ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions 5.1 )] Hepatoxicity [see Warnings and Precautions 5.2 )] Dermatologic Adverse Reactions [see Warnings and Precautions 5.3 )] Bradycardia [see Warnings and Precautions 5.4 )] Hyperglycemia [see Warnings and Precautions 5.5 )] Visual Disturbances [see Warnings and Precautions 5.6 )] Increased Creatine Phosphokinase [see Warnings and Precautions 5.7 )] Hyperuricemia [see Warnings and Precautions 5.8 )] FD&C Yellow No. (Tartrazine) [see Warnings and Precautions 5.10) . Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions 5.1 )] Hepatoxicity [see Warnings and Precautions 5.2 )] Dermatologic Adverse Reactions [see Warnings and Precautions 5.3 )] Bradycardia [see Warnings and Precautions 5.4 )] Hyperglycemia [see Warnings and Precautions 5.5 )] Visual Disturbances [see Warnings and Precautions 5.6 )] Increased Creatine Phosphokinase [see Warnings and Precautions 5.7 )] Hyperuricemia [see Warnings and Precautions 5.8 )] FD&C Yellow No. (Tartrazine) [see Warnings and Precautions 5.10) . Most common adverse reactions (incidence >=20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. (6.1)Most common Grade 3-4 laboratory abnormality (incidence >=2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Xcovery Holdings, Inc. at (866) 367-2268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions (incidence >=20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. (6.1). Most common Grade 3-4 laboratory abnormality (incidence >=2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ENSACOVE as single agent in 458 patients with locally advanced or metastatic ALK-positive NSCLC in the following trials: eXALT3 Study (N=143) [see Clinical Studies 14.1 ], Study 101 (NCT01625234, N=98), Study BTP-28311 (NCT02959619, N=35), and Study BTP-42322 (NCT03215693, N=182). Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among 458 patients who received ENSACOVE, 63% were exposed for months or longer and 47% were exposed for greater than one year. In this pooled safety population, the most common adverse reactions (>=20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. The most frequent Grade or laboratory abnormalities (>=2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase.TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLCThe safety of ENSACOVE was evaluated in the eXALT3 study [see Clinical Studies (14.1) ]. Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among patients who received ENSACOVE, 78% were exposed for months or longer and 66% were exposed for greater than one year.The median age of patients who received ENSACOVE was 54 years (range: 25-86); 50% male; 54% Asian, 43% White; 0.7% Black or African American; and 11% Hispanic or Latino.Serious adverse reactions occurred in 23% of patients treated with ENSACOVE. Serious adverse reactions that occurred in >=1% were pneumonia (4.9%), hemorrhage (2.1%), rash (2.1%) and cellulitis (1.4%). One fatal adverse reaction (0.7%) occurred due to bronchopneumonia.Permanent discontinuation of ENSACOVE due to an adverse reaction occurred in 12% of patients. Adverse reactions which resulted in permanent discontinuation of ENSACOVE (>=1%) included increased blood bilirubin (1.4%), increased conjugated bilirubin (1.4%), increased ALT (2.1%), increased AST (2.1%), and pneumonitis/ILD (2.1%).Dose interruptions of ENSACOVE due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dose interruptions (>=2%) included rash (13%), increased ALT (6%), edema (2.8%), pruritus (2.8%), pyrexia (2.8%), pneumonia (3.5%), increased AST (2.1%), hemorrhage (2.1%), and decreased appetite (2.1%).Dose reductions of ENSACOVE due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reductions (>=2%) included rash (11%), increased ALT (4.2%), pruritus (2.8%), and edema (2.1%).Tables and summarize the most frequent adverse reactions and laboratory abnormalities, respectively.Table 3: Adverse Reactions >=10%) in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study ENSACOVE = 143 Crizotinib = 146 Adverse Reaction All Grades Grade or % All Grades% Grade or 4% Skin and Subcutaneous Tissue Disorders Rasha 66 12100 Pruritusb 302.14.10 Alopecia1104.80 Dry Skin100.70.70 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Painc 361.4200 Respiratory, Thoracic and Mediastinal Disorders Coughd 310.7160 Gastrointestinal Disorders Constipation310260 Nausea281.4302.1 Vomitinge 160.7320 General Disorders and Administration Site Conditions Edemaf 27 2.1282.1 Pyrexiag 220.7100.7 Fatigueh 210.7141.4 Metabolism and Nutrition Disorders Decreased appetite 150121.4 Infection and Infestation Respiratory Tract Infection 130.7100 Nervous System Disorders Dizzinessi 120.7140.7 Dysgeusia100110 Vascular Disorders Hemorrhagej 101.44.80 Adverse reactions were graded using NCI CTCAE version 4.03. Includes dermatitis, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, exfoliative rash, palmar-plantar erythrodysaesthesia, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, skin exfoliation, and vulvovaginal rash