Emend Information
Emend () Indications And Usage
Emend () for Injection is a substance P/neurokinin-1 (NK) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the:
Emend () for Injection has not been studied for the treatment of established nausea and vomiting.
Chronic continuous administration is not recommended .
Emend () Dosage And Administration
Emend () for Injection 150 mg is administered intravenously on Day 1 only as an infusion initiated approximately 30 minutes prior to chemotherapy. No capsules of Emend () are administered on Days 2 and 3. Emend () for Injection should be administered in conjunction with a corticosteroid and a 5-HT antagonist as specified in Table 1. The recommended dosage of dexamethasone with Emend () for Injection 150 mg differs from the recommended dosage of dexamethasone with Emend () for Injection 115 mg on Days 3 and 4.
Emend () for Injection 115 mg is administered on Day 1 only as an infusion initiated 30 minutes prior to chemotherapy. Capsules of Emend () 80 mg should be administered on Days 2 and 3. Emend () for Injection 115 mg should be administered in conjunction with a corticosteroid and a 5-HT antagonist as specified in Table 2. The recommended dosage of dexamethasone with Emend () for Injection 115 mg differs from the recommended dosage of dexamethasone with Emend () for Injection 150 mg on Days 3 and 4.
Capsules of Emend () 125 mg may be substituted for Emend () for Injection 115 mg on Day 1.
Emend () for Injection 115 mg is administered on Day 1 only as an infusion initiated 30 minutes prior to chemotherapy. Capsules of Emend () 80 mg should be administered on Days 2 and 3. Emend () for Injection 115 mg should be administered in conjunction with a corticosteroid and a 5-HT antagonist as specified in Table 3. The recommended dosage of dexamethasone with Emend () for Injection 115 mg differs from the recommended dosage of dexamethasone with Emend () for Injection 150 mg on Days 3 and 4.
Capsules of Emend () 125 mg may be substituted for Emend () for Injection 115 mg on Day 1.
The reconstituted final drug solution is stable for 24 hours at ambient room temperature (at or below 25°C).
Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.
Caution:
Emend () Dosage Forms And Strengths
One 150 mg single dose glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).
One 115 mg single dose glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).
Emend () Warnings And Precautions
Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant .
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.
In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered.
Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied .
Emend () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Since Emend () for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with Emend () for Injection.
The overall safety of fosaprepitant was evaluated in approximately 1100 individuals and the overall safety of aprepitant was evaluated in approximately 6500 individuals.
Oral Aprepitant
Highly Emetogenic Chemotherapy (HEC)
In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone.
In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy.
The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥1% and greater than standard therapy are listed in Table 5.
A listing of adverse reactions in the aprepitant regimen (incidence
In an additional active-controlled clinical study in 1169 patients receiving aprepitant and highly emetogenic chemotherapy, the adverse experience profile was generally similar to that seen in the other HEC studies with aprepitant.
Moderately Emetogenic Chemotherapy (MEC)
In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy, 868 patients were treated with the aprepitant during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In both studies, oral aprepitant was given in combination with ondansetron and dexamethasone (aprepitant regimen).
In the combined analysis of Cycle 1 data for these 2 studies, adverse reactions were reported in approximately 14% of patients treated with the aprepitant regimen compared with approximately 15% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.7% of patients treated with the aprepitant regimen compared with 0.2% of patients treated with standard therapy.
The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥1% and greater than standard therapy are listed in Table 6.
A listing of adverse reactions in the aprepitant regimen (incidence
Less Common Adverse Reactions
Adverse reactions reported in either HEC or MEC studies in patients treated with the aprepitant regimen with an incidence
In another chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy.
The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1.
Fosaprepitant
In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving the 1-day regimen of Emend () for Injection 150 mg compared to 1169 patients receiving the 3-day regimen of Emend () (aprepitant). The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.
The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above.
Other Studies with Postoperative Nausea and Vomiting
In well-controlled clinical studies in patients receiving general balanced anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron intravenously.
Adverse reactions were reported in approximately 4% of patients treated with 40 mg aprepitant compared with approximately 6% of patients treated with 4 mg ondansetron intravenously.
In patients treated with aprepitant, increased ALT (1.1%) was seen at a greater incidence than with ondansetron (1.0%). The following additional adverse reactions were observed in patients treated with aprepitant at an incidence
In addition, two serious adverse reactions were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of subileus.
Other Studies
Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study.
The following adverse reactions have been identified during post approval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug.
Skin and subcutaneous tissue disorders:
Immune system disorders:
Emend () Drug Interactions
Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant.
Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9.
Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4, and does not induce CYP3A4. Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.
The following information was derived from data with oral aprepitant, two studies conducted with fosaprepitant and oral midazolam, and one study conducted with fosaprepitant and dexamethasone.
Emend () Use In Specific Populations
Teratogenic effects
Pregnancy Category B:
Emend () Overdosage
There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.
In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective.
Aprepitant cannot be removed by hemodialysis.
Thirteen patients in the randomized controlled trial of Emend () for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population.
Emend () Description
Emend () (fosaprepitant dimeglumine) for Injection is a sterile, lyophilized prodrug of aprepitant, a substance P/neurokinin-1 (NK) receptor antagonist, and is chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2,3)-2-[(1)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1-1,2,4-triazol-1-yl]phosphonate (2:1) (salt).
Its empirical formula is CHFNOP · 2(CHNO) and its structural formula is:
Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water.
Emend () for Injection is a lyophilized prodrug of aprepitant containing polysorbate 80 (PS80), to be administered intravenously as an infusion.
