Zykadia

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each hard capsule contains 150 mg ceritinib. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Hard capsule. 

 

Capsule with white opaque body and blue opaque cap, with “LDK 150MG” imprinted on the cap and 

“NVR” on the body, containing white to almost white powder. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

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. 

 

4.2 Posology and method of administration 

 

Treatment with Zykadia should be initiated and supervised by a physician experienced in the use of 

anti-cancer medicinal products. 

 

ALK testing 

 

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. 

 

  



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Posology 

 

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. 

 

Dose adjustment due to adverse reactions 

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. 



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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 recovery to asymptomatic bradycardia or to a 

heart rate of 60 bpm or above, with frequent 

monitoringb. 

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 

 

Strong CYP3A inhibitors 

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. 

 

CYP3A substrates 

When ceritinib is co-administered with other medicinal products, the Summary of Product 

Characteristics (SmPC) for the other product must be consulted for the recommendations regarding 

co-administration with CYP3A4 inhibitors. 

 

  



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Co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substrates 

known to have narrow therapeutic indices (e.g. alfuzosin, amiodarone, cisapride, ciclosporin, 

dihydroergotamine, ergotamine, fentanyl, pimozide, quetiapine, quinidine, lovastatin, simvastatin, 

sildenafil, midazolam, triazolam, tacrolimus, alfentanil and sirolimus) should be avoided and 

alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible. 

If unavoidable, dose reduction for co-administered medicinal products that are CYP3A substrates with 

narrow therapeutic indices should be considered. 

 

Special populations 

 

Renal impairment 

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). 

 

Hepatic impairment 

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. 

 

Elderly (≥65 years) 

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. 

 

Paediatric population 

The safety and efficacy of ceritinib in children and adolescents aged up to 18 years have not been 

established. No data are available. 

 

Method of administration 

 

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). The capsules should be swallowed whole with 

water and should not be chewed or crushed. 

 

For patients who develop a concurrent medical condition and are unable to take Zykadia with food 

please refer to section 4.5. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

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. 

 



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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 sections 4.2 and 

4.8). Particular caution should be exercised when treating patients with severe hepatic impairment, and 

the dose should be adjusted (see section 4.2). Limited experience in these patients showed a worsening 

of the underlying condition (hepatic encephalopathy) in 2 out of 10 patients exposed to 750 mg single 

doses of ceritinib under fasted conditions (see sections 4.2, 4.8 and 5.2). 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. No dose adjustment is necessary in 

patients with mild or moderate hepatic impairment (see section 4.2). 

 

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. Other potential 

causes of ILD/pneumonitis should be excluded, and Zykadia permanently discontinued in patients 

diagnosed with any grade treatment-related ILD/pneumonitis (see sections 4.2 and 4.8). 

 

QT interval prolongation 

 

QTc prolongation has been observed in clinical studies in patients treated with ceritinib (see 

sections 4.8 and 5.2), 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 sections 4.2, 4.8 and 5.2). 

 

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 



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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 sections 4.2 and 4.8). 

 

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 section 4.8). 

 

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 sections 4.2 and 4.8). 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 sections 4.2 and 4.8). 

 

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 sections 4.2 and 4.8). Cases of pancreatitis have 

been reported in patients treated with ceritinib (see section 4.8). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Agents that may increase ceritinib plasma concentrations 

 

Strong CYP3A inhibitors 

In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole 

(200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold 

increase in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. The 

steady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mg 

twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib 

alone. Avoid concomitant use of strong CYP3A inhibitors during treatment with Zykadia. If it is not 

possible to avoid concomitant use with strong CYP3A inhibitors (including, but not limited to, 

ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and 

nefazodone), reduce the ceritinib dose by approximately one third, rounded to the nearest multiple of 

the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ceritinib 

dose that was taken prior to initiating the strong CYP3A inhibitor. 

 



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P-gp inhibitors 

Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If 

ceritinib is administered with medicinal products that inhibit P-gp, an increase in ceritinib 

concentration is likely. Caution should be exercised with concomitant use of P-gp inhibitors and 

ADRs carefully monitored. 

