6.1Clinical 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.
