palonosetron hydrochloride

RECENT MAJOR CHANGES Indication ( 1.2 ) 05/2014 Dosage and Administration, Pediatric Cancer Patients ( 2.1 ) 05/2014 Warnings and Precautions, Serotonin Syndrome ( 5.2 ) 09/2014

1 INDICATIONS AND USAGE Palonosetron Hydrochloride Injection is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in adults for: Moderately emetogenic cancer chemotherapy - prevention of acute and delayed nausea and vomiting associated with initial and repeat courses ( 1 .1) Highly emetogenic cancer chemotherapy - prevention of acute nausea and vomiting associated with initial and repeat courses ( 1.1 ) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated ( 1.3 ) Palonosetron Hydrochloride Injection is indicated in 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 ( 1.2 ) 1.1 Chemotherapy-Induced Nausea and Vomiting in Adults Palonosetron Hydrochloride Injection is indicated for: Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 Month to Less than 17 Years Palonosetron Hydrochloride Injection is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. 1.3 Postoperative Nausea and Vomiting in Adults Palonosetron Hydrochloride Injection is indicated for prevention of 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.

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 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 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 *Note different dosing units in pediatrics Postoperative Nausea and Vomiting The recommended dosage of palonosetron hydrochloride 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 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. • Discard unused portion.

3 DOSAGE FORM AND STRENGTHS Palonosetron Hydrochloride Injection is supplied as a single-use sterile, clear, colorless solution in glass vials that provide: 0.25 mg (free base) per 5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.25 mg/5mL (free base) single-use vial ( 3 )

4 CONTRAINDICATIONS Palonosetron Hydrochloride Injection is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [ see Adverse Reactions ( 6.2 ) ]. Palonosetron Hydrochloride Injection is contraindicated in patients known to have hypersensitivity to the drug or any of its components ( 4 )

6 ADVERSE REACTIONS 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. The most common adverse reactions in chemotherapy-induced nausea and vomiting in adults (incidence ≥5%) are headache and constipation ( 6.1 ). The most common adverse reactions in postoperative nausea and vomiting (incidence ≥ 2%) are QT prolongation, bradycardia, headache, and constipation ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Cipla USA, Inc., at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Chemotherapy-Induced Nausea and Vomiting Adults In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with Palonosetron Hydrochloride Injection and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group Event Palonosetron Hydrochloride Injection 0.25 mg (N=633) Ondansetron 32 mg I.V. (N=410) Dolasetron 100 mg I.V. (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of Palonosetron Hydrochloride Injection to adult patients receiving concomitant cancer chemotherapy: Cardiovascular : 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to Palonosetron Hydrochloride Injection was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence. General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Pediatrics In a pediatric clinical trial for the prevention of chemotherapy-induced nausea and vomiting 163 cancer patients received a single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron 30 minutes before beginning the first cycle of emetogenic chemotherapy. Patients had a mean age of 8.4 years (range 2 months to 16.9 years) and were 46% male; and 93% white. The following adverse reactions were reported for palonosetron: Nervous System: <1%: headache, dizziness, dyskinesia. General: <1%: infusion site pain. Dermatological: <1%: allergic dermatitis, skin d …

7 DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. 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) [ see Warnings and Precautions ( 5.2 ) ]. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, C max : 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, Palonosetron Hydrochloride Injection has been safely administered with corticosteroids, analgesics, antiemetics /antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. The potential for clinically significant drug interactions with palonosetron appears to be low ( 7 )

8 USE IN SPECIFIC POPULATIONS Chemotherapy-Induced Nausea and Vomiting Pediatric use: Safety and effectiveness in neonates (less than 1 month of age) have not been established ( 8.4) Postoperative Nausea and Vomiting Safety and Effectiveness in patients below the age of 18 years have not been established ( 8.4 ) 8.1 Pregnancy Pregnancy Category B Risk Summary Adequate and well controlled studies with Palonosetron Hydrochloride Injection have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively. Because animal reproduction studies are not always predictive of human response, Palonosetron Hydrochloride Injection should be used during pregnancy only if clearly needed. Animal Data In animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis. 8.3 Nursing Mothers It is not known whether Palonosetron Hydrochloride Injection is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study [ see Nonclinical Toxicology ( 13.1 )] , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use 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 highly emetogenic cancer chemotherapy. Use is supported by a clinical trial where 165 pediatric patients aged 2 months to <17 years were randomized to receive a single dose of palonosetron 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 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 efficacy 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 (max 0.075 mg) versus 3 mcg/kg (max 0.25 mg). A total of 150 pediatric surgical patients participated, age range 1 month to <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 I.V. palonosetron (1 mcg/kg, max 0.075 mg) versus I.V. ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to <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 - …

12.1 Mechanism of Action Palonosetron is a 5-HT 3 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-HT 3 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-HT 3 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-HT 3 receptor has been demonstrated to selectively participate in the emetic response.

11 DESCRIPTION Palonosetron hydrochloride injection contains palonosetron as palonosetron hydrochloride, 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: (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 C 19 H 24 N 2 O.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, non-pyrogenic, isotonic, buffered solution for intravenous administration. Palonosetron hydrochloride injection is available as 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, and disodium edetate and citrate buffer in water for intravenous administration. The pH of the solution in the 5 mL vial is 4.5 to 5.5. Structure.jpg

10 OVERDOSAGE There is no known antidote to Palonosetron Hydrochloride Injection. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Palonosetron hydrochloride injection is supplied as a sterile, clear and colorless solution: • NDC 36000-326-02: 0.25 mg palonosetron in 5 mL in a single-dose vial (0.05 mg/mL); individually packaged in a carton. Storage • Store at 20o to 25oC (68o to 77oF); excursions permitted between 15o to 30 °C (59o to 86°F) [see USP Controlled Room Temperature]. • Protect from freezing. • Protect from light.