Data from FDA - Curated by Marshall Pearce - Last updated 06 December 2017

Indication(s)

1 INDICATIONS AND USAGE Palonosetron Hydrochloride (HCl) Injection is a serotonin-3 (5-HT3) 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. (1.2) 1.1 Chemotherapy-Induced Nausea and Vomiting in Adults Palonosetron Hydrochloride (HCl) 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 Postoperative Nausea and Vomiting in Adults Palonosetron HCl 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 HCl Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low.

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Advisory information

contraindications
4 CONTRAINDICATIONS Palonosetron HCl Injection is contraindicated in patients known to have hypersensitivity to the drug or any of its components [see Adverse Reactions (6.2)]. Hypersensitivity to the drug or any of its components. (4)
Adverse reactions
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 safety of Palonosetron HCl Injection has been established from adequate and well-controlled studies of another intravenous formulation of palonosetron HCl [see Clinical Studies (14)]. Below is a display of the adverse reactions of palonosetron HCl in these adequate and well-controlled studies. The most common adverse reactions in chemotherapy-induced nausea and vomiting ( ≥5%) are headache and constipation. (6.1) The most common adverse reactions in postoperative nausea and vomiting (≥ 2%) are QT prolongation, bradycardia, 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 Chemotherapy-Induced Nausea and Vomiting In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1,374 adult patients received a single 0.25 mg dose of palonosetron HCl. Adverse reactions were similar in frequency and severity with intravenous palonosetron HCl and ondansetron or dolasetron. The 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 Adverse Reaction Palonosetron HCl 0.25 mg Intravenous (N=633) Ondansetron 32 mg Intravenous (N=410) Dolasetron 100 mg Intravenous (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 HCl dose of approximately 0.75 mg, three times the recommended dose. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of palonosetron HCl to adult patients receiving concomitant cancer chemotherapy: Cardiovascula r: 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 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. Postoperative Nausea and Vomiting The adverse reactions cited in Table 2 were reported in ≥ 2% of adults receiving intravenous palonosetron HCl 0.075 mg immediately before induction of anesthesia in 3 randomized placebo-controlled trials. Rates of events between palonosetron HCl and placebo groups were similar. Some adverse reactions are known to be associated with, or may be exacerbated by concomitant perioperative and intraoperative medications administered in this surgical population. See Clinical Pharmacology (12.2), for thorough QT/QTc study results and for data demonstrating the lack of palonosetron effect on QT/QTc. Table 2: Adverse Reactions from Postoperative Nausea and Vomiting Studies ≥ 2% in any Treatment Group Adverse Reaction Palonosetron HCl 0.075 mg Intravenous (N=336) Placebo (N=369) Electrocardiogram QT prolongation 16 (5%) 11 (3%) Bradycardia 13 (4%) 16 (4%) Headache 11 (3%) 14 (4%) Constipation 8 (2%) 11(3%) In these clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of palonosetron HCl to adult patients receiving concomitant perioperative and intraoperative medications including those associated with anesthesia: Cardiovascular: 1%: electrocardiogram QTc prolongation, sinus bradycardia, tachycardia, < 1%: 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: 1%: pruritus. Gastrointestinal System: 1%: flatulence, < 1%: dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia. General: < 1%: chills. Liver: 1%: increases in AST and/or ALT, < 1%: hepatic enzyme increased. Metabolic: < 1%: hypokalemia, anorexia. Nervous System: < 1%: dizziness. Respiratory: < 1%: hypoventilation, laryngospasm. Urinary System: 1%: urinary retention. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of another intravenous formulation 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. Very rare cases (<1/10,000) of hypersensitivity reactions including anaphylaxis and anaphylactic shock and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of palonosetron HCl 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Chemotherapy-Induced Nausea and Vomiting • The recommended adult dosage is 0.25 mg as a single intravenous dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. (2.1) Postoperative Nausea and Vomiting • 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) Instructions for Administration • For a dose of 0.25 mg, use the entire contents (5 mL) of the pre-filled syringe. Do not use the pre-filled syringe to administer a dose less than 0.25 mg. Use the single-dose vial to administer a dose of 0.075 mg. (2.2) 2.1 Recommended Dosage Chemotherapy-Induced Nausea and Vomiting The recommended adult dosage of Palonosetron HCl Injection is 0.25 mg administered as a single intravenous dose over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Postoperative Nausea and Vomiting The recommended adult dosage of Palonosetron HCl Injection 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 • Do not mix 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. • For a dose of 0.25 mg, use the entire contents (5 mL) of the pre-filled syringe. Do not use the pre-filled syringe to administer a dose less than 0.25 mg. Use the single-dose vial to administer a dose of 0.075 mg.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 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 to rats and rabbits 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. 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. 8.2 Lactation Risk Summary There are no data on the presence of palonosetron in human milk, the effects of palonosetron on the breastfed infant, or the effects of palonosetron on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Palonosetron HCl Injection and any potential adverse effects on the breastfed infant from palonosetron or from the underlying maternal condition. 8.4 Pediatric Use This product has not been approved for use in pediatric patients for prevention of chemotherapy-induced nausea and vomiting. The safety and effectiveness of Palonosetron HCl Injection for prevention of postoperative nausea and vomiting in pediatric patients have not been established. 8.5 Geriatric Use Of the 1,374 adult cancer patients in clinical studies of intravenously administered palonosetron HCl for CINV, 316 (23%) were aged 65 years and over, while 71 (5%) were aged 75 years and over. Of the 1,520 adult patients in clinical studies of intravenously administered palonosetron HCl for PONV, 73 (5%) were aged 65 years and over [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and the 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 or special monitoring are required for geriatric patients. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, palonosetron HCl efficacy in geriatric patients has not been adequately evaluated.

Interactions

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

More information

Category Value
Authorisation number NDA208109
Agency product number 23310D4I19
Orphan designation No
Product NDC 63323-942
Date Last Revised 01-06-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Fresenius Kabi USA, LLC