Fosaprepitant 150 mg/5mL Injection, Powder, Lyophilized, For Solution, 1 vial — NDC 43598-948-11 (Billing 43598-0948-11)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Fosaprepitant is a prodrugof aprepitant and accordingly, its antiemetic effectsare attributable to aprepitant.Aprepitant is a selectivehigh-affinity antagonist of human substanceP/neurokinin 1(NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapiesfor chemotherapy-induced nausea and vomiting(CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxicchemotherapeutic 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 humanstudies have shown that aprepitant augmentsthe antiemetic activityof the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibitsboth the acuteand delayed phasesof cisplatin-induced emesis.

12.2Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mgdose of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc interval.

12.3Pharmacokinetics Aprepitant after Fosaprepitant Administration Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant administered as a 20-minute infusion to healthy subjects, the mean AUC 0-∞ of aprepitant was 37.4 (±14.8) mcg • hr/mL and the mean maximal aprepitant concentration (C max ) was 4.2 (±1.2) mcg/mL. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion. Distribution Aprepitant is greater than 95% bound to plasma proteins.

The mean apparent volume of distribution at steady state(Vd ss ) was approximately 70 L in humans. Aprepitant crossesthe blood brainbarrier in humans[see Clinical Pharmacology ( 12.1 )]. Elimination Metabolism Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and 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. 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 [ 14 C]-aprepitant, indicating a substantial presence of metabolites in the plasma.

Seven metabolites of aprepitant, which are only weakly active, havebeen identified in human plasma. Excretion Following administration of a singleintravenous 100-mg dose of [ 14 C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces.Aprepitant is eliminated primarilyby metabolism; aprepitant is not renally excreted. The apparent terminal half-liferanged from approximately 9 to 13 hours.

Specific Populations Age: Geriatric Population 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 0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relativeto 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 [see Use in Specific Populations (8.5)]. Sex Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are 9% and 17% higher in females as co… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Fosaprepitant is a prodrugof aprepitant and accordingly, its antiemetic effectsare attributable to aprepitant.Aprepitant is a selectivehigh-affinity antagonist of human substanceP/neurokinin 1(NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapiesfor chemotherapy-induced nausea and vomiting(CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxicchemotherapeutic 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 humanstudies have shown that aprepitant augmentsthe antiemetic activityof the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibitsboth the acuteand delayed phasesof cisplatin-induced emesis.

12.3Pharmacokinetics Aprepitant after Fosaprepitant Administration Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant administered as a 20-minute infusion to healthy subjects, the mean AUC 0-∞ of aprepitant was 37.4 (±14.8) mcg • hr/mL and the mean maximal aprepitant concentration (C max ) was 4.2 (±1.2) mcg/mL. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion. Distribution Aprepitant is greater than 95% bound to plasma proteins.

The mean apparent volume of distribution at steady state(Vd ss ) was approximately 70 L in humans. Aprepitant crossesthe blood brainbarrier in humans[see Clinical Pharmacology ( 12.1 )]. Elimination Metabolism Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and 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. 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 [ 14 C]-aprepitant, indicating a substantial presence of metabolites in the plasma.

Seven metabolites of aprepitant, which are only weakly active, havebeen identified in human plasma. Excretion Following administration of a singleintravenous 100-mg dose of [ 14 C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces.Aprepitant is eliminated primarilyby metabolism; aprepitant is not renally excreted. The apparent terminal half-liferanged from approximately 9 to 13 hours.

Specific Populations Age: Geriatric Population 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 0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relativeto 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 [see Use in Specific Populations (8.5)]. Sex Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are 9% and 17% higher in females as compared with males.

The half-life of aprepitantis approximately 25% lower in femalesas compared with males and T max occursat approximately the same time. These differences are not considered clinically meaningful. Race/Ethnicity Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are approximately 27% and 19% higher in Hispanicsas compared with Caucasians.

The AUC 0-24hr and C max were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hr or C max between Caucasians and Blacks.These differences are not considered clinicallymeaningful. Renal Impairment A single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease(ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC 0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing h… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mgdose of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc interval.

14 CLINICAL STUDIES

14.1Prevention of Nausea and Vomiting Associated with HEC in Adults In a randomized, parallel,double-blind, active-controlled study, fosaprepitant for injection 150 mg as a single intravenous infusion(N=1147) was comparedto a 3-day oral aprepitant regimen (N=1175) in patientsreceiving a HEC regimen that included cisplatin (≥70 mg/m 2 ). All patients in both groups received dexamethasone and ondansetron (see Table 11). Patient demographics were similar betweenthe two treatment groups.

