ENSARTINIB: 19 Adverse Event Reports & Safety Profile

ENSACOVE capsules contain ensartinib, a kinase inhibitor, present as ensartinib hydrochloride with the chemical name 6-amino-5-[(1 R )-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-{4-[(3 R ,5 S )- 3,5-dimethylpiperazine-1-carbonyl]phenyl}pyridazine-3-carboxamide, dihydrochloride. The molecular formula is C26H27Cl2FN6O3·2HCl and its molecular weight is 634.4 g/mol with the following structure: ENSACOVE capsules are intended for oral administration and are available in two dosage strengths: 25 mg ensartinib (equivalent to 28.25 mg ensartinib hydrochloride) and 100 mg ensartinib (equivalent to 113.02 mg ensartinib hydrochloride). The inactive ingredients of ENSACOVE capsules are microcrystalline cellulose and stearic acid. The inactive ingredients of the 25 mg empty capsule shells are hypromellose and titanium dioxide. The inactive ingredients of the 100 mg empty capsules shells are black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 5, hypromellose, red iron oxide, and titanium dioxide. The imprinting ink for the 25 mg capsules contains butyl alcohol, dehydrated alcohol, FD&C Blue No. 2, isopropyl alcohol, propylene glycol, shellac, and strong ammonia solution. The imprinting ink for the 100 mg capsules contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, povidone, propylene glycol, shellac, sodium hydroxide, and titanium dioxide.

Chemical

Structure

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 )

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> and fasting blood glucose <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span>.

2.3 Recommended Dosage The recommended dosage of ENSACOVE is 225 mg orally once daily, with or without food <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , 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.

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 )

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. 5 (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 .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 a single agent in 458 patients with locally advanced or metastatic ALK-positive NSCLC in the following trials: eXALT3 Study (N=143) <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 ) ]</span>, 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 6 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 3 or 4 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 NSCLC The 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 6 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

3 and 4 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 N = 143 Crizotinib N = 146 Adverse Reaction All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Skin and Subcutaneous Tissue Disorders Rash a 66 12 10 0 Pruritus b 30 2.1 4.1 0 Alopecia 11 0 4.8 0 Dry Skin 10 0.7 0.7 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain c 36 1.4 20 0 Respiratory, Thoracic and Mediastinal Disorders Cough d 31 0.7 16 0 Gastrointestinal Disorders Constipation 31 0 26 0 Nausea 28 1.4 30

2.1 Vomiting e 16 0.7 32 0 General Disorders and Administration Site Conditions Edema f 27 2.1 28

2.1 Pyrexia g 22 0.7 10

0.7 Fatigue h 21 0.7 14

1.4 Metabolism and Nutrition Disorders Decreased appetite 15 0 12

1.4 Infection and Infestation Respiratory Tract Infection 13 0.7 10 0 Nervous System Disorders Dizziness i 12 0.7 14

0.7 Dysgeusia 10 0 11 0 Vascular Disorders Hemorrhage j 10 1.4 4.8 0 Adverse reactions were graded using NCI CTCAE version 4.03. a 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 b Includes ear pruritus, eye pruritus, eyelids pruritus, lip pruritus, pruritus, and pruritus generalized c Includes arthritis, spinal pain, myalgia, musculoskeletal pain, back pain, pain in extremity, neck pain, arthralgia, non-cardiac check pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort d Includes cough, productive cough, upper-airway cough syndrome e Includes vomiting and retching f Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, gravitational edema, skin edema, eye edema, and periorbital edema. g Includes pyrexia and hyperthermia h Includes fatigue and asthenia. i Includes dizziness, vertigo, postural dizziness j 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 N = 143 Crizotinib N = 146 Lab Abnormality All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Chemistry Alanine aminotransferase increased 73 5 74 8 Alkaline phosphatase increased 64 2.2 50

0.7 Aspartate aminotransferase increased 64 1.4 62

3.5 Glucose increased 49 5 35

0.7 Albumin decreased 46 0.7 56

1.4 Phosphate decreased 39 7 42

4.9 Urate increased 39 39 27 27 Creatinine increased 37 0 27 0 Calcium decreased 36 1.4 64

4.9 Sodium decreased 27 4.3 27

4.2 Hematology Lymphocytes decreased 57 7 47 5 Hemoglobin decreased 43 0.7 31

1.4 Adverse reactions were graded using NCI CTCAE version 4.03. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase Clinically relevant adverse reactions in &lt;10% of patients who received ENSACOVE included interstitial lung disease, photosensitivity, increased creatinine phosphokinase, bradycardia, and visual disturbances.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

5.2 Hepatotoxicity ENSACOVE can cause hepatotoxicity including drug-induced liver injury. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) ]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

5.4 Bradycardia ENSACOVE can cause symptomatic bradycardia. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .

5.5 Hyperglycemia ENSACOVE can cause hyperglycemia. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

5.7 Increased Creatine Phosphokinase In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Adverse Reactions ( 6.1 )]</span>.

5.8 Hyperuricemia ENSACOVE can cause hyperuricemia. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>, based on adverse reactions, 6% of patients experienced hyperuricemia, with 0.4% Grade 3 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

5.9 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ENSACOVE can cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )]</span>.

5.10 FD&amp;C Yellow No. 5 (Tartrazine) This product contains FD&amp;C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&amp;C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

INTERACTIONS Moderate or Strong CYP3A Inhibitors : Avoid concomitant use with ENSACOVE. ( 7.1 ) Moderate or Strong CYP3A Inducers : Avoid concomitant use with ENSACOVE. ( 7.1 ) P-gp Inhibitor : Avoid concomitant use with ENSACOVE. ( 7.1 )

7.1 Effect of Other Drugs on ENSACOVE Table 5 describes drug interactions where concomitant use of another drug affects ENSACOVE.

Table

5: Effect of Other Drugs on ENSACOVE Strong or Moderate CYP3A Inhibitors Prevention or Management Avoid concomitant use of strong or moderate CYP3A inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro [see Clinical Pharmacology ( 12.3 )] . Concomitant use with strong or moderate CYP3A inhibitors may increase ensartinib exposure; however, this has not been studied clinically. Strong or Moderate CYP3A Inducers Prevention or Management Avoid concomitant use of strong or moderate CYP3A inducers with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro [see Clinical Pharmacology ( 12.3 )] . Concomitant use with strong or moderate CYP3A inducers may decrease ensartinib exposure; however, this has not been studied clinically. P-gp Inhibitors Prevention or Management Avoid concomitant use of P-gp inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a P-gp substrate in vitro [see Clinical Pharmacology ( 12.3 )] . Concomitant use with P-gp inhibitors may increase ensartinib exposure; however, this has not been studied clinically.