INDICATIONS

PAZOPANIB TABLETS are indicated for the treatment of adults with advanced renal cell carcinoma (RCC).
PAZOPANIB TABLETS are indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of PAZOPANIB TABLETS for the treatment of patients with adipocytic STS or gastrointestinal (GI) stromal tumors has not been demonstrated.

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

Hepatic Toxicity: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. Increases in serum transaminase levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert's syndrome. In patients with preexisting moderate hepatic impairment, the starting dose of PAZOPANIB TABLETS should be reduced to 200 mg per day or alternatives to PAZOPANIB TABLETS should be considered. Treatment with PAZOPANIB TABLETS is not recommended in patients with severe hepatic impairment. Concomitant use of PAZOPANIB TABLETS and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating PAZOPANIB TABLETS and during treatment.

Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has occurred. In the RCC trials, cardiac dysfunction was observed in 0.6% of 586 patients without routine on-study LVEF monitoring. In the randomized RCC trial (VEG105192), myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal. In a randomized RCC trial of PAZOPANIB TABLETS compared with sunitinib, myocardial dysfunction occurred in 13% of the 362 patients on PAZOPANIB TABLETS who had baseline and postbaseline LVEF measurements. CHF occurred in 0.5% of patients. In the randomized STS trial, myocardial dysfunction occurred in 11% of the 142 patients who had baseline and postbaseline LVEF measurements. One percent (3/240) of patients who received PAZOPANIB TABLETS had CHF, which did not resolve in 1 patient. Fourteen of the 16 patients with myocardial dysfunction treated with PAZOPANIB TABLETS had concurrent hypertension (HTN) which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy), possibly by increasing cardiac afterload. Monitor blood pressure (BP), and manage as appropriate. Monitor for clinical signs or symptoms of CHF. Conduct baseline and periodic evaluation of LVEF in patients at risk of cardiac dysfunction, including previous anthracycline exposure. Withhold or permanently discontinue PAZOPANIB TABLETS based on severity of cardiac dysfunction.

Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials, and cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with PAZOPANIB TABLETS. In the randomized RCC trial, 13% (37/290) of patients treated with PAZOPANIB TABLETS compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with PAZOPANIB TABLETS who had hemorrhagic events experienced serious events, including pulmonary, GI, and genitourinary hemorrhage. One percent of patients treated with PAZOPANIB TABLETS died from hemorrhage. In the randomized STS trial, 22% of 240 patients treated with PAZOPANIB TABLETS experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events occurred in 1% of patients and included intracranial hemorrhage, subarachnoid hemorrhage, and peritoneal hemorrhage. PAZOPANIB TABLETS has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant GI hemorrhage in the past 6 months. Withhold PAZOPANIB TABLETS and resume at a reduced dose, or permanently discontinue, based on severity of hemorrhagic events.

Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving PAZOPANIB TABLETS experienced myocardial infarction (MI) or ischemia, 0.3% (1/290) had a cerebrovascular accident (CVA), and 1% (4/290) had an event of transient ischemic attack. In the randomized STS trial, 2% of 240 patients who received PAZOPANIB TABLETS experienced MI or ischemia and 0.4% had a CVA. PAZOPANIB TABLETS has not been studied in patients who have had an arterial thromboembolic event within the past 6 months. Permanently discontinue PAZOPANIB TABLETS in case of an arterial thromboembolic event.

Venous Thromboembolic Events (VTEs): VTEs, including venous thrombosis and fatal pulmonary embolus (PE), have occurred. In the randomized RCC trial, VTEs were reported in 1% of patients treated with PAZOPANIB TABLETS and in 1% of patients treated with placebo. In the randomized STS trial, VTEs were reported in 5% of 240 patients who received PAZOPANIB TABLETS. Fatal PE occurred in 1% (2/240). Monitor for signs and symptoms of VTE and PE. Withhold PAZOPANIB TABLETS and then resume at the same dose, or permanently discontinue, based on severity of VTE.

Thrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been reported in clinical trials of PAZOPANIB TABLETS as monotherapy, in combination with bevacizumab, and in combination with topotecan. PAZOPANIB TABLETS is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of PAZOPANIB TABLETS. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue PAZOPANIB TABLETS in patients developing TMA. Manage as clinically indicated.

GI Perforation and Fistula: In the RCC and STS trials, GI perforation or fistula occurred in 0.9% of 586 patients and 1% of 382 patients who received PAZOPANIB TABLETS, 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 GI perforation or fistula. Withhold PAZOPANIB TABLETS in case of grade 2 or grade 3 GI fistula, and resume based on medical judgment. Permanently discontinue PAZOPANIB TABLETS in case of GI perforation or grade 4 GI fistula.

Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, has been reported in 0.1% of patients in the clinical trials treated with PAZOPANIB TABLETS. Monitor patients for ILD/pneumonitis, and discontinue PAZOPANIB TABLETS if symptoms of ILD or pneumonitis develop.

Posterior Reversible Encephalopathy Syndrome (PRES): PRES has been reported in patients who received PAZOPANIB TABLETS and may be fatal. PRES is a neurologic disorder, which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Permanently discontinue PAZOPANIB TABLETS in patients developing PRES.

Hypertension: HTN, including hypertensive crisis, has occurred in clinical trials. HTN occurs early in the course of treatment (approximately 40% of cases occurred by Day 9, and 90% of cases occurred in the first 18 weeks). Do not initiate PAZOPANIB TABLETS in patients with uncontrolled HTN. Optimize BP prior to initiating PAZOPANIB TABLETS. Monitor BP 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 HTN. Approximately 1% of patients required permanent discontinuation of PAZOPANIB TABLETS because of HTN.

Risk of Impaired Wound Healing: Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, PAZOPANIB TABLETS has the potential to adversely affect wound healing. Withhold PAZOPANIB TABLETS at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing occurs. The safety of resuming PAZOPANIB TABLETS after wound healing complications have resolved has not been established.

Hypothyroidism: Hypothyroidism was reported in 7% of 290 patients treated with PAZOPANIB TABLETS in the randomized RCC trial and in no patients receiving placebo, and in 5% of 240 patients treated with PAZOPANIB TABLETS in the randomized STS trial and in no patients receiving placebo. Monitor thyroid tests at baseline, during treatment, and as clinically indicated. Manage hypothyroidism as appropriate.

Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction (AR) in 9% (27/290) of patients receiving PAZOPANIB TABLETS, leading to treatment discontinuation in 2 patients. In the randomized STS trial, proteinuria occurred in 1% of 240 patients. Nephrotic syndrome occurred in 1 patient, and treatment was discontinued in this patient. 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.

Tumor Lysis Syndrome (TLS): Cases of TLS, including fatal cases, have been reported in patients with RCC and STS treated with PAZOPANIB TABLETS. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated.

Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of PAZOPANIB TABLETS.

Increased Toxicity with Other Cancer Therapy: PAZOPANIB TABLETS is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering PAZOPANIB TABLETS in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

Increased Toxicity in Developing Organs: The safety and effectiveness of PAZOPANIB TABLETS in pediatric patients have not been established. PAZOPANIB TABLETS is not indicated for use in pediatric patients. Animal studies have demonstrated PAZOPANIB TABLETS can severely affect organ growth and maturation during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. PAZOPANIB TABLETS may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

Embryo-Fetal Toxicity: PAZOPANIB TABLETS can cause fetal harm when administered to a pregnant woman based on animal reproduction studies and its mechanism of action. In animal developmental and reproductive toxicology studies, oral administration of PAZOPANIB TABLETS to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose of 800 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PAZOPANIB TABLETS and for at least 2 weeks following the final dose. Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with PAZOPANIB TABLETS and for at least 2 weeks after the last dose.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the RCC and STS clinical trials. Patients should be advised how to manage mild diarrhea and to notify their health care 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. In the RCC trials of PAZOPANIB TABLETS, clinical pancreatitis was observed in <1% (4/586) of patients.

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

Bradycardia: In the randomized trial of PAZOPANIB TABLETS for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute [bpm]) was observed in 19% (52/280) of patients treated with PAZOPANIB TABLETS and in 11% (16/144) of patients on the placebo arm. In the randomized trial of PAZOPANIB TABLETS for the treatment of STS, bradycardia based on vital signs (<60 bpm) was observed in 19% (45/238) of patients treated with PAZOPANIB TABLETS and in 4% (5/121) of patients on the placebo arm.

Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of PAZOPANIB TABLETS and should be avoided, but, if warranted, reduce the dose of PAZOPANIB TABLETS to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of PAZOPANIB TABLETS. PAZOPANIB TABLETS should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of P-glycoprotein (PgP) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to PAZOPANIB TABLETS.

CYP Substrates: Concomitant use of PAZOPANIB TABLETS 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 ARs. Concomitant use of PAZOPANIB TABLETS and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for PAZOPANIB TABLETS, consider alternatives to PAZOPANIB TABLETS, or consider discontinuing simvastatin. Insufficient data exist to assess the risk of concomitant administration of alternative statins and PAZOPANIB TABLETS.

Drugs That Raise Gastric pH: Avoid concomitant use of PAZOPANIB TABLETS with drugs that raise gastric pH (e.g., esomeprazole) due to the potential to decrease concentrations of PAZOPANIB TABLETS. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate antacid and PAZOPANIB TABLETS dosing by several hours.

Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on PAZOPANIB TABLETS. The PAZOPANIB TABLETS dose was reduced for 36% of patients.

The most common ARs (≥20%) for PAZOPANIB TABLETS vs placebo were diarrhea (52% vs 9%), HTN (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking PAZOPANIB TABLETS vs placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). Adverse Reactions in the Randomized STS Trial: A dose interruption was required for 58% of patients on PAZOPANIB TABLETS. The PAZOPANIB TABLETS dose was reduced for 38% of patients. PAZOPANIB TABLETS therapy was discontinued due to ARs in 17% of patients.

The most common ARs (≥20%) in patients who received PAZOPANIB TABLETS vs placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), HTN (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), GI pain (23% vs 9%), and dyspnea (20% vs 17%).

Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving PAZOPANIB TABLETS vs placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%).

In a pooled analysis of PAZOPANIB TABLETS clinical trials, East Asian patients had a higher frequency of neutropenia, thrombocytopenia, and palmar-plantar erythrodysesthesia syndrome than non-East Asian patients. (See Adverse Reactions, Section 6.1, in full Prescribing Information.)

Please see full Prescribing Information, including Boxed WARNING.