VOTRIENT

GlaxoSmithKline LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VOTRIENT safely and effectively. See full prescribing information for VOTRIENT. VOTRIENT (pazopanib) tablets, for oral useInitial U.S. Approval: 2009RECENT MAJOR CHANGES Dosage and Administration, Dose Modification Guidelines (2.2) 08/2013 Warnings and Precautions, Thrombotic Microangiopathy (5.7) 08/2013 BOXED WARNINGWARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and Precautions (5.1)]. INDICATIONS AND USAGEVOTRIENT is a kinase inhibitor indicated for the treatment of patients with: •advanced renal cell carcinoma. (1) •advanced soft tissue sarcoma who have received prior chemotherapy. (1) Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated.DOSAGE AND ADMINISTRATION •800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). (2.1) •Baseline moderate hepatic impairment – 200 mg orally once daily. Not recommended in patients with severe hepatic impairment. (2.2) DOSAGE FORMS AND STRENGTHS200 mg tablets (3)CONTRAINDICATIONSNone (4)WARNINGS AND PRECAUTIONS •Increases in serum transaminase levels and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Measure liver chemistries before the initiation of treatment and regularly during treatment. (5.1) •Prolonged QT intervals and torsades de pointes have been observed. Use with caution in patients at higher risk of developing QT interval prolongation. Monitoring electrocardiograms and electrolytes should be considered. (5.2) •Cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction (LVEF) have occurred. Monitor blood pressure and manage hypertension promptly. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction. (5.3) •Fatal hemorrhagic events have been reported. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. (5.4) •Arterial thromboembolic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events. (5.5) •Venous thromboembolic events (VTE) have been observed, including fatal pulmonary emboli (PE). Monitor for signs and symptoms of VTE and PE. (5.6) •Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been observed. Permanently discontinue VOTRIENT if TMA occurs. (5.7) •Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. (5.8) •Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed and can be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. (5.9) •Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating VOTRIENT. Monitor blood pressure within one week after starting VOTRIENT and frequently thereafter. (5.10) •Interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. (5.11) •Hypothyroidism may occur. Monitoring of thyroid function tests is recommended. (5.12) •Proteinuria: Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. (5.13) •Infection: Serious infections (with or without neutropenia), some with fatal outcome, have been reported. Monitor for signs and symptoms and treat active infection promptly. Interrupt or discontinue VOTRIENT. (5.14) •Animal studies have demonstrated VOTRIENT can severely affect organ growth and maturation during early post-natal development. The safety and effectiveness in pediatric patients have not been established. (5.16) •VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. (5.17, 8.1) Side EffectsThe most common adverse reactions in patients with advanced renal cell carcinoma (≥20%) are diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting. (6.1)The most common adverse reactions in patients with advanced soft tissue sarcoma (≥20%) are fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS •CYP3A4 Inhibitors: Avoid use of strong CYP3A4 inhibitors. If coadministration is warranted, reduce the dose of VOTRIENT to 400 mg. (7.1) •CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. (7.1) •CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. (7.3) •Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring. (7.4) •Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours. (7.5)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: HEPATOTOXICITY
• 1 VOTRIENT INDICATIONS AND USAGE
• 2 VOTRIENT DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dosing
  • 2.2 Dose Modification Guidelines
• 3 DOSAGE FORMS AND STRENGTHS
• 4 VOTRIENT CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hepatic Toxicity and Hepatic Impairment
  • 5.2 QT Prolongation and Torsades de Pointes
  • 5.3 Cardiac Dysfunction
  • 5.4 Hemorrhagic Events
  • 5.5 Arterial Thromboembolic Events
  • 5.6 Venous Thromboembolic Events
  • 5.8 Gastrointestinal Perforation and Fistula
  • 5.9 Reversible Posterior Leukoencephalopathy Syndrome
  • 5.10 Hypertension
  • 5.11 Wound Healing
  • 5.12 Hypothyroidism
  • 5.13 Proteinuria
  • 5.14 Infection
  • 5.15 Increased Toxicity With Other Cancer Therapy
  • 5.16 Increased Toxicity in Developing Organs
  • 5.17 Pregnancy
• 6 VOTRIENT ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes
  • 7.2 Drugs That Inhibit Transporters
  • 7.3 Effects of Pazopanib on CYP Substrates
  • 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin
  • 7.5 Drugs That Raise Gastric pH
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
  • 8.7 Renal Impairment
• 10 OVERDOSAGE
• 11 VOTRIENT DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.5 Pharmacogenomics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Renal Cell Carcinoma
  • 14.2 Soft Tissue Sarcoma
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)]. The dose of VOTRIENT should not exceed 800 mg.

