Fosaprepitant

Fosaprepitant is a prodrug of aprepitant, a selective, high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Given intravenously, it is converted rapidly to aprepitant, and the antiemetic effect is attributed to aprepitant. It is always combined with other antiemetics rather than used alone.

Mechanism of Action

• Conversion to aprepitant: after infusion, fosaprepitant is converted to aprepitant within 30 minutes. In vitro the conversion took place in human liver preparations and also in kidney, lung and ileum preparations, so it can occur in several tissues. The contribution of fosaprepitant itself to the antiemetic effect has not been fully characterised, although a transient contribution in the initial phase cannot be excluded.
• NK1 receptor blockade: aprepitant blocks substance P at NK1 receptors. Animal and human PET studies show that it crosses the blood–brain barrier and occupies NK1 receptors in the brain.
• Antiemetic effect: in animal models aprepitant inhibited vomiting induced by cytotoxic chemotherapy such as cisplatin through central actions. It added to the effect of the 5-HT3 antagonist ondansetron and of a corticosteroid, and it inhibited both the acute and the delayed phase of cisplatin-induced vomiting.
• Selectivity: aprepitant has little or no affinity for serotonin 5-HT3, dopamine or corticosteroid receptors, the targets of other antiemetic treatments.

Pharmacokinetics

• Conversion and exposure: plasma fosaprepitant falls below quantifiable levels within 30 minutes of the end of the infusion. After a single 150 mg dose given over 20 minutes to healthy adults, the mean AUC of aprepitant was 35.0 µg·h/mL and the mean peak concentration was 4.01 µg/mL.
• Distribution: aprepitant is about 97% bound to plasma proteins; its volume of distribution at steady state is about 82 L.
• Metabolism: aprepitant is extensively metabolised, mainly by CYP3A4 with minor contributions from CYP1A2 and CYP2C19, largely by oxidation at the morpholine ring and its side chains. Twelve metabolites have been identified in human plasma, and they are only weakly active. Aprepitant itself accounted for about 19% of plasma radioactivity over 72 hours after a radiolabelled dose.
• Elimination: aprepitant is not excreted unchanged in urine. Its half-life is about 9–13 hours.
• Special populations: no dose adjustment is needed for elderly patients, by sex, or in renal impairment, including end-stage renal disease on haemodialysis. Mild hepatic impairment needs no adjustment; data are limited in moderate and absent in severe impairment.

• Prevention of chemotherapy-induced nausea and vomiting: prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and in paediatric patients aged 6 months and older.
• Ivemend 150 mg is given as part of a combination therapy: with a corticosteroid and a 5-HT3 antagonist in adults, and with a 5-HT3 antagonist, with or without a corticosteroid, in children (see Administration and Dosage).

• Hypersensitivity to fosaprepitant, to polysorbate 80 or to any of the other excipients.
• Co-administration with pimozide, terfenadine, astemizole or cisapride.

The SmPC lists the reactions seen with aprepitant (the active form) and a few additional ones seen with fosaprepitant itself. In clinical studies, various fosaprepitant formulations were given to 2,687 adults (371 healthy subjects and 2,084 patients) and 299 children and adolescents. Compared with standard therapy, the most common reactions in adults on highly emetogenic chemotherapy were hiccups, raised ALT, dyspepsia, constipation, headache and decreased appetite; on moderately emetogenic chemotherapy it was fatigue. In children the most common were hiccups and flushing. The profile over up to 6 further chemotherapy cycles was generally similar to that in the first cycle.

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

Uncommon (≥1/1,000 to <1/100): febrile neutropenia, anaemia, anxiety, dizziness, somnolence, palpitations, flushing, eructation, nausea and vomiting (counted as adverse reactions only after the first 5 days following chemotherapy, because earlier they are efficacy measures), gastro-oesophageal reflux disease, abdominal pain, dry mouth, flatulence, rash, acne, dysuria, asthenia, malaise, raised AST and alkaline phosphatase. With fosaprepitant: thrombophlebitis (mainly at the infusion site), erythema, infusion-site erythema, pain and pruritus, and raised blood pressure.

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, postnasal 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 loss, decreased neutrophil count, glucose in urine, increased urine output. With fosaprepitant: infusion-site induration.

Not known: hypersensitivity reactions including anaphylactic reactions, pruritus, urticaria. With fosaprepitant: immediate hypersensitivity reactions including flushing, erythema, dyspnoea and anaphylactic reaction or shock.

The serious reactions to watch for are immediate hypersensitivity reactions including anaphylaxis, severe infusion-site reactions (thrombophlebitis, vasculitis and, with vesicant chemotherapy, necrosis) and, rarely, Stevens–Johnson syndrome/toxic epidermal necrolysis.

