ENSACOVE

2 DOSAGE AND ADMINISTRATION Select patients with ALK-positive locally advanced or metastatic NSCLC for treatment with ENSACOVE. ( 2.1 ) Prior to initiating ENSACOVE, evaluate liver function tests and fasting blood glucose. ( 2.2 ) Recommended dosage: 225 mg orally once daily with or without food until disease progression or unacceptable toxicity. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of locally advanced or metastatic NSCLC with ENSACOVE based on the presence of ALK rearrangement(s) in tumor specimens [see Clinical Studies ( 14.1 )] . Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Testing and Advice Prior to Initiating ENSACOVE Prior to initiating ENSACOVE, evaluate liver function tests [see Warnings and Precautions ( 5.2 )] and fasting blood glucose [see Warnings and Precautions ( 5.5 )]. 2.3 Recommended Dosage The recommended dosage of ENSACOVE is 225 mg orally once daily, with or without food [see Clinical Pharmacology ( 12.3 )] , until disease progression or unacceptable toxicity. Swallow capsules whole, do not crush or chew. Do not open or dissolve the contents of the capsule. Take ENSACOVE at the same time each day. Missed dose If a dose is missed, then take the missed dose as soon as possible unless the next dose is due within 12 hours. Do not take 2 doses on the same day. Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at its scheduled time. 2.4 Dosage Modification for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 1. Table 1: Recommended Dose Reductions for Adverse Reactions Dose Reduction Recommended Dose and Schedule First 200 mg orally once daily Second 150 mg orally once daily Permanently discontinue ENSACOVE if patients are unable to tolerate 150 mg orally once daily. Once the dose has been reduced for adverse reactions, do not subsequently increase the dose of ENSACOVE. The recommended dosage modifications for the management of adverse reactions are provided in Table 2. Table 2: Recommended ENSACOVE Dosage Modifications for Adverse Reactions Adverse Reaction Severity* ENSACOVE Dose Modification and Management for Adverse Reactions Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.1 )] Any Grade Permanently discontinue ENSACOVE. Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Grade 3 or 4 elevation (greater than 5 times ULN) of either ALT or AST with concurrent total bilirubin less than or equal to 2 times ULN Withhold ENSACOVE until recovery to Grade ≤1 (≤3 times ULN) or to baseline. Resume ENSACOVE at reduced dose as per Table 1. Grade 2 to 4 elevation (greater than 3 times ULN) of either ALT or AST with concurrent total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis Permanently discontinue ENSACOVE. Dermatologic Adverse Reactions [see Warnings and Precautions ( 5.3 )] Grade 1 Consider topical corticosteroids. Grade 2 Administer topical corticosteroids. If not improved in ≤7 days after initiation of topical corticosteroids, administer oral corticosteroids. If not improved in ≤7 days after initiation of oral corticosteroids, withhold ENSACOVE until recovery to Grade ≤1. Resume ENSACOVE at reduced dose as per Table 1. Grade 3 Withhold ENSACOVE. Administer topical corticosteroids. If not improved after 7 days of initiation of topical corticosteroids, administer oral corticosteroids. Resume ENSACOVE at reduced dose as per Table 1 upon improvement to Grade ≤1. Grade 4 Permanently discontinue ENSACOVE. Administer systemic corticosteroids and consider antibiotic use. Bradycardia (HR less than 60 bpm) [see Warnings and Precautions ( 5.4 )] Symptomatic bradycardia Withhold ENSACOVE until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ENSACOVE at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ENSACOVE at reduced dose as per Table 1 upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. Bradycardia with life-threatening consequences, urgent intervention indicated Permanently discontinue ENSACOVE if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or dose- adjusted, resume ENSACOVE at reduced dose as per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. For recurrence, permanently discontinue ENSACOVE. Hyperglycemia [see Warnings and Precautions ( 5.5 )] Grade 3 (greater than 250 mg/dL) despite optimal anti- hyperglycemic therapy OR Grade 4 Withhold ENSACOVE until hyperglycemia is adequately controlled, then resume ENSACOVE at reduced dose as per Table 1. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ENSACOVE. Visual Disturbance [see Warnings and Precautions ( 5.6 )] Grade 2 or 3 Withhold ENSACOVE until recovery to Grade 1 or baseline, then consider resuming at reduced dose as per Table 1. Grade 4 Permanently discontinue ENSACOVE. Increased Creatine Phosphokinase [see Warnings and Precautions ( 5.7 )] CPK elevation greater than 5 times ULN Temporarily withhold ENSACOVE until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose. CPK elevation greater than 10 times ULN or second occurrence of CPK elevation of greater than 5 times ULN Temporarily withhold ENSACOVE until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at reduced dose as per Table 1. Hyperuricemia [see Warnings and Precautions ( 5.8 )] Symptomatic or Grade 4 Initiate urate-lowering medication. Withhold ENSACOVE until improvement of signs or symptoms. Resume ENSACOVE at same or reduced dose. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Withhold ENSACOVE until recovery to Grade 1 or baseline. Resume ENSACOVE at reduced dose as per Table 1. Recurrent Grade 4 Permanently discontinue ENSACOVE. ALT = alanine aminotransferase; AST = aspartate aminotransferase; bpm = beats per minute; HR = heart rate; ULN = upper limit of normal *Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03.

See official label

1 INDICATIONS AND USAGE ENSACOVE is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)as detected by an FDA-approved test [see Dosage and Administration ( 2.1 )] who have not previously received an ALK-inhibitor.