Palonosetron Hydrochloride (Page 3 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron HCl at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (plasma AUC) of about 150 to 289 times the human exposure (AUC = 29.8 h•mcg/L) at the recommended intravenous dose of 0.25 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (plasma AUC) of 137 and 308 times the human exposure at the recommended dose. Treatment with palonosetron HCl produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.

Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test.

Palonosetron HCl at oral doses up to 60 mg/kg/day (about 1894 times the recommended human intravenous dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES

The safety and efficacy of Palonosetron HCl Injection have been established based on adequate and well-controlled adult studies of another intravenous formulation of palonosetron HCl in chemotherapy induced nausea and vomiting. Below is a display of the results of these adequate and well-controlled studies of palonosetron HCl.

14.1 Chemotherapy-Induced Nausea and Vomiting

Efficacy of a single intravenous dose of palonosetron HCl in preventing acute and delayed nausea and vomiting induced by both moderately and highly emetogenic chemotherapy was studied in 4 trials. In these double-blind trials, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy. The safety and efficacy of palonosetron HCl in repeated courses of chemotherapy was also assessed.

Moderately Emetogenic Chemotherapy:

Two double-blind trials (Study 1 and Study 2) involving 1132 patients compared a single intravenous dose of palonosetron HCl with either a single intravenous dose of ondansetron (Study 1) or dolasetron (Study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m², cyclophosphamide < 1500 mg/m², doxorubicin > 25 mg/m², epirubicin, irinotecan, and methotrexate > 250 mg/m². Concomitant corticosteroids were not administered prophylactically in Study 1 and were only used by 4 to 6% of patients in Study 2. The majority of patients in these studies were women (77%), White (65%) and naïve to previous chemotherapy (54%). The mean age was 55 years.

Highly Emetogenic Chemotherapy:

A double-blind, dose-ranging trial evaluated the efficacy of single-dose intravenous palonosetron from 0.3 to 90 mcg/kg (equivalent to < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naïve adult cancer patients receiving highly emetogenic chemotherapy (either cisplatin ≥ 70 mg/m² or cyclophosphamide >1100 mg/m²). Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.

A double-blind trial involving 667 patients compared a single intravenous dose of palonosetron HCl with a single intravenous dose of ondansetron (Study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥ 60 mg/m², cyclophosphamide > 1500 mg/m², and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, 60% White, and 59% naïve to previous chemotherapy. The mean age was 52 years.

Efficacy Results:

The antiemetic activity of palonosetron HCl was evaluated during the acute phase (0-24 hours) [Table 3], delayed phase (24-120 hours) [Table 4], and overall phase (0-120 hours) [Table 5] post-chemotherapy in Studies 1, 2 and 3.

T able 3: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates

^a Intent-to-treat cohort
^b 2-sided Fisher’s exact test. Significance level α=0.025.
^c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between palonosetron HCl and comparator.^d Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.

These trials show that palonosetron HCl was effective in the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy.

In Study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly. Clinical superiority over other 5-HT₃ receptor antagonists has not been adequately demonstrated in the acute phase.

T able 4: Prevention of Delayed Nausea and Vomiting (24-120 hours): Complete Response Rates

^a Intent-to-treat cohort
^b 2-sided Fisher’s exact test. Significance level α=0.025.
^c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between palonosetron HCl and comparator.^d Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.

These trials show that palonosetron HCl was effective in the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy.

T able 5: Prevention of Overall Nausea and Vomiting (0-120 hours): Complete Response Rates

^a Intent-to-treat cohort
^b 2-sided Fisher’s exact test. Significance level α=0.025.
^c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between palonosetron HCl and comparator.
^d Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.

These trials show that palonosetron HCl was effective in the prevention of nausea and vomiting throughout the 120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy.