Votrient

1 INDICATIONS AND USAGE VOTRIENT is a kinase inhibitor indicated for the treatment of adults with: advanced renal cell carcinoma (RCC). advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of Use : The efficacy of VOTRIENT for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated.

1.1Renal Cell Carcinoma

VOTRIENT ® is indicated for the treatment of adults with advanced renal cell carcinoma (RCC).

1.2Soft Tissue Sarcoma

VOTRIENT is indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of Use : The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

Recommended Dosage : 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). Moderate Hepatic Impairment : 200 mg orally once daily.

2.1Recommended 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 . The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs . Swallow tablets whole. Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure . If a dose is missed, it should not be taken if it is < 12 hours until the next dose.

2.2Dosage 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. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.

Adverse reaction Severity a Dosage modification Hepatic Toxicity 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 Symptomatic or Grade 3 Withhold until improvement to Grade < 3. Resume treatment based on medical judgement. Grade 4 Permanently discontinue. Hemorrhagic Events Grade 2 Withhold until improvement to Grade ≤ 1. Resume at reduced dose . Permanently discontinue if Grade 2 recurs after dose interruption and reduction.

Grade 3 or 4 Permanently discontinue. Arterial Thromboembolic Events Any grade Permanently discontinue. Venous Thromboembolic Events 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 Any grade Permanently discontinue.

Gastrointestinal Perforation Any grade Permanently discontinue. Gastrointestinal Fistula Grade 2 or 3 Withhold and resume based on medical judgement. Grade 4 Permanently discontinue. Interstitial Lung Disease / Pneumonitis Any grade Permanently discontinue. Posterior Reversible Encephalopathy Syndrome Any grade Permanently discontinue.

Hypertension Grade 2 or 3 Reduce dose 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 24-hour urine protein ≥ 3 grams Withhold until improvement to Grade ≤ 1.

Resume at a reduced dose . Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions. Confirmed nephrotic syndrome Permanently discontinue.

2.3Dosage Modifications for Hepatic Impairment Moderate

and Severe Hepatic Impairment In patients with moderate hepatic impairment [total bilirubin > 1.5 to 3 × upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to VOTRIENT. If VOTRIENT is used in patients with moderate hepatic impairment, reduce the VOTRIENT dose to 200 mg orally once daily. VOTRIENT is not recommended in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any ALT value) .

2.4Dosage Modifications for Drug Interactions Strong

CYP3A4 Inhibitors Avoid concomitant use of strong CYP3A4 inhibitors by use of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg . Strong CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT is not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers . Gastric Acid-Reducing Agents Avoid concomitant use of gastric acid-reducing agents.

If concomitant use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate short-acting antacid and VOTRIENT dosing by several hours .

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 , 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 VOTRIENT 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 VOTRIENT based on severity of cardiac dysfunction. ( 2.2 , 5.3 ) 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 , 5.4 ) 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 , 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 VOTRIENT 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 VOTRIENT 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 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 , 5.8 ) 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 , 5.9 ) Posterior Reversible Encephalopathy Syndrome : Can be fatal. Permanently discontinue VOTRIENT in patients who develop posterior reversible encephalopathy syndrome (PRES). ( 2.2 , 5.10 ) 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 , 5.11 ) 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. Hypothyroidism : 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 , 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. 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. 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 )

5.1Hepatic 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 . 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 . 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 . 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 . Concomitant Use of Simvastatin Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations . Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

5.2QT 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 . 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.

5.3Cardiac 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 . 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 .

5.4Hemorrhagic 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 .

5.5Arterial 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 .

5.6Venous 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 .

5.7Thrombotic 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.

5.8Gastrointestinal 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 .

5.9Interstitial 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 .

5.10Posterior 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.

5.11Hypertension 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 . 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 .

5.12Risk 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.

5.13Hypothyroidism 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.

5.14Proteinuria 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 .

5.15Tumor Lysis Syndrome Cases of

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

5.16Infection 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.

5.17Increased Toxicity With Other Cancer Therapy

VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT 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.

5.18Increased Toxicity in Developing Organs The

safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT 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 .

