These Highlights Do Not Include All The Information Needed To Use Palonosetron Hydrochloride Injection Safely And Effectively. See Full Prescribing Information For Palonosetron Hydrochloride Injection.

Palonosetron Hydrochloride Injection is indicated in adults for prevention of:

• acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).
• acute nausea and vomiting associated with initial and repeat courses highly emetogenic cancer chemotherapy (HEC).
• postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated.

As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, Palonosetron Hydrochloride Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low.

Palonosetron Hydrochloride Injection is indicated in pediatric patients 1 month to less than 17 years of age for prevention of:

• acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

Do not freeze.

Protect from light.

Discard unused portion.

There is no known antidote to palonosetron. Overdose should be managed with supportive care.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron hydrochloride overdose. A single intravenous dose of palonosetron hydrochloride at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

Palonosetron Hydrochloride Injection contains palonosetron as palonosetron hydrochloride, an antiemetic and antinauseant agent. It is a serotonin-3 (5-HT₃) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C₁₉H₂₄N₂O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula:

Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

Palonosetron Hydrochloride Injection is a sterile, clear, colorless, nonpyrogenic, isotonic, buffered solution for intravenous administration. Palonosetron Hydrochloride Injection is available as a 5 mL single-dose vial.

Each 5 mL vial contains: 0.25 mg palonosetron (equivalent to 0.28 mg palonosetron hydrochloride), 207.5 mg mannitol, USP, edetate disodium dihydrate, USP, and citrate and citric acid buffers in water for intravenous administration.

Hydrochloric acid, NF or sodium hydroxide, NF may have been added to adjust the pH of the solution to 4.5 to 5.5.

Chemotherapy-Induced Nausea and Vomiting

Safety and effectiveness of palonosetron hydrochloride injection have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including HEC. Use is supported by a clinical trial where 165 pediatric patients aged 2 months to less than 17 years were randomized to receive a single dose of palonosetron hydrochloride injection 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [see Clinical Studies (14.2)]. While this study demonstrated that pediatric patients require a higher palonosetron hydrochloride injection dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [see Adverse Reactions (6.1)].

Safety and effectiveness of palonosetron hydrochloride injection in neonates (less than 1 month of age) have not been established.

Postoperative Nausea and Vomiting Studies

Safety and effectiveness have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed.

Pediatric Study 1, a dose finding study was conducted to compare two doses of palonosetron, 1 mcg/kg (maximum 0.075 mg) versus 3 mcg/kg (maximum 0.25 mg). A total of 150 pediatric surgical patients participated, age range 1 month to less than 17 years. No dose response was observed.

Pediatric Study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared intravenous palonosetron hydrochloride (1 mcg/kg, maximum 0.075 mg) versus intravenous ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to less than 17 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults.

Of the 1374 adult cancer patients in clinical studies of intravenously administered palonosetron hydrochloride, 316 (23%) were 65 years and over, while 71 (5%) were at least 75 years and over. Of the 1520 adult patients in clinical studies of intravenously administered palonosetron hydrochloride, 73 (5%) were at least 65 years old [see Clinical Studies (14.1 , 14.3)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity in some older individuals cannot be ruled out. Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients 65 years of age and older compared to younger patients [see Clinical Pharmacology (12.3)]. No dose adjustment is required for geriatric patients.

Palonosetron hydrochloride is contraindicated in patients known to have hypersensitivity to palonosetron [see Warnings and Precautions (5.1)].

Serious or otherwise clinically significant adverse reactions reported in other sections of labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]

Serotonergic Drugs: Monitor for serotonin syndrome; if symptoms occur, discontinue palonosetron hydrochloride and initiate supportive treatment. (7.1)

After intravenous dosing of palonosetron hydrochloride injection 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 hydrochloride injection 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 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

Elimination

After a single intravenous dose of 10 mcg/kg [¹⁴C]-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-HT₃ 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.

Prevention of Chemotherapy-Induced Nausea and Vomiting

The recommended dosage of palonosetron hydrochloride injection for prevention of nausea and vomiting associated with HEC and MEC in adults and associated with emetogenic chemotherapy, including HEC in pediatric patients 1 month to less than 17 years of age is shown in Table 1.

