Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 13 July 2018

Indication(s)

1 INDICATIONS AND USAGE ZYKADIA® is indicated for the treatment of 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 patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] QT Interval Prolongation [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)] Hyperglycemia [see Warnings and Precautions (5.5)] Bradycardia [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.2) ] Pancreatitis [see Warnings and Precautions (5.7)] The most common adverse reactions (incidence of at least 25%) in patients treated with ZYKADIA 750 mg fasted are diarrhea, nausea, fatigue, vomiting, abdominal pain, decreased appetite, and weight loss. (6) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 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 (greater than or equal to 25% incidence) were diarrhea, nausea, fatigue, vomiting, 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. In ASCEND-8, a dose optimization study, ZYKADIA 450 mg daily with food (N=89) was compared to 750 mg daily under fasted conditions (N=90) 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 [see Clinical Pharmacology (12.3)]. The incidence and severity of gastrointestinal adverse reactions (diarrhea 56%, nausea 45%, vomiting 35%) were reduced for patients treated with ZYKADIA 450 mg with food; the only Grade ≥3 adverse reaction was Grade 3 diarrhea in one patient (1.1%) [see Gastrointestinal Adverse Reactions (5.1)]. In patients treated with ZYKADIA 450 mg with food, 10% of patients had an adverse reaction that required at least one dose reduction and 42% 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-P ositive M etastatic NSCLC The safety evaluation of ZYKADIA is based on 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 plus maintenance chemotherapy (N=187). Chemotherapy regimens were pemetrexed (500 mg/m2) plus investigator’s choice of cisplatin (75 mg/m2) or carboplatin (AUC of 5 - 6 mg*min/mL) administered every 21 days. Patients who completed 4 cycles of chemotherapy without progressive disease received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. 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 median duration of exposure to ZYKADIA was 18 months. Serious adverse reactions were reported in 72 patients (38%) 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: ALT increased (48%), AST increased (34%), vomiting (15%), blood creatinine increased (14%), GGT increased (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 blood creatinine increased (2.1%), amylase increased (1.1%), and lipase increased (1.1%). The following fatal adverse reactions occurred in 4 patients treated with ZYKADIA: myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause. Tables 3 and 4 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-4. Table 3: Adverse Reactions (>10% for All NCI CTCAE* 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 1.1 Nausea 69 2.6 55 5 Vomiting 67 5 36 6 Abdominal painb 40 3.7 13 0 Constipation 20 0 22 0 Esophageal disorderc 15 0.5 8 0.6 G eneral Fatigued 45 7 49 6 Non-cardiac chest pain 21 1.1 10 0.6 Back pain 19 1.6 18 2.3 Pain in extremity 13 0 7 0 Musculoskeletal pain 11 0.5 6 0.6 Pruritus 11 0.5 5 0 Pyrexia 19 0 14 1.1 Metabolism And Nutrition Decreased appetite 34 1.1 32 1.1 Weight loss 24 3.7 15 0.6 Respiratory Cough 25 0 17 0 Neurologic Headache 19 0.5 13 1.1 Dizziness 12 1.1 10 0.6 Skin Rashe 21 1.1 8 0.6 Cardiac Prolonged QT interval 12 2.6 1.1 0.6 Pericarditisf 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, see Gastrointestinal Adverse Reactions (5.1) and Clinical Trials Experience (6.1). aTwelve patients randomized to chemotherapy did not receive study drug. bAbdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort) cEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia) dFatigue (fatigue and asthenia) eRash (rash, dermatitis acneiform, rash maculo-papular) fPericarditis (pericardial effusion and pericarditis) Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg fasted 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%). Table 4: Laboratory Abnormalities Occurring in >10% (All NCI CTCAE Grades) of Patients in ASCEND-4 ZYKADIA N=189 Chemotherapy N=175 a All Grades Grade 3–4 All Grades Grade 3–4 % % % % Hematology Anemia 67 4.2 84 11 Neutropenia 27 2.1 58 20 Thrombocytopenia 16 1.0 38 4.6 Chemistry Increased alanine transaminase (ALT) 91 34 65 3.4 Increased aspartate transaminase (AST) 86 21 58 2.3 Increased gamma-glutamyl transpeptidase (GGT) 84 49 67 10 Increased alkaline phosphatase 81 12 47 1.7 Increased creatinine 77 4.2 37 0.6 Hyperglycemia 53 10 67 10 Increased amylase 37 8 43 4.5 Decreased phosphate 38 3.7 27 4.0 Increased bilirubin (total) 15 0.5 6 0.6 Increased lipaseb 13 6 7 0.6 aTwelve patients randomized to chemotherapy did not receive study drug. bIn 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 evaluation of ZYKADIA is based on 255 ALK-positive patients in ASCEND-1 (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%), Caucasian (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), ECOG PS 0 or 1 (89%), brain metastases (49%), and number of prior therapies 2 or more (67%). 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%). Serious adverse drug reactions reported in 2% or more of patients in ASCEND-1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. 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). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with ZYKADIA. The most frequent adverse drug 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 the common adverse reactions and laboratory abnormalities observed in ZYKADIA-treated patients. Table 5: Adverse Reactions (>10% for All NCI CTCAE* 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 paina 54 2 Constipation 29 0 Esophageal disorderb 16 1 General Fatiguec 52 5 Metabolism and N utrition Decreased appetite 34 1 Skin Rashd 16 0 Respiratory Interstitial lung disease/pneumonitis 4 3 *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, see Gastrointestinal Adverse Reactions (5.1) and Clinical Trials Experience (6.1). aAbdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, epigastric discomfort) bEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia) cFatigue (fatigue, asthenia) dRash (rash, maculopapular rash, acneiform dermatitis) Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg fasted 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%). Table 6: Key Laboratory Abnormalities Occurring in >10% (All NCI CTCAE 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 alanine transaminase (ALT) 80 27 Increased aspartate transaminase (AST) 75 13 Increased creatinine 58 2 Hyperglycemia 49 13 Decreased phosphate 36 7 Increased lipase 28 10 Increased bilirubin (total) 15 1

