Inlyta Special Precautions

Specific safety events should be monitored before initiation of, and periodically throughout, treatment with axitinib as described as follows.
Cardiac failure events: In a controlled clinical study with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiopulmonary failure, left ventricular dysfunction, and right ventricular failure) were reported in 6/359 patients (1.7%) receiving axitinib and 3/355 patients (0.8%) receiving sorafenib. Grade 3/4 cardiac failure events were observed in 2/359 patients (0.6%) receiving axitinib and 1/355 patients (0.3%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (0.6%) receiving axitinib and 1/355 patients (0.3%) receiving sorafenib.
In clinical studies with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 12/672 patients (1.8%) receiving axitinib. Grade 3/4 cardiac failure events were reported in 7/672 patients (1.0%) and fatal cardiac failure events were reported in 2/672 patients (0.3%) receiving axitinib.
Monitor for signs or symptoms of cardiac failure periodically throughout treatment with axitinib. Management of cardiac failure events may require temporary interruption or permanent discontinuation and/or dose reduction of axitinib therapy.
Hypertension: 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 hypertension was observed in 55/359 patients (15%) receiving axitinib and 38/355 patients (11%) receiving sorafenib and Grade 4 hypertension was observed in 1/359 patients (<1%) receiving axitinib and 1/355 patients (<1%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving axitinib and none of the patients (0%) 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 or sorafenib 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 (0%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, hypertension was reported in 344/672 patients (51%) receiving axitinib. Grade 3 hypertension was reported in 148/672 patients (22%) receiving axitinib. Grade 4 hypertension was reported in 7/672 patients (1%) receiving axitinib.
Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. In the case of persistent hypertension despite use of antihypertensive medications, the axitinib dose should be reduced. For patients who develop severe hypertension, temporarily interrupt axitinib treatment and restart at a lower dose once the patient is normotensive (see Dosage & Administration). If axitinib is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.
In case of severe or persistent arterial hypertension and symptoms suggestive of posterior reversible encephalopathy syndrome (see as follows), a diagnostic brain magnetic resonance image (MRI) should be considered.
Aneurysms and artery dissections: The use of Vascular Endothelial Growth Factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating axitinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. In pooled clinical studies with axitinib for the treatment of patients with RCC, aneurysms and artery dissections was not reported in patients receiving axitinib.
Thyroid dysfunction: 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.
In pooled clinical studies with axitinib for the treatment of patients with RCC, hypothyroidism was reported in 165/672 patients (25%) receiving axitinib. Hyperthyroidism was reported in 11/672 patients (2%) receiving axitinib.
Monitor thyroid function before initiation of, and periodically throughout, treatment with axitinib. Hypothyroidism and hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state.
Arterial thromboembolic events: 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. The most frequent arterial thromboembolic event was transient ischemic attack (1%). Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving axitinib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, arterial thromboembolic events were reported in 19/672 patients (3%) receiving axitinib. Grade 3 arterial thromboembolic events were reported in 8/672 patients (1%). Grade 4 arterial thromboembolic events were reported in 9/672 patients (1%). Fatal arterial thromboembolic events were reported in 2 patients (<1%) receiving axitinib.
In monotherapy studies with axitinib, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 16/699 patients (2%).
Axitinib should be used 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.
Venous thromboembolic events: 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, and retinal-vein occlusion/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 (0%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, venous thromboembolic events were reported in 19/672 patients (3%) receiving axitinib. Grade 3 venous thromboembolic events were reported in 6/672 patients (1%). Grade 4 venous thromboembolic events were reported in 8/672 patients (1%). Fatal venous thromboembolic events were reported in 1/672 patients (<1%) receiving axitinib.
Axitinib should be used 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.
Elevation of hemoglobin or hematocrit: Increases in hemoglobin or hematocrit, reflective of increases in red blood cell mass, may occur during treatment with axitinib. An increase in red blood cell mass may increase the risk of thromboembolic events.
Elevated hemoglobin above the upper limit of normal (ULN) was observed in 31/320 patients (10%) receiving axitinib and 3/316 patients (1%) receiving sorafenib.
Monitor hemoglobin or hematocrit before initiation of, and periodically throughout, treatment with axitinib. If hemoglobin or hematocrit becomes elevated above the normal level, patients should be treated according to standard medical practice to decrease hemoglobin or hematocrit to an acceptable level.
Hemorrhage: In a controlled clinical study with axitinib for the treatment of patients with RCC, in which patients with untreated brain metastasis were excluded, hemorrhagic events were reported in 58/359 patients (16%) receiving axitinib and 64/355 patients (18%) receiving sorafenib. The most common hemorrhagic events in patients treated with axitinib were epistaxis (6%), hematuria (3%), hemoptysis (2%), and rectal hemorrhage (2%). Grade 3/4 hemorrhagic events were reported in 5/359 patients (1%) receiving axitinib (including cerebral hemorrhage, haematuria, hemoptysis, lower gastrointestinal hemorrhage, and melaena) 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.
In pooled clinical studies with axitinib for the treatment of patients with RCC, hemorrhagic events were reported in 173/672 patients (26%) receiving axitinib. Grade 3 hemorrhagic events were reported in 20/672 patients (3%). Grade 4 hemorrhagic events were reported in 7/672 patients (1%) and fatal hemorrhagic events were reported in 3/672 patients (<1%) receiving axitinib.
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.
Gastrointestinal perforation and fistula formation: 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 (0%) receiving sorafenib. In addition to cases of gastrointestinal perforation, fistulas were reported in 2/359 patients (1%) receiving axitinib and 1/355 patients (<1%) receiving sorafenib. In pooled clinical studies with axitinib for the treatment of patients with RCC, gastrointestinal perforation and fistula were reported in 13/672 patients (2%) receiving axitinib. In monotherapy studies with axitinib (N=699), fatal gastrointestinal perforation was reported in 1/699 patient (<1%). 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.
Wound healing complications: No formal studies of the effect of axitinib on wound healing have been conducted.
Treatment with axitinib should be stopped 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.
Reversible posterior leukoencephalopathy syndrome: 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 (0%) receiving sorafenib.
In pooled clinical studies with axitinib for the treatment of patients with RCC, RPLS was reported in 2/672 patients (<1%) receiving 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. In patients with signs/symptoms of RPLS, temporarily interrupt or permanently discontinue axitinib. The safety of reinitiating axitinib therapy in patients previously experiencing RPLS is not known.
Proteinuria: 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.
In pooled clinical studies with axitinib for the treatment of patients with RCC, proteinuria was reported in 142/672 patients (21%) receiving axitinib. Grade 3 proteinuria was reported in 32/672 patients (5%) receiving axitinib. Grade 4 proteinuria was reported in 1/672 patients (<1%) receiving axitinib.
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.
Elevation of liver enzymes: In a clinical dose-finding study, concurrent elevations of alanine aminotransferase [ALT] (12 times the ULN) and bilirubin (2.3 times the ULN), considered to be drug-related hepatotoxicity, were observed in 1 patient who received axitinib at a starting dose of 20 mg twice daily (4 times the recommended starting dose). In a controlled clinical study with axitinib for the treatment of patients with RCC, no concurrent elevations of ALT (>3 times the ULN) and bilirubin (>2 times the ULN) were observed for axitinib (N=359) or sorafenib (N=355).
Monitor liver function tests before initiation of, and periodically throughout, treatment with axitinib.
Hepatic impairment: In clinical studies with axitinib, the systemic exposure to axitinib was approximately 2-fold 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 (Child-Pugh class B). Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Effects on ability to drive and use machines: No studies on the effect of axitinib on the ability to drive and use machines have been performed. Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with axitinib.