The development of serotonin syndrome has been reported with 5-HT₃ receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT₃ receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g. agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of palonosetron hydrochloride and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue palonosetron hydrochloride and initiate supportive treatment.

Patients should be informed of the increased risk of serotonin syndrome, especially if palonosetron hydrochloride is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1)].

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT₃ receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue palonosetron hydrochloride and initiate supportive treatment [see Warnings and Precautions (5.2)].

Palonosetron Hydrochloride Injection is a serotonin-3 (5-HT₃) receptor antagonist indicated in:

Adults for prevention of:

• acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). (1)
• acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC). (1)
• postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated (1)

Pediatric patients aged 1 month to less than 17 years for prevention of:

• acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (HEC). (1)

Palonosetron is a 5-HT₃ 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-HT₃ 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-HT₃ 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-HT₃ receptor has been demonstrated to selectively participate in the emetic response.

• Hypersensitivity reactions, including anaphylaxis and anaphylactic shock: reported in patients with or without known hypersensitivity to other selective 5-HT₃ receptor antagonists. If symptoms occur, discontinue palonosetron hydrochloride and initiate appropriate medical treatment. (5.1)
• Serotonin syndrome: reported with 5-HT₃ receptor antagonists alone, but particularly with concomitant use of serotonergic drugs. (5.2 , 7.1)

Chemotherapy-Induced Nausea and Vomiting (2.1)

Postoperative Nausea and Vomiting (2.1)

• The recommended adult dosage is 0.075 mg as a single intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

Palonosetron Hydrochloride Injection is sterile, clear, and colorless solution:

• 0.25 mg palonosetron in 5 mL (0.05 mg per mL) in a single-dose vial

The following adverse reactions have been identified during postapproval use of palonosetron hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria, anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1)]
• Injection site reactions: including burning, induration, discomfort and pain

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of palonosetron hydrochloride injection [see Adverse Reactions (6.2)]. These reactions occurred in patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists. If hypersensitivity reactions occur, discontinue palonosetron hydrochloride injection and initiate appropriate medical treatment. Do not reinitiate palonosetron hydrochloride injection in patients who have previously experienced symptoms of hypersensitivity [see Contraindications (4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chemotherapy-Induced Nausea and Vomiting

Adults

In double-blind randomized clinical trials for the prevention of nausea and vomiting induced by MEC or HEC, 1374 adult patients received a single dose of palonosetron hydrochloride injection, ondansetron (Studies 1 and 3) or dolasetron (Study 2) administered 30 minutes prior to chemotherapy [see Clinical Studies (14.1)]. Adverse reactions were similar in frequency and severity in all 3 treatment groups. Common adverse reactions reported in at least 2% of patients in these trials are shown in Table 2.

Palonosetron Hydrochloride Injection is a sterile, clear and colorless solution, and is supplied as follows:

• Palonosetron hydrochloride injection is supplied ready for intravenous administration at a concentration of 0.05 mg per mL (50 mcg per mL).
• Do not mix palonosetron hydrochloride injection with other drugs.
• Flush the infusion line with normal saline before and after administration of palonosetron hydrochloride injection.
• Inspect palonosetron hydrochloride injection visually for particulate matter and discoloration before administration.
• Discard unused portion.

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron hydrochloride 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 hydrochloride 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.

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 38years. 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 hydrochloride injection doses were superior to placebo.

Complete Response Rates for palonosetron hydrochloride injection 0.075 mg and placebo in this trial are described in the Table 9.

NDC 71288-409-05

Rx Only

Palonosetron HCl Injection

0.25 mg per 5 mL

(0.05 mg per mL)

For Intravenous Injection Only

1 x 5 mL Single-Dose Vial

NDC 71288-409-05

Rx Only

Palonosetron HCl Injection

0.25 mg per 5 mL

(0.05 mg per mL)

For Intravenous Injection Only

5 mL Single-Dose Vial

Discard unused portion.

