Aprepitant

Aprepitant is a selective, high-affinity antagonist of the human substance P/neurokinin 1 (NK1) receptor. It has little or no affinity for the serotonin (5-HT3), dopamine and corticosteroid receptors, which are the targets of other medicines used against chemotherapy-induced nausea and vomiting (CINV). In animal and human studies it added to the antiemetic effect of a 5-HT3 antagonist (ondansetron) and a corticosteroid (dexamethasone), and it is always used as part of combination therapy.

Mechanism of Action

• NK1 receptor blockade: aprepitant blocks the receptor through which substance P acts. In animal models it inhibited vomiting induced by cytotoxic agents such as cisplatin, through actions in the brain.
• Brain penetration: it crosses the blood–brain barrier and occupies NK1 receptors in the brain. In PET studies in healthy young men, occupancy rose with dose and plasma concentration, and the concentrations reached with the adult 3-day regimen are predicted to give more than 95% occupancy of brain NK1 receptors.
• Both phases of emesis: in animal and human studies it inhibited both the acute and the delayed phase of cisplatin-induced vomiting.
• Enzyme effects: aprepitant is a substrate, a moderate inhibitor and an inducer of CYP3A4, and an inducer of CYP2C9. This is the basis of its interactions (see Drug Interactions).

Pharmacokinetics

• Absorption: absolute oral bioavailability is 67% for the 80 mg capsule and 59% for the 125 mg capsule, with peak plasma concentrations after about 4 hours. A standard breakfast of about 800 kcal raised exposure (AUC) by up to 40%, which is not clinically relevant, so it can be taken with or without food. The pharmacokinetics are non-linear: clearance and bioavailability fall as the dose rises. With 125 mg on Day 1 and 80 mg on Days 2 and 3 in adults, the 24-hour AUC was 19.6 µg·h/mL on Day 1 and 21.2 µg·h/mL on Day 3 (peak concentrations 1.6 and 1.4 µg/mL).
• Distribution: about 97% bound to plasma proteins; the apparent volume of distribution at steady state is about 66 L.
• Metabolism: extensive. Twelve metabolites have been identified in human plasma; they are formed largely by oxidation at the morpholine ring and its side chains and are only weakly active. In vitro, CYP3A4 is the main enzyme, with minor contributions from CYP1A2 and CYP2C19.
• Elimination: no unchanged aprepitant is excreted in urine; metabolites leave in urine and, through bile, in faeces. In a radiolabelled study with intravenous fosaprepitant (a prodrug of aprepitant), 57% of the radioactivity was recovered in urine and 45% in faeces. Plasma clearance is dose-dependent, about 60–72 mL/min in the therapeutic range, and the terminal half-life is about 9–13 hours.
• Sex: peak concentration is 16% higher and the half-life 25% shorter in women than in men; these differences are not clinically meaningful.
• Hepatic impairment: mild impairment (Child-Pugh class A) does not change the pharmacokinetics to a clinically relevant extent. No conclusions can be drawn for moderate impairment (class B) and there are no data in severe impairment (class C).
• Renal impairment: in severe renal impairment total aprepitant exposure (AUC) was 21% lower, and in end-stage renal disease on haemodialysis 42% lower, but exposure to the active unbound drug was not significantly affected. Haemodialysis removed less than 0.2% of the dose.
• Children and adolescents: with the 125/80/80 mg capsule regimen in adolescents (12–17 years) and the 3/2/2 mg/kg suspension regimen in children from 6 months to under 12 years, the 24-hour AUC on Day 1 was above 17 µg·h/mL in most patients. Peak concentrations were about 1.3 µg/mL at about 4 hours (capsules) and about 1.2 µg/mL at 5–7 hours (suspension). Sex and race had no clinically meaningful effect.

Aprepitant is always given as part of combination therapy for the prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy:

• Hard capsules (80 mg and 125 mg): adults and adolescents from the age of 12 years.
• Powder for oral suspension (125 mg sachet): infants, toddlers and children from the age of 6 months to less than 12 years.

