r tyrosine kinase (RTK) inhibition and cardiac function remains unclear.
Patients who presented with cardiac events within 12 months prior to sunitinib administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from sunitinib clinical studies. . It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction.
Close monitoring for clinical signs and symptoms of CHF should be performed, especially in patients with cardiac risk factors and/or history of coronary artery disease.
Physicians are advised to weigh this risk against the potential benefits of sunitinib. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib. Baseline and periodic eva luations of LVEF should also be considered while the patient is receiving sunitinib. In patients without cardiac risk factors, a baseline eva luation of ejection fraction should be considered.
In the presence of clinical manifestations of CHF, discontinuation of sunitinib is recommended. The administration of sunitinib should be interrupted and/or the dose reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.
QT Interval prolongation
Data from non-clinical (in vitro and in vivo) studies, at doses higher than the recommended human dose, indicate that sunitinib has the potential to inhibit the cardiac action potential repolarisation process (e.g. prolongation of QT interval).
Increases in the QTc interval to over 500 msec occurred in 0.5% and changes from baseline in excess of 60 msec occurred in 1.1% of the 450 solid tumour patients; both of these parameters are recognized as potentially significant changes. At approximately twice therapeutic concentrations, sunitinib has been shown to prolong the QTcF Inteva l (Frederica's Correction).
QTc interval prolongation was investigated in a trial in 24 patients, ages 20-87 years, with advanced malignancies. The results of this study demonstrated that sunitinib had an effect on QTc interval (defined as a mean placebo-adjusted change of > 10 msec with a 90% CI upper limit > 15 msec) at therapeutic concentration (day 3) using the within-day baseline correction method, and at greater than therapeutic concentration (Day 9) using both baseline correction methods. No patients had a QTc interval >500 msec. Although an effect on QTcF interval was observed on Day 3 at 24 hours post-dose (i.e. at therapeutic plasma concentration expected after the recommended starting dose of 50 mg) with the within-day baseline correction method, the clinical significance of this finding is unclear.
Using comprehensive serial ECG assessments at times corresponding to either therapeutic or greater than therapeutic exposures, none of the patients in the eva luable or ITT populations were observed to develop QTc interval prolongation considered as “severe” (i.e. equal to or greater than Grade 3 by CTCAE version 3.0).
At therapeutic plasma concentrations, the maximum QTcF interval (Frederica's correction) mean change from baseline was 9.6 msec (90% CI 15.1msec). At approximately twice therapeutic concentrations, the maximum QTcF interval change from baseline was 15.4 mse |
