Pazopanib Hydrochloride

5 WARNINGS AND PRECAUTIONS Hepatic Toxicity : Severe and fatal hepatotoxicity has occurred. Monitor liver tests at baseline, regularly during treatment and as clinically indicated. Withhold pazopanib and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity. ( 2.2 , 5.1 ) QT Prolongation and Torsades de Pointes : Monitor patients who are at significant risk of developing QT interval prolongation. Monitor electrocardiograms (ECGs) and electrolytes at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating pazopanib and during treatment. ( 5.2 , 12.2 ) Cardiac Dysfunction : Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, have occurred. Monitor blood pressure and manage as appropriate. Monitor for clinical signs or symptoms of congestive heart failure. Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction. Withhold or permanently discontinue pazopanib based on severity of cardiac dysfunction. ( 2.2 , 5.3 ) Hemorrhagic Events : Fatal hemorrhagic events have occurred. Pazopanib has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months. Withhold pazopanib and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events. ( 2.2 , 5.4 ) Arterial Thromboembolic Events : Arterial thromboembolic events have been observed and can be fatal. Pazopanib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue pazopanib in case of an arterial thromboembolic event. ( 2.2 , 5.5 ) Venous Thromboembolic Events : Venous thromboembolic events (VTEs) have been observed, including fatal pulmonary emboli (PE). Monitor for signs and symptoms of VTE and PE. Withhold pazopanib and then resume at same dose or permanently discontinue based on severity of VTE. ( 2.2 , 5.6 ) Thrombotic Microangiopathy : Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been observed. Permanently discontinue pazopanib if TMA occurs. ( 2.2 , 5.7 ) Gastrointestinal Perforation and Fistula : Fatal perforation events have occurred. Monitor for signs and symptoms of gastrointestinal perforation or fistula. Withhold pazopanib in case of Grade 2 or Grade 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue pazopanib in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula. ( 2.2 , 5.8 ) Interstitial Lung Disease/Pneumonitis : Can be fatal. Monitor patients for pulmonary symptoms. Permanently discontinue pazopanib in patients who develop interstitial lung disease (ILD) or pneumonitis. ( 2.2 , 5.9 ) Posterior Reversible Encephalopathy Syndrome : Can be fatal. Permanently discontinue pazopanib in patients who develop posterior reversible encephalopathy syndrome (PRES). ( 2.2 , 5.10 ) Hypertension : Hypertension, including hypertensive crisis, has been observed. Do not initiate pazopanib in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating pazopanib. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce pazopanib or permanently discontinue based on severity of hypertension. ( 2.2 , 5.11 ) Risk of Impaired Wound Healing : Withhold pazopanib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of pazopanib after resolution of wound healing complications has not been established. ( 5.12 ) Hypothyroidism : Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate. ( 5.13 ) Proteinuria : Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated. Withhold pazopanib then resume at a reduced dose or permanently discontinue based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome. ( 2.2 , 5.14 ) Tumor Lysis Syndrome : Cases of tumor lysis syndrome (TLS) (some fatal) have been reported in patients with RCC and STS. Closely monitor patients at risk and treat as clinically indicated. ( 5.15 ) Infection : Serious infections (with or without neutropenia), some with fatal outcome, have been reported. Monitor for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly. Consider interruption or discontinuation of pazopanib. ( 5.16 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and patients to use effective contraception. ( 5.19 , 8.1 , 8.3 ) 5.1 Hepatic Toxicity Hepatotoxicity, manifested as increases in ALT, aspartate aminotransferase (AST) and bilirubin, occurred in patients who received pazopanib. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5) ] . Transaminase elevations occur early in the course of treatment; 92% of all transaminase elevations of any grade occurred in the first 18 weeks. In the randomized RCC trial (VEG105192), ALT > 3 × ULN occurred in 18% and ALT > 10 × ULN occurred in 4% of the 290 patients who received pazopanib. Concurrent elevation in ALT > 3 × ULN and bilirubin > 2 × ULN in the absence of significant alkaline phosphatase > 3 × ULN occurred in 2%. In the monotherapy trials, 2 patients died with disease progression and hepatic failure. In the randomized STS trial (VEG110727), ALT > 3 × ULN occurred in 18% and ALT > 8 × ULN occurred in 5% of the 240 patients who received pazopanib. Concurrent elevation in ALT > 3 × ULN and bilirubin > 2 × ULN in the absence of significant alkaline phosphatase > 3 × ULN occurred in 2%. One patient died of hepatic failure. Monitor liver tests at baseline; at weeks 3, weeks 5, weeks 7, and weeks 9; at month 3 and month 4; and then periodically as clinically indicated. Increase to weekly monitoring for patients with elevated ALT until ALT returns to Grade 1 or baseline. Withhold pazopanib and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity [see Dosage and Administration (2.2) ]. Gilbert’s Syndrome Pazopanib is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) ] . In patients with only a mild indirect hyperbilirubinemia known as Gilbert’s syndrome, manage elevation in ALT > 3 × ULN per the recommendations outlined for isolated ALT elevations [see Dosage and Administration (2.2) ] . Concomitant Use of Simvastatin Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations [see Drug Interactions (7.3) ] . Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib. 5.2 QT Prolongation and Torsades de Pointes In the RCC trials, 558/586 patients were subject to routine electrocardiogram (ECG) monitoring and QT prolongation ≥ 500 msec was identified in 2% of these 558 patients. In monotherapy trials, torsades de pointes occurred in < 1% of 977 patients who received pazopanib. In the randomized RCC (VEG105192) and STS (VEG110727) trials, 1% (3/290) and 0.4% (1/240) of patients, respectively, who received pazopanib had post-baseline values between 500 msec to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease [see Drug Interactions (7.5) ] . Monitor ECG and electrolytes (e.g., calcium, magnesium, potassium) at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating pazopanib and during treatment. 5.3 Cardiac Dysfunction Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, occurred in patients who received pazopanib. In the RCC trials, cardiac dysfunction was observed in 0.6% of 586 patients without routine on-study LVEF monitoring. In the randomized RCC trial (VEG105192), myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥ 15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥ 10% compared with baseline that is also below the lower limit of normal. In an RCC trial (COMPARZ), myocardial dysfunction occurred in 13% of the 362 patients on pazopanib who had a baseline and post-baseline LVEF measurements. Congestive heart failure occurred in 0.5% of patients. In the randomized STS trial (VEG110727), myocardial dysfunction occurred in 11% of the 142 patients who had a baseline and a post-baseline LVEF measurements. One percent (3/240) of patients who received pazopanib had congestive heart failure, which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with pazopanib had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Monitor blood pressure and manage as appropriate [see Warnings and Precautions (5.11) ] . Monitor for clinical signs or symptoms of congestive heart failure. Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction, including previous anthracycline exposure. Withhold or permanently discontinue pazopanib based on severity of cardiac dysfunction [see Dosage and Administration (2.2) ] . 5.4 Hemorrhagic Events In the RCC trials, fatal hemorrhage occurred in 0.9% of 586 patients, and cerebral/intracranial hemorrhage was observed in < 1% (2/586) of patients treated with pazopanib. In the randomized RCC trial (VEG105192), 13% of 290 patients treated with pazopanib experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with pazopanib who had hemorrhagic events experienced serious events, including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent of patients treated with pazopanib died from hemorrhage. In the randomized STS trial (VEG110727), 22% of 240 patients treated with pazopanib experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events occurred in 1% of patients and included intracranial hemorrhage, subarachnoid hemorrhage, and peritoneal hemorrhage. Pazopanib has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months. Withhold pazopanib and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events [see Dosage and Administration (2.2) ] . 5.5 Arterial Thromboembolic Events In the RCC trials, fatal arterial thromboembolic events occurred in 0.3% of 586 patients. In the randomized RCC trial (VEG105192), 2% of 290 patients who received pazopanib experienced myocardial infarction or ischemia, 0.3% had a cerebrovascular accident, and 1% had an event of transient ischemic attack. In the randomized STS trial (VEG110727), 2% of 240 patients who received pazopanib experienced a myocardial infarction or ischemia and 0.4% had a cerebrovascular accident. Pazopanib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue pazopanib in case of an arterial thromboembolic event [see Dosage and Administration (2.2) ] . 5.6 Venous Thromboembolic Events Venous thromboembolic events (VTEs), including venous thrombosis and fatal pulmonary embolus (PE), occurred in patients who received pazopanib. In the randomized RCC trial (VEG105192), VTEs occurred in 1% of 290 patients who received pazopanib. In the randomized STS trial (VEG110727), VTEs were reported in 5% of 240 patients who received pazopanib. Fatal PE occurred in 1% (2/240). Monitor for signs and symptoms of VTE and PE. Withhold pazopanib and then resume at same dose or permanently discontinue based on severity of VTE [see Dosage and Administration (2.2) ] . 