Palonosetron Hydrochloride

1 INDICATIONS AND USAGE Palonosetron 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 is recommended even where the incidence of postoperative nausea and/or vomiting is low. Palonosetron HCl 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 serotonin-3 (5-HT 3 ) 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 )

2 DOSAGE AND ADMINISTRATION Chemotherapy - Induced Nausea and Vomiting ( 2.1 ) Age Dose* Infusion Time Adults 0.25 mg as a single-dose Infuse over 30 seconds beginning approximately 30 minutes before the start of chemotherapy Pediatrics (1 month to less than 17 years) 20 micrograms per kilogram (maximum 1.5 mg) as a single-dose Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy *Note different dosing units in pediatrics 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. 2.1 Recommended Dosage Prevention of Chemotherapy-Induced Nausea and Vomiting The recommended dosage of palonosetron HCl 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 . Table 1: Recommended Dosage of Palonosetron HCl Injection for the Prevention of Nausea and Vomiting Associated with Chemotherapy in Adults and Pediatric Patients 1 Month to Less than 17 Years Age Dose Note different dosing units in pediatrics Infusion Time Adults 0.25 mg as a single-dose Infuse over 30 seconds beginning approximately 30 minutes before the start of chemotherapy Pediatrics (1 month to less than 17 years) 20 micrograms per kilogram (max 1.5 mg) as a single-dose Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy Postoperative Nausea and Vomiting The recommended dosage of palonosetron HCl injection in adults for PONV is 0.075 mg administered as a single intravenous dose over 10 seconds immediately before the induction of anesthesia. 2.2 Instructions for Intravenous Administration • Palonosetron HCl injection is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/mL). • Do not mix palonosetron HCl injection with other drugs. • Flush the infusion line with normal saline before and after administration of palonosetron HCl injection. • Inspect palonosetron HCl injection visually for particulate matter and discoloration before administration. • Discard unused portion.

4 CONTRAINDICATIONS Palonosetron HCl injection is contraindicated in patients known to have hypersensitivity to palonosetron [see Warnings and Precautions ( 5.1 )]. Hypersensitivity to palonosetron or any of its components. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions, including anaphylaxis and anaphylactic shock: reported in patients with or without known hypersensitivity to other selective 5-HT 3 receptor antagonists. If symptoms occur, discontinue palonosetron and initiate appropriate medical treatment. ( 5.1 ) • Serotonin syndrome : reported with 5-HT 3 receptor antagonists alone, but particularly with concomitant use of serotonergic drugs. ( 5.2 , 7.1 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of palonosetron HCl injection [see Adverse Reactions ( 6.2 )] . These reactions occurred in patients with or without known hypersensitivity to other 5-HT 3 receptor antagonists. If hypersensitivity reactions occur, discontinue palonosetron HCl injection and initiate appropriate medical treatment. Do not reinitiate palonosetron HCl injection in patients who have previously experienced symptoms of hypersensitivity [see Contraindications ( 4 )]. 5.2 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 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-HT 3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT 3 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 HCl injection and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue palonosetron HCl injection and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if palonosetron HCl injection is used concomitantly with other serotonergic drugs [see Drug Interactions ( 7.1 )].

7 DRUG INTERACTIONS Serotonergic Drugs : Monitor for serotonin syndrome; if symptoms occur, discontinue palonosetron and initiate supportive treatment. ( 7.1 ) 7.1 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 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 )].