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.

Moderately 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.

Highly 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-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 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].

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.

Palonosetron Hydrochloride Injection is indicated in adults for prevention of:

• acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).
• acute nausea and vomiting associated with initial and repeat courses highly emetogenic cancer chemotherapy (HEC).
• postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated.

As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, Palonosetron Hydrochloride Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low.

Palonosetron Hydrochloride Injection is indicated in pediatric patients 1 month to less than 17 years of age for prevention of:

• acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

Do not freeze.

Protect from light.

Discard unused portion.

There is no known antidote to palonosetron. Overdose should be managed with supportive care.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron hydrochloride overdose. A single intravenous dose of palonosetron hydrochloride at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

Palonosetron Hydrochloride Injection contains palonosetron as palonosetron hydrochloride, an antiemetic and antinauseant agent. It is a serotonin-3 (5-HT₃) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C₁₉H₂₄N₂O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula:

Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

Palonosetron Hydrochloride Injection is a sterile, clear, colorless, nonpyrogenic, isotonic, buffered solution for intravenous administration. Palonosetron Hydrochloride Injection is available as a 5 mL single-dose vial.

Each 5 mL vial contains: 0.25 mg palonosetron (equivalent to 0.28 mg palonosetron hydrochloride), 207.5 mg mannitol, USP, edetate disodium dihydrate, USP, and citrate and citric acid buffers in water for intravenous administration.

Hydrochloric acid, NF or sodium hydroxide, NF may have been added to adjust the pH of the solution to 4.5 to 5.5.

Chemotherapy-Induced Nausea and Vomiting

Safety and effectiveness of palonosetron hydrochloride injection have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including HEC. Use is supported by a clinical trial where 165 pediatric patients aged 2 months to less than 17 years were randomized to receive a single dose of palonosetron hydrochloride injection 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [see Clinical Studies (14.2)]. While this study demonstrated that pediatric patients require a higher palonosetron hydrochloride injection dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [see Adverse Reactions (6.1)].

Safety and effectiveness of palonosetron hydrochloride injection in neonates (less than 1 month of age) have not been established.

Postoperative Nausea and Vomiting Studies

Safety and effectiveness have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed.

Pediatric Study 1, a dose finding study was conducted to compare two doses of palonosetron, 1 mcg/kg (maximum 0.075 mg) versus 3 mcg/kg (maximum 0.25 mg). A total of 150 pediatric surgical patients participated, age range 1 month to less than 17 years. No dose response was observed.

Pediatric Study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared intravenous palonosetron hydrochloride (1 mcg/kg, maximum 0.075 mg) versus intravenous ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to less than 17 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults.

Of the 1374 adult cancer patients in clinical studies of intravenously administered palonosetron hydrochloride, 316 (23%) were 65 years and over, while 71 (5%) were at least 75 years and over. Of the 1520 adult patients in clinical studies of intravenously administered palonosetron hydrochloride, 73 (5%) were at least 65 years old [see Clinical Studies (14.1 , 14.3)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity in some older individuals cannot be ruled out. Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients 65 years of age and older compared to younger patients [see Clinical Pharmacology (12.3)]. No dose adjustment is required for geriatric patients.

Palonosetron hydrochloride is contraindicated in patients known to have hypersensitivity to palonosetron [see Warnings and Precautions (5.1)].

Serious or otherwise clinically significant adverse reactions reported in other sections of labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]

Serotonergic Drugs: Monitor for serotonin syndrome; if symptoms occur, discontinue palonosetron hydrochloride and initiate supportive treatment. (7.1)

After intravenous dosing of palonosetron hydrochloride injection 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 hydrochloride injection 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 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

Elimination

After a single intravenous dose of 10 mcg/kg [¹⁴C]-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-HT₃ 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.

Prevention of Chemotherapy-Induced Nausea and Vomiting

The recommended dosage of palonosetron hydrochloride injection for prevention of nausea and vomiting associated with HEC and MEC in adults and associated with emetogenic chemotherapy, including HEC in pediatric patients 1 month to less than 17 years of age is shown in Table 1.

