Votrient

• Recommended Dosage
  : 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). (
  2.1      Recommended Dosage

  The recommended dosage of VOTRIENT is 800 mg (four 200 mg tablets) orally once daily without food (at least 1 hour before or 2 hours after a meal) until disease progression or unacceptable toxicity

  [see Clinical Pharmacology (12.3)]

  . The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs

  [see Dosage and Administration (2.3, 2.4)]

  .

  Swallow tablets whole. Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure

  [see Clinical Pharmacology (12.3)]

  .

  If a dose is missed, it should not be taken if it is < 12 hours until the next dose.
  )
  
• Moderate Hepatic Impairment
  : 200 mg orally once daily. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  )

Tablets: 200 mg, modified capsule-shaped, gray or pink, film-coated with ‘GS JT’ debossed on one side.

• Lactation
  : Advise not to breastfeed. (
  8.2     Lactation

  Risk Summary

  There is no data on the presence of pazopanib or its metabolites in human milk or their effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with VOTRIENT and for 2 weeks after the final dose.
  )

• Hepatic Toxicity
  : Severe and fatal hepatotoxicity has occurred. Monitor liver tests at baseline, regularly during treatment and as clinically indicated. Withhold VOTRIENT 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      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.1      Hepatic Toxicity

  Hepatotoxicity, manifested as increases in ALT, aspartate aminotransferase (AST) and bilirubin, occurred in patients who received VOTRIENT. 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 VOTRIENT. 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 VOTRIENT. 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, 5, 7, and 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 VOTRIENT 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

  VOTRIENT 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 VOTRIENT 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 VOTRIENT.
  )
  
• 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 VOTRIENT and during treatment. (
  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 VOTRIENT.

  In the randomized RCC (VEG105192) and STS (VEG110727) trials, 1% (3/290) and 0.4% (1/240) of patients, respectively, who received VOTRIENT had post-baseline values between 500 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 preexisting 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 VOTRIENT and during treatment.
  ,
  12.2     Pharmacodynamics

  Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations.

  Cardiac Electrophysiology

  The QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel trial (N = 96) using moxifloxacin as a positive control. VOTRIENT 800 mg orally under fasting conditions was administered on Days 2 to 8 and 1,600 mg was administered on Day 9 after a meal in order to increase exposure to pazopanib and its metabolites. No large changes (i.e., > 20 msec) in QTc interval following exposure to pazopanib were detected in this QT trial. The trial was not able to exclude small changes (< 10 msec) in QTc interval, because assay sensitivity below this threshold (< 10 msec) was not established in this trial

  [see Warnings and Precautions (5.2)]

  .
  )
• 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 VOTRIENT based on severity of cardiac dysfunction. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.3      Cardiac Dysfunction

  Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, occurred in patients who received VOTRIENT.

  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 VOTRIENT 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 VOTRIENT had congestive heart failure, which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT 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 VOTRIENT based on severity of cardiac dysfunction

  [see Dosage and Administration (2.2)]

  .
  )
• Hemorrhagic Events
  : Fatal hemorrhagic events have occurred. VOTRIENT 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 VOTRIENT and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  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 VOTRIENT.

  In the randomized RCC trial (VEG105192), 13% of 290 patients treated with VOTRIENT 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 VOTRIENT who had hemorrhagic events experienced serious events, including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent of patients treated with VOTRIENT died from hemorrhage.

  In the randomized STS trial (VEG110727), 22% of 240 patients treated with VOTRIENT 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.

  VOTRIENT 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 VOTRIENT and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events

  [see Dosage and Administration (2.2)]

  .
  )
• Arterial Thromboembolic Events
  : Arterial thromboembolic events have been observed and can be fatal. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue VOTRIENT in case of an arterial thromboembolic event. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  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 VOTRIENT 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 VOTRIENT experienced a myocardial infarction or ischemia and 0.4% had a cerebrovascular accident.

  VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue VOTRIENT in case of an arterial thromboembolic event

  [see Dosage and Administration (2.2)]

  .
  )
• 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 VOTRIENT and then resume at same dose or permanently discontinue based on severity of VTE. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.6      Venous Thromboembolic Events

  Venous thromboembolic events (VTEs), including venous thrombosis and fatal pulmonary embolus (PE), occurred in patients who received VOTRIENT.

