pazopanib 200 MG Oral Tablet [Votrient]

INDICATIONS AND USAGE Pazopanib tablets are a kinase inhibitor indicated for the treatment of adults with: advanced renal cell carcinoma (RCC). ( 1.1 ) advanced soft tissue sarcoma (STS) who have received prior chemotherapy. ( 1.2 ) Limitations of Use : The efficacy of pazopanib tablets for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated. 1.1 Renal Cell Carcinoma Pazopanib tablets are indicated for the treatment of adults with advanced renal cell carcinoma (RCC). 1.2 Soft Tissue Sarcoma Pazopanib tablets are indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of Use : The efficacy of pazopanib tablets for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

DOSAGE AND ADMINISTRATION Recommended Dosage : 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). ( 2.1 ) Moderate Hepatic Impairment : 200 mg orally once daily. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of pazopanib tablets 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. 2.2 Dosage Modifications for Adverse Reactions Table 1 summarizes the recommended dose reductions. Table 1. Recommended Dose Reductions of Pazopanib Tablets 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 pazopanib tablets 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 Pazopanib Tablets for Adverse Reactions Adverse Reaction Severity a 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 pazopanib tablets 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 pazopanib tablets 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. Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 5. 2.3 Dosage 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 pazopanib tablets. If pazopanib tablets are used in patients with moderate hepatic impairment, reduce the pazopanib tablets dose to 200 mg orally once daily. Pazopanib tablets are not recommended in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any ALT value) [see Use in Specific Populations ( 8.7 )] . 2.4 Dosage 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 pazopanib tablets to 400 mg [see Drug Interactions ( 7.1 )] . Strong CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib tablets are not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions ( 7.1 )] . 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 pazopanib tablets dosing by several hours [see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] .

WARNINGS AND PRECAUTIONS Hepatic Toxicity: Severe and fatal hepatotoxicity has occurred. Monitor liver tests at baseline, regularly during treatment and as clinically indicated. Withhold pazopanib tablets and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity. ( 2.2 , 5.1 ) QT Prolongation and Torsades de Pointes: Monitor patients who are at significant risk of developing QT interval prolongation. Monitor electrocardiograms (ECGs) and electrolytes at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating pazopanib tablets and during treatment. ( 5.2 , 12.2 ) Cardiac Dysfunction: Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, have occurred. Monitor blood pressure and manage as appropriate. Monitor for clinical signs or symptoms of congestive heart failure. Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction. Withhold or permanently discontinue pazopanib tablets based on severity of cardiac dysfunction. ( 2.2 , 5.3 ) Hemorrhagic Events: Fatal hemorrhagic events have occurred. Pazopanib tablets have not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months. Withhold pazopanib tablets and resume at reduced dose or permanently discontinue based on severity of hemorrhagic events. ( 2.2 , 5.4 ) Arterial Thromboembolic Events: Arterial thromboembolic events have been observed and can be fatal. Pazopanib tablets have not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue pazopanib tablets in case of an arterial thromboembolic event. ( 2.2 , 5.5 ) Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have been observed, including fatal pulmonary emboli (PE). Monitor for signs and symptoms of VTE and PE. Withhold pazopanib tablets and then resume at same dose or permanently discontinue based on severity of VTE. ( 2.2 , 5.6 ) Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been observed. Permanently discontinue pazopanib tablets if TMA occurs. ( 2.2 , 5.7 ) Gastrointestinal Perforation and Fistula: Fatal perforation events have occurred. Monitor for signs and symptoms of gastrointestinal perforation or fistula. Withhold pazopanib tablets in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue pazopanib tablets in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula. ( 2.2 , 5.8 ) Interstitial Lung Disease/Pneumonitis: Can be fatal. Monitor patients for pulmonary symptoms. Permanently discontinue pazopanib tablets in patients who develop interstitial lung disease (ILD) or pneumonitis. ( 2.2 , 5.9 ) Posterior Reversible Encephalopathy Syndrome: Can be fatal. Permanently discontinue pazopanib tablets in patients who develop posterior reversible encephalopathy syndrome (PRES). ( 2.2 , 5.10 ) Hypertension: Hypertension, including hypertensive crisis, has been observed. Do not initiate pazopanib tablets in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating pazopanib tablets. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce pazopanib tablets or permanently discontinue based on severity of hypertension. ( 2.2 , 5.11 ) Risk of lmpaired Wound Healing: Withhold pazopanib tablets for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of pazopanib tablets after resolution of wound healing complications has not been established. ( 5.12 ) Hypothyroidism: Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate. ( 5.13 ) Proteinuria: Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated. Withhold pazopanib tablets then resume at a reduced dose or permanently discontinue based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome. ( 2.2 , 5.14 ) Tumor Lysis Syndrome: Cases of tumor lysis syndrome (TLS) (some fatal) have been reported in patients with RCC and STS. Closely monitor patients at risk and treat as clinically indicated. ( 5.15 ) Infection: Serious infections (with or without neutropenia), some with fatal outcome, have been reported. Monitor for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly. Consider interruption or discontinuation of pazopanib tablets. ( 5.16 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and patients to use effective contraception. ( 5.19 , 8.1 , 8.3 ) 5.1 Hepatic Toxicity Hepatotoxicity, manifested as increases in ALT, aspartate aminotransferase (AST) and bilirubin, occurred in patients who received pazopanib tablets. 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 x ULN occurred in 18% and ALT > 10 x ULN occurred in 4% of the 290 patients who received pazopanib tablets. 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%. In the monotherapy trials, 2 patients died with disease progression and hepatic failure. In the randomized STS trial (VEG110727), ALT > 3 x ULN occurred in 18% and ALT > 8 x ULN occurred in 5% of the 240 patients who received pazopanib tablets. 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%. 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 pazopanib tablets and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity [see Dosage and Administration ( 2.2 )]. Gilbert's Syndrome Pazopanib tablets 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 x ULN per the recommendations outlined for isolated ALT elevations [see Dosage and Administration ( 2.2 )]. Concomitant Use of Simvastatin Concomitant use of pazopanib tablets and simvastatin increases the risk of ALT elevations [see Drug Interactions ( 7.3 )]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib tablets. 5.2 QT Prolongation and Torsades de Pointes In the RCC trials, 558/586 patients were subject to routine electrocardiogram (ECG) monitoring and QT prolongation ≥ 500 msec was identified in 2% of these 558 patients. In monotherapy trials, torsades de pointes occurred in < 1% of 977 patients who received pazopanib tablets. In the randomized RCC (VEG105192) and STS (VEG

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet‑derived growth factor receptor (PDGFR)-α and PDGFR-β, fibroblast growth factor receptor (FGFR)-1 and FGFR-3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro , pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors. In vivo , pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.