PALONOSETRON

Palonosetron Hydrochloride Injection contains palonosetron as palonosetron HCl, an antiemetic and antinauseant agent. It is a serotonin-3 (5-HT 3 ) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3a S )-2-[( S )- 1-Azabicyclo [2.2.2]oct-3- yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1 H benz[ de ] isoquinoline hydrochloride. Palonosetron hydrochloride exists as a single isomer and has the following structural formula: C 19 H 24 N 2 O•HCl M.W. 332.87 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, non-pyrogenic, isotonic, buffered solution for intravenous administration. Palonosetron Hydrochloride Injection is available as a 5 mL single-dose prefilled syringe. Each 5 mL syringe contains: 0.25 mg palonosetron (equivalent to 0.28 mg palonosetron HCl), 202.4 mg mannitol, 2.5 mg edetate disodium dihydrate, 18 mg trisodium citrate dihydrate, and 7 mg citric acid anhydrous in water for intravenous administration. The pH of the solution in the 5 mL syringe is 4.5 to 5.5. Structural Formula

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). 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 Hydrochloride Injection 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 ) 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 )

Chemotherapy-Induced Nausea and Vomiting ( 2.1 ) *Note different dosing units in pediatrics 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 Instructions for Intravenous Administration For a dose of 0.25 mg, use the entire contents (5 mL) of the prefilled syringe. Do not use the prefilled syringe to administer a dose of less than 0.25 mg (5 mL). ( 2.2 ) 2.1 Recommended Dosage 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 . Table 1: Recommended Dosage of Palonosetron Hydrochloride Injection for the Prevention of Nausea and Vomiting Associated with Chemotherapy in Adults and Pediatric Patients 1 Month to Less than 17 Years *Note different dosing units in pediatrics 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 (max 1.5 mg) as a single dose Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy 2.2 Instructions for Intravenous Administration Palonosetron Hydrochloride Injection is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/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. Expel air from syringe prior to administration. For a dose of 0.25 mg, use the entire contents (5mL) of the prefilled syringe. Do not use the prefilled syringe to administer a dose less than 0.25mg (5mL) Use aseptic technique while handling the syringe

Palonosetron Hydrochloride 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 )

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 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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, 1,374 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 . Table 2: Common Adverse Reactions* in Adults with Receiving MEC (Studies 1 and 2) or HEC (Study 3) * Reported in at least 2% of patients in any treatment group Adverse Reaction Palonosetron Hydrochloride 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 Hydrochloride 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 Hydrochloride 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 Hydrochloride 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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

Serotonergic Drugs : Monitor for serotonin syndrome; if symptoms occur, discontinue Palonosetron Hydrochloride Injection 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 Hydrochloride Injection and initiate supportive treatment [see Warnings and Precautions ( 5.2 )] .

Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing. Protect from light. Discard unused portion