Includes ear pruritus, eye pruritus, eyelids pruritus, lip pruritus, pruritus, and pruritus generalized Includes arthritis, spinal pain, myalgia, musculoskeletal pain, back pain, pain in extremity, neck pain, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort Includes cough, productive cough, upper-airway cough syndrome Includes vomiting and retching Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, gravitational edema, skin edema, eye edema, and periorbital edema Includes pyrexia and hyperthermia Includes fatigue and asthenia Includes dizziness, vertigo, postural dizziness Includes hemoptysis, intracranial hemorrhage, gastrointestinal hemorrhage, hematuria, upper gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, vitreous hemorrhage, epistaxis, rectal hemorrhage, anal hemorrhage Table 4: Select Laboratory Abnormalities (>=20%) That Worsened from Baseline in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study ENSACOVE = 143 Crizotinib = 146 Lab Abnormality All Grades Grade or % All Grades Grade or % Chemistry Alanine aminotransferase increased 735748 Alkaline phosphatase increased642.2500.7 Aspartate aminotransferase increased641.4623.5 Glucose increased495350.7 Albumin decreased460.7561.4 Phosphate decreased397424.9 Urate increased39392727 Creatinine increased370270 Calcium decreased361.4644.9 Sodium decreased274.3274.2 Hematology Lymphocytes decreased 577475 Hemoglobin decreased430.7311.4Adverse reactions were graded using NCI CTCAE version 4.03. ALT Alanine aminotransferase; AST Aspartate aminotransferaseClinically relevant adverse reactions in <10% of patients who received ENSACOVE included interstitial lung disease, photosensitivity, increased creatinine phosphokinase, bradycardia, and visual disturbances.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 TKI-naiveALK-PositiveLocally Advanced or Metastatic NSCLC (eXALT3 Study). The efficacy of ENSACOVE was evaluated in eXALT3 (NCT02767804), an open-label, randomized, active-controlled, multicenter study in adult patients with locally advanced (stage IIIB following prior chemotherapy or chemoradiation or not amenable to curative intent therapy) or metastatic ALK-positive NSCLC. Patients were required to have ALK-positive NSCLC in tumor specimens as determined in local laboratories using immunohistochemistry (IHC), next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests. Of these patients, 85% (247/290) had centrally confirmed ALK rearrangements with the Vysis Break Apart FISH Probe Kit. Patients could have received one prior regimen of chemotherapy but could not have previously received an ALK-targeted therapy; patients with an ECOG performance status of 0, 1, or were eligible. Patients with asymptomatic, untreated brain metastases who were not on corticosteroids and patients with asymptomatic, treated brain metastases who were on stable or decreasing dose of corticosteroids were eligible. Patients were required to have completed radiation therapy at least weeks, or chemotherapy at least weeks, prior to enrollment. Patients with leptomeningeal disease were ineligible.Patients were randomized 1:1 to receive ENSACOVE 225 mg orally once daily or crizotinib 250 mg orally twice daily in 28-day cycles until disease progression or unacceptable toxicity. Randomization was stratified by prior chemotherapy (0 vs. 1), ECOG performance status (0 or vs. 2), presence of central nervous system (CNS) metastases (yes or no), and geographic region (Asia vs. the rest of the world). Tumor assessments were performed every weeks.The main efficacy outcome measure was progression-free survival (PFS) as evaluated by Blinded Independent Central Review (BICR) according to RECIST version 1.1. The key secondary efficacy outcome measure was overall survival (OS); other secondary outcome measures included CNS response rate, time to CNS progression, and overall response rate (ORR).A total of 290 patients were randomized to ENSACOVE (n=143) or crizotinib (n=147). The baseline demographic characteristics of the overall study population were median age 54 years (range: 25-90); 16% age 65 years; 51% male; 56% Asian; 41% White and 1% Black; 7% Hispanic or Latino; ECOG PS or (95%); and 62% never smokers. Patients had Stage IIIB (8%) or Stage IV NSCLC (92%); 32% had received prior chemotherapy and 17% had received prior radiation. Baseline CNS metastases were present in 36% of the patients.The eXALT3 study demonstrated statistically significant improvement in PFS for patients randomized to ENSACOVE compared to patients randomized to crizotinib. The efficacy results as assessed by BICR are summarized in Table and Figure 1.Table 6: Efficacy Results for eXALT3 Study According to BICR Assessment Efficacy Parameter ENSACOVE N=143 Crizotinib N=147 Progression-free survival Number of events, (%) 59 (41%) 80 (54%) Progressive disease, (%) 51 (36%) 77 (52%) Death, (%) (6%) (2%) Median, months (95% CI)25.8 (21.8, NE)12.7 (9.2, 16.6) Hazard ratio (95% CI) 0.56 (0.40, 0.79) p-valuea 0.0008 Overall response rate Overall response