CHAPTER 3-58: ONDANSETRON

INTRODUCTION

1. Pharmacology. Ondansetron is a selective serotonin (5-HT₃) receptor antagonist with antiemetic activity due to its actions on serotonin receptors located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone. The mean peak plasma level occurred at 10 minutes after a 4-mg IV injection and 1.7-2.2 hours after an oral 8-mg dose given to normal adult volunteers. The drug is metabolized extensively in the liver via hydroxylation, followed by glucuronide or sulfate conjugation. Ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, primarily CYP3A4, and to a lesser extent CYP1A2, CYP2D6. The mean elimination half-life in adults is 3.1-6.2 hours, increasing to as long as 20 hours in patients with severe liver disease.

2. Indications

   1. FDA-approved for the prevention of nausea and vomiting associated with cancer chemotherapy, radiation therapy, and in the postoperative period.

   2. Ondansetron is used to treat intractable nausea and vomiting, particularly when the ability to administer activated charcoal or antidotal therapy (eg, N- acetylcysteine) is compromised. These are not FDA-approved indications.

3. Contraindications/Warnings

   1. Hypersensitivity to ondansetron or any component of the formulation. Hypersensitivity reactions, including anaphylaxis and bronchospasm, have also been reported in patients who have experienced hypersensitivity to other selective 5-HT₃ receptor antagonists.

   2. The concomitant use of apomorphine with ondansetron is contraindicated on the basis of reports of profound hypotension and loss of consciousness.

   3. Concurrent use of ondansetron and other medications known to cause prolonged QT interval increases the risk for torsades de pointes

   4. ECG monitoring is recommended in patients with electrolyte abnormalities, (eg, hypokalemia or hypomagnesemia), congestive heart failure, or bradydysrhythmias.

   5. Avoid in patients with congenital long QT syndrome.

   6. Patients with phenylketonuria should be informed that Zofran ODT orally disintegrating tablets contain phenylalanine (a component of aspartame). Use with caution in patients with phenylketonuria.

   7. Ondansetron is metabolized by hepatic cytochrome P-450 enzymes CYP3A4, CYP2D6, CYP1A2, and inducers or inhibitors of these enzymes may change the clearance and half-life of ondansetron.

4. Adverse effects

   1. Rare cases of immediate hypersensitivity reactions including anaphylactic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, and laryngeal edema have been reported. Also, delayed hypersensitivity reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

   2. Dose-dependent QT interval prolongation and dysrhythmias. Postmarketing cardiovascular events reported have included: torsade de pointes, ventricular and supraventricular tachycardia, PVCs, atrial fibrillation, bradycardia, second-degree heart block, and QT/QTc interval prolongation. Risk factors included IV administration of ondansetron, concomitant use of another QT interval prolonging medication, and preexisting cardiac disease or disorders associated with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia).

   3. Anxiety, headache, drowsiness, fatigue, fever, dizziness, paresthesias, and migraine headaches. Rare cases of grand mal seizure.

   4. Rare reports consistent with, but not diagnostic of, extrapyramidal reactions. Oculogyric crisis, appearing either alone or with other dystonic reactions.

   5. Hepatic necrosis and increased liver enzymes associated with IV administration and concomitant hepatotoxic medications. Do not exceed a total daily dose of 8 mg in patients with severe liver disease.

   6. Diarrhea, constipation, and xerostomia.

   7. Injection site reactions (pain, redness), pruritus, and rash.

   8. Cases ...