Ondansetron (Zofran) vs. alosetron (Lotronex)

• Ondansetron and alosetron are serotonin-3 (5-HT3) receptor antagonists used to treat different conditions.
• Ondansetron is used to prevent nausea and vomiting caused by cancer chemotherapy and to prevent vomiting and nausea after surgery.
• Alosetron is used to treat diarrhea and abdominal discomfort that occurs in some women with irritable bowel syndrome (IBS).
• Brand names for ondansetron include Zofran, Zofran ODT, and Zuplenz.
• A brand name for alosetron is Lotronex.
• Side effects of ondansetron and alosetron that are similar include constipation.
• Side effects of ondansetron that are different from alosetron include headache, feeling unwell (malaise), fatigue, drowsiness, dizziness, diarrhea, and abnormal heart rate and rhythm.
• Side effects of alosetron that are different from ondansetron include nausea, hemorrhoids, and abdominal distention.

Ondansetron is an anti-nausea medication used to prevent nausea and vomiting caused by cancer chemotherapy. Chemotherapy drugs increase production of serotonin that stimulates serotonin (5-HT3) receptors in the brain, causing nausea and vomiting. Ondansetron selectively blocks serotonin (5-HT3) receptors, reducing the effect of increased serotonin due to chemotherapy. Ondansetron is also prescribed to prevent vomiting and nausea after surgery.

Alosetron is a serotonin-3 (5-HT3) receptor antagonist 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 to prevent nausea and vomiting. Experts believe that the discomfort and diarrhea of IBS is caused by abnormal activity of the intestinal muscles and/or the nerves that control the muscles. 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. Alosetron, by blocking 5-HT3 receptors, reduces the actions of serotonin.

Ondansetron

Side effects of ondansetron are

• headache,
• malaise,
• fatigue,
• drowsiness,
• constipation,
• dizziness, and
• diarrhea.

Some individuals may develop abnormal heart rate and rhythm.

Alosetron

WARNING

Alosetron (Lotronex) was approved for marketing by the FDA in February, 2000, but was withdrawn from the market in November, 2000, because of serious, life-threatening, gastrointestinal side effects.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, irritable bowel syndrome (IBS) who have failed to respond to conventional treatment for IBS.

Common side effects

The most common side effect of 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.

Ondansetron

Dosing for adults:

• Highly nauseating chemotherapy: 24 mg orally dissolved on tongue 30 minutes prior to start of a single-day chemotherapy.
• Moderately nauseating chemotherapy: Take 8 mg tablet 30 minutes prior to chemotherapy and repeat in 8 hours, then 8 mg every 12 hours for 1 to 2 days after chemotherapy.
• Radiation-induced nausea and vomiting: Take 8 mg orally 1 to 2 hours prior to radiation and every 8 hours after first dose, as needed.
• Post-surgery nausea and vomiting: 16 mg orally 1 hour before anesthesia.

Dosing for children:

• Moderately nauseating chemotherapy (12 years and older): 8 mg orally prior to chemotherapy and repeat in 8 hours, then 8 mg every 12 hours for 1 to 2 days after chemotherapy.
• Moderately nauseating chemotherapy (4 to 11 years): 4 mg orally 30 minutes prior to chemotherapy and repeat in 4 and 8 hours after the first dose, then every 8 hours for 1 to 2 days after chemotherapy.
• Not recommended for children under 4 years old.

Alosetron

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.

Ondansetron

Ondansetron and apomorphine should not be used together due to sudden lowering in blood pressure and loss of consciousness.

Phenytoin, carbamazepine, and rifampin can increase ondansetron elimination and decrease blood levels, possibly lowering the effects of ondansetron.

Dronedarone can increase blood levels of ondansetron by reducing its breakdown in the liver. This may increase side effects of ondansetron. This combination may also increase the risk of abnormal heartbeats.

Alosetron

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.

Ondansetron

There are no adequate studies of ondansetron in pregnant women to determine its safe and effective use during pregnancy.

It is not known whether ondansetron enters breast milk; therefore, it is best to be cautious before using it in nursing mothers.

Alosetron

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