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In a controlled clinical study with Axitinib for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving Axitinib and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving Axitinib and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of Axitinib treatment and blood pressure increases have been observed as early as 4 days after starting Axitinib. Hypertension was managed with standard antihypertensive therapy. Discontinuation of Axitinib treatment due to hypertension occurred in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib.
Blood pressure should be well-controlled prior to initiating Axitinib. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the Axitinib dose. Discontinue Axitinib if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of Axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis. If Axitinib is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.
In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with Axitinib for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving Axitinib and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib.
In clinical trials with Axitinib, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.
Use Axitinib with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.
In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with Axitinib for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving Axitinib and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving Axitinib (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. In clinical trials with Axitinib, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.
Use Axitinib with caution in patients who are at risk for, or who have a history of, these events. Axitinib has not been studied in patients who had a venous thromboembolic event within the previous 6 months.
In a controlled clinical study with Axitinib for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving Axitinib and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving Axitinib (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving Axitinib (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.
Axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the Axitinib dose.
In a controlled clinical study with Axitinib for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. In clinical trials with Axitinib, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).
Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with Axitinib.
In a controlled clinical study with Axitinib for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving Axitinib and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving Axitinib and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving Axitinib and 25/232 patients (11%) receiving sorafenib.
Monitor thyroid function before initiation of, and periodically throughout, treatment with Axitinib. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.
No formal studies of the effect of Axitinib on wound healing have been conducted. Stop treatment with Axitinib at least 24 hours prior to scheduled surgery. The decision to resume Axitinib therapy after surgery should be based on clinical judgment of adequate wound healing.
In a controlled clinical study with Axitinib for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving Axitinib and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with Axitinib.
RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue Axitinib in patients developing RPLS. The safety of reinitiating Axitinib therapy in patients previously experiencing RPLS is not known.
In a controlled clinical study with Axitinib for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving Axitinib and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving Axitinib and 6/355 patients (2%) receiving sorafenib.
Monitoring for proteinuria before initiation of, and periodically throughout, treatment with Axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt Axitinib treatment.
In a controlled clinical study with Axitinib for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the Axitinib arm and 2% of patients on the sorafenib arm.
Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with Axitinib.
The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering Axitinib to patients with moderate hepatic impairment (ChildPugh class B). Axitinib has not been studied in patients with severe hepatic impairment (ChildPugh class C).
Axitinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using Axitinib. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Axitinib. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
FDA，2012.01
