palonosetron HCl injection Clinical Studies

14.1 Prevention of Nausea and Vomiting Associated with MEC and HEC in Adults

Efficacy of a single intravenous dose of Palonosetron HCl 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 HCl Injection in repeated courses of chemotherapy was also assessed.

Efficacy Results

Studies 1, 2 and 3 show that Palonosetron HCl 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-HT3 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 HCl 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

* Intent-to-treat cohort † 2-sided Fisher's exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron HCl injection and comparator.
Chemotherapy	Study	Treatment Group	N*	% with Complete Response	p-value†	97.5% Confidence Interval Palonosetron HCl Injection minus Comparator‡
Moderately Emetogenic	1	Palonosetron HCl Injection 0.25 mg intravenously	189	81	0.009
		Ondansetron 32 mg intravenously	185	69
	2	Palonosetron HCl Injection 0.25 mg intravenously	189	63	NS
		Dolasetron 100 mg intravenously	191	53
Highly Emetogenic	3	Palonosetron HCl Injection 0.25 mg intravenously	223	59	NS
		Ondansetron 32 mg intravenously	221	57

Table 6: Prevention of Delayed Nausea and Vomiting (24 to 120 Hours) Associated with MEC in Adults in Studies 1 and 2: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher's exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron HCl injection and comparator. § Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
Chemotherapy	Study	Treatment Group	N*	% with Complete Response	p-value†	97.5% Confidence Interval Palonosetron HCl Injection minus Comparator‡
Moderately Emetogenic	1	Palonosetron HCl Injection 0.25 mg intravenously	189	74	<0.001
		Ondansetron 32 mg intravenously §	185	55
	2	Palonosetron HCl Injection 0.25 mg intravenously	189	54	0.004
		Dolasetron 100 mg intravenously	191	39

Table 7: Prevention of Overall Nausea and Vomiting (0 to 120 Hours) Associated with MEC in Adults in Studies 1 and 2: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher's exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between Palonosetron HCl Injection and comparator. § Ondansetron 32 mg intravenously was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
Chemotherapy	Study	Treatment Group	N*	% with Complete Response	p-value†	97.5% Confidence Interval Palonosetron HCl Injection minus Comparator‡
Moderately Emetogenic	1	Palonosetron HCl Injection 0.25 mg intravenously	189	69	<0.001
		Ondansetron 32 mg intravenously §	185	50
	2	Palonosetron HCl Injection 0.25 mg intravenously	189	46	0.021
		Dolasetron 100 mg intravenously	191	34

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 HCl Injection 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron 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 (<1,500 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 HCl 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 HCl Injection minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.

14.3 Prevention of Postoperative Nausea and Vomiting in Adults

In a multicenter, randomized, stratified, double-blind, parallel-group, clinical trial, Palonosetron HCl 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 HCl 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 palonosetron was evaluated during the 0 to 72-hour time period after surgery.

Of the 138 patients treated with palonosetron 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:

• Complete Response (CR) 0 to 48 hours and 0 to 72 hours
• Complete Control (CC) defined as CR and no more than mild nausea
• 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 injection 0.075 mg and placebo in this trial are described in Table 9.

Palonosetron HCl 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 HCl 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 HCl 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 HCl 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.