 

Agents that may decrease ceritinib plasma concentrations 

 

Strong CYP3A and P-gp inducers 

In healthy subjects, co-administration of a single 750 mg fasted ceritinib dose with rifampicin (600 mg 

daily for 14 days), a strong CYP3A/P-gp inducer, resulted in 70% and 44% decreases in ceritinib 

AUCinf and Cmax, respectively, compared to when ceritinib was given alone. Co-administration of 

ceritinib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Concomitant 

use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, 

phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum). Caution 

should be exercised with concomitant use of P-gp inducers. 

 

Agents that affect gastric pH 

Ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. 

Acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) can alter the 

solubility of ceritinib and reduce its bioavailability. Co-administration of a single 750 mg fasted 

ceritinib dose with a proton pump inhibitor (esomeprazole) 40 mg daily for 6 days in healthy, fasting 

subjects decreased ceritinib AUC by 76% and Cmax by 79%. The drug-drug interaction study was 

designed to observe the impact of proton pump inhibitor in the worst scenario, but in clinical use the 

impact of proton pump inhibitor on ceritinib exposure appears to be less pronounced. A dedicated 

study to evaluate the effect of gastric acid-reducing agents on the bioavailability of ceritinib under 

steady state has not been conducted. Caution is advised with concomitant use of proton pump 

inhibitors, as exposure of ceritinib may be reduced. There is no data with concomitant use of H2 

blockers or antacids. However, the risk for a clinically relevant decrease in bioavailability of ceritinib 

is possibly lower with concomitant use of H2 blockers if they are administered 10 hours before or 

2 hours after the ceritinib dose, and with antacids if they are administered 2 hours before or 2 hours 

after the ceritinib dose. 

 

Agents whose plasma concentration may be altered by ceritinib 

 

CYP3A and CYP2C9 substrates 

Based on in vitro data, ceritinib competitively inhibits the metabolism of a CYP3A substrate, 

midazolam, and a CYP2C9 substrate, diclofenac. Time-dependent inhibition of CYP3A was also 

observed. 

 

Ceritinib has been classified in vivo as a strong CYP3A4 inhibitor and has the potential to interact with 

medicinal products that are metabolised by CYP3A, which may lead to increased serum 

concentrations of the other product. Co-administration of a single dose of midazolam (a sensitive 

CYP3A substrate) following 3 weeks of ceritinib dosing in patients (750 mg daily fasted) increased 

the midazolam AUCinf (90% CI) by 5.4-fold (4.6, 6.3) compared to midazolam alone. 

Co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substrates 

known to have narrow therapeutic indices (e.g. alfuzosin, amiodarone, cisapride, ciclosporin, 

dihydroergotamine, ergotamine, fentanyl, pimozide, quetiapine, quinidine, lovastatin, simvastatin, 

sildenafil, midazolam, triazolam, tacrolimus, alfentanil and sirolimus) should be avoided and 

alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible. 

If unavoidable, dose reduction for co-administered medicinal products that are CYP3A substrates with 

narrow therapeutic indices should be considered. 

 

Ceritinib has been classified in vivo as a weak CYP2C9 inhibitor. Co-administration of a single dose 

of warfarin (a CYP2C9 substrate) following 3 weeks of ceritinib dosing in patients (750 mg daily 

fasted) increased the S-warfarin AUCinf (90% CI) by 54% (36%, 75%) compared to warfarin alone. 

Co-administration of ceritinib with substrates primarily metabolised by CYP2C9 or CYP2C9 



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substrates known to have narrow therapeutic indices (e.g. phenytoin and warfarin) should be avoided. 

If unavoidable, dose reduction for co-administered medicinal products that are CYP2C9 substrates 

with narrow therapeutic indices should be considered. Increasing the frequency of international 

normalised ratio (INR) monitoring may be considered if co-administration with warfarin is 

unavoidable. 

 

CYP2A6 and CYP2E1 substrates 

Based on in vitro data, ceritinib also inhibits CYP2A6 and CYP2E1 at clinically relevant 

concentrations. Therefore, ceritinib may have the potential to increase plasma concentrations of 

co-administered medicinal products that are predominantly metabolised by these enzymes. Caution 

should be exercised with concomitant use of CYP2A6 and CYP2E1 substrates and ADRs carefully 

monitored. 

