Palonosetron .25 mg/5mL Injection — NDC 60505-6439-1 (Billing 60505-6439-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Palonosetron is a 5-HT 3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema.

It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT 3 receptors located on vagal afferents to initiate the vomiting reflex. Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract.

The 5-HT 3 receptor has been demonstrated to selectively participate in the emetic response.

12.2Pharmacodynamics Cardiac Electrophysiology The effect of intravenous palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to intravenous ondansetron and dolasetron in CINV clinical trials. In PONV clinical trials the effect of palonosetron on the QTc interval was no different from placebo. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration.

At a dose of 9 times the maximum recommended adult dose, Palonosetron Hydrochloride Injection does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics After intravenous dosing of palonosetron HCl in healthy subjects and cancer patients, an initial decline in palonosetron plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (C max ) and area under the concentration-time curve (AUC 0-∞ ) are generally dose-proportional over the dose range of 0.3 to 90 mcg/kg in healthy subjects and in cancer patients. Following a single intravenous dose of palonosetron HCl at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9 h·mcg/L.

Following intravenous administration of Palonosetron Hydrochloride Injection 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42±34%. Following intravenous administration of Palonosetron Hydrochloride Injection 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%. After intravenous dosing of Palonosetron Hydrochloride Injection in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

Distribution Palonosetron has a volume of distribution of approximately 8.3 ±

2.5L/kg. Approximately 62% of palonosetron is bound to plasma proteins. Elimination After a single intravenous dose of 10 mcg/kg [ 14 C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40% of the administered dose.

In healthy subjects, the total body clearance of palonosetron was 0.160 ± 0.035 L/h/kg and renal clearance was 0.067 ± 0.018 L/h/kg. Mean terminal elimination half-life is approximately 40 hours. Metabolism Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron.

These metabolites each have less than 1% of the 5-HT 3 receptor antagonist activity of palonosetron. In vitro metabolism s… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Palonosetron is a 5-HT 3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema.

It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT 3 receptors located on vagal afferents to initiate the vomiting reflex. Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract.

The 5-HT 3 receptor has been demonstrated to selectively participate in the emetic response.

12.3Pharmacokinetics After intravenous dosing of palonosetron HCl in healthy subjects and cancer patients, an initial decline in palonosetron plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (C max ) and area under the concentration-time curve (AUC 0-∞ ) are generally dose-proportional over the dose range of 0.3 to 90 mcg/kg in healthy subjects and in cancer patients. Following a single intravenous dose of palonosetron HCl at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9 h·mcg/L.

Following intravenous administration of Palonosetron Hydrochloride Injection 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42±34%. Following intravenous administration of Palonosetron Hydrochloride Injection 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%. After intravenous dosing of Palonosetron Hydrochloride Injection in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

Distribution Palonosetron has a volume of distribution of approximately 8.3 ±

2.5L/kg. Approximately 62% of palonosetron is bound to plasma proteins. Elimination After a single intravenous dose of 10 mcg/kg [ 14 C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40% of the administered dose.

In healthy subjects, the total body clearance of palonosetron was 0.160 ± 0.035 L/h/kg and renal clearance was 0.067 ± 0.018 L/h/kg. Mean terminal elimination half-life is approximately 40 hours. Metabolism Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron.

These metabolites each have less than 1% of the 5-HT 3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.

Specific Populations Pediatric Patients Pharmacokinetic data was obtained from a subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg as a single intravenous dose of Palonosetron Hydrochloride Injection. When the dose was increased from 10 mcg/kg to 20 mcg/kg a dose-proportional increase in mean AUC was observed. Peak plasma concentrations (CT) reported at the end of the 15-minute infusion of 20 mcg/kg were highly variable in all age groups and tended to be lower in patients less than 6 years than in older patients as shown in Table 4.

The median half-life was 30 hours in overall age groups and ranged from about 20 to 30 hours across age groups after administration of 20 mcg/kg. The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg.

Table 4: Pharmacokinetics Parameters in Pediatric Cancer Patients following Intravenous Infusion of 20 mcg/kg Palonosetron Hydrochloride Injection Over 15 minutes PK Parameter Geometric Mean (CV) except for t1/2 which is median values Pediatric Age Group Less than 2 years 2 years to less than 6 years 6 years to less than 12 years 12 years to less than 17 years N=12 N=42 N=38 N=44 C T C T is the plasma palonosetron concentration at the end of the 15-minute infusion , ng/L 9025 (197) 9414 (252) 16275 (203) 11831 (176) N=5 N=7 N=10 AUC 0-∞ , h·mcg/L 103.5 (40.4) 98.7 (47.7) 124.5 (19.1) N=6 N=14 N=13 N=19 Clearan… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology The effect of intravenous palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to intravenous ondansetron and dolasetron in CINV clinical trials. In PONV clinical trials the effect of palonosetron on the QTc interval was no different from placebo. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration.

At a dose of 9 times the maximum recommended adult dose, Palonosetron Hydrochloride Injection does not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Prevention of Nausea and Vomiting Associated with MEC and HEC in Adults Efficacy of a single intravenous dose of Palonosetron Hydrochloride Injection in preventing acute and delayed nausea and vomiting associated with MEC or HEC were studied in 4 trials. In these double-blind studies, 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 Hydrochloride Injection in repeated courses of chemotherapy was also assessed.

M o d e r at e l y Emetogenic Chemotherapy Two double-blind trials (Study 1 and Study 2) involving 1132 patients compared a single dose of Palonosetron Hydrochloride Injection with either a single-dose of ondansetron (Study 1) or dolasetron (Study 2) given 30 minutes prior to MEC, 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. H i g h l y Emetogenic Chemotherapy A double-blind, dose-ranging trial evaluated the efficacy of a single intravenous dose of Palonosetron Hydrochloride Injection 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 HEC, 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 associated with HEC. A double-blind trial involving 667 patients compared a single intravenous dose of Palonosetron Hydrochloride Injection with a single intravenous dose of ondansetron (Study 3) given 30 minutes prior to HEC, 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 Studies 1, 2 and 3 show that Palonosetron Hydrochloride Injection was effective in the prevention of nausea and vomiting associated with initial and repeat courses of MEC and HEC in the acute phase (0 to 24 hours) [Table 5]. Clinical superiority over other 5-HT 3 receptor antagonists has not been adequately demonstrated in the acute phase. In Study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly.

Studies 1 and 2 show that Palonosetron Hydrochloride Injection was effective in the prevention of nausea and vomiting associated with initial and repeat course of MEC in the delayed phase (24 to 120 hours) [Table 6] and overall phase (0 to 120 hours) [Table 7]. Table 5: Prevention of Acute Nausea and Vomiting (0 to 24 Hours) in Adults with Nausea and Vomiting Associated with MEC or HEC in Studies 1, 2 and 3: Complete Response Rates Chemotherapy Study Treatment Group N Intent-to-treat cohort % with Complete Response p -value 2-sided Fisher's exact test.

Significance level at α=0.025. 97.5% Confidence Interval Palonosetron Hydrochloride Injection minus Comparator These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron Hydrochloride Injection and comparator.

Moderately Emetogenic 1 Palonosetron Hydrochloride Injection 0.25 mg intravenously 189 81 0.009 Ondansetron 32 mg intravenously 185 69 2 Palonosetron Hydrochloride Injection 0.25 mg intravenously 189 63 NS Dolasetron 100 mg intravenously 191 53 Highly Emetogenic 3 Palonosetron Hydrochloride Injection 0.25 mg intra… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 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.