rate (95% CI) 74% (66, 81) 67% (58, 74) Complete response 12% 5% Partial response 62% 61% Duration of response Number of responders, 106 98 Median, months (95% CI) NE (22.0, NE) 27.3 (12.9, NE)CI Confidence Interval, NE=not estimable, BICR Blinded Independent Central Review p-value based on unstratified log-rank testFigure Kaplan-Meier Plot of Progression-Free Survival by IRR from Study 301 (eXALT3)At the time of the primary PFS analysis, OS results were immature. At the time of final analysis of OS, there was no statistically significant difference (p-value 0.4570) between ENSACOVE and crizotinib. Median OS was 63.2 months in the ENSACOVE arm and 55.7 months in the crizotinib arm, with the hazard ratio of 0.88 (95% CI: 0.63, 1.23). The results of the pre-specified analyses of CNS response rate by BICR in patients with baseline measurable CNS disease are summarized in Table 7.Table 7: IRR-assessed CNS Responses in Patients with Measurable CNS Disease at Baseline in Study 301 (eXALT3) Efficacy Parameter ENSACOVE N=17 crizotinib N=24 CNS overall response rate (95% CI) 59% (33, 82) 21% (7, 42) Complete response 24% 8% Partial response 35% 13% Duration of Response Number of responders, 105 Patients with DOR >= 12 months 30% 40% BICR Blinded Independent Central Review; CI Confidence Interval. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

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). 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 doseIf dose is missed, then take the missed dose as soon as possible unless the next dose is due within 12 hours. Do not take doses on the same day.VomitingIf vomiting occurs after taking 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 ReactionsDose Reduction Recommended Dose and ScheduleFirst200 mg orally once dailySecond150 mg orally once dailyPermanently 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 SeverityENSACOVE 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 or elevation (greater than times ULN) of either ALT or AST with concurrent total bilirubin less than or equal to times ULNWithhold ENSACOVE until recovery to Grade <=1 (<=3 times ULN) or to baseline.Resume ENSACOVE at reduced dose as per Table 1.Grade to elevation (greater than times ULN) of either ALT or AST with concurrent total bilirubin elevation greater than times ULN in the absence of cholestasis or hemolysisPermanently discontinue ENSACOVE.Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)]Grade 1Consider topical corticosteroids.Grade 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 Withhold ENSACOVE. Administer topical corticosteroids.If not improved after days of initiation of topical corticosteroids, administer oral corticosteroids.Resume ENSACOVE at reduced dose as per Table upon improvement to Grade <=1. Grade 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 resting heart rate of 60 bpm or above.If 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 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 upon recovery to asymptomatic bradycardia or to 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 (greater than 250 mg/dL) despite optimal anti- hyperglycemic therapy OR Grade 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 or 3Withhold ENSACOVE until recovery to Grade or baseline, then consider resuming at reduced dose as per Table 1.Grade 4Permanently discontinue ENSACOVE.Increased Creatine Phosphokinase [see Warnings and Precautions (5.7)]CPK elevation greater than times ULNTemporarily 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 times ULNTemporarily 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 4Initiate 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 or 4Withhold ENSACOVE until recovery to Grade or baseline.Resume ENSACOVE at reduced dose as per Table 1. Recurrent Grade 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.. Withhold ENSACOVE until recovery to Grade <=1 (<=3 times ULN) or to baseline.. Resume ENSACOVE at reduced dose as per Table 1.. 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.. Withhold ENSACOVE. Administer topical corticosteroids.. If not improved after days of initiation of topical corticosteroids, administer oral corticosteroids.. Resume ENSACOVE at reduced dose as per Table upon improvement to Grade <=1.. Permanently discontinue ENSACOVE.. Administer systemic corticosteroids and consider antibiotic use.. Withhold ENSACOVE until recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.. If 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 upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.. 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 upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.. For recurrence, permanently discontinue ENSACOVE.. 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.. Temporarily withhold ENSACOVE until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose.. 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.. Initiate urate-lowering medication.. Withhold ENSACOVE until improvement of signs or symptoms.. Resume ENSACOVE at same or reduced dose.. Withhold ENSACOVE until recovery to Grade or baseline.. Resume ENSACOVE at reduced dose as per Table 1.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Interstitial Lung Disease (ILD)/PneumonitisInform patients of the risk of severe ILD/pneumonitis during treatment with ENSACOVE. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions 5.1 )]. HepatoxicityInform patients of the potential risk of hepatoxicity during treatment with ENSACOVE and of the need to monitor for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin elevations during treatment with ENSACOVE. Advise patients to inform their healthcare provider of any new or worsening symptoms [see Warnings and Precautions 5.2 )]. Dermatologic Adverse ReactionsInform patients of the potential risk of dermatologic adverse reactions, including rash, pruritus, and photosensitivity during treatment with ENSACOVE. If dermatologic reactions occur, advise patients to limit sun exposure while taking ENSACOVE and for at least week after the final dose [see Warnings and Precautions 5.3 )]. BradycardiaAdvise patients of the risk of bradycardia during treatment with ENSACOVE and to report any symptoms of bradycardia. Advise patients to inform their healthcare provider about the use of any heart or blood pressure medications during treatment with ENSACOVE [see Warnings and Precautions 5.4 )]. HyperglycemiaInform patients of the risks of new or worsening hyperglycemia during treatment with ENSACOVE and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that antihyperglycemic medications may need to be adjusted during treatment with ENSACOVE [see Warnings and Precautions 5.5 )]. Visual DisturbancesAdvise patients to inform their healthcare provider of any new or worsening vision symptoms during treatment with ENSACOVE [see Warnings and Precautions 5.6 )]. Creatine Phosphokinase (CPK) ElevationInform patients of the signs and symptoms of creatine phosphokinase (CPK) elevation and the need for monitoring during treatment with ENSACOVE. Advise patients to inform their healthcare provider of any new or worsening symptoms [see Warnings and Precautions 5.7 )]. HyperuricemiaInform patients of the signs and symptoms of hyperuricemia. Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia during treatment with ENSACOVE [see Warnings and Precautions 5.8 )]. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for week after the last dose [see Warnings and Precautions 5.9 and Use in Specific Populations 8.1, 8.3 )].Advise males with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for week after the last dose [see Warnings and Precautions 5.9 and Use in Specific Populations 8.3 )].FD&C Yellow No. (tartrazine)Advise patients that this product contains FD&C Yellow No. (tartrazine) which may cause allergic-type or asthma-type reactions in certain susceptible persons (e.g., patients who also have aspirin hypersensitivity) [see Warnings and Precautions 5.10 )]. Advise patients to contact their healthcare provider and seek medical help right away if they develop symptoms of an allergic reaction to FD&C Yellow No. (tartrazine).LactationAdvise women not to breastfeed during treatment with ENSACOVE and for week after the last dose [see Use in Specific Populations 8.2 )].AdministrationInstruct patients to take ENSACOVE once day with or without food and to swallow ENSACOVE capsules whole [see Dosage and Administration 2.2 )].Missed DoseAdvise patients to take ENSACOVE at the same time each day. If dose is missed, then they should take the missed dose as soon as possible unless the next dose is due within 12 hours. Patients should be instructed not to take doses at the same time to make up for missed dose. In addition, instruct patients not to take an extra dose if they vomit after taking ENSACOVE [see Dosage and Administration 2.2 )]. Manufactured for: Xcovery Holdings, Inc. Miami, FL 33131ENSACOVE is trademark of Xcovery Holdings, Inc.(C)2026, Xcovery Holdings, Inc. All rights reserved.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION ENSACOVETM (En-sa-kowv) (ensartinib) capsules, for oral useWhat is ENSACOVEENSACOVE is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC):that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene,that has spread to other parts of your body, andwho have not received medicines called ALK-inhibitors.Your healthcare provider will perform test to make sure that ENSACOVE is right for you. It is not known if ENSACOVE is safe and effective in children.Do not use ENSACOVE if you are allergic to ENSACOVE, FD&C No. (tartrazine), or to any of the ingredients in ENSACOVE. See the end of this leaflet for complete list of ingredients in ENSACOVE.Before using ENSACOVE, tell your healthcare provider about all of your medical conditions, including if you:have lung or breathing problemshave liver problemshave problems with your heartbeathave diabetes mellitus or glucose intolerancehave problems with your visionare pregnant or plan to become pregnant. ENSACOVE can harm your unborn baby. Your healthcare provider will do pregnancy test before you start treatment with ENSACOVE.