Palonosetron

POSFREA 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, POSFREA is recommended even where the incidence of postoperative nausea and/or vomiting is low. POSFREA 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. POSFREA 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 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 (HEC). ( 1 )

POSFREA injection is sterile, clear, and colorless solution in a single-dose vial: 0.25 mg palonosetron in 5 mL (0.05 mg/mL) 0.075 mg palonosetron in 1.5 mL (0.05 mg/mL) Injection: 0.25 mg palonosetron in 5 mL (0.05 mg/mL) in a single-dose vial ( 3 ) 0.075 mg palonosetron in 1.5 mL (0.05 mg/mL) in a single-dose vial ( 3 )

POSFREA 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 )

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 POSFREA 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 [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 POSFREA and initiate appropriate medical treatment. Do not reinitiate POSFREA 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 POSFREA and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue POSFREA and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if POSFREA is used concomitantly with other serotonergic drugs [see Drug Interactions (7.1) ] .

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 Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatc h.

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. The safety of POSFREA has been established from adequate and well-controlled studies of another intravenous formulation of palonosetron [see Clinical Studies (14) ] . Below is a display of the adverse reactions of palonosetron in these adequate and well-controlled studies. Chemotherapy-Induced Nausea and Vomiting (CINV) 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, ondansetron (Studies 1 and 3) or dolasetron (Study 2) administered intravenously 30 minutes prior to chemotherapy [see Clinical Studies (14.1) ] . Adverse reactions were similar in frequency and severity in all three 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 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 any treatment group, in Studies 1, 2 and 3 were: Cardiac disorders : non-sustained tachycardia, bradycardia, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles. Skin & subcutaneous tissue disorders : allergic dermatitis, rash. Ear &labyrinth disorders : motion sickness, tinnitus. Gastrointestinal disorders : diarrhea, dyspepsia, abdominal pain, dry mouth, hiccups and flatulence. General disorders and administration site conditions : weakness, fatigue, fever, hot flash, flu-like syndrome. Investigations : QT prolongation, transient, asymptomatic increases in AST and/or ALT and bilirubin and these changes occurred predominantly in patients receiving HEC. Metabolism and nutrition disorders : hyperkalemia, electrolyte fluctuations, hyperglycemia, metabolic acidosis, appetite decrease, anorexia. Musculoskeletal and connective tissue disorders : arthralgia. Nervous System disorders : dizziness, somnolence, insomnia, hypersomnia, paresthesia. Psychiatric disorders : anxiety, euphoric mood. Renal and urinary disorders : urinary retention, glycosuria. Vascular disorders : vein discoloration, vein distention, hypotension, hypertension. In other studies, two subjects experienced severe constipation following a single 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 eight years received a single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron 30 minutes before beginning the first cycle of emetogenic chemotherapy [see Clinical Studies (14.2) ] . Adverse reactions were evaluated in pediatric patients receiving palonosetron for up to four chemotherapy cycles. The following adverse reactions were reported in less than 1% of palonosetron-treated patients: Nervous System disorders : headache, dizziness, dyskinesia. General disorders and administration site conditions : infusion site pain. Skin and subcutaneous tissue disorders : allergic dermatitis, skin disorder. Postoperative Nausea and Vomiting (PONV) The most common adverse reactions reported in at least 2% of adults receiving palonosetron 0.075 mg intravenously immediately before induction of anesthesia in three randomized placebo-controlled trials [see Clinical Studies (14.3) ] are shown in Table 3. Rates of adverse reactions between palonosetron 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 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 *Reported in at least 2% of patients in any treatment group Adverse Reaction Palonosetron 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% or less of patients, in these PONV clinical trials were: Cardiac disorders : sinus bradycardia, tachycardia, arrhythmia, ventricular extrasystoles. The frequency of these adverse effects did not appear to be different from placebo. Skin and subcutaneous tissue disorders : pruritus. Gastrointestinal disorders : flatulence, dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility. General disorders and administration site conditions : chills, generalized edema. Investigations : increases in AST and/or ALT, hepatic enzyme increased, QTc prolongation, blood pressure decreased, platelet count decreased, T wave amplitude decreased. Metabolism and nutrition disorders : hypokalemia, anorexia. Nervous System disorders : dizziness. Respiratory, thoracic and mediastinal disorders : hypoventilation, laryngospasm. Renal and urinary disorders : Urinary retention. Vascular disorders : Hypotension, Hypertension.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of palonosetron. 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 POSFREA 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 POSFREA and initiate supportive treatment [see Warnings and Precautions (5.2) ] .

8.1 Pregnancy Risk Summary There are no available data on palonosetron 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 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 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 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 POSFREA and any potential adverse effect on the breastfed infant from palonosetron or from the underlying maternal condition.

8.4 Pediatric Use Chemotherapy-Induced Nausea and Vomiting (CINV) Safety and effectiveness of POSFREA 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 HEC. Use is supported by a clinical trial where 165 pediatric patients aged two months to less than 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 POSFREA in neonates (less than 1 month of age) have not been established. Postoperative Nausea and Vomiting Studies (PONV) Safety and effectiveness have not been established in pediatric patients for PONV. Two pediatric trials were performed. Pediatric Study 1, a dose finding study was conducted to compare two doses of palonosetron, 1 mcg/kg (maximum 0.075 mg) versus 3 mcg/kg (maximum 0.25 mg). A total of 150 pediatric surgical patients participated, age range one month to less than 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 intravenous palonosetron (1 mcg/kg, maximum 0.075 mg) versus intravenous ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to less than 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 -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults.

8.5 Geriatric Use Of the 1374 adult cancer patients in clinical studies of intravenously administered palonosetron for CINV, 316 (23%) were 65 years and over, while 71 (5%) were at least 75 years and over. Of the 1520 adult patients in clinical studies of intravenously administered palonosetron for PONV, 73 (5%) were at least 65 years old [see Clinical Studies (14.1, 14.3) ] . No overall differences in safety or effectiveness were observed between these subjects and 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 dosage adjustment is required for geriatric patients.

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.