 

A risk for induction of other PXR regulated enzymes apart from CYP3A4 cannot be completely 

excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced. 

 

Agents that are substrates of transporters 

 

Based on in vitro data, ceritinib does not inhibit apical efflux transporter MRP2, hepatic uptake 

transporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the 

organic cation uptake transporters OCT1 or OCT2 at clinically relevant concentrations. Therefore, 

clinical drug-drug interactions as a result of ceritinib-mediated inhibition of substrates for these 

transporters are unlikely to occur. Based on in vitro data, ceritinib is predicted to inhibit intestinal P-gp 

and BCRP at clinically relevant concentrations. Therefore, ceritinib may have the potential to increase 

plasma concentrations of co-administered medicinal products transported by these proteins. Caution 

should be exercised with concomitant use of BCRP substrates (e.g. rosuvastatin, topotecan, 

sulfasalazine) and P-gp substrates (digoxin, dabigatran, colchicine, pravastatin) and ADRs carefully 

monitored. 

 

Pharmacodynamic interactions 

 

In clinical studies, QT prolongation was observed with ceritinib. Therefore, ceritinib should be used 

with caution in patients who have or may develop prolongation of the QT interval, including those 

patients taking anti-arrhythmic medicinal products such as class I (e.g. quinidine, procainamide, 

disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) anti-arrhythmics or other 

medicinal products that may lead to QT prolongation such as domperidone, droperidol, chloroquine, 

halofantrine, clarithromycin, haloperidol, methadone, cisapride and moxifloxacin. Monitoring of the 

QT interval is indicated in the event of combinations of such medicinal products (see sections 4.2 and 

4.4). 

 

Food/drink interactions 

 

Zykadia should be taken with food. The bioavailability of ceritinib is increased in the presence of 

food. 

 

For patients who develop a concurrent medical condition and are unable to take Zykadia with food, 

Zykadia can be taken on an empty stomach as the alternate continued treatment regimen, in which no 

food should be eaten for at least two hours before and one hour after the dose. Patients should not 

alternate between fasted and fed dosing. Dose must be adjusted properly, i.e for patients treated with 

450 mg or 300 mg with food, the dose should be increased to 750 mg or 450 mg taken on an empty 

stomach, respectively (see section 5.2) and for patients treated with 150 mg with food treatment 

should be discontinued. For subsequent dose adjustment and management recommendations for 

ADRs, please follow table 1 (see section 4.2). The maximum allowable dose under fasted condition is 

750 mg (see section 5.2). 

 

Patients should be instructed to avoid grapefruit and grapefruit juice as they may inhibit CYP3A in the 

gut wall and may increase the bioavailability of ceritinib. 



10 

 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/Contraception 

 

Women of childbearing potential should be advised to use a highly effective method of contraception 

while taking Zykadia and for up to 3 months after discontinuing treatment (see section 4.5). 

 

Pregnancy 

 

There are no or limited amount of data from the use of ceritinib in pregnant women. 

 

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). 

 

Zykadia should not be used during pregnancy unless the clinical condition of the woman requires 

treatment with ceritinib. 

 

Breast-feeding 

 

It is unknown whether ceritinib/metabolites are excreted in human milk. A risk to the newborn/infant 

cannot be excluded. 

 

A decision must be made whether to discontinue breast-feeding or discontinue/abstain from Zykadia 

therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the 

woman (see section 5.3). 

 

Fertility 

 

The potential for Zykadia to cause infertility in male and female patients is unknown (see section 5.3). 

 

4.7 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. 
 

4.8 Undesirable effects 

 

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 



11 

 

reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure 

(see section 5.1 and subsection ‘Gastrointestinal adverse reactions’ below). 

 

Tabulated list of ADRs 

 

Table 2 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). 