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 less than 12 hours until the next dose.

2.2 Dose Modification Guidelines

In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability.

In STS, a decrease or increase should be in 200 mg steps based on individual tolerability.

Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider 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. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS

200 mg tablets of VOTRIENT — modified capsule-shaped, gray, film-coated with GS JT debossed on one side. Each tablet contains 216.7 mg of pazopanib hydrochloride equivalent to 200 mg of pazopanib.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Toxicity and Hepatic Impairment

In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)].

In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo.

In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo.

Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure and 0.4% of patients (1/240) in the randomized STS trial died of hepatic failure.

• •Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4.
• •Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline.
• •Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued.
• •If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5)]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.

Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.2 QT Prolongation and Torsades de Pointes

In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials.

In the randomized RCC and STS trials, 1% (3/290) of patients 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. None of the 268 patients who received placebo on the two trials had post-baseline QTc values ≥500 msec.

VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed.

5.3 Cardiac Dysfunction

In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10% compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient.

Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial 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. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure.

5.4 Hemorrhagic Events

Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials; there were no reports of fatal hemorrhage in the STS trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT 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 (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT.

In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo 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 in the STS population occurred in 1% (3/240) 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, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

5.5 Arterial Thromboembolic Events

Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials and in no patients in the STS trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo in either trial. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients.

5.6 Venous Thromboembolic Events

In RCC and STS trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. In the randomized RCC trial, the rate was 1% in both arms. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE.

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported 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.

5.8 Gastrointestinal Perforation and Fistula

In the RCC and STS trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients and 1% (4/382) of patients receiving 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.

5.9 Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal.

RPLS 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. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS.

5.10 Hypertension

In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)].

Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)].

5.11 Wound Healing

No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence.

5.12 Hypothyroidism

Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm of either trial had hypothyroidism. In RCC and STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) and 5% (20/382) of patients, respectively. Proactive monitoring of thyroid function tests is recommended.

5.13 Proteinuria

In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome.

Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)].

5.14 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.

5.15 Increased 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 concerns over 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.

5.16 Increased 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 during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)].

5.17 Pregnancy

VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient.

There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Potentially serious adverse reactions with VOTRIENT included:

• •Hepatotoxicity [see Warnings and Precautions (5.1)]
• •QT prolongation and torsades de pointes [see Warnings and Precautions (5.2)]
• •Cardiac dysfunction [see Warnings and Precautions (5.3)]
• •Hemorrhagic events [see Warnings and Precautions (5.4)]
• •Arterial and venous thromboembolic events [see Warnings and Precautions (5.5 and 5.6)]
• •Thrombotic microangiopathy [see Warnings and Precautions (5.7)]
• •Gastrointestinal perforation and fistula [see Warnings and Precautions (5.8)]
• •Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.9)]
• •Hypertension [see Warnings and Precautions (5.10)]
• •Infection [see Warnings and Precautions (5.14)]
• •Increased toxicity with other cancer therapies [see Warnings and Precautions (5.15)]

Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.

The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1)]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

^a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

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 (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below:

Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

^a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 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.

The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2)]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 3 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

^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.

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 4 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

^a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in both the RCC and STS clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm.

Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo.

6.2 Postmarketing 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.

Gastrointestinal Disorders: Pancreatitis

7 DRUG INTERACTIONS

7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes

In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3)]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib.

CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)].

7.2 Drugs That Inhibit Transporters

In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP.

Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered.

7.3 Effects of Pazopanib on CYP Substrates

Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3)].

Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3)].

7.4 Effect of Concomitant use of VOTRIENT and Simvastatin

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

7.5 Drugs That Raise Gastric pH

In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and C_max). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.17)].

VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women.

In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated).

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver, and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality.

In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)].

8.5 Geriatric Use

In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. In the STS trials, 24% (93/382) of patients were aged ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%), and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)].

An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N = 11). The median steady-state C_max and AUC_(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N = 14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT.

There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE

Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.

Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT.

Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

11 DESCRIPTION

VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C₂₁H₂₃N₇O₂S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure: