2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens [see Clinical Studies (14.1, 14.2)].
Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at http://www.fda.gov/companiondiagnostics.
2.2 Recommended Dosage
The recommended dosage of XALKORI is 250 mg orally twice daily, with or without food, until disease progression or no longer tolerated by the patient.
Swallow capsules 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, take the next dose at the regular time.
2.3 Dosage Modifications for Adverse Reactions
The recommended dose reductions are:
- First dose reduction: XALKORI 200 mg taken orally twice daily
- Second dose reduction: XALKORI 250 mg taken orally once daily
- Permanently discontinue if unable to tolerate XALKORI 250 mg taken orally once daily.
Dosage modifications for adverse reactions for XALKORI are provided in Tables 1 and 2.
| Severity of Adverse Reaction† | XALKORI Dosage Modification |
|---|---|
| Grade 3 | Withhold until recovery to Grade 2 or less, then resume at the same dosage |
| Grade 4 | Withhold until recovery to Grade 2 or less, then resume at next lower dosage |
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.
| Severity of Adverse Reaction* | XALKORI Dosage Modification |
|---|---|
| Hepatotoxicity [see Warnings and Precautions (5.1)] | |
| Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN | Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage. |
| ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) | Permanently discontinue. |
| Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)] | |
| Any grade drug-related interstitial lung disease/pneumonitis | Permanently discontinue. |
| QT Interval Prolongation [see Warnings and Precautions (5.3)] | |
| QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs) | Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage. |
| QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia | Permanently discontinue. |
| Bradycardia [see Warnings and Precautions (5.4)] | |
| Bradycardia† (symptomatic, may be severe and medically significant, medical intervention indicated) | Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. |
| Bradycardia†,‡ (life-threatening consequences, urgent intervention indicated) | Permanently discontinue if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring. |
| Severe Vision Loss [see Warnings and Precautions (5.5)] | |
| Visual Loss (Grade 4 Ocular Disorder) | Discontinue during evaluation of severe vision loss. |
2.4 Dosage Modifications for Moderate and Severe Hepatic Impairment
The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment [any aspartate aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than or equal to 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 greater than 3 times ULN) is 250 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
2.5 Dosage Modification for Severe Renal Impairment
The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (CLcr) less than 30 mL/min, calculated using the modified Cockcroft-Gault equation] not requiring dialysis is 250 mg orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
2.6 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors
Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to 250 mg orally once daily [see Drug Interactions (7.1)]. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.