 

Table 2 ADRs in patients treated with Zykadia 

 

System organ class 

Preferred term 

Zykadia 

N=925 

% 

Frequency category 

Blood and lymphatic system disorders 

Anaemia 15.2 Very common 

Metabolism and nutrition disorders 

Decreased appetite 39.5 Very common 

Hyperglycaemia 9.4 Common 

Hypophosphataemia 5.3 Common 

Eye disorders 

Vision disordera 7.0 Common 

Cardiac disorders 

Pericarditisb 5.8 Common 

Bradycardiac 2.3 Common 

Respiratory, thoracic and mediastinal disorders 

Pneumonitisd 2.1 Common 

Gastrointestinal disorders 

Diarrhoeae 56.2 Very common 

Nauseae 44.9 Very common 

Vomitinge 34.8 Very common 

Abdominal painf 46.1 Very common 

Constipation 24.0 Very common 

Oesophageal disorderg 14.1 Very common 

Pancreatitis 0.5 Uncommon 

Hepatobiliary disorders 

Abnormal liver function testsh 2.2 Common 

Hepatotoxicityi 1.1 Common 

Skin and subcutaneous tissue disorders 

Rashj 19.6 Very common 

Renal and urinary disorders 

Renal failurek 1.8 Common 

Renal impairmentl 1.0 Common 

General disorders and administration site conditions 

Fatiguem 48.4 Very common 



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Investigations 

Liver laboratory test abnormalitiesn 60.5 Very common 

Weight decreased 27.6 Very common 

Blood creatinine increased 22.1 Very common 

Electrocardiogram QT prolonged 9.7 Common 

Lipase increased 4.8 Common 

Amylase increased 7.0 Common 

Includes cases reported within the clustered terms: 
a Vision disorder (vision impairment, vision blurred, photopsia, vitreous floaters, visual acuity 

reduced, accommodation disorder, presbyopia) 
b Pericarditis (pericardial effusion, pericarditis) 
c Bradycardia (bradycardia, sinus bradycardia) 
d Pneumonitis (interstitial lung disease, pneumonitis) 
e The frequency of these selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) is based on 

patients treated with the recommended dose of ceritinib 450 mg with food (N=89) in the study A2112 

(ASCEND-8) (see subsection ‘Gastrointestinal adverse reactions’ below) 
f Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, epigastric 

discomfort) 
g Oesophageal disorder (dyspepsia, gastro-oesophageal reflux disease, dysphagia) 
h Abnormal liver function test (hepatic function abnormal, hyperbilirubinaemia) 
i Hepatotoxicity (drug-induced liver injury, hepatitis cholestatic, hepatocellular injury, hepatotoxicity) 
j Rash (rash, dermatitis acneiform, rash maculopapular) 
k Renal failure (acute renal injury, renal failure) 
l Renal impairment (azotaemia, renal impairment) 
m Fatigue (fatigue, asthenia) 
n Liver laboratory test abnormalities (alanine aminotransferase increased, aspartate aminotransferase 

increased, gamma-glutamyltransferase increased, blood bilirubin increased, transaminases increased, 

hepatic enzyme increased, liver function test abnormal, liver function test increased, blood alkaline 

phosphatase increased) 

 

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 section 4.2). 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. 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 sections 4.2 and 4.4). 

 

Liver laboratory tests including ALT, AST and total bilirubin should be performed prior to the start of 

treatment, every 2 weeks during the first three months of treatment 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 sections 4.2 and 4.4. 

 

Gastrointestinal adverse reactions 

 

Nausea, diarrhoea and vomiting were among 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 



13 

 

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 sections 4.2 and 4.4. 

 

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 sections 4.4 and 4.5). 

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 sections 4.2 and 

4.4. 

 

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 sections 4.2 

and 4.4. 

 

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 sections 4.2 

and 4.4). 

 

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 sections 4.2 and 4.4). 

 



14 

 

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 

listed in Appendix V. 

 

4.9 Overdose 

 

There is no reported experience with overdose in humans. General supportive measures should be 

initiated in all cases of overdose. 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: antineoplasic and immunomodulating agents, ATC code: L01XE28. 

 

Mechanism of action 

 

Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation 

of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of 

ALK-dependent cancer cells both in vitro and in vivo. 

 

ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK 

signaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this 

generates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the 

N-terminal part of EML4. Ceritinib was demonstrated to be effective against EML4-ALK activity in a 

NSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of 

tumours in H2228-derived xenografts in mouse and rat. 

 

Clinical efficacy and safety 

 

Previously untreated ALK-positive advanced NSCLC - randomised phase 3 Study A2301 (ASCEND-4) 

The efficacy and safety of Zykadia for the treatment of advanced ALK-positive NSCLC patients who 

have not received previous systemic treatment anti-cancer therapy (including ALK inhibitor) with the 

exception of neo-adjuvant or adjuvant therapy, was demonstrated in a global multicentre, randomised, 

open-label phase 3 Study A2301. 

 

A total of 376 patients were randomised in a 1:1 ratio (stratified by WHO performance status, prior 

adjuvant/neoadjuvant chemotherapy and presence/absence of brain metastasis at screening) to receive 

either ceritinib (750 mg daily, fasted) or chemotherapy (based on investigator’s choice - pemetrexed 

[500 mg/m2] plus cisplatin [75 mg/m2] or carboplatin [AUC 5-6], administered every 21 days). 

Patients who completed 4 cycles of chemotherapy (induction) without progressive disease 

subsequently received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. 

One hundred and eighty-nine (189) patients were randomised to ceritinib and one hundred eighty-

seven (187) were randomised to chemotherapy. 

 

The median age was 54 years (range: 22 to 81 years); 78.5% of patients were younger than 65 years. A 

total of 57.4% of patients were female. 53.7% of the study population was Caucasian, 42.0% Asian, 

1.6% Black and 2.6% other races The majority of patients had adenocarcinoma (96.5%) and had either 

never smoked or were former smokers (92.0%). The Eastern Cooperative Oncology Group (ECOG) 

performance status was 0/1/2 in 37.0%/56.4%/6.4% of patients, and 32.2% had brain metastasis at 

baseline. 59.5% of patients with brain metastasis at baseline received no prior radiotherapy to the 

brain. Patients with symptomatic CNS (central nervous system) metastases who were neurologically 

unstable or had required increasing doses of steroids within the 2 weeks prior to screening to manage 

CNS symptoms, were excluded from the study. 



15 

 

 

Patients were allowed to continue the assigned study treatment beyond initial progression in case of 

continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy 

arm could cross-over to receive ceritinib upon RECIST-defined disease progression confirmed by 

blinded independent review committee (BIRC). One hundred and five (105) patients out of the 

145 patients (72.4%) that discontinued treatment in the chemotherapy arm received subsequent ALK 

inhibitor as first antineoplastic therapy. Of these patients 81 received ceritinib. 

 

The median duration of follow-up was 19.7 months (from randomisation to cut-off date). 

 

The study met its primary objective demonstrating a statistically significant improvement in 

progression free survival (PFS) by BIRC (see Table 3 and Figure 1). The PFS benefit of ceritinib was 

consistent by investigator assessment and across various subgroups including age, gender, race, 

smoking class, ECOG performance status and disease burden. 

 

The overall survival (OS) data was not mature with 107 deaths representing approximately 42.3% of 

the required events for the final OS analysis. 

 

Efficacy data from Study A2301 are summarised in Table 3, and the Kaplan-Meier curves for PFS and 

OS are shown in Figure 1 and Figure 2, respectively. 

 

Table 3 ASCEND-4 (Study A2301) - Efficacy results in patients with previously untreated 

ALK-positive advanced NSCLC 

 

 Ceritinib 

(N=189) 

Chemotherapy 

(N=187) 

Progression-free survival (based on BIRC)   

Number of events, n (%) 89 (47.1) 113 (60.4) 

Median, monthsd (95% CI) 16.6 (12.6, 27.2) 8.1 (5.8, 11.1) 

HR (95% CI)a 0.55 (0.42, 0.73) 

p-valueb <0.001 

Overall survivalc   

Number of events, n (%) 48 (25.4) 59 (31.6) 

Median, monthsd (95% CI) NE (29.3, NE) 26.2 (22.8, NE) 

OS rate at 24 monthsd, % (95% CI) 70.6 (62.2, 77.5) 58.2 (47.6, 67.5) 

HR (95% CI)a 0.73 (0.50,1.08) 

p-valueb 0.056 

Tumour response (based on BIRC)   

Overall response rate (95% CI) 72.5% (65.5, 78.7) 26.7% (20.5, 33.7) 

Duration of response (based on BIRC)   

Number of responders 137 50 

Median, monthsd (95% CI) 23.9 (16.6, NE) 11.1 (7.8, 16.4) 

Event-free rate at 18 monthsd, % (95% 

CI) 

59.0 (49.3, 67.4) 30.4 (14.1, 48.6) 

HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; 

NE=not estimable 
a Based on the Cox proportional hazards stratified analysis. 
b Based on the stratified log-rank test. 
c OS analysis was not adjusted for the effects of cross-over. 
d Estimated using the Kaplan-Meier method. 