5.19Embryo-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 .

None. None.

8.1Pregnancy Risk Summary Based on

animal reproduction studies and its mechanism of action , 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) . 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).

The following clinically significant adverse reactions are elsewhere in the labeling: Hepatic Toxicity QT Prolongation and Torsades de Pointes Cardiac Dysfunction Hemorrhagic Events Arterial Thromboembolic Events Venous Thromboembolic Events Thrombotic Microangiopathy (TMA) Gastrointestinal Perforation and Fistula Interstitial Lung Disease (ILD)/Pneumonitis Posterior Reversible Encephalopathy Syndrome (PRES) Hypertension Hypothyroidism Proteinuria Tumor Lysis Syndrome Infection The most common adverse reactions in patients with RCC (≥ 20%) are diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting. The most common adverse reactions in patients with STS (≥ 20%) are fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation. To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure of 977 patients who received VOTRIENT as a single agent, including 586 VOTRIENT-treated patients with RCC. With a median duration of treatment of 7.4 months (range, 0.1 to 27.6) in these 977 patients, the most common adverse reactions (≥ 20%) in these 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described in the WARNINGS AND PRECAUTIONS also reflects exposure of 382 patients with advanced soft tissue sarcoma who received VOTRIENT as a single agent, with a median duration of treatment of 3.6 months (range, 0 to 53).

The most common adverse reactions (≥ 20%) in these 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation. Renal Cell Carcinoma The safety of VOTRIENT was evaluated in 290 patients with RCC who participated in VEG105192, a randomized, double-blind, placebo-controlled trial . The median duration of treatment was 7.4 months (range, 0 to 23) for patients who received VOTRIENT. Forty-two percent of patients on VOTRIENT required a dose interruption and 36% required a dose reduction. Table 3 presents adverse reactions in VEG105192.

Table 3. Adverse Reactions (≥ 10%) in Patients with RCC Who Received VOTRIENT in VEG105192 Abbreviation: RCC, renal cell carcinoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. VOTRIENT (N = 290) Placebo (N = 145) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Adverse reactions % % % % % % Diarrhea 52 3 < 1 9 < 1 0 Hypertension 40 4 0 10 < 1 0 Hair color changes 38 < 1 0 3 0 0 Nausea 26 < 1 0 9 0 0 Anorexia 22 2 0 10 < 1 0 Vomiting 21 2 < 1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in < 10% (any grade) were alopecia (8% versus < 1%), chest pain (5% versus 1%), dysgeusia (8% versus < 1%), dyspepsia (5% versus < 1%), dysphonia (4% versus < 1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (6% versus < 1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Table 4 presents the laboratory abnormalities in VEG105192. Table 4. Select Laboratory Abnormalities (> 10%) in Patients with RCC Who Received VOTRIENT with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG105192 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RCC, renal cell carcinoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

VOTRIENT (N = 290) Placebo (N = 145) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Parameters % % % % % % Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 < 1 19 < 1 0 Glucose increased 41 < 1 0 33 1 0 Total bilirubin increased 36 3 < 1 10 1 < 1 Phosphorus decreased 34 4 0 11 0 0 Sodium decreased 31 4 1 24 4 0 Magnesium decreased 26 < 1 1 14 0 0 Glucose decreased 17 0 < 1 3 0 0 Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 < 1 6 0 0 Thrombocytopenia 32 < 1 < 1 5 0 < 1 Lymphocytopenia 31 4 < 1 24 1 0 Additional adverse reactions from other clinical trials in patients with RCC who received VOTRIENT include arthralgia and muscle spasms. Soft Tissue Sarcoma The safety of VOTRIENT was evaluated in 240 patients who participated in VEG110727, a randomized, double-blind, placebo-controlled trial . The median duration of treatment was 4.5 months (range, 0 to 24) for patients who received VOTRIENT. Fifty-eight percent of patients on VOTRIENT required a dose interruption and 38% required a dose reduction. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions.

