Zykadia Drug Information

® is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test . ZYKADIA is a kinase inhibitor indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

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 data in the Warnings and Precautions section reflect exposure to ZYKADIA 750 mg once daily under fasted conditions in 925 patients with ALK-positive NSCLC across seven clinical studies, including ASCEND-4 and ASCEND-1, described below, a randomized active-controlled study, two single arm studies, and two dose-escalation studies. The majority of patients enrolled in these studies had received prior treatment with chemotherapy and/or crizotinib for NSCLC. Among these 925 patients, the most common adverse reactions (≥ 25% incidence) were diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and weight loss.

Approximately 45% of patients initiating treatment with ZYKADIA 750 mg under fasted conditions had an adverse reaction that required at least one dose reduction and 66% of patients had an adverse reaction that required at least one dose interruption. The median time to first dose reduction due to any reason was 7 weeks. Dose Optimization Study: Dosing Regimen of 450 mg Daily With Food In ASCEND-8, a dose optimization study, ZYKADIA 450 mg daily with food (N = 108) was compared to 750 mg daily under fasted conditions (N = 110) in both previously treated and untreated patients with ALK-positive NSCLC. The overall safety profile of ZYKADIA 450 mg with food was consistent with ZYKADIA 750 mg fasted, except for a reduction in gastrointestinal adverse reactions, while achieving comparable steady-state exposure . The most common adverse reactions (≥ 25% incidence) in the 450 mg with food arm were diarrhea, nausea, abdominal pain, vomiting, and fatigue.

The incidence and severity of gastrointestinal adverse reactions (diarrhea 59%, nausea 43%, and vomiting 38%) were reduced for patients treated with ZYKADIA 450 mg with food; Grade ≥ 3 adverse reactions were reported in two patients (1.9%): Grade 3 diarrhea and Grade 3 vomiting in one patient each . In patients treated with ZYKADIA 450 mg with food, 24% of patients had an adverse reaction that required at least one dose reduction and 56% of patients had an adverse reaction that required at least one dose interruption. The median time to first dose reduction due to any reason was 8 weeks. Previously Untreated ALK-Positive Metastatic NSCLC The safety of ZYKADIA was evaluated in ASCEND-4, an open-label, randomized, active-controlled multicenter study of 376 previously untreated ALK-positive NSCLC patients . Patients received ZYKADIA 750 mg daily (N = 189) under fasted conditions or chemotherapy and maintenance chemotherapy (N = 187). Chemotherapy regimens were pemetrexed (500 mg/m 2 ) and investigator’s choice of cisplatin (75 mg/m 2 ) or carboplatin administered every 21 days.

Patients who completed 4 cycles of chemotherapy without progressive disease received pemetrexed (500 mg/m 2 ) as single-agent maintenance therapy every 21 days. The median duration of exposure to ZYKADIA was 18 months. The demographic characteristics of the study population were 57% female, median age 54 years (range, 22 to 81 years), 22% age 65 years or older, 54% white, 42% Asian, 2% black, and 2% other races.

Patients were enrolled in Europe (53%), Asia Pacific (42%), and South America (5%) regions. The majority of patients had adenocarcinoma (97%), never smoked (61%), and 32% had brain metastases at screening. The following fatal adverse reactions occurred in 4 patients treated with ZYKADIA: Myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause.

Serious adverse reactions were reported in 38% of patients treated with ZYKADIA. The most frequent serious adverse reactions were pneumonia (4%), pleural effusion (4%), vomiting (4%), nausea (3%), dyspnea (3%), hyperglycemia (3%), AST increased (2%), lung infection (2%), and pericardial effusion (2%). Among patients treated with ZYKADIA, dose interruptions due to adverse reactions occurred in 77%, dose reductions were required in 66%, and adverse reactions that led to discontinuation of therapy occurred in 12% of patients. The most frequent adverse reactions, reported in at least 10% of patients treated with ZYKADIA, that led to dose interruptions or reductions were: Increased ALT (48%), increased AST (34%), vomiting (15%), increased blood creatinine (14%), increased gamma-glutamyl transpeptidase (GGT) (13%), diarrhea (13%), and nausea (13%). The most frequent adverse reactions that led to discontinuation of ZYKADIA in 1% or more of patients in ASCEND-4 were increased blood creatinine (2.1%), increased amylase (1.1%), and increased lipase (1.1%). Tables 3 and 4 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-4. Table 3: Adverse Reactions (> 10% for All Grades* or ≥ 2% for Grades 3-4) of Patients in ASCEND-4 ZYKADIA N = 189 Chemotherapy N = 175 a All Grades Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal** Diarrhea 85 4.8 11

