Palonosetron

Palonosetron is a second-generation 5-HT3 receptor antagonist with a very long half-life of about 40 hours and higher receptor affinity than older agents. A single dose gives cover for acute and delayed chemotherapy-induced nausea and vomiting, making it a preferred 5-HT3 antagonist in moderately and highly emetogenic regimens.

Classification. 5-HT3 receptor antagonist; antiemetic.

Mechanism. Binds 5-HT3 receptors with high affinity and positive cooperativity, causing receptor internalisation and prolonged inhibition. It also inhibits crosstalk between 5-HT3 and NK1 receptor signalling, which may explain activity against delayed emesis.

Pharmacodynamics. Prolonged receptor inhibition outlasts plasma levels. Single 0.25 mg IV doses show no clinically relevant QT change in healthy volunteers.

Pharmacokinetics. Oral bioavailability about 97%. Half-life about 40 hours. Protein binding about 62%. About 40% is excreted unchanged in urine.

Metabolism. Roughly half of a dose is metabolised by CYP2D6, with CYP3A and CYP1A2 contributing. Metabolites are inactive. Pharmacokinetics are not clinically altered by CYP2D6 genotype.

Adult doses unless stated. Do not repeat doses within 7 days.

Moderately emetogenic chemotherapy. 0.25 mg IV as a single dose over 30 seconds, 30 minutes before chemotherapy on day 1 of each cycle; or 0.5 mg orally 1 hour before chemotherapy. Give with dexamethasone.

Highly emetogenic chemotherapy. 0.25 mg IV (or 0.5 mg orally) on day 1 only, with dexamethasone and an NK1 antagonist (aprepitant or fosaprepitant). A fixed-dose oral combination of netupitant 300 mg and palonosetron 0.5 mg is also used on day 1 with dexamethasone.

Postoperative nausea and vomiting. 0.075 mg IV as a single dose over 10 seconds immediately before induction of anaesthesia.

Paediatric chemotherapy-induced nausea (age 1 month to 17 years). 20 micrograms/kg IV (maximum 1.5 mg) infused over 15 minutes, starting 30 minutes before chemotherapy; a single dose each cycle.

Kidney and liver adjustment. No adjustment is needed in kidney or liver impairment, including dialysis.

Contraindications. Hypersensitivity to palonosetron or other 5-HT3 antagonists.

Common adverse effects. Headache, constipation, dizziness and transient liver enzyme rise.

Serious adverse effects.

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

• Serotonin syndrome with other serotonergic drugs.

• QT changes are minimal at the usual 0.25 mg IV dose, but caution is advised in congenital long QT, electrolyte disturbance and heart disease.

• Masking of progressive ileus.

• Injection site reactions.

Major interactions.

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

• QT prolonging drugs: additive risk, though smaller than with older agents.

• Apomorphine: avoid.

• No clinically important interaction with dexamethasone, aprepitant or fosaprepitant.

Special groups.

• Pregnancy: limited data; avoid unless essential.

• Breastfeeding: avoid because of the long half-life.

• Children: single IV dose from 1 month.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment.

• Regional: availability and cost limit use in many East African settings; ondansetron or granisetron are used where it is unavailable.

Formulations. Injection 0.25 mg in 5 mL (some markets 0.075 mg in 1.5 mL); capsules 0.5 mg; fixed-dose capsule with netupitant.

IV administration.

• Inject undiluted over 30 seconds; no dilution is needed for adults.

• Flush the line with sodium chloride 0.9% before and after.

• Do not mix with other drugs in the same line.

• In children, dilute and infuse over 15 minutes.

Baseline. ECG in congenital long QT, heart disease or QT-prolonging coprescription. Potassium and magnesium.

Monitoring.

• Control of nausea and vomiting during days 1 to 5.

• Bowel function and abdominal distension.

• Injection site reaction.

Therapeutic drug monitoring. Not applicable.

Stopping. Single dose each cycle; no taper. Stop for hypersensitivity or serotonin syndrome.

Referral and escalation. Add or escalate an NK1 antagonist and dexamethasone for breakthrough emesis. Seek oncology review for persistent nausea beyond day 5.