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ENSACOVE. Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. Talk to your healthcare provider about birth control choices that are right for you during treatment with ENSACOVE.Males who who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. are breastfeeding or plan to breastfeed. It is not known if ENSACOVE passes into your breast milk. Do not breastfeed during treatment with ENSACOVE and for week after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the other medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.Certain other medicines may affect the way that ENSACOVE works and may increase your risk of certain side effects.Know the medicines you take. Keep list of them to show to your healthcare provider and pharmacist when you get new medicine.How should take ENSACOVETake ENSACOVE exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ENSACOVE unless your healthcare provider tells you to.Swallow ENSACOVE capsules whole. Do not crush or chew capsules. Do not open or dissolve the contents of the capsule.Take ENSACOVE time day, at the same time each day.You may take ENSACOVE with or without food.If you miss dose, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take your next dose at your regular time. Do not take doses of ENSACOVE on the same day to make up for the missed dose.If you vomit after taking dose of ENSACOVE, do not take an extra dose. Take your next dose at your regular time. What should avoid while taking ENSACOVE Limit your time in the sun during treatment with ENSACOVE and for at least week after your last dose. ENSACOVE may make your skin sensitive to sunlight. You may burn more easily and get severe sunburns. When you are in the sun, wear hat and protective clothing, and use broad-spectrum sunscreen and lip balm with Sun Protection Factor (SPF) of 30 or greater to protect against sunburn. What are the possible side effects of ENSACOVEENSACOVE can cause serious side effects, including:Lung problems. ENSACOVE can cause severe or life-threatening swelling (inflammation) of the lungs. Symptoms may be similar to those from lung cancer. Tell your healthcare provider right away if you get any new or worsening symptoms of lung problems during treatment with ENSACOVE, including: trouble breathing or shortness or breathchest pain cough with or without mucusfever Liver problems. ENSACOVE can increase enzymes called aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and levels of bilirubin in your blood. Tell your healthcare provider if you get new or worsening signs or symptoms of liver problems, including:yellowing of your skin or the white part of your eyesdark or brown (tea color) urinenausea or vomitingpain on the right side of your stomach areableed or bruise more easily than normalitchy skindecreased appetitefeeling tiredSkin reactions. ENSACOVE may cause skin reactions that require treatment. Tell your healthcare provider if you get symptoms of skin reactions, such as rash, itching, or skin swellingSlow heart rate (bradycardia). ENSACOVE can cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate during treatment with ENSACOVE. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint during treatment with ENSACOVE. Tell your healthcare provider if you take any heart or blood pressure medicines.High blood sugar (hyperglycemia). ENSACOVE can increase your blood sugar levels. Hyperglycemia is common with ENSACOVE treatment but can be serious. If you take medicine for diabetes or glucose intolerance your healthcare provider may change your medicine during treatment with ENSACOVE. Tell your healthcare provider if you get new or worsening signs and symptoms of hyperglycemia, including:feeling very thirstyneeding to urinate more than usualfeeling very hungry feeling sick to your stomachfeeling weak or tiredfeeling confused Vision problems. ENSACOVE may cause vision problems. Your healthcare provider may refer you to an eye specialist if you develop new or worsening vision problems during treatment with ENSACOVE. Tell your healthcare provider if you have any loss of vision or any change in vision, includingblurry visiondouble visionseeing flashes of lightlight hurting eyes new or increased floatersMuscle pain, tenderness, and weakness (myalgia). ENSACOVE can increase the level of an enzyme in your blood called creatine phosphokinase (CPK), which may be sign of muscle damage. Myalgia is common with ENSACOVE treatment but can be serious. Tell your healthcare provider if you get new or worsening signs and symptoms of muscle problems, including unexplained muscle pain or muscle pain that does not go away, tenderness, or weakness. Increased uric acid level in your blood (hyperuricemia). ENSACOVE can cause too much uric acid in your blood. Hyperuricemia is common with ENSACOVE treatment but can be serious. Your healthcare provider may prescribe medicines if you have