5.7 Thrombotic Microangiopathy Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), occurred in clinical trials of pazopanib as monotherapy, in combination with bevacizumab, and in combination with topotecan. Pazopanib is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of pazopanib. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue pazopanib in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula In the RCC and STS trials, gastrointestinal perforation or fistula occurred in 0.9% of 586 patients and 1% of 382 patients who received pazopanib, respectively. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials and in 0.3% (1/382) of these patients in the STS trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. Withhold pazopanib in case of Grade 2 or Grade 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue pazopanib in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula [see Dosage and Administration (2.2) ] . 5.9 Interstitial Lung Disease/Pneumonitis Interstitial lung disease (ILD)/pneumonitis, which can be fatal, has been reported with pazopanib across clinical trials. ILD/pneumonitis occurred in 0.1% of patients treated with pazopanib. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue pazopanib in patients who develop ILD or pneumonitis [see Dosage and Administration (2.2) ] . 5.10 Posterior Reversible Encephalopathy Syndrome Posterior Reversible Encephalopathy Syndrome (PRES) has been reported in patients who received pazopanib and may be fatal. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. Confirm diagnosis of PRES by magnetic resonance imaging. Permanently discontinue pazopanib in patients who develop PRES. 5.11 Hypertension Hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg) and hypertensive crisis were observed in patients treated with pazopanib. Approximately 40% of patients who received pazopanib experienced hypertension, with Grade 3 occurring in 4% to 7% of patients [see Adverse Reactions (6.1) ] . About 40% of cases occurred by Day 9 and about 90% of cases occurred in the first 18 weeks across clinical trials. Approximately 1% of patients required permanent discontinuation of pazopanib because of hypertension. Do not initiate pazopanib in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating pazopanib. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce pazopanib or permanently discontinue based on severity of hypertension [see Dosage and Administration (2.2) ] . 5.12 Risk of Impaired Wound Healing Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, pazopanib has the potential to adversely affect wound healing. Withhold pazopanib at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of pazopanib after resolution of wound healing complications has not been established. 5.13 Hypothyroidism Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, occurred in 7% of 290 patients who received pazopanib in the randomized RCC trial (VEG105192) and in 5% of 240 patients who received pazopanib in the randomized STS trial (VEG110727). Hypothyroidism occurred in 4% of the 586 patients in the RCC trials and 5% of the 382 patients in the STS trials. Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate. 5.14 Proteinuria In the randomized RCC trial (VEG105192), proteinuria occurred in 9% of 290 patients who received pazopanib. In 2 patients, proteinuria led to discontinuation of pazopanib. In the randomized STS trial (VEG110727), proteinuria occurred in 1% of 240 patients and nephrotic syndrome occurred in 1 patient. Treatment was discontinued in the patient with nephrotic syndrome. Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated. Withhold pazopanib then resume at a reduced dose or permanently discontinue based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome [see Dosage and Administration (2.2) ] . 5.15 Tumor Lysis Syndrome Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported in RCC and STS patients treated with pazopanib [see Adverse Reactions (6.2) ] . Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated. 5.16 Infection Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of pazopanib for serious infections. 5.17 Increased Toxicity with Other Cancer Therapy Pazopanib is not indicated for use in combination with other agents. Clinical trials of pazopanib in combination with pemetrexed and lapatinib were terminated early due to increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.18 Increased Toxicity in Developing Organs The safety and effectiveness of pazopanib in pediatric patients have not been established. Pazopanib is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation in patients younger than 2 years of age [see Use in Specific Populations (8.4) ] . 5.19 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pazopanib can cause fetal harm when administered to a pregnant woman. Administration of pazopanib to pregnant rats and rabbits during the period of organogenesis resulted in maternal toxicity, teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose (MRHD) of 800 mg (based on area under the curve [AUC]). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pazopanib and for at least 2 weeks following the final dose. Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with pazopanib and for at least 2 weeks after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .