Pazopanibside effects

The following clinically significant adverse reactions are elsewhere in the labeling: Hepatic Toxicity QT Prolongation and Torsades de Pointes Cardiac Dysfunction Hemorrhagic Events Arterial Thromboembolic Events Venous Thromboembolic Events Thrombotic Microangiopathy (TMA) Gastrointestinal Perforation and Fistula Interstitial Lung Disease (ILD)/Pneumonitis Posterior Reversible Encephalopathy Syndrome (PRES) Hypertension Hypothyroidism Proteinuria Tumor Lysis Syndrome Infection The most common adverse reactions in patients with RCC (≥ 20%) are diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting. 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. To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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. The median duration of treatment was 4.5 months (range, 0 to 24) for patients who received pazopanib tablets. Fifty-eight percent of patients on pazopanib tablets required a dose interruption and 38% required a dose reduction. Seventeen percent of patients who received pazopanib tablets discontinued therapy due to adverse reactions. Table 5 presents the adverse reactions in VEG110727. Table 5. Adverse Reactions (≥ 10%) in Patients with STS Who Received Pazopanib Tablets in VEG110727 Adverse Reactions Pazopanib Tablets (N = 240) Placebo (N = 123) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % Fatigue 65 13 1 48 4 1 Diarrhea 59 5 0 15 1 0 Nausea 56 3 0 22 2 0 Weight decreased 48 4 0 15 0 0 Hypertension 42 7 0 6 0 0 Appetite decreased 40 6 0 19 0 0 Hair color changes 39 0 0 2 0 0 Vomiting 33 3 0 11 1 0 Tumor pain 29 8 0 21 7 2 Dysgeusia 28 0 0 3 0 0 Headache 23 1 0 8 0 0 Musculoskeletal pain 23 2 0 20 2 0 Myalgia 23 2 0 9 0 0 Gastrointestinal pain 23 3 0 9 4 0 Dyspnea 20 5 < 1 17 5 1 Exfoliative rash 18 < 1 0 9 0 0 Cough 17 < 1 0 12 < 1 0 Peripheral edema 14 2 0 9 2 0 Mucositis 12 2 0 2 0 0 Alopecia 12 0 0 1 0 0 Dizziness 11 1 0 4 0 0 Skin disorder b 11 2 0 1 0 0 Skin hypopigmentation 11 0 0 0 0 0 Stomatitis 11 < 1 0 3 0 0 Chest pain 10 2 0 6 0 0 Abbreviation: STS, soft tissue sarcoma. 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 pazopanib tablets 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 6 presents the laboratory abnormalities in VEG110727. Table 6. Select Laboratory Abnormalities (> 10%) in Patients with STS Who Received Pazopanib Tablets with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG110727 Parameters Pazopanib Tablets (N = 240) Placebo (N = 123) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % Chemistry AST increased 51 5 3 22 2 0 ALT increased 46 8 2 18 2 1 Glucose increased 45 < 1 0 35 2 0 Albumin decreased 34 1 0 21 0 0 Alkaline phosphataseincreased 32 3 0 23 1 0 Sodium decreased 31 4 0 20 3 0 Total bilirubin increased 29 1 0 7 2 0 Potassium increased 16 1 0 11 0 0 Hematologic Leukopenia 44 1 0 15 0 0 Lymphocytopenia 43 10 0 36 9 2 Thrombocytopenia 36 3 1 6 0 0 Neutropenia 33 4 0 7 0 0 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; STS, soft tissue sarcoma. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 Other Clinically Relevant Adverse Reactions Lipase Elevations In a single-arm RCC trial (VEG102616), elevated lipase was observed for 27% of 181 patients with available laboratory data. Elevated lipase as an adverse reaction was reported for 4% of 225 patients, including 2.7% (6/225) with Grade 3 and 0.4% (1/225) with Grade 4. In the RCC trials, clinical pancreatitis was observed in < 1% of 586 patients. Pneumothorax Two of 290 patients (0.7%) treated with pazopanib tablets in the randomized RCC trial (VEG105192) and 8 of 240 patients (3.3%) treated with pazopanib tablets in the randomized STS trial (VEG110727) developed a pneumothorax. Bradycardia In the randomized RCC trial (VEG105192), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 280 patients treated with pazopanib tablets. Bradycardia was reported as an adverse reaction in 2% of 290 patients. In the randomized STS trial (VEG110727), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 238 patients treated with pazopanib tablets. Bradycardia was reported as an adverse reaction in 2% of 240 patients. Adverse Reactions in East Asian Patients In an analysis of pooled clinical trial data (N = 1,938) with pazopanib tablets, Grade 3 and Grade 4 neutropenia (12% versus 2%), thrombocytopenia (6% versus < 1%) and palmar-plantar erythrodysesthesia (6% versus 2%) were observed more frequently in patients of East Asian descent than in patients of non-East Asian descent.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of pazopanib tablets. 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. Blood and Lymphatic System Disorders: Polycythemia Eye Disorders: Retinal detachment/tear Gastrointestinal Disorders: Pancreatitis Metabolic and Nutrition Disorder: Tumor lysis syndrome (including fatal cases) Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture (including fatal cases)