alosetron (Lotronex)

Alosetron is used to treat diarrhea and abdominal discomfort that occurs in some women with irritable bowel syndrome (IBS). It works in a similar fashion as granisetron (Kytril), ondansetron (Zofran) and dolasetron (Anzemet) that are used for preventing nausea and vomiting. The discomfort and diarrhea of IBS is believed to be due to abnormal activity of the muscles of the intestines and/or the nerves that control the muscles. One of the chemical messengers which is important in coordinating the activity of intestinal nerves is serotonin. (Chemical messengers are chemicals produced and released by nerve cells that and cause changes in the activity of other nerve cells.) Alosetron belongs to a class of drugs that block one type of serotonin receptor called the 5-HT3 receptor. Serotonin and its receptors in the intestines may control pain sensation, contraction of intestinal muscle, and release of fluid into the intestines. These actions of serotonin can result in pain and diarrhea. The exact cause of IBS is unknown, but it is thought that stimuli such as food, medications, hormonal changes, or stress may trigger an excessive release or excessive response to serotonin. This may cause pain, and diarrhea seen in patients with diarrhea-predominant IBS. Alosetron, by blocking 5-HT3 receptors, reduces the actions of serotonin. Alosetron (Lotronex) was approved for marketing by the FDA in February, 2000 but was withdrawn from the market in November 2000, because of serious, life-threatening, gastrointestinal side effects. In June 2002, it was approved again by the FDA for marketing but in a restricted manner as part of a drug company-sponsored program for managing the risks associated with treatment. Use of alosetron is allowed only among women with severe, diarrhea-predominant IBS who have failed to respond to conventional treatment for IBS.

What brand names are available for alosetron?

Lotronex

Is alosetron available as a generic drug?

GENERIC AVAILABLE: No

Do I need a prescription for alosetron?

Yes

Alosetron is prescribed for the treatment of severe-predominant IBS among women who have chronic IBS symptoms lasting longer than 6 months and have not responded to conventional IBS treatment.

The most common side effect with alosetron is constipation. One-quarter to one-third of patients may develop this side effect. Severe constipation or intestinal inflammation caused by poor circulation of blood (ischemic colitis) are rare but life-threatening, may require surgery, and may cause death. Therefore, alosetron must be discontinued immediately, and immediate medical attention should be sought if constipation or the signs of ischemic colitis (rectal bleeding or a sudden worsening of abdominal pain) occur.

Other important but less common side effects include:

• nausea,
• hemorrhoids, and
• abdominal distention.

The starting dose is 0.5 mg twice daily. If constipation develops at this dose alosetron should be discontinued until the constipation resolves. It may be restarted at 0.5 mg once daily. If 0.5 mg once daily causes constipation, then alosetron should be discontinued. After 4 weeks, patients whose symptoms are not adequately controlled may receive up to 1 mg twice daily. Patients without adequate control after 4 weeks of treatment with 1 mg twice daily should discontinue alosetron. Alosetron may be taken with or without food.

In vivo data suggest that alosetron is primarily metabolized by cytochrome P450 (CYP) 1A2, with minor contributions from CYP3A4 and CYP2C9. Therefore, 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/ 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.

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 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.

It is not known if alosetron is excreted in breast milk. Therefore, it should be used cautiously by nursing mothers.

What preparations of alosetron are available?

Tablet: 0.5 and 1 mg.

How should I keep alosetron stored?

Tablets should be stored at room temperature, 15 C to 30 C (59 F to 86 F).