Pazopanib

1 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.

2 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…

5 WARNINGS AND PRECAUTIONS Hepatic Toxicity : Severe and fatal hepatotoxicity has occurred. Monitor liver tests at baseline, regularly during treatment and as clinically indicated. Withhold pazopanib and resume at reduced dose with continued weekly monitoring for 8 weeks, or permanently discontinue with weekly monitoring until resolution based on severity of hepatotoxicity. ( 2.2 , 5.1 ) QT Prolongation and Torsades de Pointes : Monitor patients who are at significant risk of developing QT interval prolongation. Monitor electrocardiograms (ECGs) and electrolytes at baseline and as clinically indicated. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating pazopanib and during treatment. ( 5.2 , 12.2 ) Cardiac Dysfunction : Cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and congestive heart failure, have occurred. Monitor blood pressure and manage as appropriate. Monitor for clinical signs or symptoms of congestive heart failure. Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction. Withhold or permanently discontinue pazopanib based on severity of cardiac dysfunction. ( 2.2 , 5.3 ) Hemorrhagic Events : Fatal hemorrhagic events have occurred. Pazopanib has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months. Withhold pazopanib 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 has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue pazopanib in case of an arterial thromboembolic event. ( 2.2 , 5.5 ) Venous Thromboembolic Events : Venous thromboembolic events (VTEs) have been observed, including fatal pulmonary emboli (PE). Monitor for signs and symptoms of VTE and PE. Withhold pazopanib and then resume at same dose or permanently discontinue based on severity of VTE. ( 2.2 , 5.6 ) Thrombotic Microangiopathy : Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been observed. Permanently discontinue pazopanib 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 in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue pazopanib in case of gastrointestinal perforation or Grade 4 gastrointestinal fistula. ( 2.2 , 5.8 ) Interstitial Lung Disease/Pneumonitis : Can be fatal. Monitor patients for pulmonary symptoms. Permanently discontinue pazopanib in patients who develop interstitial lung disease (ILD) or pneumonitis. ( 2.2 , 5.9 ) Posterior Reversible Encephalopathy Syndrome : Can be fatal. Permanently discontinue pazopanib in patients who develop posterior reversible encephalopathy syndrome (PRES). ( 2. 2, 5.10 ) Hypertension : Hypertension, including hypertensive crisis, has been observed. Do not initiate pazopanib in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating pazopanib. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce pazopanib or permanently discontinue based on severity of hypertension. ( 2.2 , 5.11 ) Risk of Impaired Wound Healing : Withhold pazopanib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of pazopanib after resolution of wound healing complications has not been established. ( 5.12 ) Hypothyroidism : Monitor thyroid tests at baseline,…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors : Avoid coadministration of pazopanib with strong CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dose of pazopanib. ( 2.4 , 7.1 ) Strong CYP3A4 Inducers : Consider an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib is not recommended if chronic use of strong CYP3A4 inducers cannot be avoided. ( 2.4 , 7.1 ) CYP Substrates : Coadministration of pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. ( 7.2 ) Concomitant Use with Simvastatin : Concomitant use of pazopanib with simvastatin increases the risk of alanine aminotransferase (ALT) elevations. Increase to weekly monitoring of liver function as recommended. Withhold pazopanib and resume at reduced dose, or permanently discontinue based on severity of hepatotoxicity. ( 7.3 ) Concomitant Use With Gastric Acid-Reducing Agents : Avoid concomitant use of pazopanib with gastric acid-reducing agents. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate antacid and pazopanib dosing by several hours. ( 2.4 , 7.4 ) 7.1 Effect of Other Drugs on Pazopanib Strong CYP3A4 Inhibitors Coadministration of pazopanib with strong inhibitors of CYP3A4 increases pazopanib concentrations [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of pazopanib with strong CYP3A4 inhibitors and consider an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the dose of pazopanib [see Dosage and Administration ( 2.4 )] . Strong CYP3A4 Inducers Coadministration of strong CYP3A4 inducers may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib is not recommended if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration ( 2.4 )] . Transporters Coadministration of strong inhibitors of P-gp or BCRP may increase pazopanib concentrations. Avoid concomitant use of pazopanib with strong inhibitors of P-gp or BCRP. Consider selection of alternative concomitant medicinal products with no or minimal potential to inhibit P-gp or BCRP. 7.2 Effects of Pazopanib on Other Drugs CYP Substrates Coadministration of pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 may result in inhibition of the metabolism of these products and create the potential for serious adverse reactions. The concomitant use of pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended [see Clinical Pharmacology ( 12.3 )] . 7.3 Concomitant Use with Simvastatin Concomitant use of pazopanib with simvastatin increases the incidence of ALT elevations. Across clinical trials of pazopanib as a single agent, ALT > 3 × 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, increase to weekly monitoring of liver function as recommended. Withhold pazopanib and resume at reduced dose, or permanently discontinue based on severity of hepatotoxicity [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )] . Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib. 7.4 Concomitant Use with Gastric Acid-Reducing Agents Concomitant use of pazopanib with esomeprazole, a PPI, decreased the exposure of pazopanib. Avoid concomitant use of pazopanib with gastric acid-reducing agents. If concomitant administration with a gastric acid-reducing agent cannot be avoided, consider short-acting antacids in place of PPIs and H2-receptor antagonists. Separate short-a…