Of the total 2322 patients, 63% were men, 56% White,26% Asian, 3% American Indian/Alaska Native,2% Black, 13% Multi-Racial, and 33% Hispanic/Latino ethnicity. Patient ages ranged from 19 to 86 years of age, with a mean age of 56 years.Other concomitant chemotherapy agents commonly administered were fluorouracil (17%),gemcitabine (16%), paclitaxel (15%), and etoposide (12%). T a ble 11: Treatment Regimens in Adult HEC Trial* Day 1 Day 2 Day 3 Day 4 Fosaprepitant Regimen Fosaprepitant for injection 150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy none none none Oral dexamethasone † 12 mg 8 mg 8 mg twice daily 8 mg twice daily Ondansetron Ondansetron ‡ none none none Oral Aprepitant Regimen Aprepitant capsules 125 mg 80 mg 80 mg none Oral dexamethasone § 12 mg 8 mg 8 mg 8 mg Ondansetron Ondansetron ‡ none none none * fosaprepitant for injection placebo, aprepitant capsules placebo and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding. † Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4.

Dexamethasone was also administered in the evenings on Days 3 and 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Day 2 reflects a dosage adjustment to account for a drug interaction with the fosaprepitant for injection regimen [see Clinical Pharmacology ( 12.3 )]. ‡Ondansetron 32 mg intravenous was used in the clinical trials of fosaprepitant. Although this dose was used in clinical trials, this is no longer the currently recommended dose.

Refer to the ondansetron prescribing information for the current recommended dose. § Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Days 2 through 4 reflects a dosage adjustment to account for a drug interaction with the oral aprepitant regimen [see Clinical Pharmacology( 12.3 )]. The efficacy of fosaprepitant for injection was evaluated based on the primary and secondary endpoints listed in Table 12 and was shown to be non-inferior to that of the 3-day oral aprepitant regimen with regard to complete response in each of the evaluated phases.

The pre-specified non-inferiority margin for complete response in the overall phase was 7%. The pre-specified non-inferiority margin for complete response in the delayedphase was 7.3%. Thepre-specified non-inferiority margin for no vomiting in the overall phase was 8.2%.

T a ble 12 Percent of Adult Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1 ENDPOINTS Fosaprepitant for Injection Regimen (N = 1106) * % Oral Ap repitant Regimen (N = 1134) * % Difference† (95% CI) PRIMARY ENDPOINT Complete Response ‡ Overall § 71.9 72.3 -0.4 (-4.1, 3.3) SECONDARYENDPOINTS Complete Response ‡ Delayedphase ¶ 74.3 74.2 0.1 (-3.5, 3.7) No Vomiting Overall § 72.9 74.6 -1.7 (-5.3, 2.0) * N: Number of patients included in the primary analysis of completeresponse. † Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for Gender. ‡ Complete Response = no vomiting and no use of rescue therapy. § Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy. ¶ Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.

14.2Prevention of Nausea and Vomiting Associated… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Carcinogenicity studieswere conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1,000 mg/kg twice daily. The highest dose produced systemic exposuresto aprepitant approximately equivalent to (female rats) or less than (male rats) the adulthuman exposure at the RHD of 150 mg.

Treatment with aprepitant at doses of 5 to 1,000 mg/kg twicedaily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1,000 mg/kg twicedaily and hepatocellular carcinomas and thyroidfollicular cell adenomasat 125 to 1000mg/kg twice daily. In the mouse carcinogenicity studies,the animals were treated with oral doses ranging from 2.5 to 2,000 mg/kg/day.

The highest dose produced a systemic exposureapproximately 2 times the adult human exposure at the RHD of 150 mg. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.

Mutagenesis Aprepitant and fosaprepitant were not genotoxicin 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 micronucleustest. Impairment of Fertility Fosaprepitant, when administered intravenously, is rapidly convertedto aprepitant. In the fertilitystudies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant.

Oral aprepitant did not affectthe fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1,000 mg/kg twice daily (providingexposure in male rats lower than the exposure at the recommended adult human dose of 150 mg and exposurein female rats approximately equivalent to the adult human exposure).