Fosaprepitant

Fosaprepitant is the intravenous phosphorylated prodrug of aprepitant, converted to aprepitant within about 30 minutes of infusion. It gives NK1 receptor blockade as a single day 1 dose, simplifying prevention of chemotherapy-induced nausea and vomiting.

Classification. NK1 receptor antagonist; antiemetic.

Mechanism. After conversion by phosphatases to aprepitant, it blocks substance P at NK1 receptors in the nucleus tractus solitarius and area postrema, controlling acute and delayed emesis.

Pharmacodynamics. Over 90% NK1 receptor occupancy within 30 minutes of infusion, maintained for 48 hours or longer after a 150 mg dose. A single dose gives moderate, short-lived CYP3A4 inhibition.

Pharmacokinetics. Fosaprepitant is undetectable in plasma within 30 minutes. A 150 mg IV dose gives aprepitant exposure similar to the 3 day oral course. Aprepitant half-life 9 to 13 hours.

Metabolism. Aprepitant is metabolised by CYP3A4, and to a lesser degree CYP1A2 and CYP2C19. Metabolites are excreted in urine and faeces.

Adult IV doses unless stated. Prevention only.

Highly and moderately emetogenic chemotherapy.

• Fosaprepitant 150 mg IV on day 1 only, infused over 20 to 30 minutes and completed about 30 minutes before chemotherapy.

• Give with a 5-HT3 antagonist and dexamethasone.

• Reduce the oral dexamethasone dose by about half: 12 mg on day 1, then 8 mg once daily on days 2 to 4 for highly emetogenic regimens.

Alternative three-day regimen. Fosaprepitant 115 mg IV over 15 minutes on day 1 instead of the oral 125 mg dose, then aprepitant 80 mg orally on days 2 and 3.

Paediatric dosing (age 6 months to 17 years).

• Age 12 years and over: 150 mg IV on day 1.

• Age 6 months to under 12 years: 3 mg/kg (maximum 150 mg) IV on day 1.

Kidney and liver adjustment.

• Kidney impairment, including dialysis: no adjustment.

• Mild to moderate liver impairment: no adjustment.

• Severe liver impairment: not studied; use with caution.

Contraindications. Hypersensitivity to fosaprepitant, aprepitant or polysorbate 80; coadministration with pimozide.

Common adverse effects. Infusion site pain, erythema and thrombophlebitis, fatigue, hiccups, constipation, headache and raised liver enzymes.

Serious adverse effects.

• Hypersensitivity and anaphylaxis during or soon after infusion: flushing, dyspnoea, hypotension and urticaria. Stop the infusion immediately and do not restart.

• Severe infusion site reactions, including necrosis, particularly with peripheral lines.

• Rare Stevens-Johnson syndrome.

Major interactions.

• Warfarin: INR falls through CYP2C9 induction; check INR 7 to 10 days after the dose.

• Hormonal contraceptives: effectiveness reduced during treatment and for 28 days after; use an alternative or additional method.

• Strong CYP3A4 inhibitors and inducers: change aprepitant exposure; avoid.

• Raised levels of dexamethasone and methylprednisolone (halve the dose), midazolam and other CYP3A4 substrates.

• Pimozide: contraindicated.

Special groups.

• Pregnancy: limited data; use only if needed.

• Breastfeeding: no human data; avoid.

• Children: weight-based dosing from 6 months.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: caution in severe impairment.

• Regional: limited availability and cost in East Africa.

Formulations. Powder for IV infusion 115 mg or 150 mg in a vial.

Preparation.

• Reconstitute the 150 mg vial with 5 mL sodium chloride 0.9% by running it down the vial wall; swirl gently without shaking.

• Add the reconstituted solution to 145 mL of sodium chloride 0.9% to give a final volume of 150 mL (about 1 mg/mL).

• Use within 24 hours at room temperature.

IV administration.

• Infuse over 20 to 30 minutes (15 minutes for 115 mg), through a large peripheral vein or central line.

• Do not mix with solutions containing divalent cations (calcium or magnesium, including Ringer solutions) or with other drugs.

• Flush before and after.

Baseline. Medication review for interactions, contraception and liver function.

Monitoring.

• Observe for hypersensitivity during infusion and for 30 minutes afterwards.

• Check the infusion site during and after infusion.

• INR 7 to 10 days after the dose in patients on warfarin.

• Liver enzymes with repeated cycles.

Therapeutic drug monitoring. Not applicable.

Stopping. Single dose each cycle. Stop the infusion at the first sign of hypersensitivity.

Referral and escalation. Manage anaphylaxis with intramuscular adrenaline using usual resuscitation practice. Oncology review for breakthrough emesis despite a three-drug regimen.