Ondansetron

Ondansetron is a selective 5-HT3 receptor antagonist and the most widely available antiemetic for chemotherapy-induced, postoperative and acute gastroenteritis-associated vomiting. It does not cause extrapyramidal effects or sedation but prolongs the QT interval in a dose-dependent manner.

Classification. 5-HT3 receptor antagonist; antiemetic.

Mechanism. Blocks serotonin at 5-HT3 receptors on vagal afferents in the gut and in the area postrema and nucleus tractus solitarius. Chemotherapy and radiation release serotonin from enterochromaffin cells, which triggers the vomiting reflex.

Pharmacodynamics. No prokinetic effect and little activity against delayed (days 2 to 5) nausea compared with an NK1 antagonist and dexamethasone. Slows colonic transit, causing constipation.

Pharmacokinetics. Oral bioavailability about 60% with first-pass metabolism. Half-life 3 to 6 hours, longer in older adults and severe liver impairment. Protein binding 70% to 76%.

Metabolism. Hepatic via CYP3A4, CYP1A2 and CYP2D6, with several pathways, so a single enzyme defect has limited effect. Inducers such as rifampicin, phenytoin and carbamazepine lower exposure.

Adult doses unless stated. Maximum single IV dose 16 mg because of QT risk.

Highly emetogenic chemotherapy (for example cisplatin).

• 8 mg IV slowly before chemotherapy (maximum single IV dose 16 mg), or 16 mg orally 1 to 2 hours before.

• Then 8 mg orally twice daily for up to 5 days.

• Give with dexamethasone and, where available, an NK1 antagonist. A single 24 mg oral dose before cisplatin is an accepted alternative in some regions.

Moderately emetogenic chemotherapy. 8 mg orally 1 to 2 hours before chemotherapy, then 8 mg 8 to 12 hours later and 8 mg twice daily for 1 to 2 days (up to 5 days where delayed nausea persists).

Radiotherapy. 8 mg orally 1 to 2 hours before each fraction, then 8 mg every 8 hours as needed while the effect persists.

Postoperative nausea and vomiting.

• Prevention: 4 mg IV slowly or IM at induction, or 16 mg orally 1 hour before anaesthesia.

• Treatment: 4 mg IV slowly.

Acute gastroenteritis in children (off-label, widely used). A single oral dose to reduce vomiting and the need for IV fluid, with oral rehydration continued:

• 8 to 15 kg: 2 mg.

• Over 15 to 30 kg: 4 mg.

• Over 30 kg: 6 to 8 mg.

• Do not repeat until review.

Hyperemesis gravidarum and other adult nausea (second-line). 4 to 8 mg orally every 8 hours as needed.

Paediatric chemotherapy-induced nausea (age 6 months and over). 5 mg/m2 IV (maximum 8 mg) before chemotherapy, then 4 mg orally every 12 hours for up to 5 days (age 12 years and over: adult dosing).

Maximum dose. Total daily dose usually does not exceed 32 mg including IV and oral doses.

Kidney and liver adjustment.

• Kidney impairment: no adjustment.

• Severe liver impairment (Child-Pugh C): maximum 8 mg daily.

• Older adults: no adjustment, with caution over QT risk.

Contraindications. Congenital long QT syndrome; coadministration with apomorphine (profound hypotension and loss of consciousness); hypersensitivity to 5-HT3 antagonists.

Common adverse effects. Headache, constipation, flushing and warmth, hiccups, and transient rises in liver enzymes.

Serious adverse effects.

• QT prolongation and torsades de pointes, dose related and more likely with IV doses over 16 mg, electrolyte disturbance and heart failure.

• Serotonin syndrome, mostly with other serotonergic drugs.

• Hypersensitivity and anaphylaxis, including cross-reactivity with other 5-HT3 antagonists.

• Masking of progressive ileus or gastric distension after abdominal surgery.

• Transient visual disturbance and rare seizures with IV use.

Major interactions.

• Apomorphine: contraindicated.

• QT prolonging drugs: antimalarials (artemether-lumefantrine, quinine, chloroquine), macrolides, fluoroquinolones, haloperidol, citalopram, methadone, domperidone, amiodarone and sotalol; avoid or use with ECG monitoring.

• Serotonergic drugs (SSRIs, SNRIs, tramadol, linezolid, triptans): risk of serotonin syndrome.

• Tramadol: ondansetron may reduce its analgesic effect.

• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine): lower ondansetron levels.

Special groups.

• Pregnancy: first trimester use is associated with a small absolute increase in oral clefts (about 3 additional cases in 10,000 births); use in hyperemesis only when other options fail.

• Breastfeeding: limited data, low milk transfer; acceptable.

• Children: weight-based dosing; avoid repeated doses without review.

• Older adults: no adjustment; check QT risk.

• Kidney impairment: no adjustment.

• Liver impairment: limit to 8 mg daily in severe impairment.

• Regional: antimalarial and antibiotic coprescription is common, so check the QT profile of the whole prescription.

Formulations. Tablets 4 mg and 8 mg; orally disintegrating tablets 4 mg and 8 mg; oral syrup 4 mg in 5 mL; injection 2 mg/mL.

Oral administration. Orally disintegrating tablets dissolve on the tongue and are swallowed with saliva, without water.

IV administration.

• Injection: 4 mg given slowly over at least 2 to 5 minutes.

• Infusion: 8 mg diluted in 50 mL sodium chloride 0.9% or glucose 5% over 15 minutes. A 16 mg IV dose must be infused over at least 15 minutes in 50 to 100 mL.

• Rapid injection causes headache and transient visual changes.

Baseline. Potassium and magnesium before repeated or high dosing. ECG in heart disease, electrolyte risk or interacting drugs.

Monitoring.

• ECG for patients with QT risk or on interacting drugs.

• Potassium and magnesium with vomiting, diarrhoea or diuretics.

• Bowel function and abdominal distension.

• Hydration in gastroenteritis; ondansetron does not replace rehydration.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for QT prolongation, torsades, serotonin syndrome or hypersensitivity.

Referral and escalation. Persistent vomiting needs assessment for obstruction, raised intracranial pressure, metabolic causes and pregnancy. Escalate chemotherapy-induced nausea to a three-drug regimen with dexamethasone and an NK1 antagonist.