and selective antagonist of the serotonin 5-HT3 receptor type. Activation of these receptors affects the regulation of visceral pain, colonic transit, and GI secretions. By blocking these receptors, alosetron is able to effectively control IBS.
Mechanism of Action
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 the enteric nervous system.
Biotrnasformation / Drug Metabolism
Hepatic, via microsomal cytochrome P450 (CYP)
LOTRONEX should not be initiated in patients with constipation.
LOTRONEX 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
- Crohnís disease or ulcerative colitis
- hypersensitivity to any component of the product
LOTRONEX should not be used by patients who are unable to understand or comply with the Patient-Physician
Agreement for LOTRONEX.
Concomitant administration of alosetron with fluvoxamine is contraindicated. Fluvoxamine, a known strong inhibitor
of CYP1A2, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the
half-life by approximately 3-fold.
Because alosetron is metabolized by a variety of hepatic CYP drug-metabolizing enzymes, inducers or inhibitors of
these enzymes may change the clearance of alosetron.
Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a
pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg per 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
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.
In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that 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, 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 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.
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.