The development of serotonin syndrome has been reported with 5-HT₃ receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT₃ receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g. agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of palonosetron hydrochloride and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue palonosetron hydrochloride and initiate supportive treatment.

Patients should be informed of the increased risk of serotonin syndrome, especially if palonosetron hydrochloride is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1)].

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT₃ receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue palonosetron hydrochloride and initiate supportive treatment [see Warnings and Precautions (5.2)].

Palonosetron Hydrochloride Injection is a serotonin-3 (5-HT₃) receptor antagonist indicated in:

Adults for prevention of:

• acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). (1)
• acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC). (1)
• postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated (1)

Pediatric patients aged 1 month to less than 17 years for prevention of:

• acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (HEC). (1)

Palonosetron is a 5-HT₃ 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-HT₃ 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-HT₃ 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-HT₃ receptor has been demonstrated to selectively participate in the emetic response.

• Hypersensitivity reactions, including anaphylaxis and anaphylactic shock: reported in patients with or without known hypersensitivity to other selective 5-HT₃ receptor antagonists. If symptoms occur, discontinue palonosetron hydrochloride and initiate appropriate medical treatment. (5.1)
• Serotonin syndrome: reported with 5-HT₃ receptor antagonists alone, but particularly with concomitant use of serotonergic drugs. (5.2 , 7.1)

Chemotherapy-Induced Nausea and Vomiting (2.1)

Postoperative Nausea and Vomiting (2.1)

• The recommended adult dosage is 0.075 mg as a single intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

Palonosetron Hydrochloride Injection is sterile, clear, and colorless solution:

• 0.25 mg palonosetron in 5 mL (0.05 mg per mL) in a single-dose vial

The following adverse reactions have been identified during postapproval use of palonosetron hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria, anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1)]
• Injection site reactions: including burning, induration, discomfort and pain

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of palonosetron hydrochloride injection [see Adverse Reactions (6.2)]. These reactions occurred in patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists. If hypersensitivity reactions occur, discontinue palonosetron hydrochloride injection and initiate appropriate medical treatment. Do not reinitiate palonosetron hydrochloride injection in patients who have previously experienced symptoms of hypersensitivity [see Contraindications (4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chemotherapy-Induced Nausea and Vomiting

Adults

In double-blind randomized clinical trials for the prevention of nausea and vomiting induced by MEC or HEC, 1374 adult patients received a single dose of palonosetron hydrochloride injection, ondansetron (Studies 1 and 3) or dolasetron (Study 2) administered 30 minutes prior to chemotherapy [see Clinical Studies (14.1)]. Adverse reactions were similar in frequency and severity in all 3 treatment groups. Common adverse reactions reported in at least 2% of patients in these trials are shown in Table 2.

Palonosetron Hydrochloride Injection is a sterile, clear and colorless solution, and is supplied as follows:

• Palonosetron hydrochloride injection is supplied ready for intravenous administration at a concentration of 0.05 mg per mL (50 mcg per mL).
• Do not mix palonosetron hydrochloride injection with other drugs.
• Flush the infusion line with normal saline before and after administration of palonosetron hydrochloride injection.
• Inspect palonosetron hydrochloride injection visually for particulate matter and discoloration before administration.
• Discard unused portion.

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron hydrochloride 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 hydrochloride 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.

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 38years. 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 hydrochloride injection doses were superior to placebo.

Complete Response Rates for palonosetron hydrochloride injection 0.075 mg and placebo in this trial are described in the Table 9.

NDC 71288-409-05

Rx Only

Palonosetron HCl Injection

0.25 mg per 5 mL

(0.05 mg per mL)

For Intravenous Injection Only

1 x 5 mL Single-Dose Vial

NDC 71288-409-05

Rx Only

Palonosetron HCl Injection

0.25 mg per 5 mL

(0.05 mg per mL)

For Intravenous Injection Only

5 mL Single-Dose Vial

Discard unused portion.

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.

Moderately 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.

Highly 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-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 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].

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.