<p><strong>Gastrointestinal Adverse Reactions</strong>: 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.<br />
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<strong>Hepatotoxicity</strong>: 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.<br />
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<strong>Interstitial Lung Disease (ILD)/Pneumonitis</strong>: 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.<br />
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<strong>QT Interval Prolongation</strong>: 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.<br />
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<strong>Hyperglycemia</strong>: 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.<br />
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<strong>Bradycardia</strong>: 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.<br />
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<strong>Pancreatitis</strong>: 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.<br />
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<strong>Embryo-Fetal Toxicity</strong>: 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.</p>