votrient

Important safety information

Hepatic Toxicity : Severe and fatal hepatotoxicity has occurred. Monitor liver tests at baseline, regularly during treatment and as clinically indicated. Withhold VOTRIENT 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 VOTRIENT 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 VOTRIENT based on severity of cardiac dysfunction. ( 2.2 , 5.3 ) Hemorrhagic Events : Fatal hemorrhagic events have occurred. VOTRIENT 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 VOTRIENT 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. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Permanently discontinue VOTRIENT 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 VOTRIENT 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 VOTRIENT 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 VOTRIENT in case of Grade 2 or 3 gastrointestinal fistula and resume based on medical judgement. Permanently discontinue VOTRIENT 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 VOTRIENT in patients who develop interstitial lung disease (ILD) or pneumonitis. ( 2.2 , 5.9 ) Posterior Reversible Encephalopathy Syndrome : Can be fatal. Permanently discontinue VOTRIENT in patients who develop posterior reversible encephalopathy syndrome (PRES). ( 2.2 , 5.10 ) Hypertension : Hypertension, including hypertensive crisis, has been observed. Do not initiate VOTRIENT in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating VOTRIENT. Monitor blood pressure as clinically indicated and initiate and adjust antihypertensive therapy as appropriate. Withhold and then dose reduce VOTRIENT or permanently discontinue based on severity of hypertension. ( 2.2 , 5.11 ) Risk of Impaired Wound Healing : Withhold VOTRIENT 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 VOTRIENT after resolution of wound healing complications has not been established. ( 5.12 ) Hypothyroidism : Monitor thyroid tests at baseline, during treatment and as clinically indicated and manage hypothyroidism as appropriate. ( 5.13 ) Proteinuria : Perform baseline and periodic urinalysis during treatment with follow up measurement of 24-hour urine protein as clinically indicated. Withhold VOTRIENT then resume at a reduced dose or permanently discontinue based on severity of proteinuria. Permanently discontinue in patients with nephrotic syndrome. ( 2.2 , 5.14 ) Tumor Lysis Syndrome : Cases of tumor lysis syndrome (TLS) (some fatal) have been reported in patients with RCC and STS. Closely monitor patients at risk and treat as clinically indicated. ( 5.15 ) Infection : Serious infections (with or without neutropenia), some with fatal outcome, have been reported. Monitor for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly. Consider interruption or discontinuation of VOTRIENT. ( 5.16 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and patients to use effective contraception. ( 5.19 , 8.1 , 8.3 ) 5.1 Hepatic Toxicity Hepatotoxicity, manifested as increases in ALT, aspartate aminotransferase (AST) and bilirubin, occurred in patients who received VOTRIENT. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5)] . Transaminase elevations occur early in the course of treatment; 92% of all transaminase elevations of any grade occurred in the first 18 weeks. In the randomized RCC trial (VEG105192), ALT > 3 × ULN occurred in 18% and ALT > 10 × ULN occurred in 4% of the 290 patients who received VOTRIENT. Concurrent elevation in ALT > 3 × ULN and bilirubin > 2 × ULN in the absence of significant alkaline phosphatase > 3 × ULN occurred in 2%. In the monotherapy trials, 2 patients died with disease progression and hepatic failure. In the randomized STS trial (VEG110727), ALT > 3 × ULN occurred in 18% and ALT > 8 × ULN occurred in 5% of the 240 patients who received VOTRIENT. Concurrent elevation in ALT > 3 × ULN and bilirubin > 2 × ULN in the absence of significant alkaline phosphatase > 3 × ULN occurred in 2%. One patient died of hepatic failure. Monitor liver tests at baseline; at Weeks 3, 5, 7, and 9; at Month 3 and Month 4; and then periodically as clinically indicated. Increase to weekly monitoring for patients with elevated ALT until ALT returns to Grade 1 or baseline. Withhold VOTRIENT 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 [see Dosage and Administration (2.2)] . Gilbert’s Syndrome VOTRIENT is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5)] . In patients with only a mild indirect hyperbilirubinemia known as Gilbert’s syndrome, manage elevation in ALT > 3 × ULN per the recommendations outlined for isolated ALT elevations [see Dosage and Administration (2.2)] . Concomitant Use of Simvastatin Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations [see Drug Interactions (7.3)] . Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 5.2 QT Prolongation and Torsades de Pointes In the RCC trials, 558/586 patients were subject to routine electrocardiogram (ECG) monitoring and QT prolongation ≥ 500 msec was identified in 2% of these 558 patients. In monotherapy trials, torsades de pointes occurred in < 1% of 977 patients who received VOTRIENT. In the randomized RCC (VEG105192) and STS (VEG110727) trials, 1% (3/290) and 0.4% (1/240) of patients, respectively, who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction.…