Nausea 69 2.6 55 5 Vomiting 67 5 36 6 Abdominal pain

b 40 3.7 13 0 Constipation 20 0 22 0 Esophageal disorder c 15 0.5 8

G eneral Fatigue d 45 7 49 6 Non-cardiac chest pain 21

1.1 10

Back pain 19 1.6 18 2.3 Pyrexia 19 0 14 1.1 Pain

in extremity 13 0 7 0 Musculoskeletal pain 11 0.5 6

Pruritus 11 0.5 5 0 Metabolism and Nutrition Decreased appetite 34 1.1

32

Weight loss 24 3.7 15 0.6 Respiratory Cough 25 0 17 0

Skin Rash e 21 1.1 8

Neurologic Headache 19 0.5 13 1.1 Dizziness 12 1.1 10 0.6 Cardiac

Prolonged QT interval 12 2.6 1.1

Pericarditis f 4.2 1.6 2.3 1.1 *National Cancer Institute Common Terminology Criteria

for Adverse Events (version 4.03). **For frequency of gastrointestinal adverse reactions at the recommended dose of 450 mg with food . a Twelve patients randomized to chemotherapy did not receive study drug. b Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, and epigastric discomfort). c Esophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia). d Fatigue (fatigue and asthenia). e Rash (rash, dermatitis acneiform, rash maculo-papular). f Pericarditis (pericardial effusion and pericarditis). Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included: vision disorder (4% comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, reduced visual acuity, or vitreous floaters), bradycardia (4%), ILD/pneumonitis (2%), hepatotoxicity (2%), and renal failure (2%). In addition, the adverse reaction of photosensitivity was reported in 1.1% of patients. Table 4: Laboratory Abnormalities Occurring in > 10% (All Grades*) of Patients in ASCEND-4 ZYKADIA N = 189 Chemotherapy N = 175 a All Grades Grade 3-4 All Grades Grade 3-4 % % % % Chemistry Increased ALT 91 34 65

Increased

AST 86 21 58

Increased

GGT 84 49 67 10 Increased alkaline phosphatase 81 12 47

Increased creatinine 77 4.2 37 0.6 Hyperglycemia 53 10 67 10 Hypophosphatemia

38 3.7 27

Increased amylase 37 8 43 4.5 Hyperbilirubinemia (total) 15 0.5 6 0.6

Increased lipase b 13 6 7

Hematology Anemia 67 4.2 84 11 Neutropenia 27 2.1 58 20 Thrombocytopenia

16 1.0 38

Abbreviations

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase. *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). a Twelve patients randomized to chemotherapy did not receive study drug. b In the ZYKADIA arm, no patients had baseline lipase laboratory assessments, 112 had post-baseline assessments. In the chemotherapy arm, one patient had baseline lipase laboratory assessments but no post-baseline assessment; 49 patients had post-baseline assessments. Previously Treated ALK-Positive Metastatic NSCLC The safety of ZYKADIA was evaluated in ASCEND-1, a multicenter, single-arm, open-label clinical study of 255 ALK-positive patients (246 patients with NSCLC and 9 patients with other cancers who received ZYKADIA at a dose of 750 mg daily under fasted conditions) . The median duration of exposure to ZYKADIA was 6 months.

The study population characteristics were: Median age 53 years, age less than 65 (84%), female (53%), white (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 (89%), brain metastases (49%), and number of prior therapies 2 or more (67%). Fatal adverse reactions in patients treated with ZYKADIA occurred in 5% of patients, consisting of: Pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each). Serious adverse reactions reported in 2% or more of patients in ASCEND-1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Dose reductions due to adverse reactions occurred in 59% of patients treated with ZYKADIA. The most frequent adverse reactions, reported in at least 10% of patients, that led to dose reductions or interruptions were: Increased ALT (29%), nausea (20%), increased AST (16%), diarrhea (16%), and vomiting (16%). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with ZYKADIA. The most frequent adverse reactions that led to discontinuation in 1% or more of patients in ASCEND-1 were pneumonia, ILD/pneumonitis, and decreased appetite. Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-1. Table 5: Adverse Reactions (> 10% for All Grades* or ≥ 2% for Grades 3-4) in ALK-Positive Patients Treated With ZYKADIA in ASCEND-1 ZYKADIA N = 255 All G rades Grade 3-4 % % Gastrointestinal** Diarrhea 86 6 Nausea 80 4 Vomiting 60 4 Abdominal pain a 54 2 Constipation 29 0 Esophageal disorder b 16 1 General Fatigue c 52 5 Metabolism and N utrition Decreased appetite 34 1 Skin Rash d 16 0 Respiratory Interstitial lung disease/pneumonitis 4 3 Abbreviation: ALK, anaplastic lymphoma kinase. *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). **For frequency of gastrointestinal adverse reactions at the recommended dose of 450 mg with food . a Abdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, and epigastric discomfort). b Esophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia). c Fatigue (fatigue and asthenia). d Rash (rash, maculopapular rash, and acneiform dermatitis). Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included neuropathy (17% comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9% comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%). In addition, the adverse reaction of photosensitivity was reported in 1.2% of patients.

