Zykadia Special Precautions

Gastrointestinal Adverse Reactions: Severe gastrointestinal adverse reactions occurred in patients treated with ZYKADIA 750 mg under fasted conditions [see Clinical Trials Experience under Adverse Reactions]. Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of 925 patients, including severe cases (Grade 3 or 4) in 14% of patients treated with ZYKADIA across clinical studies. Diarrhea, nausea, vomiting, or abdominal pain leading to dose interruptions or reductions occurred in 36% of patients and leading to treatment discontinuation occurred in 1.6% of patients.
The incidence and severity of gastrointestinal adverse reactions were reduced for patients treated with ZYKADIA 450 mg with food in a dose optimization study (ASCEND-8). Diarrhea, nausea, vomiting, or abdominal pain occurred in 79% of 108 patients treated with ZYKADIA at the recommended dose of 450 mg with food. Of these, 53% were Grade 1 events and 24% were Grade 2 events. One patient (0.9%) experienced Grade 3 diarrhea, and one patient (0.9%) experienced Grade 3 vomiting. One patient (0.9%) required dose adjustment due to vomiting. Eleven (10%) patients had diarrhea, nausea, vomiting, or abdominal pain that required at least one dose interruption.
Monitor and manage patients using standard of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold ZYKADIA if gastrointestinal adverse reaction is severe or intolerable and is not responsive to antiemetics or antidiarrheals. Upon improvement, resume ZYKADIA at a reduced dose [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Hepatotoxicity: Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA [see Clinical Trials Experience under Adverse Reactions]. Elevations in alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) occurred in 28% and elevations in aspartate aminotransferase (AST) >5 times ULN occurred in 16% of 925 patients across clinical studies. Concurrent elevations in ALT >3 times the ULN and total bilirubin >2 times the ULN, with alkaline phosphatase <2 times the ULN occurred in 0.3% of patients across clinical studies. Approximately 1% of patients required permanent discontinuation due to hepatotoxicity.
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 reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Interstitial Lung Disease/Pneumonitis: Severe, life-threatening, or fatal interstitial lung diseases (ILD)/pneumonitis occurred in patients treated with ZYKADIA [see Clinical Trials Experience under Adverse Reactions]. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with ZYKADIA. 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.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
QT Interval Prolongation: QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmia (e.g., torsades de pointes) or sudden death, occurred in patients treated with ZYKADIA [see Clinical Trials Experience under Adverse Reactions]. Across clinical studies, 6% of 919 patients with at least one post-baseline electrocardiogram (ECG) assessment had an increase from baseline of QTc >60 msec. Approximately 1.3% of patients taking ZYKADIA 750 mg under fasted conditions were found to have a QTc >500 msec. ZYKADIA causes concentration-dependent increases in the QTc interval [see Pharmacology: Pharmacodynamics under Actions]. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc prolongation.
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. Based on the severity of the adverse reaction, withhold ZYKADIA, with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Hyperglycemia: Hyperglycemia occurred in patients treated with ZYKADIA [see Clinical Trials Experience under Adverse Reactions]. Across clinical studies, Grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients.
Monitor fasting serum glucose prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Bradycardia: Bradycardia occurred in patients treated with ZYKADIA [see Clinical Trials Experience under Adverse Reactions]. Across clinical studies, sinus bradycardia, defined as a heart rate <50 beats per minute, was noted as a new finding in 1.1% of 925 patients. Bradycardia was reported as an adverse reaction in 1% of patients. No patient required discontinuation and 0.1% required interruption with subsequent dose reduction for bradycardia.
Avoid using ZYKADIA in combination with other products known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose upon resolution of bradycardia, or permanently discontinue ZYKADIA [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Pancreatitis: Pancreatitis occurred in patients treated with ZYKADIA [see Clinical Trials Experience under Adverse Reactions]. Pancreatitis, including one fatality, occurred in less than 1% of patients receiving ZYKADIA in clinical studies. Grade 3 or 4 elevations of amylase occurred in 7% of patients receiving ZYKADIA across clinical studies, while Grade 3 or 4 elevations of lipase occurred in 14% of patients.
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 [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from 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 below the recommended human dose caused increases in skeletal anomalies in rats and rabbits.
Advise pregnant women of the potential risk to a fetus. Advise females 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 males with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy [see Pregnancy & Females and Males of Reproductive Potential under Use in Pregnancy & Lactation, Pharmacology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].
Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of ZYKADIA [see Dosage Modification for Patients With Severe Hepatic Impairment under Dosage & Administration]. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
Use in Children: The safety and effectiveness of ZYKADIA in pediatric patients have not been established.
Use in the Elderly: 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.