Zykadia

Treatment with ceritinib should be initiated and supervised by a physician experienced in the use of anti-cancer medicinal products. 1). ALK-positive NSCLC status should be established prior to initiation of ceritinib therapy. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised.

Posology The recommended dose of ceritinib is 450 mg taken orally once daily with food at the same time each day. The maximum recommended dose with food is 450 mg taken orally once daily. Treatment should continue as long as clinical benefit is observed.

If a dose is missed, the patient should make up that dose, unless the next dose is due within 12 hours. If vomiting occurs during the course of treatment, the patient should not take an additional dose, but 3 should continue with the next scheduled dose.

Ceritinib should be discontinued in patients unable to tolerate 150 mg daily taken with food. Dose adjustment due to adverse reactions Temporary dose interruption and/or dose reduction of ceritinib may be required based on individual safety and tolerability.

If dose reduction is required due to an adverse drug reaction (ADR) not listed in Table 1, then this should be achieved by decrements of 150 mg daily. Early identification and management of ADRs with standard supportive care measures should be considered.

6% of patients had an adverse event that required at least one dose interruption. 7 weeks. Table 1 summarises recommendations for dose interruption, reduction or discontinuation of ceritinib in the management of selected ADRs. Table 1 Ceritinib dose adjustment and management recommendations for ADRs Criteria Ceritinib dosing Severe or intolerable nausea, vomiting or diarrhoea despite optimal anti-emetic or anti-diarrhoeal therapy Withhold ceritinib until improved, then reinitiate ceritinib with dose reduced by 150 mg.

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation >5 times upper limit of normal (ULN) with concurrent total bilirubin ≤2 times ULN Withhold ceritinib until recovery to baseline ALT/AST levels or to ≤3 times ULN, then reinitiate with dose reduced by 150 mg.

ALT or AST elevation >3 times ULN with concurrent total bilirubin elevation >2 times ULN (in the absence of cholestasis or haemolysis) Permanently discontinue ceritinib. Any grade treatment-related interstitial lung disease (ILD)/pneumonitis Permanently discontinue ceritinib.

Summary of the safety profile Adverse drug reactions (ADRs) described below reflect exposure to ceritinib 750 mg once daily fasted in 925 patients with ALK-positive advanced NSCLC across a pool of seven clinical studies including two randomised, active-controlled, phase 3 studies (studies A2301 and A2303).

1 weeks). ADRs with an incidence of ≥10% in patients treated with ceritinib 750 mg fasted were diarrhoea, nausea, vomiting, fatigue, liver laboratory test abnormalities, abdominal pain, decreased appetite, weight decreased, constipation, blood creatinine increased, rash, anaemia and oesophageal disorder.

Grade 3-4 ADRs with an incidence of ≥5% in patients treated with ceritinib 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea. 1 and subsection ‘Gastrointestinal adverse reactions’ below).

Tabulated list of ADRs Table 2 shows the frequency category of ADRs reported for ceritinib in patients treated at a dose of 750 mg fasted (N=925) in seven clinical studies. The frequency of selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) are based on patients treated with a dose of 450 mg once-daily with food (N=108).

ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).

Within each frequency grouping, ADRs are presented in the order of decreasing seriousness. 2%) treated with ceritinib were aged 65 years or older. 2). There are no safety data in patients older than 85 years of age. Hepatotoxicity Concurrent elevations of ALT or AST greater than 3× ULN and total bilirubin greater than 2× ULN without elevated alkaline phosphatase have been observed in less than 1% of patients in clinical studies with ceritinib.

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 6 thereafter. 8). 2). 2). Other factors apart from study treatment could have impacted on observed events of hepatic encephalopathy, however, the relation between study treatment and events cannot be fully ruled out.

2). 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. 8). g. torsade de pointes) or sudden death. Use of ceritinib 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.

g. potassium) is recommended in these patients. In the event of vomiting, diarrhoea, dehydration or impaired renal function, correct electrolytes as clinically indicated. Ceritinib 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.

1.