Table 5 presents the adverse reactions in VEG110727. Table 5. Adverse Reactions (≥ 10%) in Patients with STS Who Received VOTRIENT in VEG110727 Abbreviation: STS, soft tissue sarcoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

VOTRIENT (N = 240) Placebo (N = 123) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Adverse reactions % % % % % % Fatigue 65 13 1 48 4 1 Diarrhea 59 5 0 15 1 0 Nausea 56 3 0 22 2 0 Weight decreased 48 4 0 15 0 0 Hypertension 42 7 0 6 0 0 Appetite decreased 40 6 0 19 0 0 Hair color changes 39 0 0 2 0 0 Vomiting 33 3 0 11 1 0 Tumor pain 29 8 0 21 7 2 Dysgeusia 28 0 0 3 0 0 Headache 23 1 0 8 0 0 Musculoskeletal pain 23 2 0 20 2 0 Myalgia 23 2 0 9 0 0 Gastrointestinal pain 23 3 0 9 4 0 Dyspnea 20 5 < 1 17 5 1 Exfoliative rash 18 < 1 0 9 0 0 Cough 17 < 1 0 12 < 1 0 Peripheral edema 14 2 0 9 2 0 Mucositis 12 2 0 2 0 0 Alopecia 12 0 0 1 0 0 Dizziness 11 1 0 4 0 0 Skin disorder b 11 2 0 1 0 0 Skin hypopigmentation 11 0 0 0 0 0 Stomatitis 11 < 1 0 3 0 0 Chest pain 10 2 0 6 0 0 Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥ 5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus < 1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%). Table 6 presents the laboratory abnormalities in VEG110727. Table 6.

Select Laboratory Abnormalities (> 10%) in Patients with STS Who Received VOTRIENT with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG110727 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; STS, soft tissue sarcoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. VOTRIENT (N = 240) Placebo (N = 123) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Parameters % % % % % % Chemistry AST increased 51 5 3 22 2 0 ALT increased 46 8 2 18 2 1 Glucose increased 45 < 1 0 35 2 0 Albumin decreased 34 1 0 21 0 0 Alkaline phosphatase increased 32 3 0 23 1 0 Sodium decreased 31 4 0 20 3 0 Total bilirubin increased 29 1 0 7 2 0 Potassium increased 16 1 0 11 0 0 Hematologic Leukopenia 44 1 0 15 0 0 Lymphocytopenia 43 10 0 36 9 2 Thrombocytopenia 36 3 1 6 0 0 Neutropenia 33 4 0 7 0 0 Other Clinically Relevant Adverse Reactions Lipase Elevations In a single-arm RCC trial (VEG102616), elevated lipase was observed for 27% of 181 patients with available laboratory data. Elevated lipase as an adverse reaction was reported for 4% of 225 patients, including 2.7% (6/225) with Grade 3 and 0.4% (1/225) with Grade 4.

In the RCC trials, clinical pancreatitis was observed in < 1% of 586 patients. Pneumothorax Two of 290 patients (0.7%) treated with VOTRIENT in the randomized RCC trial (VEG105192) and 8 of 240 patients (3.3%) treated with VOTRIENT in the randomized STS trial (VEG110727) developed a pneumothorax. Bradycardia In the randomized RCC trial (VEG105192), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 280 patients treated with VOTRIENT. Bradycardia was reported as an adverse reaction in 2% of 290 patients.

In the randomized STS trial (VEG110727), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 238 patients treated with VOTRIENT. Bradycardia was reported as an adverse reaction in 2% of 240 patients. Adverse Reactions in East Asian Patients In an analysis of pooled clinical trial data (N = 1938) with VOTRIENT, Grade 3 and Grade 4 neutropenia (12% versus 2%), thrombocytopenia (6% versus < 1%) and palmar-plantar erythrodysesthesia (6% versus 2%) were observed more frequently in patients of East Asian descent than in patients of non-East Asian descent.

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : Polycythemia Eye Disorders : Retinal detachment/tear Gastrointestinal Disorders : Pancreatitis Metabolic and Nutrition Disorder : Tumor lysis syndrome (including fatal cases) Vascular Disorders : Arterial (including aortic) aneurysms, dissections, and rupture (including fatal cases)