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VOTRIENT (Pazopanib) Tablets Gastrointestinal Perforation Or Fistula

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VOTRIENT (Pazopanib) Tablets Gastrointestinal Perforation Or Fistula HIGHLIGHTS OF PRESCRIBING INFORMATION Venous thrombotic events (VTE) have been observed, including fatal These highlights do not include all the information needed to use pulmonary emboli (PE). Monitor for signs and symptoms of VTE and PE. VOTRIENT safely and effectively. See full prescribing information for (5.6) VOTRIENT. Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for VOTRIENT (pazopanib) tablets gastrointestinal perforation or fistula. (5.7) Initial U.S. Approval: 2009 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been WARNING: HEPATOTOXICITY observed. Permanently discontinue VOTRIENT if signs or symptoms of See full prescribing information for complete boxed warning. RPLS occur. (5.8) Severe and fatal hepatotoxicity has been observed in clinical trials. Hypertension including hypertensive crisis has been observed. Blood pressure Monitor hepatic function and interrupt, reduce, or discontinue dosing as should be well-controlled prior to initiating VOTRIENT. Monitor blood recommended [see Warnings and Precautions (5.1)]. pressure within one week after starting VOTRIENT and frequently thereafter. (5.9) Interruption of therapy with VOTRIENT is recommended in patients ---------------------------RECENT MAJOR CHANGES -------------------- undergoing surgical procedures. (5.10) Indications and Usage (1) 04/2012 Dosage and Administration (2.2) 04/2012 Hypothyroidism may occur. Monitoring of thyroid function tests is Warnings and Precautions (5.1-5.9, 5.11-5.14) 04/2012 recommended. (5.11) Proteinuria: Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥ 3 grams and discontinue for repeat episodes despite dose ----------------------------INDICATIONS AND USAGE--------------------- reductions. (5.12) VOTRIENT is a kinase inhibitor indicated for the treatment of patients with: Infection: Serious infections (with or without neutropenia), some with fatal advanced renal cell carcinoma. (1) outcome, have been reported. Monitor for signs and symptoms and treat advanced soft tissue sarcoma who have received prior chemotherapy. (1) active infection promptly. Consider discontinuation of VOTRIENT. (5.13) Limitations of Use: VOTRIENT can cause fetal harm when administered to a pregnant woman. The efficacy of VOTRIENT for the treatment of patients with adipocytic soft Women of childbearing potential should be advised of the potential hazard tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated. to the fetus and to avoid becoming pregnant while taking VOTRIENT. (5.15, 8.1) ----------------------- DOSAGE AND ADMINISTRATION ---------------- 800 mg orally once daily without food (at least 1 hour before or 2 hours after a ------------------------------ ADVERSE REACTIONS ----------------------- meal). (2.1) The most common adverse reactions in patients with advanced renal cell Baseline moderate hepatic impairment – 200 mg orally once daily. Not carcinoma (20%) are diarrhea, hypertension, hair color changes recommended in patients with severe hepatic impairment. (2.2) (depigmentation), nausea, anorexia, and vomiting. (6.1) The most common adverse reactions in patients with advanced soft tissue --------------------- DOSAGE FORMS AND STRENGTHS -------------- sarcoma (20%) are fatigue, diarrhea, nausea, decreased weight, hypertension, 200 mg tablets (3) decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. (6.1) -------------------------------CONTRAINDICATIONS------------------------ None (4) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or ----------------------- WARNINGS AND PRECAUTIONS----------------- www.fda.gov/medwatch. Increases in serum transaminase levels and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Measure liver chemistries before the -------------------------------DRUG INTERACTIONS------------------------ initiation of treatment and regularly during treatment. (5.1) CYP3A4 Inhibitors: Avoid use of strong inhibitors. Reduce the dose of Prolonged QT intervals and torsades de pointes have been observed. Use with VOTRIENT when administered with strong CYP3A4 inhibitors. (7.1) caution in patients at higher risk of developing QT interval prolongation. CYP3A4 Inducers: Consider an alternate concomitant medication with no Monitoring electrocardiograms and electrolytes should be