  In the randomized RCC trial (VEG105192), VTEs occurred in 1% of 290 patients who received VOTRIENT. In the randomized STS trial (VEG110727), VTEs were reported in 5% of 240 patients who received VOTRIENT. Fatal PE occurred in 1% (2/240).

  Monitor for signs and symptoms of VTE and PE. Withhold VOTRIENT and then resume at same dose or permanently discontinue based on severity of VTE

  [see Dosage and Administration (2.2)]

  .
  )
• Thrombotic Microangiopathy
  : Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been observed. Permanently discontinue VOTRIENT if TMA occurs. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.7      Thrombotic Microangiopathy

  Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), occurred in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued.

  Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated.
  )
• Gastrointestinal Perforation and Fistula
  : Fatal perforation events have occurred. Monitor for signs and symptoms of gastrointestinal perforation or fistula. Withhold VOTRIENT in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue VOTRIENT in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  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 VOTRIENT, 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 VOTRIENT in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue VOTRIENT in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula

  [see Dosage and Administration (2.2)]

  .
  )
• Interstitial Lung Disease/Pneumonitis
  : Can be fatal. Monitor patients for pulmonary symptoms. Permanently discontinue VOTRIENT in patients who develop interstitial lung disease (ILD) or pneumonitis. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.9      Interstitial Lung Disease/Pneumonitis

  Interstitial lung disease (ILD)/pneumonitis, which can be fatal, has been reported with VOTRIENT across clinical trials. ILD/pneumonitis occurred in 0.1% of patients treated with VOTRIENT.

  Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue VOTRIENT in patients who develop ILD or pneumonitis

  [see Dosage and Administration (2.2)]

  .
  )
• Posterior Reversible Encephalopathy Syndrome
  : Can be fatal. Permanently discontinue VOTRIENT in patients who develop posterior reversible encephalopathy syndrome (PRES). (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.10      Posterior Reversible Encephalopathy Syndrome

  Posterior Reversible Encephalopathy Syndrome (PRES) has been reported in patients who received VOTRIENT 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 VOTRIENT in patients who develop PRES.
  )
• Hypertension
  : Hypertension, including hypertensive crisis, has been observed. Do not initiate VOTRIENT in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating VOTRIENT. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce VOTRIENT or permanently discontinue based on severity of hypertension. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.11      Hypertension

  Hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg) and hypertensive crisis were observed in patients treated with VOTRIENT.

  Approximately 40% of patients who received VOTRIENT 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 VOTRIENT because of hypertension.

  Do not initiate VOTRIENT in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating VOTRIENT. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce VOTRIENT or permanently discontinue based on severity of hypertension

  [see Dosage and Administration (2.2)]

  .
  )
• Risk of Impaired Wound Healing
  : Withhold VOTRIENT 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 VOTRIENT after resolution of wound healing complications has not been established. (
  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, VOTRIENT has the potential to adversely affect wound healing.

  Withhold VOTRIENT 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 VOTRIENT after resolution of wound healing complications has not been established.
  )
• Hypothyroidism
  : Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate. (
  5.13      Hypothyroidism

  Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, occurred in 7% of 290 patients who received VOTRIENT in the randomized RCC trial (VEG105192) and in 5% of 240 patients who received VOTRIENT 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.
  )
• Proteinuria
  : Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated. Withhold VOTRIENT then resume at a reduced dose or permanently discontinue based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome. (
  2.2      Dosage Modifications for Adverse Reactions

  Table 1 summarizes the recommended dose reductions.

  Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions

  Dose reduction	For renal cell carcinoma	For soft tissue sarcoma
  First	400 mg orally once daily	600 mg orally once daily
  Second	200 mg orally once daily	400 mg orally once daily

  Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

  Table 2 summarizes the recommended dosage modifications for adverse reactions.

  Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions

  Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5.
  Adverse reaction	Severitya	Dosage modification
  Hepatic Toxicity [see Warnings and Precautions (5.1)]	Isolated ALT elevations between 3 × ULN and 8 × ULN	Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.
  	Isolated ALT elevations of > 8 × ULN	Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).
  	ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN	Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.
  Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]	Symptomatic or Grade 3	Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.
  	Grade 4	Permanently discontinue.
  Hemorrhagic Events [see Warnings and Precautions (5.4)]	Grade 2	Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction.
  	Grade 3 or 4	Permanently discontinue.
  Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]	Any grade	Permanently discontinue.
  Venous Thromboembolic Events [see Warnings and Precautions (5.6)]	Grade 3	Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.
  	Grade 4	Permanently discontinue.
  Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]	Any grade	Permanently discontinue.
  Gastrointestinal Perforation [see Warnings and Precautions (5.8)]	Any grade	Permanently discontinue.
  Gastrointestinal Fistula [see Warnings and Precautions (5.8)]	Grade 2 or 3	Withhold and resume based on medical judgement.
  	Grade 4	Permanently discontinue.
  Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)]	Any grade	Permanently discontinue.
  Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]	Any grade	Permanently discontinue.
  Hypertension [see Warnings and Precautions (5.11)]	Grade 2 or 3	Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.
  	Grade 4 or hypertensive crisis	Permanently discontinue.
  Proteinuria [see Warnings and Precautions (5.14)]	24-hour urine protein ≥ 3 grams	Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.
  	Confirmed nephrotic syndrome	Permanently discontinue.
  ,
  5.14      Proteinuria

  In the randomized RCC trial (VEG105192), proteinuria occurred in 9% of 290 patients who received VOTRIENT. In 2 patients, proteinuria led to discontinuation of VOTRIENT.

  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 VOTRIENT 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)]

  .
  )
• 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      Tumor Lysis Syndrome

  Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported in RCC and STS patients treated with VOTRIENT

  [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.
  )
• 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 VOTRIENT. (
  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 VOTRIENT for serious infections.
  )
• 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      Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman. Administration of VOTRIENT 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 VOTRIENT 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 VOTRIENT and for at least 2 weeks after the last dose

  [see Use in Specific Populations (8.1, 8.3)]

  .
  ,
  8.1     Pregnancy

  Risk Summary

  Based on animal reproduction studies and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no available data on VOTRIENT use in pregnant women to evaluate for a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the MRHD of 800 mg/day (based on AUC) (

  see Data

  ). Advise pregnant women of the potential risk to a fetus.

  The estimated 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 in clinically recognized pregnancies and miscarriage is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  In a female fertility and early embryonic development study, female rats were administered oral pazopanib at least 15 days prior to mating and for 6 days after mating, which resulted in increased pre-implantation loss and early resorptions at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8-fold the AUC at the MRHD of 800 mg/day). Postimplantation loss, embryolethality, and decreased fetal body weights were noted in females administered doses greater than or equal to 10 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day).

  In embryo-fetal developmental toxicity studies in rats and rabbits, oral pazopanib was administered to pregnant animals during organogenesis. In rats, dose levels of greater than or equal to 3 mg/kg/day (approximately 0.1-fold the AUC at the MRHD of 800 mg/day) resulted in teratogenic effects, including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, increases in postimplantation loss, embryolethality and reduced fetal body weight. In rabbits, maternal toxicity, increased postimplantation loss and abortion were observed at doses greater than or equal to 30 mg/kg/day (approximately 0.007-fold the AUC at the MRHD of 800 mg/day). In addition, severe maternal body weight loss and 100% litter loss were observed at doses greater than or equal to 100 mg/kg/day (0.02-fold the AUC at the MRHD of 800 mg/day), while fetal weight was reduced at doses greater than or equal to 3 mg/kg/day (AUC not calculated).
  ,
  8.3     Females and Males of Reproductive Potential

  VOTRIENT can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  .

  Pregnancy Testing

  Verify pregnancy status of females of reproductive potential prior to starting treatment with VOTRIENT.

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment with VOTRIENT and for at least 2 weeks after the last dose.

  Males

  Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose.

  Infertility

  Based on findings from animal studies, VOTRIENT may impair fertility in females and males of reproductive potential while receiving treatment

  [see Nonclinical Toxicology (13.1)].
  )