Aprepitant

Aprepitant is an oral substance P and neurokinin-1 (NK1) receptor antagonist that prevents acute and delayed chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. It adds benefit to a 5-HT3 antagonist and dexamethasone but is a moderate CYP3A4 inhibitor and a CYP2C9 inducer, so it interacts with many drugs.

Classification. NK1 receptor antagonist; antiemetic.

Mechanism. Crosses the blood brain barrier and blocks substance P at NK1 receptors in the nucleus tractus solitarius and area postrema. Substance P is the main driver of delayed emesis (days 2 to 5), which 5-HT3 antagonists control poorly.

Pharmacodynamics. High NK1 receptor occupancy (over 90%) lasts beyond 24 hours after a dose. It has no prokinetic or dopaminergic activity and no meaningful effect on the QT interval.

Pharmacokinetics. Oral bioavailability about 60% to 65%, unaffected by food. Protein binding over 95%. Half-life 9 to 13 hours.

Metabolism. Mainly CYP3A4, with minor CYP1A2 and CYP2C19 contributions. Metabolites are weakly active and are excreted in urine and faeces. Aprepitant is a dose-dependent moderate CYP3A4 inhibitor and induces CYP2C9.

Adult oral doses unless stated. Prevention only; it does not treat established nausea.

Highly emetogenic chemotherapy (for example cisplatin).

• Aprepitant 125 mg orally 1 hour before chemotherapy on day 1, then 80 mg once daily in the morning on days 2 and 3.

• Give with a 5-HT3 antagonist on day 1 and dexamethasone.

• With aprepitant, reduce the oral dexamethasone dose by about half: 12 mg on day 1, then 8 mg once daily on days 2 to 4.

Moderately emetogenic chemotherapy. Aprepitant 125 mg orally on day 1 and 80 mg on days 2 and 3, with a 5-HT3 antagonist and dexamethasone (12 mg on day 1). Some regimens use aprepitant only when risk factors are present, such as anthracycline with cyclophosphamide or carboplatin.

Postoperative nausea and vomiting. 40 mg orally within 3 hours before induction of anaesthesia, as a single dose.

Paediatric dosing (age 6 months and over, weight 6 kg or more).

• Age 12 years and over: adult doses.

• Age 6 months to under 12 years (oral suspension): 3 mg/kg (maximum 125 mg) on day 1, then 2 mg/kg (maximum 80 mg) on days 2 and 3.

Kidney and liver adjustment.

• Kidney impairment, including dialysis: no adjustment.

• Mild to moderate liver impairment (Child-Pugh A and B): no adjustment.

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

Contraindications. Hypersensitivity to aprepitant; coadministration with pimozide (raised pimozide levels and QT risk).

Common adverse effects. Fatigue, hiccups, constipation, headache, dizziness, anorexia and raised liver enzymes.

Serious adverse effects.

• Hypersensitivity reactions, including anaphylaxis, angioedema and urticaria.

• Rare severe skin reactions, including Stevens-Johnson syndrome.

• Raised liver enzymes with repeated cycles.

Major interactions.

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

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

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, voriconazole): raise aprepitant levels; avoid.

• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St John's wort): lower levels and reduce effect; avoid.

• Raised levels of CYP3A4 substrates: dexamethasone and methylprednisolone (halve the dose), midazolam, alprazolam and triazolam (use lower doses); pimozide is contraindicated.

• Chemotherapy metabolised by CYP3A4 (for example docetaxel, etoposide, vinorelbine, irinotecan): monitor for increased toxicity.

• Ciclosporin, tacrolimus and sirolimus: monitor levels.

Special groups.

• Pregnancy: limited human 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: avoid in severe impairment.

• Regional: limited availability and high cost in many East African settings; ondansetron with dexamethasone is the usual alternative.

Formulations. Capsules 40 mg, 80 mg and 125 mg; oral suspension for children.

Administration. Swallow capsules whole, with or without food. Take the day 1 dose 1 hour before chemotherapy and days 2 and 3 doses in the morning.

Baseline. Medication review for CYP3A4 and CYP2C9 interactions, contraception and liver function.

Monitoring.

• INR 7 to 10 days after each cycle in patients on warfarin.

• Liver enzymes with repeated cycles.

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

• Hypersensitivity signs after the first dose.

Therapeutic drug monitoring. Not applicable.

Stopping. Course of 3 days each cycle; no taper. Stop for hypersensitivity or severe skin reaction.

Referral and escalation. Oncology review for breakthrough emesis despite a three-drug regimen. Add olanzapine 5 to 10 mg orally at night as a fourth agent in specialist practice.