Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Zykadia as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
Zykadia as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.
Treatment with Zykadia should be initiated and supervised by a physician experienced in the use of anti-cancer medicinal products.
An accurate and validated ALK assay is necessary for the selection of ALK-positive NSCLC patients (see section 5.1).
ALK-positive NSCLC status should be established prior to initiation of Zykadia therapy. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised.
The recommended dose of Zykadia 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 should continue with the next scheduled dose.
Zykadia should be discontinued in patients unable to tolerate 150 mg daily taken with food.
Temporary dose interruption and/or dose reduction of Zykadia 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.
In patients treated with Zykadia 450 mg with food, 10% of patients had an adverse event that required at least one dose reduction and 42% of patients had an adverse event that required at least one dose interruption. The median time to first dose reduction due to any reason was 8 weeks.
Table 1 summarises recommendations for dose interruption, reduction or discontinuation of Zykadia in the management of selected ADRs.
Table 1. Zykadia dose adjustment and management recommendations for ADRs:
| Criteria | Zykadia dosing |
|---|---|
| Severe or intolerable nausea, vomiting or diarrhoea despite optimal anti-emetic or anti-diarrhoeal therapy | Withhold Zykadia until improved, then reinitiate Zykadia 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 Zykadia 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 Zykadia. |
| Any grade treatment-related interstitial lung disease (ILD)/pneumonitis | Permanently discontinue Zykadia. |
| QT corrected for heart rate (QTc) >500 msec on at least 2 separate electrocardiograms (ECGs) | Withhold Zykadia until recovery to baseline or to a QTc ≤480 msec, check and if necessary correct electrolytes, then reinitiate with dose reduced by 150 mg. |
| QTc >500 msec or >60 msec change from baseline and torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia | Permanently discontinue Zykadia |
| Bradycardiaa (symptomatic, may be severe and medically significant, medical intervention indicated) | Withhold Zykadia until recovery to asymptomatic (grade ≤1) bradycardia or to a heart rate of 60 beats per minute (bpm) or above. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, reinitiate Zykadia at the previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, reinitiate Zykadia with dose reduced by 150 mg upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. |
| Bradycardiaa (life-threatening consequences, urgent intervention indicated) | Permanently discontinue Zykadia if no contributing concomitant medicinal product is identified. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, reinitiate Zykadia with dose reduced by 150 mg upon |
| Persistent hyperglycaemia greater than 250 mg/dl despite optimal anti-hyperglycaemic therapy | Withhold Zykadia until hyperglycaemia is adequately controlled, then reinitiate Zykadia with dose reduced by 150 mg. If adequate glucose control cannot be achieved with optimal medical management, permanently discontinue Zykadia. |
| Lipase or amylase elevation grade ≥3 | Withhold Zykadia until lipase or amylase returns to grade ≤1, then reinitiate with dose reduced by 150 mg. |
a Heart rate less than 60 beats per minutes (bpm)
b Permanently discontinue in the event of recurrence
Avoid concomitant use of strong CYP3A inhibitors during treatment with Zykadia (see section 4.5). If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose by approximately one third (dose not clinically verified), rounded to the nearest multiple of the 150 mg dosage strength. Patients should be carefully monitored for safety.
If long-term concomitant treatment with a strong CYP3A inhibitor is necessary and the patient tolerates the reduced dose well, the dose may be increased again with careful monitoring for safety, to avoid potential under-treatment.
After discontinuation of a strong CYP3A inhibitor, resume at the dose that was taken prior to initiating the strong CYP3A inhibitor.
A dedicated pharmacokinetic study in patients with renal impairment has not been conducted. However, based on available data, ceritinib elimination via the kidney is negligible. Therefore, no dose adjustment is necessary in patients with mild to moderate renal impairment. Caution should be used in patients with severe renal impairment, as there is no experience with ceritinib in this population (see section 5.2).
Based on available data, ceritinib is eliminated primarily via the liver. Particular caution should be exercised when treating patients with severe hepatic impairment and the dose should be reduced by approximately one third, rounded to the nearest multiple of the 150 mg dosage strength (see sections 4.4 and 5.2). No dose adjustment is necessary in patients with mild or moderate hepatic impairment.
The limited data on the safety and efficacy of ceritinib in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see section 5.2). There are no available data on patients over 85 years of age.
The safety and efficacy of ceritinib in children and adolescents aged up to 18 years have not been established. No data are available.
Zykadia is for oral use. The capsules should be administered orally once daily with food at the same time every day. It is important that Zykadia is taken with food to reach the appropriate exposure. Food can range from a light to a full meal (see section 5.2).
For patients who develop a concurrent medical condition and are unable to take Zykadia with food please refer to section 4.5.
The capsules should be swallowed whole with water and should not be chewed or crushed.
There is no reported experience with overdose in humans. General supportive measures should be initiated in all cases of overdose.
Shelf life: 2 years.
This medicinal product does not require any special storage conditions.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters containing 10 hard capsules.
Packs containing 40, 90 or 150 (3 packs of 50) hard capsules.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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