high blood uric acid levels. Tell your healthcare provider if you develop any of the following symptoms of hyperuricemia: red, hot, tender, or swollen joints, especially your big toepain in your stomach-area or sides nausea or vomitingpink or brown urine Allergic reactions to FD&C Yellow No. (tartrazine). ENSACOVE 100 mg capsules contain FD&C Yellow No. 5. FD&C Yellow No. (tartrazine) that can cause allergic reactions in certain people, especially people who also have an allergy to aspirin. Tell your healthcare provider if you get hives, rash, or trouble breathing during treatment with ENSACOVE.Your healthcare provider will do certain blood tests before and during treatment with ENSACOVE to check you for side effects.If you have serious side effects during treatment with ENSACOVE, your healthcare provider may change your dose, stop your treatment for period of time (temporary), or completely stop treatment with ENSACOVE.The most common side effects of ENSACOVE are:rashmuscle or bone painconstipationitchingcoughingnauseaskin swelling (edema)vomitingtirednessfeverincreased levels of liver and pancreatic enzymesdecreased white blood cell countschanges in blood levels of phosphate, magnesium, sodium, and potassiumdecreased protein (hemoglobin) in red blood cellsincreased bilirubin blood levelsThese are not all the possible side effects with ENSACOVE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ENSACOVEStore ENSACOVE at room temperature between 68oF to 77oF (20oC to 25oC).Keep ENSACOVE capsules in the original bottle.The bottle of ENSACOVE capsules contains drying agent (desiccant) to help keep your medicine dry. Do not remove the desiccant from the bottle after opening. Do not open or eat the desiccant.Keep ENSACOVE and all medicines out of the reach of children.General information about the safe and effective use of ENSACOVE. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ENSACOVE for condition for which it was not prescribed. Do not give ENSACOVE to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ENSACOVE that is written for health professionals.What are the ingredients in ENSACOVEActive ingredient: ensartinib hydrochlorideInactive ingredients: butyl alcohol, dehydrated alcohol, hypromellose, isopropyl alcohol, microcrystalline cellulose, propylene glycol, shellac, stearic acid, and titanium dioxide. The 25 mg capsules also contain the following inactive ingredients: FD&C Blue No. and strong ammonia solution. The 100 mg capsules also contain the following inactive ingredients: black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 5, povidone, red iron oxide, and sodium hydroxide.Manufactured for: Xcovery Holdings, Inc., Miami, FL, 33131 ENSACOVE is trademark of Xcovery Holdings, Inc. (C)2024, Xcovery Holdings, Inc. All rights reserved. For more information, call Xcovery Holdings, Inc. at (866) 367-2268. This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 12/2024. that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene,. that has spread to other parts of your body, and. who have not received medicines called ALK-inhibitors.. have lung or breathing problems. have liver problems. have problems with your heartbeat. have diabetes mellitus or glucose intolerance. have problems with your vision. are pregnant or plan to become pregnant. ENSACOVE can harm your unborn baby. Your healthcare provider will do pregnancy test before you start treatment with ENSACOVE.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ENSACOVE. Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. Talk to your healthcare provider about birth control choices that are right for you during treatment with ENSACOVE.Males who who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. Your healthcare provider will do pregnancy test before you start treatment with ENSACOVE.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ENSACOVE. Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. Talk to your healthcare provider about birth control choices that are right for you during treatment with ENSACOVE.Males who who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE. Talk to your healthcare provider about birth control choices that are right for you during treatment with ENSACOVE.. Males who who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for week after the last dose of ENSACOVE.. are breastfeeding or plan to breastfeed. It is not known if ENSACOVE passes into your breast milk. Do not breastfeed during treatment with ENSACOVE and for week after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time.. Take ENSACOVE exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ENSACOVE unless your healthcare provider tells you to.. Swallow ENSACOVE capsules whole. Do not crush or chew capsules. Do not open or dissolve the contents of the capsule.. Take ENSACOVE time day, at the same time each day.. You may take ENSACOVE with or without food.. If you miss dose, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take your next dose at your regular time. Do not take doses