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 450 mg orally once daily with food. (2.2) 2.1 Patient Selection Select patients for treatment of metastatic NSCLC with ZYKADIA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and 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 Dosing and Administration The recommended dose of ZYKADIA is 450 mg orally once daily with food until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)] . If a dose of ZYKADIA is missed, make up that dose unless the next dose is due within 12 hours. If vomiting occurs during the course of treatment, do not administer an additional dose and continue with the next scheduled dose of ZYKADIA. 2. 3 Dose Modifications for Adverse Reactions Recommendations for dose modifications of ZYKADIA for adverse reactions are provided in Table 2. Discontinue ZYKADIA for patients unable to tolerate 150 mg daily with food. Table 1: ZYKADIA Dose Reductions Dose Reduction Schedule Dose Level Starting dose 450 mg taken orally once daily with food First dose reduction 300 mg taken orally once daily with food Second dose reduction 150 mg taken orally once daily with food Table 2: ZYKADIA Dose Modifications for Adverse Reactions Adverse Reaction ZYKADIA Dose Modification Gastrointestinal Adverse Reactions Lipase or amylase elevation greater than 2 times ULN Withhold and monitor serum lipase and amylase. Resume ZYKADIA with a 150 mg dose reduction after recovery to less than 1.5 times ULN. Severe or intolerable nausea, vomiting or diarrhea despite optimal antiemetic or antidiarrheal therapy Withhold until improved, then resume ZYKADIA with a 150 mg dose reduction. Hyperglycemia Persistent hyperglycemia greater than 250 mg/dL despite optimal antihyperglycemic therapy Withhold until hyperglycemia is adequately controlled, then resume ZYKADIA with a 150 mg dose reduction. If adequate hyperglycemic control cannot be achieved with optimal medical management, discontinue ZYKADIA. Pneumonitis Any Grade treatment-related ILD/pneumonitis Permanently discontinue ZYKADIA. Cardiac Arrhythmias QTc interval greater than 500 msec on at least 2 separate ECGs Withhold until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume ZYKADIA with a 150 mg dose reduction. QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue ZYKADIA. Symptomatic bradycardia that is not life-threatening Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate concomitant medications known to cause bradycardia, and adjust the dose of ZYKADIA. Clinically significant bradycardia requiring intervention or life-threatening bradycardia in patients taking a concomitant medication also known to cause bradycardia or a medication known to cause hypotension Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If the concomitant medication can be adjusted or discontinued, resume ZYKADIA with a 150 mg dose reduction, with frequent monitoring. Life-threatening bradycardia in patients who are not taking a concomitant medication also known to cause bradycardia or known to cause hypotension Permanently discontinue ZYKADIA. Hepatotoxicity ALT or AST elevation greater than 5 times ULN with total bilirubin elevation less than or equal to 2 times ULN Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume ZYKADIA with a 150 mg dose reduction. ALT or AST elevation greater than 3 times ULN with total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis Permanently discontinue ZYKADIA. AST: aspartate aminotransferase; ALT: alanine aminotransferase; ULN: upper limit of normal; ILD: interstitial lung disease; ECG: electrocardiogram; bpm: beats per minute 2. 4 Dose Modification for Strong CYP3A Inhibitors Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the ZYKADIA dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ZYKADIA dose that was taken prior to initiating the strong CYP3A inhibitor. 2.5 Dose Modification for Patients with Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of ZYKADIA by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, ZYKADIA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 greater than 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 greater than 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. 8. 2 Lactation Risk Summary There are no data regarding the presence of ceritinib or its metabolites in human milk, the effects of ceritinib on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions including gastrointestinal adverse reactions, hepatotoxicity, pneumonitis, bradycardia and pancreatitis, advise a woman not to breastfeed during treatment with ZYKADIA and for 2 weeks following completion of therapy. 8.3 Females and M ales of R eproductive P otential Contraception Females ZYKADIA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for 6 months following completion of therapy. M ales Based on the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy [see Nonclinical Toxicology (13 .1)]. 8.4 Pediatric Use The safety and effectiveness of ZYKADIA in pediatric patients have not been established. 8.5 Geriatric Use Of the 925 patients in clinical studies of ZYKADIA, 18% were 65 years or older, while 5% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 8.6 Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of ZYKADIA by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Interactions

