FOSAPREPITANT DIMEGLUMINE 150 mg/5mL Injection, Powder, Lyophilized, For Solution — NDC 55150-299-01 (Billing 55150-0299-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 (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 have shown 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 dose 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 crosses the blood brain barrier 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, have been identified in human plasma. Excretion Following administration of a single intravenous 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 primarily by metabolism; aprepitant is not renally excreted.

The apparent terminal half-life ranged 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) 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) ]. Age: Pediatric Population Single-Dose Fosaprepitant for Injection Regimen: Simulated systemic exposures of aprepitant in patients… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 (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 have shown 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 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 crosses the blood brain barrier 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, have been identified in human plasma. Excretion Following administration of a single intravenous 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 primarily by metabolism; aprepitant is not renally excreted.

The apparent terminal half-life ranged 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) 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) ]. Age: Pediatric Population Single-Dose Fosaprepitant for Injection Regimen: Simulated systemic exposures of aprepitant in patients 2 years to less than 12 years and observed systemic exposures in patients 6 months to less than 2 years and 12 to 17 years are shown in Table 9, including AUC 0-24hr , peak plasma concentration (C max ) on Day 1 and concentrations at the end of Day 1 (C 24 ), Day 2 (C 48 ) and Day 3 (C 72 ).

Table 9 Systemic Exposures of Aprepitant for Single-Dose Fosaprepitant for Injection Regimen in Pediatric Patients *ND = Not Determined. Pharmacokinetic samples were not collected to support the parameter value of interest. †NE = Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification.

Population Single-Dose of Fosaprepitant for Injection Regimen Geometric Mean AUC 0-24hr . (mcg*hr/mL) C max (mcg/mL) C 24 (mcg/mL) C 48 (mcg/mL) C 72 (mcg/mL) 12 Years to 17 Years 150 mg 29.4 3.4

0.7ND* ND* 6 Years to less than 12 Years 4 mg/kg 35.2 3.6 0.7 0.2 0.05 2 Years to less than 6 Years 28.2 3.1 0.4 0.1 0.02 6 Months to less than 2 Years 5 mg/kg 32.7 3.3

0.4NE † ND* 3-Day IV/Oral/Oral Fosaprepitant Regimen: Simulated aprepitant systemic exposures in patients 6 months to less than 12 years and observed systemic exposures in patients 12 to 17 years are shown in Table 10, including AUC 0-24hr ,… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200 mg dose 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 = 1,147) was compared to a 3-day oral aprepitant regimen (N = 1,175) in patients receiving a HEC regimen that included cisplatin (≥70 mg/m 2 ). All patients in both groups received dexamethasone and ondansetron (see Table 12). Patient demographics were similar between the two treatment groups.

Of the total 2,322 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 12 Treatment Regimens in Adult HEC Trial* Day 1 Day 2 Day 3 Day 4 *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) ].

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 The efficacy of fosaprepitant for injection was evaluated based on the primary and secondary endpoints listed in Table 13 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 13 Percent of Adult Patients Receiving HEC Responding by Treatment Group and Phase - Cycle 1 *N: Number of patients included in the primary analysis of complete response. † 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.

ENDPOINTS Fosaprepitant for Injection Regimen (N = 1106)* % Oral Aprepitant Regimen (N = 1134)* % Difference † (95% CI) PRIMARY ENDPOINT Complete Response ‡ Overall § 71.9 72.3 -0.4 (-4.1, 3.3) SECONDARY ENDPOINTS Complete Response ‡ Delayed phase ¶ 74.3 74.2 0.1 (-3.5, 3.7) No Vomiting Overall § 72.9 74.6 -1.7 (-5.3, 2.0)

14.2Prevention of Nausea and Vomitin… [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 1,000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant approximately equivalent to (female rats) or less than (male rats) the adult human exposure at the RHD of 150 mg.

Treatment with aprepitant at doses of 5 to 1,000 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 to 1,000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1,000 mg/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 exposure approximately 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 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 Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant.

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 1,000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended adult human dose of 150 mg and exposure in female rats approximately equivalent to the adult human exposure).