Zykadia Special Precautions

Hepatotoxicity: Cases of hepatotoxicity occurred in 1.1% of patients receiving ceritinib in clinical studies. Increases to grade 3 or 4 ALT elevations were observed in 25% of patients. The majority of cases were manageable with dose interruption and/or dose reduction. Few events required discontinuation of treatment.
Patients should be monitored with liver laboratory tests (including ALT, AST and total bilirubin) prior to the start of treatment, every 2 weeks during the first three months of treatment and monthly thereafter. In patients who develop transaminase elevations, more frequent monitoring of liver transaminases and total bilirubin should be carried out as clinically indicated (see Dosage & Administration and Adverse Reactions). Ceritinib is not recommended for patients with moderate to severe hepatic impairment (see Dosage & Administration and Adverse Reactions).
Interstitial lung disease / Pneumonitis: Severe, life-threatening or fatal ILD/pneumonitis have been observed in patients treated with ceritinib in clinical studies. Most of these severe/life-threatening cases improved or resolved with interruption of treatment.
Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potential causes of ILD/pneumonitis should be excluded, and Zykadia permanently discontinued in patients diagnosed with any grade treatment-related ILD/pneumonitis (see Dosage & Administration and Adverse Reactions).
QT interval prolongation: QTc prolongation has been observed in clinical studies in patients treated with ceritinib (see Pharmacology: Pharmacokinetics under Actions and Adverse Reactions), which may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death.
Use of Zykadia in patients with congenital long QT syndrome should be avoided. The benefits and potential risks of ceritinib should be considered before beginning therapy in patients who have pre-existing bradycardia (heart rate less than 60 beats per minute [bpm]), patients who have a history of or predisposition for QTc prolongation, patients who are taking anti-arrhythmics or other medicinal products that are known to prolong the QT interval and patients with relevant pre-existing cardiac disease and/or electrolyte disturbances. Periodic monitoring with ECGs and periodic monitoring of electrolytes (e.g. potassium) is recommended in these patients. In the event of vomiting, diarrhoea, dehydration or impaired renal function, correct electrolytes as clinically indicated. Zykadia should be permanently discontinued in patients who develop QTc >500 msec or >60 msec change from baseline and torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Zykadia should be withheld in patients who develop QTc >500 msec on at least two separate ECGs until recovery to baseline or a QTc ≤480 msec, then reinitiated with dose reduced by 150 mg (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration and Adverse Reactions).
Bradycardia: Asymptomatic cases of bradycardia (heart rate less than 60 bpm) have been observed in 21 out of 925 (2.3%) patients treated with ceritinib in clinical studies.
Use of Zykadia in combination with other agents known to cause bradycardia (e.g. beta blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin) should be avoided as far as possible. Heart rate and blood pressure should be monitored regularly. In cases of symptomatic bradycardia that is not life-threatening, Zykadia should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, the use of concomitant medicinal products should be evaluated and the Zykadia dose adjusted if necessary. In the event of life-threatening bradycardia Zykadia should be permanently discontinued if no contributing concomitant medicinal product is identified; however, if associated with a concomitant medicinal product known to cause bradycardia or hypotension, Zykadia should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If the concomitant medicinal product can be adjusted or discontinued, Zykadia should be reinitiated with dose reduced by 150 mg on recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring (see Dosage & Administration and Adverse Reactions).
Gastrointestinal adverse reactions: Diarrhoea, nausea, or vomiting occurred in 74.2% of 89 patients treated with Zykadia at the recommended dose of 450 mg taken with food in a dose optimisation study and were mainly grade 1 events (49.4%). One patient (1.1%) experienced grade 3 diarrhoea. Seven patients (7.9%) required study drug interruption due to diarrhoea or nausea. The incidence and severity of gastrointestinal adverse drug reactions were higher for patients treated with Zykadia 750 mg fasted (diarrhoea 76%, nausea 50%, vomiting 56%; 12% reported a grade 3/4 event) compared to 450 mg with food (diarrhoea 56%, nausea 45%, vomiting 35%; 1.1% reported a grade 3/4 event).
No patients required dose reduction or discontinuation of Zykadia due to diarrhoea, nausea or vomiting (see Adverse Reactions).
Patients should be monitored and managed using standards of care, including anti-diarrhoeals, anti-emetics or fluid replacement, as clinically indicated. Dose interruption and dose reduction should be employed as necessary (see Dosage & Administration and Adverse Reactions). If vomiting occurs during the course of treatment, the patient should not take an additional dose, but should continue with the next scheduled dose.
Hyperglycaemia: Cases of hyperglycaemia (all grades) have been reported in less than 10% of patients treated with ceritinib in clinical studies; grade 3-4 hyperglycaemia was reported in 5.4% of patients. The risk of hyperglycaemia was higher in patients with diabetes mellitus and/or concurrent steroid use.
Patients should be monitored for fasting plasma glucose prior to the start of Zykadia treatment and periodically thereafter as clinically indicated. Anti-hyperglycaemic medicinal products should be initiated or optimised as indicated (see Dosage & Administration and Adverse Reactions).
Lipase and/or amylase elevations: Elevations of lipase and/or amylase have occurred in patients treated with ceritinib in clinical studies. Patients should be monitored for lipase and amylase elevations prior to the start of Zykadia treatment and periodically thereafter as clinically indicated (see Dosage & Administration and Adverse Reactions). Cases of pancreatitis have been reported in patients treated with ceritinib (see Adverse Reactions).
Effects on ability to drive and use machines: Zykadia has minor influence on the ability to drive or use machines. Caution should be exercised when driving or using machines during treatment as patients may experience fatigue or vision disorders.