Each vial of Emend () for Injection 115 mg for intravenous administration contains 188 mg of fosaprepitant dimeglumine equivalent to 115 mg of fosaprepitant free acid and the following inactive ingredients: edetate disodium (14.4 mg), polysorbate 80 (57.5 mg), lactose anhydrous (287.5 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment). Each vial of Emend () for Injection 150 mg for intravenous administration contains 245.3 mg of fosaprepitant dimeglumine equivalent to 150 mg of fosaprepitant free acid and the following inactive ingredients: edetate disodium (18.8 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment). Fosaprepitant dimeglumine hereafter will be referred to as fosaprepitant.
Emend () Clinical Pharmacology
Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK) receptor antagonist. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion . Upon conversion of 188 mg of fosaprepitant dimeglumine (equivalent to 115 mg fosaprepitant free acid) to aprepitant, 18.3 mg of phosphoric acid and 73 mg of meglumine are liberated. Upon conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant free acid) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.
Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK) receptors. Aprepitant has little or no affinity for serotonin (5-HT), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant 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 aprepitant have shown that it crosses the blood brain barrier and occupies brain NK receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.
NK Receptor Occupancy
In two single-blind, multiple-dose, randomized, and placebo control studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK receptor occupancies were ~50% and ~90%, respectively. The oral aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations >500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in >95% brain NK receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK receptor occupancy and the clinical efficacy of aprepitant has not been established.
Cardiac Electrophysiology
In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval.
Aprepitant after Fosaprepitant Administration
Following a single intravenous 115-mg dose of fosaprepitant administered as a 15-minute infusion to healthy volunteers the mean AUC of aprepitant was 31.7 (± 14.3) mcg•hr/mL and the mean maximal aprepitant concentration (C) was 3.27 (± 1.16) mcg/mL. The mean aprepitant plasma concentration at 24 hours postdose was similar between the 125-mg oral aprepitant dose and the 115-mg intravenous fosaprepitant dose. (See Figure 1.)
Following a single, intravenous 150-mg dose of fosaprepitant administered as a 20-minute infusion to healthy volunteers, the mean AUC of aprepitant was 37.38 (± 14.75) mcg•hr/mL and the mean maximal aprepitant concentration (C) was 4.15 (± 1.15) mcg/mL.
Distribution
Fosaprepitant is rapidly converted to aprepitant. Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vd) is approximately 70 L in humans.
Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans .
Metabolism
Fosaprepitant was rapidly converted to aprepitant in incubations with liver preparations from nonclinical species (rat and dog) and humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver. In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of infusion.
Aprepitant undergoes extensive metabolism. studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.
Excretion
Following administration of a single intravenous 100-mg dose of [C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces.
Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent terminal half-life ranged from approximately 9 to 13 hours.
Special Populations
Gender
Following oral administration of a single 125-mg dose of aprepitant, no difference in AUC was observed between males and females. The C for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and T occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on gender.
Geriatric
Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (≥65 years) relative to younger adults. The Cwas 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dosage adjustment is necessary in elderly patients.
Pediatric
Fosaprepitant has not been evaluated in patients below 18 years of age.
Race
Following oral administration of a single 125-mg dose of aprepitant, the AUC is approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, respectively. The C is 22% and 31% higher in Hispanics as compared with Whites and Blacks, respectively. These differences are not considered clinically meaningful. There was no difference in AUC or C between Whites and Blacks. No dosage adjustment is necessary based on race.
Hepatic Insufficiency
Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant.
Following administration of a single 125-mg dose of oral aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC are not considered clinically meaningful; therefore, no dosage adjustment is necessary in patients with mild to moderate hepatic impairment.
There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) .
Renal Insufficiency
A single 240-mg dose of oral aprepitant was administered to patients with severe renal impairment (CrCl
In patients with severe renal impairment, the AUCof total aprepitant (unbound and protein bound) decreased by 21% and C decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing hemodialysis, the AUCof total aprepitant decreased by 42% and C decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
No dosage adjustment is necessary for patients with renal impairment or for patients with ESRD undergoing hemodialysis.
Emend () Clinical Studies
Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant.
Oral administration of aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy including high-dose cisplatin, and nausea and vomiting associated with moderately emetogenic chemotherapy.
Emend () How Supplied/storage And Handling
No. 3884 — One 115 mg single dose glass vial: White to off-white lyophilized solid. Supplied as follows:
NDC 0006-3884-32 1 vial per carton.
No. 3941 — One 150 mg single dose glass vial: White to off-white lyophilized solid. Supplied as follows:
NDC 0006-3941-32 1 vial per carton.
Vials: Store at 2-8°C (36-46°F).
Sterile lyophilized powder for intravenous use only after reconstitution and dilution.
Manufactured by:DSM Pharmaceuticals, Inc., 5900 Martin Luther King Jr. Highway, Greenville, NC 27834, USA
9995307
Copyright © 2008, 2009 Merck Sharp & Dohme Corp., a subsidiary of All rights reserved
U.S. Patent Nos.: 5,512,570; 5,691,336
Emend () Patient Counseling Information
Physicians should instruct their patients to read the patient package insert before starting therapy with Emend () for Injection and to reread it each time the prescription is renewed.
Patients should follow the physician’s instructions for the Emend () for Injection regimen.
Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using Emend () and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely.
Patients who develop an infusion site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation.
Emend () for Injection 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 fosaprepitant with each chemotherapy cycle.
Administration of Emend () for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.
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