7 DRUG INTERACTIONS CYP3A Inhibitors and Inducers: Avoid concurrent use of ZYKADIA with strong CYP3A inhibitors or inducers. If concurrent use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ZYKADIA. (2.4, 7.1) CYP3A and CYP2C9 Substrates: Avoid concurrent use of ZYKADIA with CYP3A or CYP2C9 substrates with narrow therapeutic indices. (7.2) 7.1 Effect of Other Drugs on Ceritinib Ceritinib is primarily metabolized by CYP3A4 and is a substrate of the efflux transporter P-glycoprotein (P-gp). Strong CYP3A Inhibitors A strong CYP3A4/P-gp inhibitor (ketoconazole) increased the systemic exposure of ceritinib [see Clinical Pharmacology (12.3)]. Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA. If concomitant use of strong CYP3A inhibitors including certain antivirals (e.g., ritonavir), macrolide antibiotics (e.g., telithromycin), antifungals (e.g., ketoconazole), and nefazodone is unavoidable, reduce the ZYKADIA dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ZYKADIA dose that was taken prior to initiating the strong CYP3A inhibitor. 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 [see Clinical Pharmacology (12.3)]. Avoid concurrent use of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) during treatment with ZYKADIA. 7.2 Effect of Ceritinib on Other Drugs Ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations [see Clinical Pharmacology (12.3)]. Avoid concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic indices or substrates primarily metabolized by CYP3A and CYP2C9 during treatment with ZYKADIA. If use of these medications is unavoidable, consider dose reduction of CYP3A substrates with narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) and CYP2C9 substrates with narrow therapeutic indices (e.g., phenytoin, warfarin).

More information

Category Value
Authorisation number NDA205755
Agency product number K418KG2GET
Orphan designation No
Product NDC 0078-0640
Date Last Revised 21-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1535462
Marketing authorisation holder Novartis Pharmaceuticals Corporation