INDICATION

ZYKADIA^® (ceritinib) capsules 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.

IMPORTANT SAFETY INFORMATION for ZYKADIA^® (ceritinib) capsules

Gastrointestinal Adverse Reactions

• Severe gastrointestinal toxicity occurred in patients treated with ZYKADIA 750 mg under fasted conditions. Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of 925 patients, including severe cases in 14% of patients treated with ZYKADIA across clinical studies
• In a dose optimization study, the incidence and severity of gastrointestinal adverse reactions were reduced for patients treated with ZYKADIA 450 mg with food. Diarrhea, nausea, vomiting, or abdominal pain occurred in 76% of 89 patients treated with ZYKADIA at the recommended dose of 450 mg with food. Of these, the majority experienced grade 1 events (51%). One patient experienced grade 3 diarrhea. No patients had diarrhea, nausea, vomiting, or abdominal pain that required dose reduction; 8% of patients had diarrhea or nausea that required at least 1 dose interruption
• Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose

Hepatotoxicity

• Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA. Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 28% and elevations in aspartate aminotransferase (AST) greater than 5 times the ULN occurred in 16% of 925 patients treated with ZYKADIA 750 mg under fasted conditions across clinical studies. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN occurred in 0.3% of patients across clinical studies. Approximately 1.0% of patients required permanent discontinuation due to hepatotoxicity. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of hepatotoxicity between the 750-mg under fasted conditions arm and the 450-mg with food arm.
• Monitor with liver laboratory tests including ALT, AST, and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose or permanently discontinue ZYKADIA

Interstitial Lung Disease/Pneumonitis

• Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with ZYKADIA. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with ZYKADIA 750 mg under fasted conditions. Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 ILD/pneumonitis was reported in 1.3% of patients with fatal events reported in 0.2% of patients. Ten patients (1.1%) discontinued ZYKADIA across clinical studies due to ILD/pneumonitis. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of ILD/pneumonitis between the 750-mg under fasted conditions arm and the 450-mg with food arm
• Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis

QTc Interval Prolongation

• QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death, occurred in patients treated with ZYKADIA in clinical studies. Across clinical studies, 6% of 919 patients with at least 1 postbaseline electrocardiogram (ECG) assessment experienced a QTc interval increase over baseline of greater than 60 milliseconds (ms). Approximately 1.3% of patients taking ZYKADIA 750 mg fasted were found to have a QTc greater than 500 ms. A pharmacokinetic/pharmacodynamic analysis suggested that ZYKADIA causes concentration-dependent increases in the QTc interval. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc interval prolongation. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of QTc interval prolongation between the 750-mg under fasted conditions arm and the 450-mg with food arm
• When possible, avoid use of ZYKADIA in patients with congenital long QT syndrome. Conduct periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold ZYKADIA in patients who develop a QTc interval greater than 500 ms on at least 2 separate ECGs until the QTc interval is less than 481 ms or recovery to baseline if the QTc interval is greater than or equal to 481 ms, then resume ZYKADIA at a reduced dose. Permanently discontinue ZYKADIA in patients who develop QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia

Hyperglycemia

• Hyperglycemia can occur in patients receiving ZYKADIA. Across clinical studies, CTCAE grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients treated with ZYKADIA 750 mg under fasted conditions. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of hyperglycemia between the 750-mg under fasted conditions arm and the 450-mg with food arm
• Monitor fasting serum glucose prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Initiate or optimize antihyperglycemic medications as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA until hyperglycemia is adequately controlled, then resume ZYKADIA at a reduced dose. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ZYKADIA

Bradycardia

• Bradycardia occurred in patients receiving ZYKADIA. Across clinical studies, sinus bradycardia, defined as a heart rate of less than 50 beats per minute (bpm), was noted as a new finding in 1% of 925 patients treated with ZYKADIA 750 mg under fasted conditions. Bradycardia was reported as an adverse drug reaction in 1% of patients. No patient required discontinuation and 0.1% required interruption with subsequent dose reduction for bradycardia. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of bradycardia between the 750-mg under fasted conditions arm and the 450-mg with food arm
• Avoid using ZYKADIA in combination with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or higher, evaluate the use of concomitant medications, and adjust the dose of ZYKADIA. Permanently discontinue ZYKADIA for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or higher, and if the concomitant medication can be adjusted or discontinued, resume ZYKADIA at a reduced dose

