FDA label dc37079e-88c6-4ce1-88d6-1ed37bd00ae9

5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT 3 receptor antagonists.

5 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other selective 5-HT 3 receptor antagonists. ( 5.1 ) • Serotonin syndrome has been reported with 5-HT 3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. ( 5.2 , 7.1 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT 3 receptor antagonists. 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 )] .

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.

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.

<table cellspacing="0" cellpadding="0" border="0" width="588.924"> <colgroup> <col width="20.5284552845528%"/> <col width="30.6458897922313%"/> <col width="24.412827461608%"/> <col width="24.412827461608%"/> </colgroup> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" align="center" valign="top"> <content styleCode="bold">Adverse Reaction</content> </td> <td styleCode="Rrule" align="center" valign="top"> <content styleCode="bold">Palonosetron HCl</content> <content styleCode="bold">0.25 mg</content> <content styleCode="bold">Intravenous</content> <content styleCode="bold">(N=633)</content> </td> <td styleCode="Rrule" align="center" valign="top"> <content styleCode="bold">Ondansetron</content> <content styleCode="bold">32 mg</content> <content styleCode="bold">Intravenous</content> <content styleCode="bold">(N=410)</content> </td> <td styleCode="Rrule" align="center" valign="top"> <content styleCode="bold">Dolasetron</content> <content styleCode="bold">100 mg</content> <content styleCode="bold">Intravenous</content> <content styleCode="bold">(N=194)</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top">Headache </td> <td styleCode="Rrule" align="center" valign="top">60 (9%) </td> <td styleCode="Rrule" align="center" valign="top">34 (8%) </td> <td styleCode="Rrule" align="center" valign="top">32 (16%) </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top">Constipation </td> <td styleCode="Rrule" align="center" valign="top">29 (5%) </td> <td styleCode="Rrule" align="center" valign="top">8 (2%) </td> <td styleCode="Rrule" align="center" valign="top">12 (6%) </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top">Diarrhea </td> <td styleCode="Rrule" align="center" valign="top">8 (1%) </td> <td styleCode="Rrule" align="center" valign="top">7 (2%) </td> <td styleCode="Rrule" align="center" valign="top">4 (2%) </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top">Dizziness </td> <td styleCode="Rrule" align="center" valign="top">8 (1%) </td> <td styleCode="Rrule" align="center" valign="top">9 (2%) </td> <td styleCode="Rrule" align="center" valign="top">4 (2%) </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top">Fatigue </td> <td styleCode="Rrule" align="center" valign="top">3 (&lt; 1%) </td> <td styleCode="Rrule" align="center" valign="top">4 (1%) </td> <td styleCode="Rrule" align="center" valign="top">4 (2%) </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="top">Abdominal Pain </td> <td styleCode="Rrule" align="center" valign="top">1 (&lt; 1%) </td> <td styleCode="Rrule" align="center" valign="top">2 (&lt; 1%) </td> <td styleCode="Rrule" align="center" valign="top">3 (2%) </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top">Insomnia </td> <td styleCode="Rrule" align="center" valign="top">1 (&lt; 1%) </td> <td styleCode="Rrule" align="center" valign="top">3 (1%) </td> <td styleCode="Rrule" align="center" valign="top">3 (2%) </td> </tr> </tbody> </table>