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 8 times ULN ALT elevations > 3 times ULN occur concurrently with bilirubin elevations > 2 times ULN Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline. 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 times ULN recur despite dose reduction(s). 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 times 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 Grade 4 Withhold until improvement to Grade 1.5 to 3 times 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 times 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)] .

3 DOSAGE FORMS AND STRENGTHS Pazopanib tablets: 200 mg, gray, modified capsule-shaped, film-coated tablets debossed with “P 200” on one side and plain on the other side. Tablets: 200 mg. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 Torrent Pharma Inc., at 1-800-912-9561 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 tablets 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 tablets 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 tablets 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 tablets. Forty-two percent of patients on pazopanib tablets 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 Tablets in VEG105192 Abbreviation: RCC, renal cell carcinoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Adverse Reactions Pazopanib Tablets (N = 290) Placebo (N = 145) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % Diarrhea 52 3 10%) in Patients with RCC Who Received Pazopanib Tablets with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG105192 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RCC, renal ce …

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Avoid coadministration of pazopanib tablets with strong CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dose of pazopanib tablets. ( 2.4 , 7.1 ) Strong CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib tablets are not recommended if chronic use of strong CYP3A4 inducers cannot be avoided. ( 2.4 , 7.1 ) CYP Substrates: Coadministration of pazopanib tablets 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 tablets with simvastatin increases the risk of alanine aminotransferase (ALT) elevations. Increase to weekly monitoring of liver function as recommended. Withhold pazopanib tablets 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 tablets 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 Tablets Strong CYP3A4 Inhibitors Coadministration of pazopanib with strong inhibitors of CYP3A4 increases pazopanib concentrations [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of pazopanib tablets 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 tablets [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 tablets are 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 tablets 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 Tablets on Other Drugs CYP Substrates Coadministration of pazopanib tablets 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 tablets 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 tablets with simvastatin increases the incidence of ALT elevations. Across clinical trials of pazopanib tablets 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 tablets 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 tablets. 7.4 Concomitant Use With Gastric Acid-Reducing Agents Concomitant use of pazopanib tablets with esomeprazole, a PPI, decreased the exposure of pazopanib. Avoid concomitant use of pazopanib tablets with gastric acid-reducing agents. If concomita …

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 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). 8.2 Lactation Risk Summary There is no data on the presence of pazopanib or its metabolites in human milk or their effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with pazopanib and for 2 weeks after the final dose. 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 …

12.1 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.

11 DESCRIPTION Pazopanib is a kinase inhibitor. 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-methylbenzolsulfonamide hydrochloride. It has the molecular formula C 21 H 23 N 7 O 2 S•HCl and a molecular weight of 473.99 g/mol. Pazopanib hydrochloride has the following chemical structure: Pazopanib hydrochloride is a white to off-white powder. It is sparingly soluble in dimethyl sulfoxide, slightly soluble in methanol, practically insoluble in acetonitrile, and in water. Pazopanib tablets are for oral use. Each tablet contains 200 mg of pazopanib free base equivalent to 216.7 mg of pazopanib hydrochloride. The inactive ingredients of pazopanib tablets are: Tablet Core : magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: Gray film-coat: hypromellose, iron oxide black, iron oxide yellow, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, and titanium dioxide. chemical structure

10 OVERDOSAGE Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily (2.5 times the recommended dose) and 1,000 mg daily (1.25 times the recommended dose), respectively. Provide general supportive measures to manage an overdose. Hemodialysis is not expected to enhance the elimination of pazopanib tablets because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

16 HOW SUPPLIED/STORAGE AND HANDLING Pazopanib 200 mg tablets are supplied as capsule-shaped, grey colored, film-coated debossed with ‘ S7 ’ on one side and plain on other side and are available in: Bottles of 30 Tablets with child-resistant closure: NDC 63304-116-30 Bottles of 120 tablets with child-resistant closure: NDC 63304-116-13 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].