• Treatment should be continued until disease progression or no longer tolerated by the patient
  • Dosing interruption and/or dose reduction may be required based on adverse reactions
• Capsules should be swallowed whole
• If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours
  • If vomiting occurs after taking a dose of XALKORI, the next dose should be taken at the regular time
• The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment (any AST and total bilirubin >1.5 times ULN and ≤3 times ULN) is 200 mg orally twice daily
• The recommended dose of XALKORI in patients with pre-existing severe hepatic impairment (any AST and total bilirubin >3 times ULN) is 250 mg orally once daily
• The recommended dose of XALKORI in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis is 250 mg orally once daily. No starting dose adjustment is needed for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis

Reduce dose as shown above if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Hematologic toxicities: Monitor complete blood counts, including differential white blood cell counts, monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1719). Increased transaminases generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, 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 increased transaminases. Permanently discontinue for ALT/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. Across clinical trials (n=1719), 2.9% of XALKORI-treated patients had any grade ILD, 1.0% had Grade 3/4, and 0.5% had fatal ILD. ILD generally occurred within 3 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. Across clinical trials (n=1616), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5% of 1582 patients had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECGs. Avoid use in patients with congenital long QT syndrome. Monitor 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 <481 ms, then resume at next lower dosage.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 13% of patients treated with XALKORI (n=1719). Avoid use in combination with other medications known to cause bradycardia. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. 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.

Severe visual loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% of 1719 patients. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss. Monthly assessment of visual symptoms is recommended. Report new visual symptoms to an eye specialist. Permanently discontinue for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified. There is insufficient information to characterize the risks of resumption of XALKORI in patients with visual loss; a decision to resume should consider the potential benefits to the patient.

XALKORI is metabolized predominantly by the CYP3A pathway and inhibits CYP3A both in vivo and in vitro

Avoid grapefruit or grapefruit juice, which may increase plasma concentrations of XALKORI.