c (90% CI 22.4 msec). Moxifloxacin (400 mg) used as a positive control showed a 5.6 msec maximum mean QTcF interval change from baseline. No subjects experienced an effect on the QTc interval greater than Grade 2 (CTCAE version 3.0).
QT interval prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de pointes. Torsade de pointes has been observed in <0.1% of sunitinib-exposed patients. sunitinib should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant administration of sunitinib with potent CYP3A4 inhibitors, should be limited because of the possible increase in sunitinib plasma concentrations, (see section 4.2 and 4.5).
Venous thromboembolic events
Treatment-related venous thromboembolic events were reported in approximately 1.0% of patients with solid tumours who received sunitinib on clinical trials, including GIST and MRCC.
Seven patients (3%) on SUTENT and none on placebo in a phase 3 GIST study experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thromboses (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.
Thirteen patients (3%) receiving sunitinib in the phase 3 for treatment-naïve MRCC study and four patients (2%) on the two cytokine-refractory MRCC studies had treatment-related venous thromboembolic events reported. Nine of these patients had pulmonary embolisms, one was Grade 2 and eight were Grade 4. Eight of these patients had DVT, one each with Grade 1, two with Grade 2, four with Grade 3 and one with Grade 4.
In treatment-naïve MRCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all with Grade 4.
No treatment-related venous thromboembolic events were reported for patients receiving sunitinib, and one Grade 2 DVT was reported for a patient receiving placebo in the phase 3 pNET study.
No cases with fatal outcome were reported in GIST and MRCC registrational studies. Cases with fatal out come have been observed in post-marketing setting (see pulmonary events and section 4.8).
Arterial thromboembolic events
Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemic attack, and cerebral infarction. Risk factors associated with ATE, in addition to the underlying malignant disease and age 65 years, included hypertension, diabetes mellitus, and prior thromboembolic disease.
Respiratory events
Patients who presented with pulmonary embolism within the previous 12 months were excluded from sunitinib clinical studies.
In patients who received sunitinib in Phase 3 registrational studies, treatment-related pulmonary events (i.e. dyspnoea, pleural effusion, pulmonary embolism or pulmonary oedema) were reported in approximately 5% of patients with GIST and in approximately 14% of patients with MRCC and in 7.2% of patients with pNET.
Approximately 8% of patients with solid tumours, including GIST and MRCC, who received sunitinib in clinical trials experienced treatment-related pulmonary events.
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