• Hypersensitivity to aprepitant or to any of the excipients.
• Co-administration with pimozide, terfenadine, astemizole or cisapride: inhibition of CYP3A4 by aprepitant could raise their plasma concentrations and cause serious or life-threatening reactions.

The safety of aprepitant was evaluated in about 6,500 adults in more than 50 studies and in 184 children and adolescents in 2 pivotal paediatric trials. In adults receiving highly emetogenic chemotherapy, the reactions reported more often with the aprepitant regimen than with standard therapy were hiccups (4.6% against 2.9%), raised alanine aminotransferase (2.8% against 1.1%), dyspepsia (2.6% against 2.0%), constipation (2.4% against 2.0%), headache (2.0% against 1.8%) and decreased appetite (2.0% against 0.5%); with moderately emetogenic chemotherapy it was fatigue (1.4% against 0.9%). In children and adolescents they were hiccups (3.3% against 0.0%) and flushing (1.1% against 0.0%). The frequencies below come from the adult studies; in the paediatric studies they were similar or lower, and some of the less common reactions seen in adults were not observed in children.

No reaction is classed as very common.

Common (≥1/100 to <1/10): decreased appetite, headache, hiccups, constipation, dyspepsia, fatigue, increased alanine aminotransferase.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia, anaemia, anxiety, dizziness, somnolence, palpitations, hot flush, eructation, nausea, vomiting, gastro-oesophageal reflux disease, abdominal pain, dry mouth, flatulence, rash, acne, dysuria, asthenia, malaise, increased aspartate aminotransferase, increased blood alkaline phosphatase. Nausea and vomiting were efficacy measures in the first 5 days after chemotherapy and were counted as side effects only after that.

Rare (≥1/10,000 to <1/1,000): candidiasis, staphylococcal infection, polydipsia, disorientation, euphoric mood, cognitive disorder, lethargy, dysgeusia, conjunctivitis, tinnitus, bradycardia, cardiovascular disorder, oropharyngeal pain, sneezing, cough, post-nasal drip, throat irritation, duodenal ulcer perforation, stomatitis, abdominal distension, hard stools, neutropenic colitis, photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, pruritic rash, Stevens-Johnson syndrome/toxic epidermal necrolysis, muscular weakness, muscle spasms, pollakiuria, oedema, chest discomfort, gait disturbance, red blood cells in urine, decreased blood sodium, weight decreased, decreased neutrophil count, glucose in urine, increased urine output.

Not known: hypersensitivity reactions including anaphylactic reactions, pruritus, urticaria.

Serious reactions to watch for are hypersensitivity including anaphylaxis, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), duodenal ulcer perforation and neutropenic colitis.

Aprepitant (125 mg/80 mg) is a substrate, a moderate inhibitor and an inducer of CYP3A4, and an inducer of CYP2C9. CYP3A4 is inhibited during the 3-day treatment; afterwards aprepitant causes a transient, mild induction of CYP2C9, CYP3A4 and glucuronidation, which is clinically insignificant by two weeks after the course. It does not appear to interact with P-glycoprotein (no interaction with digoxin).

