ensartinib 25 MG Oral Capsule

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. ENSACOVE is a kinase inhibitor 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 who have not previously received an ALK-inhibitor. ( 1 , 2.1 )

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.

WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD)/Pneumonitis : Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis. Permanently discontinue in patients with ILD/pneumonitis. ( 5.1 ) Hepatotoxicity : Monitor liver function tests during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.2 ) Dermatologic Adverse Reaction : Monitor for dermatologic adverse reactions during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. ( 5.3 ) Bradycardia : Monitor heart rate regularly during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. ( 5.4 ) Hyperglycemia : Monitor serum glucose periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. ( 5.5 ) Visual Disturbances : Advise patients to report visual symptoms during treatment with ENSACOVE. Withhold ENSACOVE and obtain ophthalmologic evaluation, then reduce the dose or permanently discontinue ENSACOVE. (5.6) Increased Creatine Phosphokinase (CPK) : Monitor CPK periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. ( 5.7 ) Hyperuricemia : Monitor uric acid periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. ( 5.8 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.9 ) 5.1 Interstitial Lung Disease/Pneumonitis ENSACOVE can cause severe interstitial lung disease (ILD)/pneumonitis. In the pooled safety population [see Adverse Reactions ( 6.1 )], ILD/pneumonitis occurred in 5% of patients treated with ENSACOVE, including Grade 3 in 1.3% and Grade 4 in 0.4%. ILD/pneumonitis leading to dose interruption occurred in 0.4% and permanent discontinuation of ENSACOVE in 1.5% of patients. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever) during treatment with ENSACOVE. Immediately withhold ENSACOVE in patients with suspected ILD/pneumonitis. Permanently discontinue ENSACOVE if ILD/pneumonitis is confirmed [see Dosage and Administration ( 2.4 )]. 5.2 Hepatotoxicity ENSACOVE can cause hepatotoxicity including drug-induced liver injury. In the pooled safety population [see Adverse Reactions ( 6.1 )], 59% of patients treated with ENSACOVE had increased alanine aminotransferase (ALT), including 5% Grade 3. Increased aspartate aminotransferase (AST) occurred in 58% of patients treated with ENSACOVE, including 1.8% Grade 3. Increased bilirubin occurred in 12% of patients treated with ENSACOVE, including 2.3% Grade 3 and 0.2% Grade 4. There was one case of drug-induced liver injury in ENSACOVE-treated patients. The median time to first onset of increased ALT or AST was 5.3 weeks (range: 0.4 to 152 weeks). The dose of ENSACOVE was interrupted in 4.6% of patients for increased ALT or AST. Increased ALT or AST leading to dose reduction occurred in 2.6% and permanent discontinuation of ENSACOVE in 1.1% of patients. The dose of ENSACOVE was interrupted in 1.3% of patients for increased bilirubin. Increased bilirubin leading to dose reduction occurred in 0.7% and permanent discontinuation of ENSACOVE in 1.3% of patients. Monitor liver function tests including ALT, AST, and total bilirubin at baseline and every 2 weeks during the first cycle of treatment with ENSACOVE, and then monthly and as clinically indicated. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on the severity of the adverse reaction [see Dosage and Administration ( 2.4 )] . 5.3 Dermatologic Adverse Reactions ENSACOVE can cause dermatologic adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), rash, pruritus, and photosensitivity. In the pooled safety population [see Adverse Reactions ( 6.1 )], dermatologic adverse reactions occurred in 80% of patients receiving ENSACOVE, including Grade 3 in 14% of patients. Rash occurred in 72% of patients receiving ENSACOVE, including Grade 3 in 12% of patients. The median time to onset of rash was 9 days (range: 1 day to 17.3 months). Pruritus occurred in 32% of patients receiving ENSACOVE, with Grade 3 in 2.4%. There was one Grade 3 case (0.2%) of drug reaction with eosinophilia and systemic symptoms (DRESS). The dose of ENSACOVE was interrupted in 12% of patients for dermatologic adverse reactions. Dermatologic adverse reactions leading to dose reduction occurred in 11% and permanent discontinuation of ENSACOVE in 1.5% of patients. In the pooled safety population [see Adverse Reactions ( 6.1 ) ], photosensitivity occurred in 0.9% of patients receiving ENSACOVE; all were Grade 1. Monitor patients for dermatologic adverse reactions during treatment with ENSACOVE. If dermatologic adverse reactions occur, treat with antihistamine, topical or systemic steroids based on the severity. Advise patients to limit direct sun exposure while taking ENSACOVE and for at least 1 week after discontinuation. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on the severity of the adverse reaction [see Dosage and Administration ( 2.4 )]. 5.4 Bradycardia ENSACOVE can cause symptomatic bradycardia. In the pooled safety population [see Adverse Reactions ( 6.1 )], bradycardia (heart rate less than 60 beats per minute) occurred in 6% of patients treated with ENSACOVE. All bradycardia events were Grade 1 or 2. Bradycardia requiring dose reduction occurred in 0.2% and led to dose interruption in 0.4% of ENSACOVE-treated patients. Monitor heart rate regularly during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration ( 2.4 )] . 5.5 Hyperglycemia ENSACOVE can cause hyperglycemia. In the pooled safety population [see Adverse Reactions ( 6.1 )], based on laboratory data, 44% of patients receiving ENSACOVE experienced increased blood glucose, including Grade 3 in 2.5%. The median time to onset of increased blood glucose was 5.9 weeks (0.4 weeks to 3.4 years). Assess fasting serum glucose at baseline and monitor serum glucose periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration ( 2.4 )]. 5.6 Visual Disturbances ENSACOVE can cause visual disturbances including blurred vision, diplopia, photopsia, vitreous floaters, visual impairment, visual field defect, and reduced visual acuity. In the pooled safety population [see Adverse Reactions ( 6.1 )], 8% of patients receiving ENSACOVE experienced visual disturbance, including 0.2% Grade 3. Visual disturbances led to dose interruption in 0.4% of patients. Obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration ( 2.4 )]. 5.7 Increased Creatine Phosphokinase In the pooled safety population [see Adverse Reactions ( 6.1 )], of the 203 patients with creatine phosphokinase (CPK) laboratory data available, increased CPK occurred in 43% of patients who received ENSACOVE. The incidence of Grade 3 increased CPK was 1.5% and 0.5% were Grade 4. The median time to onset of increased CPK was 123 days (range: 13 days to 22 months). Increased CPK leading to dose interruption occurred in 0.2% and dose reduction in 0.4%. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration ( 2.4 ), Adverse Reactions ( 6.1 )]. 5.8 Hyperuricemia ENSACOVE can cause hyperuricemia. In the

CONTRAINDICATIONS ENSACOVE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components [see Warnings and Precautions ( 5.10 )] . Hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components. ( 4 )

Mechanism of Action Ensartinib is a kinase inhibitor of anaplastic lymphoma kinase (ALK) and inhibits other kinases including MET and ROS1. In vitro, ensartinib inhibited phosphorylation of ALK and its downstream signaling proteins AKT, ERK, and S6, thereby blocking ALK-mediated signaling pathways and inhibiting proliferation in cell lines harboring ALK fusions and mutations. In vivo, ensartinib showed anti-tumor activity in a mouse xenograft model of human NSCLC harboring an ALK fusion.