8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , pazopanib can cause fetal harm when administered to a pregnant woman. There are no available data on pazopanib use in pregnant women to evaluate for a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the MRHD of 800 mg/day (based on AUC) (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies and miscarriage is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral pazopanib at least 15 days prior to mating and for 6 days after mating, which resulted in increased pre-implantation loss and early resorptions at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8-fold the AUC at the MRHD of 800 mg/day). Postimplantation loss, embryolethality, and decreased fetal body weights were noted in females administered doses greater than or equal to 10 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day). In embryo-fetal developmental toxicity studies in rats and rabbits, oral pazopanib was administered to pregnant animals during organogenesis. In rats, dose levels of greater than or equal to 3 mg/kg/day (approximately 0.1-fold the AUC at the MRHD of 800 mg/day) resulted in teratogenic effects, including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, increases in postimplantation loss, embryolethality and reduced fetal body weight. In rabbits, maternal toxicity, increased postimplantation loss and abortion were observed at doses greater than or equal to 30 mg/kg/day (approximately 0.007-fold the AUC at the MRHD of 800 mg/day). In addition, severe maternal body weight loss and 100% litter loss were observed at doses greater than or equal to 100 mg/kg/day (0.02-fold the AUC at the MRHD of 800 mg/day), while fetal weight was reduced at doses greater than or equal to 3 mg/kg/day (AUC not calculated).

8.3 Females and Males of Reproductive Potential Pazopanib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to starting treatment with pazopanib. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with pazopanib and for at least 2 weeks after the last dose. Males Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with pazopanib and for at least 2 weeks after the last dose. Infertility Based on findings from animal studies, pazopanib may impair fertility in females and males of reproductive potential while receiving treatment [see Nonclinical Toxicology ( 13.1 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are elsewhere in the labeling: Hepatic Toxicity [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 Thromboembolic Events [see Warnings and Precautions ( 5.5 )] Venous Thromboembolic Events [see Warnings and Precautions ( 5.6 )] Thrombotic Microangiopathy (TMA) [see Warnings and Precautions ( 5.7 )] Gastrointestinal Perforation and Fistula [see Warnings and Precautions ( 5.8 )] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.9 )] Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions ( 5.10 )] Hypertension [see Warnings and Precautions ( 5.11 )] Hypothyroidism [see Warnings and Precautions ( 5.13 )] Proteinuria [see Warnings and Precautions ( 5.14 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.15 )] Infection [see Warnings and Precautions ( 5.16 )] The most common adverse reactions in patients with RCC (≥ 20%) are diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 pazopanib as a single agent, including 586 pazopanib-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 pazopanib 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 pazopanib was evaluated in 290 patients with RCC who participated in VEG105192, 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 pazopanib. Forty-two percent of patients on pazopanib 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 Pazopanib in VEG105192 Adverse Reactions Pazopanib (N = 290) Placebo (N = 145) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % 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 Abbreviation: RCC, renal cell carcinoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in …