• Must not be combined with pimozide, terfenadine, astemizole or cisapride.
• Oral CYP3A4 substrates with a narrow therapeutic range: caution with ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, fentanyl, dihydroergotamine, ergotamine and quinidine. Exposure to orally given CYP3A4 substrates can rise up to about 3-fold during the 3 days; the effect on intravenously given substrates is expected to be smaller. Combination with irinotecan needs particular caution because it might increase toxicity.
• Dexamethasone: the usual oral dose is reduced by about 50% (aprepitant raised dexamethasone exposure 2.2-fold). The dexamethasone doses in the adult regimens already allow for this.
• Methylprednisolone: the usual intravenous dose is reduced by about 25% and the usual oral dose by about 50%. Exposure rose 1.3-fold on Day 1 and 2.5-fold on Day 3; during continuous treatment it may later fall because of CYP3A4 induction, more so with the oral form.
• Chemotherapy: intravenous docetaxel and vinorelbine were not affected. An interaction with orally given chemotherapy metabolised by CYP3A4 (for example etoposide, vinorelbine) cannot be excluded, so caution and extra monitoring may be appropriate. Neurotoxicity, a possible reaction to ifosfamide, has been reported after combined use with aprepitant.
• Immunosuppressants metabolised by CYP3A4 (ciclosporin, tacrolimus, everolimus, sirolimus): a transient moderate rise followed by a mild fall in exposure is expected during the 3-day regimen; a dose reduction is not recommended for those 3 days.
• Benzodiazepines metabolised by CYP3A4 (midazolam, alprazolam, triazolam): their higher plasma levels should be considered. Oral midazolam exposure rose 2.3-fold on Day 1 and 3.3-fold on Day 5; with intravenous midazolam the changes were not clinically important.
• CYP2C9 substrates (warfarin, acenocoumarol, tolbutamide, phenytoin): caution during the two weeks after starting. With chronic warfarin the INR must be monitored closely during treatment and for 2 weeks after each 3-day course; one study showed a 34% fall in S-warfarin trough levels and a 14% fall in INR 5 days after the course. Tolbutamide exposure fell by 23% on Day 4, 28% on Day 8 and 15% on Day 15.
• Hormonal contraceptives: their effect may be reduced during treatment and for 28 days afterwards. Use non-hormonal back-up contraception during treatment and for 2 months after the last dose. In a study, ethinylestradiol trough levels fell by up to 64% and norethisterone levels by up to 60%.
• 5-HT3 antagonists: no clinically important effect on ondansetron, granisetron or hydrodolasetron (the active metabolite of dolasetron).
• CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, protease inhibitors): approach cautiously, as aprepitant levels are expected to rise several-fold. With ketoconazole, aprepitant exposure rose about 5-fold and its half-life about 3-fold.
• Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital): avoid, because aprepitant levels fall and efficacy may drop; with rifampicin, exposure fell by 91%. Herbal products containing St John’s wort are not recommended.
• Children: interaction studies have been done only in adults.
• Food: aprepitant can be taken with or without food.

Aprepitant is given for 3 days as part of a regimen that includes a 5-HT3 antagonist and, in adults, a corticosteroid. The 5-HT3 antagonist is dosed according to its own SmPC; efficacy data with other corticosteroids and 5-HT3 antagonists are limited. Capsules are swallowed whole. The oral suspension is prepared and the dose measured by healthcare professionals only. Both forms can be taken with or without food.

Adults (Capsules)

Aprepitant 125 mg orally once daily one hour before chemotherapy on Day 1, then 80 mg orally once daily in the morning on Days 2 and 3.

• Highly emetogenic chemotherapy: aprepitant 125 mg, 80 mg, 80 mg on Days 1–3 (none on Day 4). Dexamethasone 12 mg orally 30 minutes before chemotherapy on Day 1, then 8 mg orally in the morning on Days 2, 3 and 4. 5-HT3 antagonist: standard dose on Day 1 only.
• Moderately emetogenic chemotherapy: aprepitant 125 mg, 80 mg, 80 mg on Days 1–3. Dexamethasone 12 mg orally 30 minutes before chemotherapy on Day 1 only. 5-HT3 antagonist: standard dose on Day 1 only.

Adolescents Aged 12–17 Years (Capsules)

125 mg orally on Day 1 and 80 mg on Days 2 and 3, one hour before chemotherapy on each of those days, as part of a regimen that includes a 5-HT3 antagonist. If no chemotherapy is given on Days 2 and 3, the capsule is taken in the morning. If a corticosteroid such as dexamethasone is given with aprepitant, its dose is 50% of the usual dose.