When given intravenously, fosaprepitant is converted rapidly to aprepitant, so its interactions are those of aprepitant. A single 150 mg dose is a weak CYP3A4 inhibitor and does not appear to interact with P-glycoprotein (oral aprepitant did not interact with digoxin). The SmPC data come from studies with oral aprepitant and with single-dose intravenous fosaprepitant in adults; no interaction studies have been done in children.

• Pimozide, terfenadine, astemizole, cisapride: must not be used with fosaprepitant. CYP3A4 inhibition could raise their levels and cause serious or life-threatening reactions.
• Other CYP3A4 substrates: exposure may rise transiently, up to 2-fold on Days 1 and 2. Use caution with substrates that have a narrow therapeutic range: ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, ergotamine, dihydroergotamine, fentanyl and quinidine.
• Dexamethasone: the oral dose should be reduced by about 50%. A single 150 mg dose raised the AUC of dexamethasone by 100% on Day 1, 86% on Day 2 and 18% on Day 3. The dexamethasone doses given in this page already allow for this.
• Chemotherapy: no clinically relevant interaction is expected with intravenous docetaxel or vinorelbine. An interaction with oral chemotherapy metabolised by CYP3A4 (for example etoposide, vinorelbine) cannot be excluded, so caution and extra monitoring are advised. Neurotoxicity, a possible reaction to ifosfamide, has been reported after aprepitant and ifosfamide were given together. With irinotecan, particular caution is needed because the combination might increase toxicity.
• Immunosuppressants (ciclosporin, tacrolimus, everolimus, sirolimus): a transient moderate rise in exposure for two days, possibly followed by a mild fall. Dose reduction guided by drug monitoring is not recommended on the day of and the day after Ivemend.
• Benzodiazepines: a single dose raised the AUC of midazolam by 77% on Day 1, with no effect on Day 4. The effect on midazolam and other CYP3A4-metabolised benzodiazepines (alprazolam, triazolam) should be considered.
• Warfarin and other CYP2C9 substrates: in patients on long-term warfarin, the INR should be monitored closely during treatment and for 14 days afterwards. Use caution with acenocoumarol, tolbutamide, phenytoin and other CYP2C9 substrates (the 3-day oral aprepitant regimen lowered CYP2C9 substrate levels by about 30–35%).
• Hormonal contraceptives: their efficacy may be reduced during and for 28 days after administration. Use non-hormonal back-up methods during treatment and for 2 months afterwards.
• 5-HT3 antagonists: no evidence of interaction (ondansetron, granisetron, hydrodolasetron).
• Diltiazem: in a study with 100 mg fosaprepitant, diltiazem exposure rose 1.4-fold with a small but clinically meaningful fall in blood pressure and no meaningful change in heart rate or PR interval. Aprepitant exposure rose 1.5-fold, which was not clinically important.
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, protease inhibitors): aprepitant levels are expected to rise several-fold, so use caution. Ketoconazole lengthened the half-life of oral aprepitant about 3-fold.
• Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital): avoid, because lower aprepitant levels may reduce efficacy; rifampicin shortened the half-life of oral aprepitant by 68%. Herbal preparations containing St John’s wort are not recommended.
• Grapefruit: grapefruit products inhibit CYP3A4 and may raise aprepitant levels; use caution.

Ivemend is given by intravenous infusion only, with chemotherapy. It must not be given into a muscle or under the skin, as a bolus injection or undiluted. The powder is reconstituted and diluted before use (see section 6.6 of the SmPC). In adults it is preferably given through a running intravenous infusion; in children from 6 months of age through a central venous catheter.

Adults

• Dose: 150 mg as an infusion over 20–30 minutes on Day 1, started about 30 minutes before chemotherapy, in conjunction with a corticosteroid and a 5-HT3 antagonist.
• Highly emetogenic chemotherapy: Ivemend on Day 1 only. Dexamethasone 12 mg orally on Day 1 (30 minutes before chemotherapy), 8 mg orally on Day 2, and 8 mg orally twice daily on Days 3 and 4. A 5-HT3 antagonist at its standard dose on Day 1.
• Moderately emetogenic chemotherapy: Ivemend 150 mg on Day 1. Dexamethasone 12 mg orally on Day 1, 30 minutes before chemotherapy. A 5-HT3 antagonist at its standard dose on Day 1.
• The dexamethasone doses allow for the interaction with fosaprepitant. For the dose of the 5-HT3 antagonist, see its own product information.

