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.

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.

This Patient Information has been approved by the U.S. Food and Drug Administration.

SAGENT^®

Mfd. for SAGENT Pharmaceuticals

Schaumburg, IL 60195 (USA)

Made in India

©2020 Sagent Pharmaceuticals, Inc.

Revised: April 2020

SAGENT Pharmaceuticals ^®

Storage Conditions

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

Do not freeze.

Protect from light. Retain in carton until time of use.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

PRINCIPAL DISPLAY PANEL – PACKAGE LABEL – Vial Label

NDC 25021-783-05

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

There is no known antidote to palonosetron hydrochloride injection. 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 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, disodium edetate dihydrate, trisodium citrate dihydrate and citrate buffer in water for intravenous administration. Hydrochloric acid or sodium hydroxide may have been added to adjust pH.

The pH of the solution is 4.5 to 5.5.

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 injection 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 and initiate supportive treatment. (7.1)

After intravenous dosing of palonosetron hydrochloride in healthy subjects and cancer patients, an initial decline in 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 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 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 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 in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

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 and initiate supportive treatment [see Warnings and Precautions (5.2)].

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 of 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.

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 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 injection. 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 [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 and initiate appropriate medical treatment. Do not reinitiate palonosetron hydrochloride 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.

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).

Palonosetron Hydrochloride Injection is supplied as follows:

Palonosetron Hydrochloride Injection is a clear and colorless solution.

• 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 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 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 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 0.075 mg and placebo in this trial are described in Table 9.

Palonosetron as a single dose of 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that palonosetron 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 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 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.

Efficacy of a single intravenous dose of palonosetron 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 in repeated courses of chemotherapy was also assessed.

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

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.

This Patient Information has been approved by the U.S. Food and Drug Administration.

SAGENT^®

Mfd. for SAGENT Pharmaceuticals

Schaumburg, IL 60195 (USA)

Made in India

©2020 Sagent Pharmaceuticals, Inc.

Revised: April 2020

SAGENT Pharmaceuticals ^®

Storage Conditions

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

Do not freeze.

Protect from light. Retain in carton until time of use.

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

PRINCIPAL DISPLAY PANEL – PACKAGE LABEL – Vial Label

NDC 25021-783-05

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

There is no known antidote to palonosetron hydrochloride injection. 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 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, disodium edetate dihydrate, trisodium citrate dihydrate and citrate buffer in water for intravenous administration. Hydrochloric acid or sodium hydroxide may have been added to adjust pH.

The pH of the solution is 4.5 to 5.5.

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 injection 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 and initiate supportive treatment. (7.1)

After intravenous dosing of palonosetron hydrochloride in healthy subjects and cancer patients, an initial decline in 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 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 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 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 in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

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 and initiate supportive treatment [see Warnings and Precautions (5.2)].

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 of 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.

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 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 injection. 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 [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 and initiate appropriate medical treatment. Do not reinitiate palonosetron hydrochloride 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.

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).

Palonosetron Hydrochloride Injection is supplied as follows:

Palonosetron Hydrochloride Injection is a clear and colorless solution.

• 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 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 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 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 0.075 mg and placebo in this trial are described in Table 9.

Palonosetron as a single dose of 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that palonosetron 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 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 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.

Efficacy of a single intravenous dose of palonosetron 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 in repeated courses of chemotherapy was also assessed.

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