of ENSACOVE on the same day to make up for the missed dose.. If you vomit after taking dose of ENSACOVE, do not take an extra dose. Take your next dose at your regular time.. Limit your time in the sun during treatment with ENSACOVE and for at least week after your last dose. ENSACOVE may make your skin sensitive to sunlight. You may burn more easily and get severe sunburns. When you are in the sun, wear hat and protective clothing, and use broad-spectrum sunscreen and lip balm with Sun Protection Factor (SPF) of 30 or greater to protect against sunburn.. Lung problems. ENSACOVE can cause severe or life-threatening swelling (inflammation) of the lungs. Symptoms may be similar to those from lung cancer. Tell your healthcare provider right away if you get any new or worsening symptoms of lung problems during treatment with ENSACOVE, including:. trouble breathing or shortness or breath. chest pain. cough with or without mucus. fever. Liver problems. ENSACOVE can increase enzymes called aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and levels of bilirubin in your blood. Tell your healthcare provider if you get new or worsening signs or symptoms of liver problems, including:. yellowing of your skin or the white part of your eyes. dark or brown (tea color) urine. nausea or vomiting. pain on the right side of your stomach area. bleed or bruise more easily than normal. itchy skin. decreased appetite. feeling tired. Skin reactions. ENSACOVE may cause skin reactions that require treatment. Tell your healthcare provider if you get symptoms of skin reactions, such as rash, itching, or skin swelling. Slow heart rate (bradycardia). ENSACOVE can cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate during treatment with ENSACOVE. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint during treatment with ENSACOVE. Tell your healthcare provider if you take any heart or blood pressure medicines.. High blood sugar (hyperglycemia). ENSACOVE can increase your blood sugar levels. Hyperglycemia is common with ENSACOVE treatment but can be serious. If you take medicine for diabetes or glucose intolerance your healthcare provider may change your medicine during treatment with ENSACOVE. Tell your healthcare provider if you get new or worsening signs and symptoms of hyperglycemia, including:. feeling very thirsty. needing to urinate more than usual. feeling very hungry. feeling sick to your stomach. feeling weak or tired. feeling confused. Vision problems. ENSACOVE may cause vision problems. Your healthcare provider may refer you to an eye specialist if you develop new or worsening vision problems during treatment with ENSACOVE. Tell your healthcare provider if you have any loss of vision or any change in vision, including. blurry vision. double vision. seeing flashes of light. light hurting eyes. new or increased floaters. Muscle pain, tenderness, and weakness (myalgia). ENSACOVE can increase the level of an enzyme in your blood called creatine phosphokinase (CPK), which may be sign of muscle damage. Myalgia is common with ENSACOVE treatment but can be serious. Tell your healthcare provider if you get new or worsening signs and symptoms of muscle problems, including unexplained muscle pain or muscle pain that does not go away, tenderness, or weakness. Increased uric acid level in your blood (hyperuricemia). ENSACOVE can cause too much uric acid in your blood. Hyperuricemia is common with ENSACOVE treatment but can be serious. Your healthcare provider may prescribe medicines if you have high blood uric acid levels. Tell your healthcare provider if you develop any of the following symptoms of hyperuricemia:. red, hot, tender, or swollen joints, especially your big toe. pain in your stomach-area or sides. nausea or vomiting. pink or brown urine. Allergic reactions to FD&C Yellow No. (tartrazine). ENSACOVE 100 mg capsules contain FD&C Yellow No. 5. FD&C Yellow No. (tartrazine) that can cause allergic reactions in certain people, especially people who also have an allergy to aspirin. Tell your healthcare provider if you get hives, rash, or trouble breathing during treatment with ENSACOVE.. rash. muscle or bone pain. constipation. itching. coughing. nausea. skin swelling (edema). vomiting. tiredness. fever. increased levels of liver and pancreatic enzymes. decreased white blood cell counts. changes in blood levels of phosphate, magnesium, sodium, and potassium. decreased protein (hemoglobin) in red blood cells. increased bilirubin blood levels. Store ENSACOVE at room temperature between 68oF to 77oF (20oC to 25oC).. Keep ENSACOVE capsules in the original bottle.. The bottle of ENSACOVE capsules contains drying agent (desiccant) to help keep your medicine dry. Do not remove the desiccant from the bottle after opening. Do not open or eat the desiccant.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Severe Hepatic Impairment: Avoid use of ENSACOVE in patients with severe hepatic impairment. (8.6). Lactation: Advise not to breastfeed. (8.2). Severe Hepatic Impairment: Avoid use of ENSACOVE in patients with severe hepatic impairment. (8.6). