NDA 21-549
`Page 5
`EMEND®
`(aprepitant)
`CAPSULES
`DESCRIPTION
`EMEND* (aprepitant) is a substance P/neurokinin 1 (NK 1) 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:
`Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble
`in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.
`Each capsule of EMEND for oral administration contains either 80 mg or 125 mg of aprepitant and the
`following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl
`sulfate. The capsule shell excipients are gelatin and titanium dioxide. The 125-mg capsule also contains red
`ferric oxide and yellow ferric oxide.
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK
`1) receptors.
`Aprepitant has little or no affinity for serotonin (5-HT 3), 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 1 receptors. Animal and
`human studies show that aprepitant augments the antiemetic activity of the 5-HT 3-receptor antagonist
`ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-
`induced emesis.
`Pharmacokinetics
`Absorption
`The mean absolute oral bioavailability of aprepitant is approximately 60 to 65% and the mean peak plasma
`concentration (C
`max) of aprepitant occurred at approximately 4 hours (T max). Oral administration of the capsule
`with a standard breakfast had no clinically meaningful effect on the bioavailability of aprepitant.
`The pharmacokinetics of aprepitant are non-linear across the clinical dose range. In healthy young adults,
`the increase in AUC 0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses
`administered in the fed state.
`Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2
`and 3, the AUC 0-24hr was approximately 19.6 mcgּhr/mL and 21.2 mcgּhr/mL on Day 1 and Day 3, respectively.
`The C max of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (T max) on Day 1 and Day 3,
`respectively.
`Distribution
`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.
`* Registered trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey, 08889 USA
` COPYRIGHT © MERCK & CO., Inc., 2003
`All rights reserved
`N
`O
`O
`CF 3
`CF 3
`F
`NNH
`NH
`O
`CH 3
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`HELSINN EXHIBIT 2016
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00947
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`NDA 21-549
`Page 6
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`Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans (see
`CLINICAL PHARMACOLOGY, Mechanism of Action).
`Metabolism
`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 IV 100-mg dose of [
`14C]-aprepitant prodrug to healthy subjects, 57% of
`the radioactivity was recovered in urine and 45% in feces. A study was not conducted with radiolabeled capsule
`formulation. The results after oral administration may differ.
`Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma
`clearance of aprepitant ranged from approximately 62 to 90 mL/min. 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 EMEND, no difference in AUC
`0-24hr was observed
`between males and females. The C max 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 max occurs at approximately the
`same time. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is
`necessary based on gender.
`Geriatric
`Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2
`through 5, the AUC
`0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly ( ≥65 years)
`relative to younger adults. The C max 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 for EMEND
`is necessary in elderly patients.
`Pediatric
`The pharmacokinetics of EMEND have not been evaluated in patients below 18 years of age.
`Race
`Following oral administration of a single 125-mg dose of EMEND, the AUC 0-24hr is approximately 25% and
`29% higher in Hispanics as compared with Whites and Blacks, respectively. The C max 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 0-24hr or Cmax between Whites and Blacks. No dosage adjustment for
`EMEND is necessary based on race.
`Hepatic Insufficiency
`EMEND was well tolerated in patients with mild to moderate hepatic insufficiency. Following administration of
`a single 125-mg dose of EMEND 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 AUC 0-24hr 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 AUC
`0-24hr 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 AUC 0-24hr are not
`considered clinically meaningful; therefore, no dosage adjustment for EMEND 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 EMEND 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 AUC
`0-∞ of total aprepitant (unbound and protein bound)
`decreased by 21% and C max decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing
`hemodialysis, the AUC 0-∞ of total aprepitant decreased by 42% and C max 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.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`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 for EMEND is necessary for patients with renal insufficiency or for patients with ESRD
`undergoing hemodialysis.
`Clinical Studies
`Oral administration of EMEND 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.
`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/m
`2 (mean cisplatin dose = 80.2 mg/m 2). 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.
`
`Treatment Regimens
`Treatment Regimen Day 1 Days 2 to 4
`Aprepitant Aprepitant 125 mg PO
`Dexamethasone 12 mg PO
`Ondansetron 32 mg IV
`Aprepitant 80 mg PO Daily (Days 2 and 3 only)
`Dexamethasone 8 mg PO Daily (morning)
`
`
`Standard Therapy Dexamethasone 20 mg PO
`Ondansetron 32 mg IV
`Dexamethasone 8 mg PO Daily (morning)
`Dexamethasone 8 mg PO Daily (evening)
`Aprepitant placebo and dexamethasone placebo were used to maintain blinding.
`
`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 follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82),
`paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).
`The antiemetic activity of EMEND was evaluated 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 evaluation of the following endpoints:
`Primary endpoint:
`• complete response (defined as no emetic episodes and no use of rescue therapy)
`Other prespecified (secondary and exploratory) 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.
