CINVANTI aprepitant 130 mg/18mL Injection, Emulsion — NDC 47426-201-01 (Billing 47426-0201-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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. 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.

12.2Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200 mg intravenous dose of fosaprepitant, a prodrug of aprepitant, had no effect on the QTc interval. In a cross-study comparison, maximum aprepitant concentrations (C max ) after a single 200 mg dose of fosaprepitant were 1.04- and 1.5-fold higher than that achieved with CINVANTI 130 mg dose and 100 mg dose given as a 30-minute infusion, respectively.

12.3Pharmacokinetics Pharmacokinetic parameters following administration of a single intravenous 130 mg dose of CINVANTI administered as a 2-minute injection or 100 mg or 130 mg dose of CINVANTI administered as a 30-minute infusion to healthy subjects are summarized in Table 10. Table 10. Aprepitant Pharmacokinetic Parameters (Mean (± Standard Deviation)) After Single Dose Intravenous Administration of CINVANTI CINVANTI 130 mg 2-minute intravenous injection CINVANTI 130 mg 30-minute intravenous infusion CINVANTI 100 mg 30-minute intravenous infusion AUC 0-72hr (mcg∙hr/mL) 45.6 (± 15.5) 43.9 (± 12.7) 27.8 (± 6.5) C max (mcg/mL) 13.9 (±3.8) 6.1 (± 1.5) 4.3 (± 1.2) Distribution Aprepitant is greater than 99% bound to plasma proteins.

The mean apparent volume of distribution at steady state (Vd ss ) was approximately 70 L in humans. Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1) ] . Elimination 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 [ 14 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 Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted.

The apparent terminal half-life ranged from approximately 9 to 13 hours. Specific Populations Geriatric Patients 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) 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 [see Use in Specific Populations (8.5) ] . Male and Female Patients 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 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. Racial or Ethnic Groups Following oral admi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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. 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.

12.3Pharmacokinetics Pharmacokinetic parameters following administration of a single intravenous 130 mg dose of CINVANTI administered as a 2-minute injection or 100 mg or 130 mg dose of CINVANTI administered as a 30-minute infusion to healthy subjects are summarized in Table 10. Table 10. Aprepitant Pharmacokinetic Parameters (Mean (± Standard Deviation)) After Single Dose Intravenous Administration of CINVANTI CINVANTI 130 mg 2-minute intravenous injection CINVANTI 130 mg 30-minute intravenous infusion CINVANTI 100 mg 30-minute intravenous infusion AUC 0-72hr (mcg∙hr/mL) 45.6 (± 15.5) 43.9 (± 12.7) 27.8 (± 6.5) C max (mcg/mL) 13.9 (±3.8) 6.1 (± 1.5) 4.3 (± 1.2) Distribution Aprepitant is greater than 99% bound to plasma proteins.

The mean apparent volume of distribution at steady state (Vd ss ) was approximately 70 L in humans. Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1) ] . Elimination 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 [ 14 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 Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted.

The apparent terminal half-life ranged from approximately 9 to 13 hours. Specific Populations Geriatric Patients 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) 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 [see Use in Specific Populations (8.5) ] . Male and Female Patients 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 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. Racial or Ethnic Groups 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 Hispanics as 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 clinically meaningful. Patients with 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 C max decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). 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 imp… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200 mg intravenous dose of fosaprepitant, a prodrug of aprepitant, had no effect on the QTc interval. In a cross-study comparison, maximum aprepitant concentrations (C max ) after a single 200 mg dose of fosaprepitant were 1.04- and 1.5-fold higher than that achieved with CINVANTI 130 mg dose and 100 mg dose given as a 30-minute infusion, respectively.

14 CLINICAL STUDIES The safety and efficacy of CINVANTI have been established based on adequate and well-controlled adult studies of a single-dose of intravenous fosaprepitant, a prodrug of aprepitant, and a 3-day regimen of oral aprepitant in chemotherapy-induced nausea and vomiting associated with HEC and MEC, respectively. Below is a description of the results of these adequate and well-controlled studies of fosaprepitant/aprepitant in these conditions.

14.1Prevention of Nausea and Vomiting Associated with HEC In a randomized, parallel, double-blind, active-controlled study, 150 mg fosaprepitant as a single intravenous infusion (N = 1147) was compared to a 3-day oral aprepitant regimen (N = 1175) in patients receiving 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 between the 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%). Table 11.

Treatment Regimens in HEC Trial Fosaprepitant placebo, aprepitant placebo and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding. Day 1 Day 2 Day 3 Day 4 Intravenous Fosaprepitant Regimen Fosaprepitant 150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy None None None Oral dexamethasone 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 regimen [see Clinical Pharmacology (12.3) ]. 12 mg 8 mg 8 mg twice daily 8 mg twice daily Ondansetron Ondansetron Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the clinical trial, this is no longer the currently recommended dose.

Refer to the ondansetron prescribing information for the current recommended dose. None None None Oral Aprepitant Regimen Aprepitant capsules 125 mg 80 mg 80 mg None Oral dexamethasone 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) ] .

12 mg 8 mg 8 mg 8 mg Ondansetron Ondansetron None None None The efficacy of a single-dose of intravenous fosaprepitant 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 delayed phase was 7.3%.

The pre-specified non-inferiority margin for no vomiting in the overall phase was 8.2%. Table 12. Percent of Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1 ENDPOINTS Intravenous Fosaprepitant Regimen (N = 1106) N: Number of patients included in the primary analysis of complete response. % Oral aprepitant Regimen (N = 1134) % Difference Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for gender.

(95% CI) PRIMARY ENDPOINT Complete Response Complete Response = no vomiting and no use of rescue therapy. Overall Overall… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were 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 1000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant approximately equivalent to (female rats) or less than (male rats) the human exposure at the CINVANTI RHD of 130 mg.

Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily 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 to1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day.

The highest dose produced a systemic exposure approximately 2 times the human exposure at the RHD of CINVANTI 130 mg. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Mutagenesis 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.

Impairment of Fertility Oral 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 RHD of CINVANTI 130 mg and exposure in female rats approximately equivalent to the human exposure).