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology 12.1 )], ENSACOVE can cause fetal harm when administered to pregnant woman. There are no available data on the use of ENSACOVE in pregnant women to inform drug-associated risk. Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC (see Data). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataIn an embryo-fetal development study, pregnant rats received 20, 40, or 80 mg/kg/day of ensartinib during the period of organogenesis (gestation day to 17). Ensartinib doses >=40 mg/kg/day (approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in an increase in the incidence of fetal malformations (aortic dislocation, ventricular septal defect, separated vertebrae) and dose-dependent delayed skeletal development, including decreased or delayed ossification of the vertebrae. Ensartinib at 80 mg/kg (approximately 6.4 times the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in maternal toxicity (reduced body weight and food consumption), decreased fetal body weight, increased pre- and post-implantation loss, decreases in the number of live fetuses, and visceral variations (missing renal papillae, pyelectasis).. 8.2 Lactation. Risk SummaryThere are no data on the presence of ensartinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with ENSACOVE and for week after the last dose.. 8.3 Females and Males ofReproductive Potential. ENSACOVE can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1 ]. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating ENSACOVE.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for at week after the last dose.MalesAdvise male patients with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for week after the last dose.. 8.4 Pediatric Use. The safety and effectiveness of ENSACOVE in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 458 patients enrolled in clinical studies and received ENSACOVE 225 mg once daily, 16% of the participants were aged 65 years or older. Clinical studies of ENSACOVE did not include sufficient numbers of patients ages 65 and over to determine whether they respond differently from younger patients. Exploratory analysis suggests higher incidence of serious adverse events (43% vs 27%), more frequent adverse events leading to treatment discontinuations (18% vs 10%) and dose modifications (34% vs 16%) in patients 65 years or older as compared to those younger than 65 years.. 8.6 Hepatic Impairment. Ensartinib is primarily metabolized by the liver and patients with hepatic impairment may have increased exposures [see Clinical Pharmacology 12.3 )]. Avoid use of ENSACOVE for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) since it has not been studied in this population. Monitor patients with moderate hepatic impairment (total bilirubin >1.5 to <= ULN and any AST) for increased adverse reactions and adjust ENSACOVE dosage as clinically indicated [see Dosage and Administration 2.4 ), Warnings and Precautions 5.2 )]. No dosage modification is recommended for patients with mild hepatic impairment (total bilirubin <= upper limit of normal (ULN) and AST ULN or total bilirubin to 1.5 ULN and any AST).

WARNINGS AND PRECAUTIONS SECTION.

5 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 fetus and to use effective contraception. (5.9). 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 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 in 1.3% and Grade 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 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 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 in 14% of patients. Rash occurred in 72% of patients receiving ENSACOVE, including Grade in 12% of patients. The median time to onset of rash was days (range: day to 17.3 months). Pruritus occurred in 32% of patients receiving ENSACOVE, with Grade in 2.4%. There was one Grade 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 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 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 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 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 pooled safety population [see Adverse Reactions 6.1 )], based on adverse reactions, 6% of patients experienced hyperuricemia, with 0.4% Grade and 0.7% Grade 4. Nine patients (1.9%) required hydration and two patients (0.4%) required urate-lowering medication.Monitor serum uric acid levels prior to initiating ENSACOVE and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration 2.4 )]. 5.9 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, ENSACOVE can cause fetal harm when administered to pregnant woman. In embryo-fetal developmental studies, oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for week after the last dose [see Use in Specific Populations 8.1 8.3 and Clinical Pharmacology 12.1 )]. 5.10 FD&C Yellow No. (Tartrazine). This product contains FD&C Yellow No. (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.