Palonosetron Hydrochloride (Page 5 of 7)

14.2 Prevention of Nausea and Vomiting Associated with Emetogenic Chemotherapy, Including HEC in Pediatric Patients

One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients. The total population (N = 327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of Palonosetron Hydrochloride injection 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of Palonosetron Hydrochloride injection) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hours after the first dose of ondansetron, with a maximum total dose of 32 mg). Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (< 1500 mg/m²), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.

Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of intravenous Palonosetron Hydrochloride injection compared to intravenous ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous Palonosetron Hydrochloride injection minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.

Efficacy Results

As shown in Table 8, intravenous Palonosetron Hydrochloride 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24-hour time interval.

Table 8: Prevention of Acute Nausea and Vomiting (0 to 24 Hours) Associated with Emetogenic Chemotherapy in Pediatric Patients: Complete Response Rates

* To adjust for multiplicity of treatment groups, a lower-bound of a 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.
Palonosetron Hydrochloride injection 20 mcg/kg intravenously (N=165)	Ondansetron 0.15 mg/kg for 3 intravenous doses (N=162)	Difference [97.5% Confidence Interval]*: Palonosetron Hydrochloride injection minus intravenous Ondansetron Comparator
59.4%	58.6%	0.36% [-11.7%, 12.4%]

In patients that received Palonosetron Hydrochloride injection at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.

14.3 Prevention of Postoperative Nausea and Vomiting in Adults

In a multicenter, randomized, stratified, double-blind, parallel-group, clinical trial, Palonosetron Hydrochloride injection was compared to placebo for PONV in 546 patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. The trial was conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of PONV and/or motion sickness.

Patients were randomized to receive a single dose of Palonosetron Hydrochloride injection 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia. Antiemetic activity of was evaluated during the 0 to 72-hour time period after surgery.

Of the 138 patients treated with Palonosetron Hydrochloride injection 0.075 mg and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers. As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian. The age of patients ranged from 21 to 74 years, with a mean age of 38 years. Three patients were greater than 65 years of age.

Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in 0 to 24 hours and 24 to 72 hours postoperatively.

Secondary efficacy endpoints included:

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Complete Response (CR) 0 to 48 hours and 0 to 72 hours

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Complete Control (CC) defined as CR and no more than mild nausea

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Severity of nausea (none, mild, moderate, severe)

The primary hypothesis was that at least one of the three palonosetron doses were superior to placebo.

Complete Response Rates for Palonosetron Hydrochloride injection 0.075 mg and placebo in this trial are described in Table 9.

Table 9: Prevention of Postoperative Nausea and Vomiting in Adults: Complete Response Rates

Δ Difference (%): palonosetron 0.075 mg minus placebo
* To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p<0.017.
Treatment	n/N (%)	Palonosetron Hydrochloride injection vs Placebo
		Δ	p-value *
Co-primary Endpoints
Complete Response Rate (0 to 24 hours)
Palonosetron Hydrochloride injection 0.075 mg intravenously	59/138 (42.8%)	16.8%	0.004
Placebo	35/135 (25.9%)
Complete Response Rate (24 to 72 hours)
Palonosetron Hydrochloride injection 0.075 mg intravenously	67/138 (48.6%)	7.8%	0.188
Placebo	55/135 (40.7%)

Palonosetron Hydrochloride injection as a single dose of 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that Palonosetron Hydrochloride injection 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.

A randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate Palonosetron Hydrochloride injection for PONV following abdominal or vaginal hysterectomy. Five intravenous doses (0.1, 0.3, 1.0, 3.0 and 30 mcg/kg) were evaluated in a total of 381 intent-to-treat patients. The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery. The lowest effective dose was Palonosetron Hydrochloride injection 1 mcg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004 and significantly reduced the severity of nausea versus placebo, p=0.009.