 



16 

 

Figure 1 ASCEND-4 (Study A2301) - Kaplan-Meier curves of progression-free survival as 

assessed by BIRC 
 
 

 

 
 
 

 

 
 
 

 
 
 
 

 

 

 

 No. of patients still at risk 

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 

ceritinib 750 mg 189 155 139 125 116 105 98 76 59 43 32 23 16 11 1 1 1 0 

Chemotherapy 187 136 114 82 71 60 53 35 24 16 11 5 3 1 1 0 0 0 

 

Figure 2 ASCEND-4 (Study A2301)- Kaplan-Meier plot of overall survival by treatment arm 

 

 

 

 

 

 

 

 

 

 

 

 

 No. of patients still at risk 

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 

ceritinib 750 mg 189 180 175 171 165 155 150 138 103 77 56 39 26 18 6 3 2 0 

Chemotherapy 187 172 161 150 146 141 134 124 97 69 49 35 19 10 5 1 0 0 

 

Patient reported outcome questionnaires (Lung cancer symptom scale [LCSS], EORTC-QLQ-C30 

[C30], EORTC QLQ-LC13 [LC13] and EQ-5D-5L) were completed by 80% or more of patients in the 

ceritinib and chemotherapy arms for all questionnaires at most of the time-points during the course of 

the study. 

 

Ceritinib significantly prolonged time to deterioration for the pre-specified lung cancer specific 

symptoms of interest of cough, pain and dyspnoea (composite endpoint LCSS: HR=0.61, 95% CI: 

10 6 4 2 0 22 20 18 16 14 12 32

 

30 28 26 24 8 34

 

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Hazard Ratio = 0.55 

95% CI (0.42, 0.73) 

Kaplan-Meier medians (95% CI) (Months) 

ceritinib 750 mg: 16.6 (12.6, 27.2) 

Chemotherapy: 8.1 (5.8, 11.1) 

Logrank p-value = <0.001 

Censoring Times 

ceritinib 750 mg (n/N = 89/189) 

Chemotherapy (n/N = 113/187) 

20 

100 

80 

60 

40 

0 

Time (Months) 

100 

80 

60 

40 

20 

0 

10 8 6 4 2 0 22 20 18 16 14 12 32

 

30 28 26 24 34

 Time (Months) 

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Hazard Ratio = 0.73 

95% CI (0.50, 1.08) 

 

Kaplan-Meier medians (95% CI) (Months) 

ceritinib 750 mg: NE (29.3, NE) 

Chemotherapy: 26.2 (22.8, NE) 

Logrank p-value = 0.056 

Censoring Times 

ceritinib 750 mg (n/N = 48/189) 

Chemotherapy (n/N = 59/187) 



17 

 

0.41, 0.90, median Time to Deterioration [TTD] NE [95% CI: 20.9, NE] in the ceritinib arm versus 

18.4 months [13.9, NE] in the chemotherapy arm; LC13: HR=0.48, 95% CI: 0.34, 0.69, median TTD 

23.6 months [95% CI: 20.7, NE] in the ceritinib arm versus 12.6 months [95% CI: 8.9, 14.9] in the 

chemotherapy arm). 

 

Patients receiving ceritinib showed significant improvements over chemotherapy in general Quality of 

Life and global Health Status measures (LCSS [p<0.001], QLQ-C30, [p<0.001] and EQ-5D-5L index 

[p<0.001]). 