Children and Adolescents (6 Months and Older, at Least 6 kg)

• Given with a 5-HT3 antagonist, with or without a corticosteroid, for single-day or multi-day regimens of highly or moderately emetogenic chemotherapy. If a corticosteroid such as dexamethasone is used, give 50% of the usual corticosteroid dose.
• The infusion runs over 30 minutes (12 years and older) or 60 minutes (under 12 years) and finishes about 30 minutes before chemotherapy.
• 3-day regimen, 12 years and older: 115 mg intravenously on Day 1, then 80 mg intravenously on Days 2 and 3 (or 80 mg orally as Emend capsules).
• 3-day regimen, 6 months to under 12 years: 3 mg/kg intravenously on Day 1 (maximum 115 mg), then 2 mg/kg on Days 2 and 3 (maximum 80 mg), intravenously or orally as Emend oral suspension.
• Alternative regimen for single-day chemotherapy only: a single intravenous dose on Day 1 of 150 mg (12 years and older), 4 mg/kg (2 to under 12 years) or 5 mg/kg (6 months to under 2 years), with a maximum of 150 mg.
• Safety and efficacy below 6 months of age have not been established.

Special Populations

• Elderly and sex: no dose adjustment.
• Renal impairment: no dose adjustment, including end-stage renal disease on haemodialysis.
• Hepatic impairment: no adjustment in mild impairment; limited data in moderate and none in severe impairment, so use with caution.

Hypersensitivity Reactions

Immediate hypersensitivity reactions, including flushing, erythema, dyspnoea and anaphylaxis or anaphylactic shock, have occurred during or soon after the infusion. They generally responded to stopping the infusion and giving appropriate treatment. Re-starting the infusion is not recommended in a patient who has had such a reaction.

Infusion-Site Reactions

Most severe infusion-site reactions, including thrombophlebitis and vasculitis, were reported with vesicant chemotherapy (for example anthracycline-based), particularly with extravasation, and necrosis occurred in some of these patients. Mild injection-site thrombosis has been seen at higher doses without vesicant chemotherapy. Ivemend must always be diluted and given as a slow infusion. If signs of local irritation appear, the infusion should be stopped and restarted in another vein.

Liver Impairment and CYP3A4 Interactions

Data are limited in moderate and absent in severe hepatic impairment, so Ivemend is used with caution. Caution also applies with CYP3A4 substrates that have a narrow therapeutic range, and with irinotecan. In patients on long-term warfarin the INR is monitored closely for 14 days after Ivemend.

Pregnancy, Breastfeeding and Fertility

• Contraception: hormonal contraceptives may work less well during and for 28 days after administration. Alternative non-hormonal back-up methods should be used during treatment and for 2 months after the last dose.
• Pregnancy: there are no clinical data on exposed pregnancies. Animal studies showed no direct or indirect harm to pregnancy or development, but exposures above the human therapeutic level could not be reached, and the effects of altered neurokinin regulation on reproduction are unknown. Ivemend should not be used in pregnancy unless clearly necessary.
• Breastfeeding: aprepitant passes into the milk of lactating rats; it is not known whether it passes into human milk. Breastfeeding is not recommended during treatment.
• Fertility: effects on fertility have not been fully characterised, again because exposures above the human therapeutic level could not be reached in animals. Animal studies showed no direct or indirect harm to mating, fertility, embryonic or foetal development, or sperm count and motility.

Sodium and Excipients

Each dose contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free. The vial also contains polysorbate 80 and anhydrous lactose; hypersensitivity to polysorbate 80 is a contraindication.

Effect on Driving

Ivemend may have a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur after administration.

Store the vials in a refrigerator at 2–8 °C. Keep the cold chain unbroken from supply to the hospital pharmacy. Storage after reconstitution and dilution is described under Shelf Life. The vial is a 10 mL type I clear glass vial with a chlorobutyl or bromobutyl rubber stopper and an aluminium seal with a grey plastic flip-off cap; packs hold 1 or 10 vials (not all pack sizes may be marketed).

2 years for the unopened vial stored in a refrigerator. After reconstitution and dilution, chemical and physical in-use stability has been shown for 24 hours at 25 °C. From a microbiological point of view the product should be used immediately; otherwise in-use storage times and conditions are the user’s responsibility and would normally not be longer than 24 hours at 2–8 °C.

Prescription only (Rx): medicinal product subject to medical prescription. Fosaprepitant is given as an intravenous infusion by healthcare professionals alongside cancer chemotherapy, so it is supplied to the hospital or clinic that administers it, with cold-chain (2–8 °C) delivery.