Fosaprepitant (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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).

14 CLINICAL STUDIES

The safety and efficacy of Fosaprepitant for Injection have been established based on adequate and well-controlled adult studies of another intravenous fosaprepitant product in chemotherapy induced nausea and vomiting. Below is a display of the results of these adequate and well-controlled studies of fosaprepitant in these conditions.

14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults

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 capsules regimen (N=1175) in patients receiving a HEC regimen that included cisplatin (≥70 mg/m2). 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 Adult HEC Trial*

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

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 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 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 capsules regimen [see Clinical Pharmacology (12.3)].

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 Adult Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1

ENDPOINTS

Intravenous Fosaprepitant Regimen

Oral Aprepitant Regimen

Difference

(N=1106)*

(N=1134)*

(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)

* 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.

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