Pancreatitis

• Pancreatitis occurred in patients receiving ZYKADIA. Pancreatitis, including 1 fatality, has been reported in less than 1% of patients receiving ZYKADIA 750 mg under fasted conditions in clinical studies. CTCAE grade 3 or 4 elevations of amylase occurred in 7% of patients receiving ZYKADIA 750 mg under fasted conditions across clinical studies, whereas CTCAE grade 3 or 4 elevations of lipase occurred in 14% of patients. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of pancreatitis between the 750-mg under fasted conditions arm and the 450-mg with food Arm
• Monitor lipase and amylase prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Based on the severity of the laboratory abnormalities, withhold ZYKADIA with resumption at a reduced dose

Embryo-fetal Toxicity

• Based on its mechanism of action and findings in animal studies, ZYKADIA can cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures the recommended human dose caused increases in skeletal anomalies in rats and rabbits
• Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during treatment with ZYKADIA and for 6 months following completion of therapy. Based on the potential for genotoxicity, advise men with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy

Lactation

• No data exist 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 toxicity, hepatotoxicity, pneumonitis, bradycardia, and pancreatitis, advise women not to breastfeed during treatment with ZYKADIA and for 2 weeks following completion of therapy

Adverse Reactions

• The most common adverse reactions in ASCEND-4, which evaluated patients treated with 750 mg under fasted conditions, (incidence ≥25% all grades) were increased ALT/AST (91%/86%), diarrhea (85%), increased gamma-glutamyl transferase (GGT) (84%), increased alkaline phosphatase (81%), increased creatinine (77%), nausea (69%), vomiting (67%), anemia (67%), hyperglycemia (53%), fatigue (45%), abdominal pain (40%), decreased phosphate (38%), increased amylase (37%), decreased appetite (34%), and neutropenia (27%)
• In ASCEND-4, which evaluated patients treated with 750 mg under fasted conditions, grade 3 or 4 adverse reactions (incidence ≥2%) were increased GGT (49%), ALT/AST (34%/21%), increased alkaline phosphatase (12%), hyperglycemia (10%), increased amylase (8%), fatigue (7%), increased lipase (6%), diarrhea (5%), vomiting (5%), weight loss (4%), abdominal pain (4%), anemia (4%), increased creatinine (4%), decreased phosphate (4%), nausea (3%), prolonged QT interval (3%), neutropenia (2%), and pericarditis (2%)
• In ASCEND-4, which evaluated patients treated with 750 mg under fasted conditions, serious adverse drug reactions reported in at least 2% or more of patients treated with ZYKADIA were pneumonia, pleural effusion, vomiting, nausea, dyspnea, hyperglycemia, increased AST, lung infection, and pericardial effusion. Adverse reactions that led to death occurred in 4 patients treated with ZYKADIA, consisting of 1 each: myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause
• The most common adverse reactions in ASCEND-1, which evaluated patients treated with 750 mg under fasted conditions, (incidence ≥25% all grades) were diarrhea (86%), nausea (80%), increased ALT/AST (80%/75%), vomiting (60%), abdominal pain (54%), fatigue (52%), decreased appetite (34%), and constipation (29%)
• In ASCEND-1, which evaluated patients treated with 750 mg under fasted conditions, grade 3/4 adverse reactions (incidence ≥2%) were increased ALT/AST (27%/13%), diarrhea (6%), fatigue (5%), nausea (4%), vomiting (4%), ILD/pneumonitis (3%), and abdominal pain (2%)
• Serious adverse drug reactions reported in ASCEND-1, which evaluated patients treated with 750 mg under fasted conditions, (incidence >2%) were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse reactions 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)
• In ASCEND-8, a dose optimization study of ZYKADIA 450 mg daily with food was compared with 750 mg daily under fasted conditions. 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 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 1 patient (1.1%)

Drug Interactions

Effect of Other Drugs on Ceritinib

• CYP3A inhibitors increase ceritinib plasma concentrations: Avoid concurrent use of ZYKADIA with strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors 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 CYP3A4 inhibitor
• CYP3A inducers decrease ceritinib plasma concentrations: Avoid concurrent use of ZYKADIA with strong CYP3A inducers

Effect of Ceritinib on Other Drugs

• Ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. 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 and CYP2C9 substrates with narrow therapeutic indices

Drug-Food/Drink Interactions

• Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A in the gut wall and increase the bioavailability of ceritinib

Please see full Prescribing Information for ZYKADIA^® (ceritinib) capsules.