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IMPORTANT SAFETY INFORMATION
Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.2% of patients treated with XALKORI across clinical trials (n=1225). Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT or AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.
Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1225), 2.5% of XALKORI-treated patients had any grade ILD, 0.9% had Grade 3/4, and 0.5% had fatal cases. These cases generally occurred within 2 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.
QT Interval Prolongation: QTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 2.7% of patients and QTc >500 ms on at least 2 separate electrocardiograms (ECGs) occurred in 1.4% of patients. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at a reduced dose.
Bradycardia: Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a heart rate <50 beats per minute (bpm) occurred in 11% of patients treated with XALKORI (n=1174). Avoid using XALKORI in combination with other agents known to cause bradycardia to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring. Otherwise, temporarily suspend and resume or dose-reduce XALKORI as indicated.
Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving XALKORI. If the patient or patient's partner becomes pregnant while taking this drug, apprise the patient of potential hazard to the fetus.
Adverse Reactions: Safety was evaluated in a phase 3 study in patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171). Serious adverse reactions were reported in 37.2% patients treated with XALKORI and 23.4% in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients occurred in 9 (5%) patients, consisting of acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (60% vs 9%), diarrhea (60% vs 19%), nausea (55% vs 37%), vomiting (47% vs 18%), constipation (42% vs 23%), edema (31% vs 16%), upper respiratory infection (26% vs 13%), and dysgeusia (26% vs 9%). Grade 3/4 events occurring at a higher incidence with XALKORI vs chemotherapy and at >2% incidence were syncope (3% vs 0%), QT prolongation (3% vs 0%), and pulmonary embolism (5% vs 2%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [76% vs 38%] or Grade 3/4 [17% vs 4%]); elevation of AST (any grade [61% vs 33%] or Grade 3/4 [9% vs 0%]); neutropenia (any grade [49% vs 28%] or Grade 3/4 [12% vs 12%]); lymphopenia (any grade [51% vs 60%] or Grade 3/4 [9% vs 25%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (4% vs 1%). Decreased appetite (27%), fatigue (27%), and neuropathy (19%) also occurred in patients taking XALKORI.
Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.
Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI.
Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.
Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.
XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.3