6 ADVERSE REACTIONS 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 )] Most common adverse reactions in • chemotherapy-induced nausea and vomiting in adults (≥5%) are: headache and constipation. ( 6.1 ) • postoperative nausea and vomiting (≥2%) are: QT prolongation, bradycardia, headache, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 HCl 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. Table 2: Common Adverse Reactions Reported in at least 2% of patients in any treatment group in Adults with Receiving MEC (Studies 1 and 2) or HEC (Study 3) Adverse Reaction Palonosetron HCl injection 0.25 mg intravenously (N=633) Ondansetron 32 mg intravenously (N=410) Dolasetron 100 mg intravenously (N=194) Headache 9% 8% 16% Constipation 5% 2% 6% Diarrhea 1% 2% 2% Dizziness 1% 2% 2% Fatigue <1% 1% 2% Abdominal Pain <1% <1% 2% Insomnia <1% 1% 2% Less common adverse reactions, reported in 1% or less of patients, in Studies 1, 2 and 3 were: • Cardiovascular: non-sustained tachycardia, bradycardia, hypotension, hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. • Dermatological: allergic dermatitis, rash • Hearing and Vision: motion sickness, tinnitus, eye irritation and amblyopia • Gastrointestinal System: diarrhea, dyspepsia, abdominal pain, dry mouth, hiccups and flatulence • General: weakness, fatigue, fever, hot flash, flu-like syndrome • Liver: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy • Metabolic: hyperkalemia, electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia • Musculoskeletal: arthralgia • Nervous System: dizziness, somnolence, insomnia, hypersomnia, paresthesia • Psychiatric: anxiety, euphoric mood • Urinary System: urinary retention • Vascular: vein discoloration, vein distention In other studies, 2 subjects experienced severe constipation following a single palonosetron HCl injection dose of approximately 0.75 mg (three times the recommended dose). Pediatrics Aged 2 Months to 17 Years In a pediatric clinical trial, 163 pediatric cancer patients with a mean age of 8 years received a single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron HCl injection 30 minutes before beginning the first cycle of emetogenic chemotherapy [see Clinical Studies ( 14.2 )] . Adverse reactions were evaluated in pediatric patients receiving palonosetron HCl injection for up to 4 chemotherapy cycles. The following adverse reactions were reported in less than 1% of patients: • Nervous System: headache, dizziness, dyskinesia. • General: infusion site pain. • Dermatological: allergic dermatitis, skin disorder. Postoperative Nausea and Vomiting The most common adverse reactions reported in at least 2% of adults receiving palonosetron HCl injection 0.075 mg intravenously immediately before induction of anesthesia in 3 randomized placebo-controlled trials [see Clinical Studies ( 14.3 )] are shown in Table 3 . Rates of adverse reactions between palonosetron HCl injection and placebo groups were similar. Some events are known to be associated with, or may be exacerbated by, concomitant perioperative and intraoperative medications administered in this surgical population. A thorough QT/QTc study demonstrated palonosetron HCl injection does not prolong the QT interval to any clinically relevant extent [see Clinical Pharmacology ( 12.2 )]. Table 3: Common Adverse Reactions* in Trials of Adults with Postoperative Nausea and Vomiting Adverse Reaction Palonosetron HCl injection 0.075 mg intravenously (N=336) Placebo (N=369) Electrocardiogram QT prolongation 5% 3% Bradycardia 4% 4% Headache 3% 4% Constipation 2% 3% Less common adverse reactions, reported in 1% of less of patients, in these PONV clinical trials were: • Cardiovascular: QTc prolongation, sinus bradycardia, tachycardia, blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema, ECG T wave amplitude decreased, platelet count decreased. The frequency of these adverse effects did not appear to be different from placebo. • Dermatological: pruritus • Gastrointestinal System: flatulence, dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia • General: chills • Liver: increases in AST and/or ALT, hepatic enzyme increased • Metabolic: hypokalemia, anorexia • Nervous System: dizziness • Respiratory: hypoventilation, laryngospasm • Urinary System: urinary retention 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of palonosetron HCl. 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

8.1 Pregnancy Risk Summary There are no available data on palonosetron HCl use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron HCl during the period of organogenesis at doses up to 1,894 and 3,789 times the recommended human intravenous dose in rats and rabbits, respectively (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In animal reproduction studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron HCl at doses up to 60 mg/kg/day (1,894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3,789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.