Zykadia Adverse Reactions

Summary of the safety profile: Adverse drug reactions (ADRs) described below reflect exposure to Zykadia 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).
The median duration of exposure to Zykadia 750 mg fasted was 44.9 weeks (range: 0.1 to 200.1 weeks).
ADRs with an incidence of ≥10% in patients treated with Zykadia 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 Zykadia 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea.
In the dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patients with ALK-positive advanced NSCLC, the overall safety profile of Zykadia at the recommended dose of 450 mg with food (N=89) was consistent with Zykadia 750 mg fasted (N=90), except for a reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure (see Pharmacology: Pharmacodynamics under Actions and subsection 'Gastrointestinal adverse reactions' below).
Tabulated list of ADRs: Table 6 shows the frequency category of ADRs reported for Zykadia 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=89).
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). (See Table 6.)

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Elderly (≥65 years): Across seven clinical studies, 168 out of 925 patients (18.2%) treated with Zykadia were aged 65 years or older. The safety profile in patients aged 65 years or older was similar to that in patients less than 65 years of age (see Dosage & Administration). There are no safety data in patients older than 85 years of age.
Hepatotoxicity: Concurrent elevations of ALT or AST greater than 3x ULN and total bilirubin greater than 2x ULN without elevated alkaline phosphatase have been observed in less than 1% of patients in clinical studies with ceritinib. Increases to grade 3 or 4 ALT elevations were observed in 25% of patients receiving ceritinib. Hepatotoxicity events were managed with dose interruptions or reductions in 40.6% of patients. 1% of patients required permanent discontinuation of treatment in clinical studies with ceritinib (see Precautions). Ceritinib is not recommended in patients with moderate or severe hepatic impairment (see Dosage & Administration).
Liver laboratory tests including ALT, AST and total bilirubin should be performed prior to the start of treatment, every 2 weeks for the first three month and monthly thereafter, with more frequent testing for grade 2, 3 or 4 elevations. Patients should be monitored for liver laboratory test abnormalities and managed as recommended in Dosage & Administration and Precautions.
Gastrointestinal effects: Nausea, diarrhoea and vomiting were the most commonly reported gastrointestinal events. In the dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patients with ALK-positive advanced NSCLC at the recommended dose of ceritinib 450 mg taken with food (N=89), adverse events of diarrhoea, nausea and vomiting were mainly grade 1 (49.4%). A grade 3 event of diarrhoea was reported in one patient (1.1%). Gastrointestinal events were managed primarily with concomitant medicinal products including anti-emetic/anti-diarrhoeal medicinal products. Seven patients (7.9%) required study drug interruption due to diarrhoea or nausea. No patients had diarrhoea, nausea, or vomiting that required dose reduction or discontinuation of study drug. The incidence and severity of gastrointestinal adverse drug reactions were reduced for patients treated with Zykadia 450 mg with food (diarrhoea 56%, nausea 45%, vomiting 35%; 1.1% reported a grade 3/4 event) compared to 750 mg fasted (diarrhoea 76%, nausea 50%, vomiting 56%; 12% reported a grade 3/4 event). Patients should be managed as recommended in Dosage & Administration and Precautions.
QT interval prolongation: QTc prolongation has been observed in patients treated with ceritinib. Across the seven clinical studies, 9.7% of patients treated with ceritinib had events of QT prolongation (any grade), including grade 3 or 4 events in 2.1% of patients. These events required dose reduction or interruption in 2.1% of patients and led to discontinuation in 0.2% of patients.
Treatment with ceritinib is not recommended in patients who have congenital long QT syndrome or who are taking medicinal products known to prolong the QTc interval (see Precautions and Interactions). Particular care should be exercised when administering ceritinib to patients with an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging medicinal product.
Patients should be monitored for QT prolongation and managed as recommended in Dosage & Administration and Precautions.
Bradycardia: Across the seven clinical studies, bradycardia and/or sinus bradycardia (heart rate less than 60 bpm) events (all grade 1) were reported in 2.3% of patients. These events required dose reduction or interruption in 0.2% of patients. None of these events led to discontinuation of ceritinib treatment. The use of concomitant medicinal products associated with bradycardia should be carefully evaluated.
Patients who develop symptomatic bradycardia should be managed as recommended in Dosage & Administration and Precautions.
Interstitial lung disease / Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD) / pneumonitis have been observed in patients treated with ceritinib. Across the seven clinical studies, any grade ILD/pneumonitis has been reported in 2.1% of patients treated with ceritinib, and grade 3 or 4 events have been reported in 1.2% of patients. These events required dose reduction or interruption in 1.1% of patients and led to discontinuation in 0.9% of patients. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. Other potential causes of ILD/pneumonitis should be excluded (see Dosage & Administration and Precautions).
Hyperglycaemia: Hyperglycaemia (all grades) was reported in 9.4% of patients treated with ceritinib across the seven clinical studies; grade 3 or 4 events were reported in 5.4% of patients. These events required dose reduction or interruption in 1.4% of patients and led to discontinuation in 0.1% of patients. The risk of hyperglycaemia was higher in patients with diabetes mellitus and/or concurrent steroid use.
Monitoring of fasting serum glucose is required prior to the start of ceritinib treatment and periodically thereafter as clinically indicated. Administration of anti-hyperglycaemic medicinal products should be initiated or optimised as indicated (see Dosage & Administration and Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.