emend (fosaprepitant dimeglumine)  injection, powder, lyophilized, for solution 
[Merck & Co., Inc.]

DESCRIPTION

EMEND1 (fosaprepitant dimeglumine) for Injection is a sterile, lyophilized prodrug of aprepitant and is chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2R ,3S)-2-[(1R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt).

Its empirical formula is C23H22F7N4O6P · 2(C7H17NO5) 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 for intravenous administration contains 188 mg of fosaprepitant dimeglumine equivalent to 115 mg of fosaprepitant 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). Fosaprepitant dimeglumine hereafter will be referred to as fosaprepitant.

Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 5-[[(2R,3S )-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its empirical formula is C23H21F7N4O3, and its structural formula is:

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1

CLINICAL PHARMACOLOGY

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Upon conversion of 115 mg of fosaprepitant to aprepitant, 18.3 mg of phosphate and 73 mg of meglumine are liberated from fosaprepitant.

Mechanism of Action

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 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), 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 NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Pharmacokinetics

Aprepitant after Fosaprepitant Administration

Following a single intravenous dose of fosaprepitant administered as a 15-minute infusion to healthy volunteers the mean AUC0-∞ of aprepitant was 31.7 (± 14.3) mcg•hr/mL and the mean maximal aprepitant concentration (Cmax) 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).

Figure 1: Mean Plasma Concentration of Aprepitant Following 125-mg Oral Aprepitant and 115-mg I.V. Fosaprepitant

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 (Vdss) is approximately 70 L in humans.

Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans (see CLINICAL PHARMACOLOGY, Mechanism of Action).

Metabolism

Fosaprepitant was rapidly converted to aprepitant in in vitro 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. In vitro 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 [14C]-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 I.V. 100-mg dose of [14C]-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 of aprepitant ranged from approximately 9 to 13 hours.

Special Populations

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant.

Gender

Following oral administration of a single 125-mg dose of aprepitant, no difference in AUC0-24hr was observed between males and females. The Cmax 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 Tmax 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 AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (≥65 years) relative to younger adults. The Cmax was 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 eva luated in patients below 18 years of age.

Race

Following oral administration of a single 125-mg dose of aprepitant, the AUC0-24hr is approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, respectively. The Cmax 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 AUC0-24hr or Cmax between Whites and Blacks. No dosage adjustment is necessary based on race.

Hepatic Insufficiency

Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic insufficiency is not expected to alter the conversion of fosaprepitant to aprepitant.

Oral aprepitant was well tolerated in patients with mild to moderate hepatic insufficiency. 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 insufficiency (Child-Pugh score 5 to 6), the AUC0-24hr 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 insufficiency (Child-Pugh score 7 to 9), the AUC0-24hr 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 AUC0-24hr are not considered clinically meaningful; therefore, no dosage adjustment is necessary in patients with mild to moderate hepatic insufficiency.

There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9) (see PRECAUTIONS).

Renal Insufficiency

A single 240-mg dose of oral aprepitant was administered to patients with severe renal insufficiency (CrCl<30 mL/min) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal insufficiency, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax 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 insufficiency 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 insufficiency or for patients with ESRD undergoing hemodialysis.

Pharmacodynamics

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.

Clinical Studies

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant. Fosaprepitant 115 mg I.V. infused over 15 minutes can be substituted for 125 mg oral aprepitant on Day 1 (see DOSAGE AND ADMINISTRATION). Pivotal efficacy studies were conducted with oral 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.

Highly Emetogenic Chemotherapy

In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see table below) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin >50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older.

Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in the table below.

During these studies 95% of the patients in the aprepitant group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant patients exposed follow: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).

The antiemetic activity of oral aprepitant was eva luated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on eva luation of the following endpoints:

Primary endpoint:

• complete response (defined as no emetic episodes and no use of rescue therapy)

Other prespecified endpoints:

• complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale)
• no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• no nausea (maximum VAS <5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale)

A summary of the key study results from each individual study analysis is shown in Table 1 and in Table 2.

In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.

In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 2.

Figure 2: Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time – Cycle 1

Patient-Reported Outcomes: The impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 of both Phase III studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients’ daily lives is defined as a FLIE total score >108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%).

Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 3. Antiemetic effectiveness for the patients receiving the aprepitant regimen is maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Figure 3: Proportion of Patients Receiving Highly Emetogenic Chemotherapy With No Emesis and No Significant Nausea by Treatment Group and Cycle

Moderately Emetogenic Chemotherapy

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see table that follows) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (≤60 mg/m2) or epirubicin (≤100 mg/m2).

In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%).

Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and <1% Other. The aprepitant-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.

Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in the table that follows.

The antiemetic activity of oral aprepitant was eva luated based on the following endpoints:

Primary endpoint:

Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy)

Other prespecified endpoints:

• no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• no nausea (maximum VAS <5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale)
• complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale)
• complete response during the acute and delayed phases.

A summary of the key results from this study is shown in Table 3.

In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the “No Emesis Endpoint”, a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, the impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the aprepitant regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the “No Vomiting Domain” of this composite endpoint.

Multiple-Cycle Extension: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles.

INDICATIONS AND USAGE

EMEND for Injection, 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 including high-dose cisplatin.
• prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80 or any other components of the product.

Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, fosaprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see PRECAUTIONS, Drug Interactions).

PRECAUTIONS

General

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 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. (See PRECAUTIONS; Drug Interactions.)

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 co-administered.

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 (see PRECAUTIONS, Drug Interactions).

Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.

Coadministration of aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of fosaprepitant followed by oral aprepitant with each chemotherapy cycle (see PRECAUTIONS, Drug Interactions).

Upon coadministration with aprepitant, the efficacy of hormonal contraceptives during and for 28 days following the last dose of aprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with aprepitant and for 1 month following the last dose of aprepitant (see PRECAUTIONS, Drug Interactions).

There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION).

Information for Patients

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.

For the prevention of CINV, patients should be given their dose of EMEND for Injection as an infusion over 15 minutes, 30 minutes prior to chemotherapy on Day 1.

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 the 3-day regimen of fosaprepitant followed by aprepitant, 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 EMEND for Injection and for 1 month following the last dose of the 3-day aprepitant regimen.

Drug Interactions

Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. The following information was derived from data with oral aprepitant and one study conducted with fosaprepitant and oral midazolam.

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.

Effect of aprepitant on the pharmacokinetics of other agents

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

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of fosaprepitant or oral 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.

Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral 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, granisetron or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids:

Dexamethasone: Oral aprepitant, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and oral 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 a regimen of fosaprepitant followed by aprepitant, to achieve exposures of dexamethasone similar to those obtained when dexamethasone is given without aprepitant. The daily dose of dexamethasone administered in clinical CINV studies with oral aprepitant reflects an approximate 50% reduction of the dose of dexamethasone (see DOSAGE AND ADMINISTRATION).

Methylprednisolone: Oral 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