Description

Effect of Other Drugs on Ceritinib: Strong CYP3A Inhibitors: A strong CYP3A4/P-gp inhibitor (ketoconazole) increased the systemic exposure of Ceritinib so it should be avoided. 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, the Ceritinib dose should be reduced by approximately one third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, the Ceritinib dose should be resumed that was taken prior to initiating the strong CYP3A inhibitor. Grapefruit and grapefruit juice should not be consumed as they may inhibit CYP3A. Strong CYP3A Inducers: A strong CYP3A4/P-gp inducer (Rifampin) decreased the systemic exposure of Ceritinib. Concurrent use of strong CYP3A inducers (e.g., Carbamazepine, Phenytoin, Rifampin, and St. John's Wort) should be avoided during treatment with Ceritinib. Effect of Ceritinib on Other Drugs: CYP3A Substrates: Ceritinib increased the systemic exposure of a sensitive CYP3A substrate (Midazolam) so it should be avoided. If concomitant use is unavoidable, dose reduction of the sensitive CYP3A substrates should be considered. If Ceritinib is coadministered with other CYP3A substrates, it should be referred to the CYP3A substrate labeling for dosage recommendation with strong CYP3A inhibitors. CYP2C9 Substrates: Ceritinib increased the systemic exposure of a CYP2C9 substrate (Warfarin). The frequency of INR monitoring should be increased if coadministration with warfarin is unavoidable as the anti-coagulant effect of Warfarin may be enhanced. Coadministration of Ceritinib should be avoided with CYP2C9 substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use of such CYP2C9 substrates is unavoidable, dose reduction should be considered for the coadministered CYP2C9 substrates.

Gastrointestinal Adverse Reactions Hepatotoxicity Interstitial Lung Disease/Pneumonitis QT Interval Prolongation Hyperglycemia Bradycardia Pancreatitis

Ceritinib can cause fetal harm when administered to a pregnant woman. If it is used during pregnancy or if the patient becomes pregnant while taking it, the patient should be apprised of the potential hazard to the fetus. 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, a woman should be advised not to breastfeed during treatment with Cerinib and for 2 weeks following completion of therapy.

Gastrointestinal Adverse Reactions: Severe gastrointestinal toxicity occurred in patients treated with Ceritinib 750 mg under fasted conditions. 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 Ceritinib 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. Patients should be monitored and managed using standards of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, Ceritinib should be withheld with resumption at a reduced dose. Hepatotoxicity: Drug-induced hepatotoxicity occurred in patients treated with Ceritinib. 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 ULN occurred in 16% of 925 patients across clinical studies. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN, with alkaline phosphatase less 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. It should be 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, Ceritinib should be withheld with resumption at a reduced dose, or permanently discontinue Ceritinib. Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, or fatal ILD/pneumonitis occurred in patients treated with Ceritinib. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with Ceritinib. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 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 Ceritinib across clinical studies due to ILD/pneumonitis. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. 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 Ceritinib. Across clinical studies, 6% of 919 patients with at least one post-baseline ECG assessment experienced a QTc interval increase over baseline of greater than 60 msec. Approximately 1.3% of patients taking Ceritinib 750 mg fasted were found to have a QTc greater than 500 msec. When possible, use of Ceritinib should be avoided in patients with congenital long QT syndrome. Periodic monitoring should be conducted with electrocardiograms (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. Hyperglycemia: Hyperglycemia occurred in patients receiving Ceritinib. Across clinical studies, CTCAE Grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients. Fasting serum glucose should be monitored prior to the start of Ceritinib treatment and periodically thereafter as clinically indicated. Based on the severity of the adverse drug reaction, Ceritinib should be withheld until hyperglycemia is adequately controlled, then resume Ceritinib at a reduced dose. Bradycardia: Bradycardia occurred in patients receiving Ceritinib. 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. 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. Using Ceritinib should be avoided in combination with other agents known to cause bradycardia (e.g., beta-blockers, nondihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Heart rate and blood pressure should be regularly monitored. In cases of symptomatic bradycardia that is not life threatening, Ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Ceritinib. Pancreatitis: Pancreatitis occurred in patients receiving Ceritinib. Pancreatitis, including one fatality, occurred in less than 1% of patients receiving Ceritinib in clinical studies. CTCAE Grade 3 or 4 elevations of amylase occurred in 7% of patients receiving Ceritinib across clinical studies, while CTCAE Grade 3 or 4 elevations of lipase occurred in 14% of patients. Lipase and amylase should be monitored prior to the start of Ceritinib treatment and periodically thereafter as clinically indicated. Based on the severity of the laboratory abnormalities, Ceritinib should be withheld with resumption at a reduced dose. Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animal studies, Ceritinib can cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Ceritinib and for 6 months following completion of therapy. Based on the potential for genotoxicity, males with female partners of reproductive potential should be advised to use condoms during treatment with Ceritinib and for 3 months following completion of therapy.

Females: Ceritinib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception during treatment with Ceritinib and for 6 months following completion of therapy. Males: Based on the potential for genotoxicity, males with female partners of reproductive potential should be advised to use condoms during treatment with Ceritinib and for 3 months following completion of therapy. Pediatric Use: The safety and effectiveness of Ceritinib in pediatric patients have not been established. Geriatric Use: Of the 925 patients in clinical studies of Ceritinib, 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. Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), the dose of Ceritinib should be reduced by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. No dose adjustment is recommended in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Store below 30°C in a cool and dry place, away from sunlight. Keep out of reach of children.