Xalkori Special Precautions

Assessment of ALK and ROS1 Status: When assessing either ALK or ROS1 status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of 1722 patients treated with crizotinib across clinical trials. Concurrent elevations in ALT and/or AST ≥3×ULN and total bilirubin ≥2×ULN without significant elevations of alkaline phosphatase (≤2×ULN) have been observed in less than 1% of patients treated with crizotinib. Increases to Grade 3 or 4 ALT or AST elevations were observed in 187 (11%) and 95 (6%) of patients, respectively. Seventeen (1%) patients required permanent discontinuation from treatment associated with elevated transaminases, suggesting that these events were generally manageable by dosing modifications as defined in Table 6 (see Recommended Dose under Dosage & Administration). Transaminase elevations generally occurred within the first 2 months of treatment. Liver function tests including ALT, AST and total bilirubin should be monitored every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevations. For patients who develop transaminase elevations, see Recommended Dose: Dose Modification under Dosage & Administration.
Interstitial Lung Disease (Pneumonitis): Crizotinib has been associated with severe, life-threatening or fatal interstitial lung disease (ILD)/pneumonitis in clinical trials at a frequency of 26 (2%) of 1722 patients treated with crizotinib. These cases generally occurred within 3 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potential causes of ILD/pneumonitis should be excluded. Crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see Recommended Dose under Dosage & Administration).
QT Interval Prolongation: Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Crizotinib should be administered with caution to patients who have a history of or pre-disposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval. When using crizotinib in these patients, periodic monitoring with electrocardiograms and electrolytes should be considered. For patients who develop QTc prolongation, see Recommended Dose: Dose Modification under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.
Bradycardia: Bradycardia has been reported in clinical studies, and it was usually asymptomatic. The full effect of crizotinib on pulse rate may not develop until several weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia (syncope, dizziness, hypotension). Monthly monitoring of pulse rate and blood pressure is recommended. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia, crizotinib should be held and the use of concomitant medications should be re-evaluated. For management of patients who develop symptomatic bradycardia, see Recommended Dose: Dose Modification under Dosage & Administration and Adverse Reactions.
Cardiac Failure: In clinical studies with crizotinib and during post-marketing surveillance, severe, life-threatening, or fatal adverse reactions of cardiac failure were reported (see Adverse Reactions).
Patients with or without pre-existing cardiac disorders, receiving crizotinib, should be monitored for signs and symptoms of heart failure (dyspnea, edema, rapid weight gain from fluid retention). Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed.
Neutropenia and Leukopenia: In clinical studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC, Grade 3 or 4 neutropenia has been very commonly (12%) reported. Grade 3 or 4 leukopenia has been commonly (3%) reported (see Adverse Reactions). Less than 0.5% of patients experienced febrile neutropenia in clinical studies with crizotinib. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs (see Recommended Dose under Dosage & Administration).
Visual Effects: In clinical studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC (N=1722), Grade 4 visual field defect with vision loss has been reported in 4 (0.2%) patients. Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss.
In patients with new onset of severe visual loss (best corrected visual acuity less than 6/60 in one or both eyes), crizotinib treatment should be discontinued (see Recommended Dose under Dosage & Administration). Ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss, should be performed. There is insufficient information to characterize the risks of resumption of crizotinib in patients with a severe visual loss. A decision to resume crizotinib should consider the potential benefit to the patient.
Ophthalmological evaluation is recommended if vision disorder persists or worsens in severity (see Adverse Reactions).
Effects on Ability to Drive and Use Machines: No studies on the effect of crizotinib on the ability to drive and use machines have been performed. However, caution should be exercised when driving or operating machinery by patients who experience vision disorder, dizziness, or fatigue while taking crizotinib (see Adverse Reactions).
Renal Impairment: If patients have severe renal impairment not requiring peritoneal dialysis or hemodialysis, the dose of crizotinib should be adjusted (see Recommended Dose under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).