Emend

Emend - General Information

Emend, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Emend is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Emend has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

Pharmacology of Emend

Emend, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Emend is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Emend has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

Emend for patients

Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.

Patients should be instructed to take EMEND only as prescribed. Patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment.

EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle.

Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.

Emend Interactions

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Effect of aprepitant on the pharmacokinetics of other agents

As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4.

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of Aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of Aprepitant with digoxin in a clinical drug interaction study.

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron or granisetron. No clinical or drug interaction study was conducted with dolasetron.

Corticosteroids:

Dexamethasone: Aprepitant, when given as a regimen of 125mg with dexamethasone coadministered orally as 20 mg on Day 1, and Aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate by 2.2-fold, on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with Aprepitant, to achieve exposures of dexamethasone similar to those obtained when it is given without Aprepitant. The daily dose of dexamethasone administered in clinical studies with Aprepitant reflects an approximate 50% reduction of the dose of dexamethasone.

Methylprednisolone

Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with Aprepitant to achieve exposures of methylprednisolone similar to those obtained when it is given without Aprepitant.

Warfarin: A single 125-mg dose of Aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of Aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-)warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with Aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle.

Tolbutamide: Aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was admini,stered orally prior to the administration of the 3-day regimen of Aprepitant and on Days 4,8, and 15.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%; therefore, the efficacy of oral contraceptives during administration of Aprepitant may be reduced. Although a 3-day regimen of Aprepitant given concomitantly with oral contraceptives has not been studied, alternative or back-up methods of contraception should be used.

Midazolam: Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of Aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with Aprepitant.

In another study with intravenous administration of midazolam, Aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of Aprepitant and on Days 4, 8, and 15. Aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of Aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

Effect of other agents on the pharmacokinefics of aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of Aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of Aprepitant.

Ketoconazole: When a single 125-mg dose of Aprepitant was administered on Day5 of a

10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of Aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of Aprepitant was administered on Day9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of Aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of Aprepitant.

Additional interactions

Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax, by approximately 20% of both aprepitant and paroxetine.

Emend Contraindications

EMEND is a moderate CYP3A4 inhibitor. EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.

EMEND is contraindicated in patients who are hypersensitive to any component of the product.

Additional information about Emend

Emend Indication: For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents).
Mechanism Of Action: Emend has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Emend have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Emend augments the antiemetic activity of the 5-HT₃-receptor antagonist ondansetron and the corticosteroid
ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis.
Drug Interactions: Alprazolam Increases the effect and toxicity of benzodiazepine
Anisindione Decreases the anticoagulant effect
Astemizole Increased risk of cardiotoxicity and arrhythmias
Carbamazepine This CYP3A4 inducer decreases the effect of aprepitant
Cisapride Increased risk of cardiotoxicity and arrhythmias
Clarithromycin The CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Dexamethasone Increases the effect and toxicity of dexamethasone
Dicumarol Decreases the anticoagulant effect
Diltiazem This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Docetaxel Emend may change levels of chemotherapy agent
Erythromycin The CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Ethinyl Estradiol Emend could decrease the effect of the oral contraceptive
Ethotoin This CYP3A4 inducer decreases the effect of aprepitant
Etoposide Emend may change levels of chemotherapy agent
Fosphenytoin The CYP3A4 inducer decreases the effect of aprepitant
Ifosfamide Emend may change levels of chemotherapy agent
Imatinib Emend may change levels of chemotherapy agent
Irinotecan Emend may change levels of chemotherapy agent
Itraconazole This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Ketoconazole This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Mephenytoin This CYP3A4 inducer decreases the effect of aprepitant
Methylprednisolone Increases the effect and toxicity of methylprednisolone
Midazolam Increases the effect and toxicity of benzodiazepine
Nefazodone This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Nelfinavir This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Acenocoumarol Decreases the anticoagulant effect
Paclitaxel Emend may change levels of chemotherapy agent
Phenytoin This CYP3A4 inducer decreases the effect of aprepitant
Pimozide Increased risk of cardiotoxicity and arrhythmias
Rifampin This CYP3A4 inducer decreases the effect of aprepitant
Ritonavir This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Triazolam Increases the effect and toxicity of benzodiazepine
Vinblastine Emend may change levels of chemotherapy agent
Vincristine Emend may change levels of chemotherapy agent
Vinorelbine Emend may change levels of chemotherapy agent
Warfarin Emend decreases the anticoagulant effect
Mestranol Emend could decrease the effect of the oral contraceptive
Troleandomycin This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Food Interactions: Take without regard to meals.
Generic Name: Aprepitant
Synonyms: Not Available
Drug Category: Antiemetics
Drug Type: Small Molecule; Approved

Other Brand Names containing Aprepitant: Emend;
Absorption: The mean absolute oral bioavailability of aprepitant is approximately 60 to 65%.
Toxicity (Overdose): Not Available
Protein Binding: >95%
Biotransformation: Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.
Half Life: 9-13 hours
Dosage Forms of Emend: Capsule Oral
Chemical IUPAC Name: 5-[[(2S,3R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one
Chemical Formula: C23H21F7N4O3
Aprepitant on Wikipedia: https://en.wikipedia.org/wiki/Aprepitant
Organisms Affected: Humans and other mammals