`
`Table 1
`
`Percent of Patients Responding by Treatment Group and Phase for Study 1 — Cycle 1
`
`
`
`ENDPOINTS
`
`
`
`Aprepitant
`Regimen
`(N= 260)†
`%
`
`Standard
`Therapy
`(N= 261) †
`%
`
`p-Value
`
`
`
`PRIMARY ENDPOINT
`
`Complete Response
`Overall‡ 73 52 <0.001
`
`OTHER PRESPECIFIED (SECONDARY AND EXPLORATORY) ENDPOINTS
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 3 of 15
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`Complete Response
`Acute phase§
`Delayed phaseװ
`89
`75
`78
`56
`<0.001
`<0.001
`Complete Protection
`Overall
`Acute phase
`Delayed phase
`63
`85
`66
`49
`75
`52
`0.001
`0.005
`<0.001
`No Emesis
`Overall
`Acute phase
`Delayed phase
`78
`90
`81
`55
`79
`59
`<0.001
`0.001
`<0.001
`No Nausea
`Overall
`Delayed phase
`48
`51
` 44
` 48
`>0.050
`>0.050
`No Significant Nausea
`Overall
`Delayed phase
`73
`75
`66
`69
`>0.050
`>0.050
`†N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one
`post-treatment efficacy evaluation.
`‡Overall: 0 to 120 hours post-cisplatin treatment.
`§Acute phase: 0 to 24 hours post-cisplatin treatment.
`װDelayed phase: 25 to 120 hours post-cisplatin treatment.
` Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be.
`Table 1 includes nominal p-values not adjusted for multiplicity.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`Table 2
`
`Percent of Patients Responding by Treatment Group and Phase for Study 2 — Cycle 1
`
`
`ENDPOINTS
`
`
`
`Aprepitant
`Regimen
`(N= 261)†
`%
`
`Standard
`Therapy
`(N= 263) †
`%
`
`p-Value
`
`
`
`PRIMARY ENDPOINT
`
`Complete Response
`Overall‡ 63 43 <0.001
`
`OTHER PRESPECIFIED (SECONDARY AND EXPLORATORY) ENDPOINTS
`
`Complete Response
`Acute phase§
`Delayed phaseװ
`83
`68
`68
`47
`<0.001
`<0.001
`Complete Protection
`Overall
`Acute phase
`Delayed phase
`56
`80
`61
` 41
` 65
` 44
`<0.001
`<0.001
`<0.001
`No Emesis
`Overall
`Acute phase
`Delayed phase
`66
`84
`72
` 44
` 69
` 48
`<0.001
`<0.001
`<0.001
`No Nausea
`Overall
`Delayed phase
`49
`53
`39
`40
`0.021
`0.004
`No Significant Nausea
`Overall
`Delayed phase
`71
`73
`64
`65
`>0.050
`>0.050
`†N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one
`post-treatment efficacy evaluation.
`‡Overall: 0 to 120 hours post-cisplatin treatment.
`§Acute phase: 0 to 24 hours post-cisplatin treatment.
`װDelayed phase: 25 to 120 hours post-cisplatin treatment.
` Visual analogue scale (VAS) score range: 0 mm = no nausea; 100 mm = nausea as bad as it could be.
`Table 2 includes nominal p-values not adjusted for multiplicity.
`
`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 1.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`Figure 1: Percent of Patients Who Remain Emesis Free Over Time – Cycle 1
`
`0 2 44 87 29 6 1 2 0
`Hours
`0
`20
`40
`60
`80
`100Percent of Patients
`Study 1
`Standard Therapy
`Aprepitant Regimen
`(N=260)
`(N=261)
`0 2 44 87 29 6 1 2 0
`0
`20
`40
`60
`80
`100
`Study 2
`Standard Therapy
`Aprepitant Regimen
`(N=261)
`(N=263)
`
`p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.
`
`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 6 cycles of chemotherapy. The proportion of patients with no emesis and no significant
`nausea by treatment group at each cycle is depicted in Figure 2. 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 2: Proportion of Patients With No Emesis and No Significant Nausea
`by Treatment Group and Cycle
`
`0
`20
`40
`60
`80
`100Percent of Patients
`Study 1
`23456
`Chemotherapy Cycle
`Aprepitant (N) 158 122 81 54 40
`Standard (N) 177 111 68 37 29 29 29 29 29 29 29 29 29 29 29 29 29 29
`Aprepitant Regimen
`Standard Therapy
`0
`20
`40
`60
`80
`100
`Study 2
`23456
`191 148 103 63 43
`216 167 112 74 43 43 43 43 43 43 43 43 43 43 43 43 43 43
`Aprepitant Regimen
`Standard Therapy
`
`INDICATIONS AND USAGE
`EMEND, 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 (see DOSAGE AND ADMINISTRATION).
`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 (see PRECAUTIONS, Drug Interactions).