Children Aged 6 Months to Under 12 Years (Powder for Oral Suspension)

For infants, toddlers and children weighing at least 6 kg, the dose of the 25 mg/mL suspension is based on body weight and is given one hour before chemotherapy on Days 1, 2 and 3 (in the morning if no chemotherapy is given on Days 2 and 3), together with a 5-HT3 antagonist:

• Day 1: 3 mg/kg orally, maximum 125 mg.
• Days 2 and 3: 2 mg/kg orally, maximum 80 mg each day.
• A corticosteroid such as dexamethasone is given at 50% of the usual dose.
• The 125 mg powder has not been shown to work in children of 12 years and older, who take the capsules. Safety and efficacy in infants under 6 months or under 6 kg have not been established; no data are available.

Special Populations

• Sex: no dose adjustment.
• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no dose adjustment, including in end-stage renal disease on haemodialysis.
• Hepatic impairment: no adjustment in mild impairment; limited data in moderate impairment and none in severe impairment, so use with caution.
• Children under 12 years: the capsules have not been shown to be safe and effective; the powder for oral suspension is used instead.

Moderate to Severe Hepatic Impairment

There are limited data in moderate and none in severe hepatic impairment, so Emend is used with caution in these patients.

CYP3A4 Interactions

Use caution in patients taking oral medicines that are mainly metabolised by CYP3A4 and have a narrow therapeutic range (ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloids, fentanyl, quinidine). Combination with irinotecan needs particular caution because it might increase toxicity.

Warfarin

In patients on chronic warfarin, the INR is monitored closely during treatment and for 14 days after each 3-day course.

Hormonal Contraceptives

The efficacy of hormonal contraceptives may be reduced during treatment and for 28 days afterwards. Alternative non-hormonal back-up methods should be used during treatment and for 2 months after the last dose.

Pregnancy, Breastfeeding and Fertility

• Contraception: see above; hormonal methods may be less reliable (during treatment and for 28 days afterwards).
• Pregnancy: there are no clinical data on exposed pregnancies. Reproductive toxicity has not been fully characterised, because exposures above those in humans could not be reached in animals; the animal studies did not indicate harmful effects on pregnancy, embryonal or foetal development, birth or postnatal development. The effects of altered neurokinin regulation on reproduction are unknown. Emend should not be used in pregnancy unless clearly necessary.
• Breastfeeding: aprepitant is excreted in the milk of lactating rats. It is not known whether it passes into human milk, so breastfeeding is not recommended during treatment.
• Fertility: potential effects have not been fully characterised for the same reason; animal studies did not indicate harmful effects on mating, fertility, embryonic or foetal development, or sperm count and motility.

Excipients

The powder for oral suspension contains sucrose and lactose. Patients with rare hereditary problems of fructose or galactose intolerance, glucose-galactose malabsorption, total lactase deficiency or sucrase-isomaltase insufficiency should not take it. The capsules also contain sucrose (80 mg in the 80 mg capsule, 125 mg in the 125 mg capsule). Each sachet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Emend may have a minor influence on the ability to ride a bicycle and use machines. Dizziness and fatigue may occur.

The capsules and the powder for oral suspension need no special temperature conditions; keep them in the original package to protect them from moisture. No cold chain is needed. Once reconstituted, the oral suspension can be kept at room temperature (not above 30 °C) for up to 3 hours, or refrigerated at 2–8 °C for up to 72 hours.

• Capsules: 4 years.
• Powder for oral suspension: 2 years for the unopened sachet.
• After reconstitution: up to 3 hours at room temperature (not above 30 °C), or up to 72 hours refrigerated at 2–8 °C.

Prescription only (Rx): Emend is subject to medical prescription (Annex II B; it is not under restricted prescription) and is prescribed as part of the antiemetic plan for a chemotherapy regimen. The capsules are taken by the patient, so they are supplied to the patient or the treating clinic on prescription. The powder for oral suspension must be prepared and measured by healthcare professionals, so it is supplied to the hospital or clinic that prepares and administers it; each single-use carton holds one sachet, a 1 mL and a 5 mL oral dispenser, a cap and a mixing cup.