Table 6: Key Laboratory Abnormalities Occurring in > 10% (All Grades*) of ALK-Positive Patients Treated With ZYKADIA in ASCEND-1 ZYKADIA N = 255 All G rades Grade 3-4 % % Hematology Anemia 84 5 Chemistry Increased ALT 80 27 Increased AST 75 13 Increased creatinine 58 2 Hyperglycemia 49 13 Hypophosphatemia 36 7 Increased lipase 28 10 Hyperbilirubinemia (total) 15 1 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALK, anaplastic lymphoma kinase. *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).

Effect of Other Drugs on

ZYKADIA Strong CYP3A Inhibitors A strong CYP3A4/P-gp inhibitor (ketoconazole) increased the systemic exposure of ceritinib , which may increase the incidence and severity of adverse reactions of ZYKADIA. Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA. If concurrent use of strong CYP3A inhibitors is unavoidable, reduce the ZYKADIA dose . Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A. Strong CYP3A Inducers A strong CYP3A4/P-gp inducer (rifampin) decreased the systemic exposure of ceritinib , which may decrease the efficacy of ZYKADIA. Avoid concurrent use of strong CYP3A inducers during treatment with ZYKADIA.

Effect of

ZYKADIA on Other Drugs CYP3A Substrates Ceritinib increased the systemic exposure of a sensitive CYP3A substrate (midazolam) . Avoid coadministration of ZYKADIA with sensitive CYP3A substrates. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A substrate(s). If ZYKADIA is coadministered with other CYP3A substrates, refer to the CYP3A substrate labeling for dosage recommendation with strong CYP3A inhibitors. CYP2C9 Substrates Ceritinib increased the systemic exposure of a CYP2C9 substrate (warfarin) . Increase the frequency of INR monitoring if coadministration with warfarin is unavoidable as the anti-coagulant effect of warfarin may be enhanced.

Avoid coadministration of ZYKADIA with CYP2C9 substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use of such CYP2C9 substrates is unavoidable, consider dose reduction for the coadministered CYP2C9 substrates.

Drugs That Prolong QT Interval

ZYKADIA causes concentration-dependent increases in the QTc interval. When possible, avoid coadministration of ZYKADIA with other products with a known potential to prolong the QTc interval .

Drugs That Cause Bradycardia

ZYKADIA can cause bradycardia. When possible, avoid coadministration of ZYKADIA with other products known to cause bradycardia .

Pregnancy Risk Summary Based on animal studies and its mechanism of action , ZYKADIA can cause fetal harm when administered to a pregnant woman. The limited available data on the use of ZYKADIA in pregnant women are insufficient to inform a risk. Administration of ceritinib to rats and rabbits during the period of organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits ( see Data ). Advise a pregnant woman of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in which pregnant rats were administered daily doses of ceritinib during organogenesis, dose-related skeletal anomalies were observed at doses as low as 50 mg/kg (less than 0.5-fold the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations. In pregnant rabbits administered ceritinib daily during organogenesis, dose-related skeletal anomalies, including incomplete ossification, were observed at doses equal to or > 2 mg/kg/day (approximately 0.015-fold the human exposure by AUC at the recommended dose). A low incidence of visceral anomalies, including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery, was observed at doses equal to or > 10 mg/kg/day (approximately 0.13-fold the human exposure by AUC at the recommended dose). Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or greater.

In addition, embryolethality was observed in rabbits at a dose of 50 mg/kg.

Pediatric Use The safety and effectiveness of ZYKADIA in pediatric patients have not been established.