considered. (5.2) or minimal enzyme induction potential or avoid VOTRIENT. (7.1) Cardiac dysfunction such as congestive heart failure and decreased left CYP Substrates: Concomitant use of VOTRIENT with agents with narrow ventricular ejection fraction have occurred. Monitor blood pressure and therapeutic windows that are metabolized by CYP3A4, CYP2D6, or manage hypertension promptly. Baseline and periodic evaluation of LVEF CYP2C8 is not recommended. (7.2) is recommended in patients at risk of cardiac dysfunction. (5.3) Concomitant use of VOTRIENT and simvastatin increases the risk of ALT Fatal hemorrhagic events have been reported. VOTRIENT has not been elevations and should be undertaken with caution and close monitoring. studied in patients who have a history of hemoptysis, cerebral, or (7.3) clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. (5.4) See 17 for PATIENT COUNSELING INFORMATION and Medication Arterial thrombotic events have been observed and can be fatal. Use with Guide. caution in patients who are at increased risk for these events. (5.5) Revised: 04/2012 1 Reference ID: 3122369 FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS WARNING: HEPATOTOXICITY 7.1 Drugs That Inhibit or Induce Cytochrome P450 1 INDICATIONS AND USAGE 3A4 Enzymes 2 DOSAGE AND ADMINISTRATION 7.2 Effects of Pazopanib on CYP Substrates 2.1 Recommended Dosing 7.3 Effect of Concomitant use of VOTRIENT and 2.2 Dose Modification Guidelines Simvastatin 3 DOSAGE FORMS AND STRENGTHS 8 USE IN SPECIFIC POPULATIONS 4 CONTRAINDICATIONS 8.1 Pregnancy 5 WARNINGS AND PRECAUTIONS 8.3 Nursing Mothers 5.1 Hepatic Toxicity and Hepatic Impairment 8.4 Pediatric Use 5.2 QT Prolongation and Torsades de Pointes 8.5 Geriatric Use 5.3 Cardiac Dysfunction 8.6 Hepatic Impairment 5.4 Hemorrhagic Events 8.7 Renal Impairment 5.5 Arterial Thrombotic Events 10 OVERDOSAGE 5.6 Venous Thromboembolic Events 11 DESCRIPTION 5.7 Gastrointestinal Perforation and Fistula 12 CLINICAL PHARMACOLOGY 5.8 Reversible Posterior Leukoencephalopathy 12.1 Mechanism of Action Syndrome 12.2 Pharmacodynamics 5.9 Hypertension 12.3 Pharmacokinetics 5.10 Wound Healing 12.5 Pharmacogenomics 5.11 Hypothyroidism 13 NONCLINICAL TOXICOLOGY 5.12 Proteinuria 13.1 Carcinogenesis, Mutagenesis, Impairment of 5.13 Infection Fertility 5.14 Increased Toxicity with Other Cancer Therapy 14 CLINICAL STUDIES 5.15 Pregnancy 14.1 Renal Cell Carcinoma 6 ADVERSE REACTIONS 14.2 Soft Tissue Sarcoma 6.1 Clinical Trials Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 6.2 Postmarketing Experience 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 3122369 ______________________________________________________________________ 1 FULL PRESCRIBING INFORMATION 2 WARNING: HEPATOTOXICITY 3 Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic 4 function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and 5 Precautions (5.1)]. 6 1 INDICATIONS AND USAGE 7 VOTRIENT® is indicated for the treatment of patients with advanced renal cell 8 carcinoma (RCC). 9 VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma 10 (STS) who have received prior chemotherapy. 11 Limitation of Use: 12 The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or 13 gastrointestinal stromal tumors has not been demonstrated. 14 2 DOSAGE AND ADMINISTRATION 15 2.1 Recommended Dosing 16 The recommended starting dose of VOTRIENT is 800 mg orally once daily without food 17 (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)]. The dose of 18 VOTRIENT should not exceed 800 mg. 19 Do not crush tablets due to the potential for increased rate of absorption which may affect 20 systemic exposure [see Clinical Pharmacology (12.3)]. 21 If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 22 2.2 Dose Modification Guidelines 23 In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or 24 increase should be in 200 mg steps based on individual tolerability. 25 In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. 26 Hepatic Impairment: No dose adjustment is required in patients with mild hepatic 27 impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be 28 considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should 29 be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic 30 impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 31 Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 32 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and 33 should be avoided. If coadministration of a strong CYP3A4
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