`EMEND is contraindicated in patients who are hypersensitive to any component of the product.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 6 of 15
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`PRECAUTIONS
`General
`EMEND should be used with caution in patients receiving concomitant medicinal products, including
`chemotherapy agents that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by
`aprepitant could result in elevated plasma concentrations of these concomitant medicinal products. The
`effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is expected to be
`greater than the effect of EMEND on the pharmacokinetics of intravenously administered CYP3A4
`substrates (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, EMEND was
`administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted
`to account for potential drug interactions.
`Due to the small number of patients in clinical studies who received the CYP3A4 substrates docetaxel,
`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 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 EMEND 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 EMEND
`with each chemotherapy cycle (see PRECAUTIONS, Drug Interactions).
`The efficacy of oral contraceptives during administration of EMEND may be reduced. Although effects on
`contraception with a 3-day regimen of EMEND given concomitantly with oral contraceptives has not been
`studied, alternative or back-up methods of contraception should be used (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 EMEND 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 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 oral contraceptives. Patients should be advised to use
`alternative or back-up methods of contraception.
`Drug 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 (see CONTRAINDICATIONS).
`Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are
`metabolized through CYP2C9. Coadministration of EMEND 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.
`EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as
`demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.
`5-HT
`3 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: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally
`as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 7 of 15
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`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 EMEND,
`to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily
`dose of dexamethasone administered in clinical studies with EMEND reflects an approximate 50% reduction of
`the dose of dexamethasone (see DOSAGE AND ADMINISTRATION).
`Methylprednisolone: EMEND, 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 EMEND to
`achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND.
`Chemotherapeutic agents: See PRECAUTIONS, General.
`Warfarin: A single 125-mg dose of EMEND 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 EMEND 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 EMEND. 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 EMEND with each chemotherapy cycle.
`Tolbutamide: EMEND, 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 administered orally prior to the administration of the 3-day regimen of EMEND
`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 EMEND may be reduced. Although a 3-day regimen of EMEND given concomitantly
`with oral contraceptives has not been studied, alternative or back-up methods of contraception should be used.
`Midazolam: EMEND 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 EMEND 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 EMEND.
`In another study with intravenous administration of midazolam, EMEND 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 EMEND and on Days 4, 8, and 15. EMEND 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 EMEND 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 pharmacokinetics of aprepitant
`Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4
`activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration
`of EMEND 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 EMEND 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 EMEND.
`Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 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
`EMEND with strong CYP3A4 inhibitors should be approached cautiously.
`Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 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 EMEND with drugs that induce CYP3A4 activity may result in reduced plasma
`concentrations and decreased efficacy of EMEND.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 8 of 15
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`NDA 21-549
`Page 13
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`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 C
`max by approximately 20% of both aprepitant and paroxetine.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Three 2-year carcinogenicity studies of aprepitant (two in Sprague-Dawley rats and one in CD-1 mice) were
`conducted with aprepitant. Dose selection for the studies was based on saturation of absorption in both species.
`In the rat carcinogenicity studies, animals were treated with oral doses of 0.05, 0.25, 1, 5, 25, 125 mg/kg twice
`daily. The highest dose tested produced a systemic exposure to aprepitant (plasma AUC
`0-24hr) of 0.4 to 1.4 times
`the human exposure (AUC 0-24hr = 19.6 mcgּhr/mL) at the recommended dose of 125 mg/day. Treatment with
`aprepitant at doses of 5 to 125 mg/kg twice per day produced thyroid follicular cell adenomas and carcinomas in
`male rats. In female rats, it produced increased incidences of hepatocellular adenoma at 25 and 125 mg/kg
`twice daily, and thyroid follicular adenoma at the 125 mg/kg twice daily dose. In the mouse carcinogenicity
`study, animals were treated with oral doses of 2.5, 25, 125, and 500 mg/kg/day. The highest tested dose
`produced a systemic exposure of about 2.2 to 2.7 times the human exposure at the recommended dose.
`Treatment with aprepitant produced skin fibrosarcomas in male mice of 125 and 500 mg/kg/day groups.
`Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the
`rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and
`the mouse micronucleus test.
`Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up
`to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the
`exposure at the recommended human dose and exposure in female rats at about 1.6 times the human
`exposure).
`Pregnancy. Teratogenic Effects: Category B. Teratology studies have been performed in rats at oral doses
`up to 1000 mg/kg twice daily (plasma AUC
`0-24hr of 31.3 mcgּhr/ml, about 1.6 times the human exposure at the
`recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC 0-24hr of 26.9 mcgּhr/ml, about
`1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or
`harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant
`women. Because animal reproduction studies are not always predictive of human response, this drug should be
`used during pregnancy only if clearly needed.
`Nursing Mothers
`Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk.
`Because many drugs are excreted in human milk and because of the potential for possible serious adverse
`reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant
`in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue
`the drug, taking into account the importance of the drug to the mother.
`Pediatric Use
`Safety and effectiveness of EMEND in pediatric patients have not been established.
`Geriatric Use
`In 2 well-controlled clinical studies, of the total number of patie