 

In Study A2301, 44 patients with measurable brain metastasis at baseline and at least one post-baseline 

brain radiological assessment (22 patients in the ceritinib arm and 22 patients in the chemotherapy 

arm) were assessed for intracranial response by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. 

up to 5 lesions in the brain). The overall intracranial response rate (OIRR) was higher with ceritinib 
(72.7%, 95% CI: 49.8, 89.3) as compared to the chemotherapy arm (27.3%, 95% CI: 10.7, 50.2). 

 

The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the 

chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. 

The median PFS in patients with brain metastases was 10.7 months (95% CI: 8.1, 16.4) versus 

6.7 months (95% CI: 4.1, 10.6) in the ceritinib and chemotherapy arms, respectively, with HR=0.70 

(95% CI: 0.44, 1.12). The median PFS in patients without brain metastases was 26.3 months (95% CI: 

15.4, 27.7) versus 8.3 months (95% CI: 6.0, 13.7) in the ceritinib and chemotherapy arms, 

respectively, with HR=0.48 (95% CI: 0.33, 0.69). 

 

Previously treated ALK-positive advanced NSCLC - randomised phase 3 Study A2303 (ASCEND-5) 

The efficacy and safety of Zykadia for the treatment of ALK-positive advanced NSCLC patients who 

have received previous treatment with crizotinib, was demonstrated in a global multicentre, 

randomised, open-label phase 3 Study A2303. 

 

A total of 231 patients with advanced ALK positive NSCLC who have received prior treatment with 

crizotinib and chemotherapy (one or two regimen including a platinum-based doublet) were included 

in the analysis. One hundred fifteen (115) patients were randomised to Zykadia and one hundred 

sixteen (116) were randomised to chemotherapy (either pemetrexed or docetaxel). Seventy-three (73) 

patients received docetaxel and 40 received pemetrexed. In the ceritinib arm, 115 patients were treated 

with 750 mg once daily fasted. The median age was 54.0 years (range: 28 to 84 years); 77.1% of 

patients were younger than 65 years. A total of 55.8% of patients were female. 64.5% of the study 

population were Caucasian, 29.4% Asian, 0.4% Black and 2.6% other races. The majority of patients 

had adenocarcinoma (97.0%) and had either never smoked or were former smokers (96.1%). The 

ECOG performance status was 0/1/2 in 46.3%/47.6%/6.1% of patients respectively, and 58.0% had 

brain metastasis at baseline. All patients were treated with prior crizotinib. All except one patient 

received prior chemotherapy (including a platinum doublet) for advanced disease; 11.3% of the 

patients in the ceritinib arm and 12.1% of the patients in the chemotherapy arm were treated with two 

prior chemotherapy regimen for advanced disease. 

 

Patients were allowed to continue the assigned study treatment beyond initial progression in case of 

continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy 

arm could further crossover to receive Zykadia upon RECIST-defined disease progression confirmed 

by BIRC. 

 

The median duration of follow-up was 16.5 months (from randomisation to data cut-off date). 

 

The study met its primary objective demonstrating a statistically significant improvement in PFS by 

BIRC with an estimated 51% risk reduction in the ceritinib arm compared to chemotherapy arm (see 

Table 4 and Figure 3). The PFS benefit of Zykadia was consistent across various subgroups including 

age, gender, race, smoking class, ECOG performance status, and presence of brain metastases or prior 

response to crizotinib. The PFS benefit was further supported by local investigator assessment, and 

analysis of overall response rate (ORR) and disease control rate (DCR). 

 



18 

 

OS data was immature with 48 (41.7%) events in the ceritinib arm and 50 (43.1%) events in the 

chemotherapy arm, corresponding to approximately 50% of the required events for the final OS 

analysis. In addition, 81 patients (69.8%) in the chemotherapy arm received subsequent Zykadia as 

first antineoplastic therapy after study treatment discontinuation. 

 

Efficacy data from Study A2303 are summarised in Table 4, and the Kaplan-Meier curves for PFS and 

OS are shown in Figure 3 and 4, respectively. 

 

Table 4 ASCEND-5 (Study A2303) – Efficacy results in patients with previously treated 

ALK-positive metastatic/advanced NSCLC 

 

 Ceritinib 

(N=115) 

Chemotherapy 

(N=116) 

Duration of follow-up 

Median (months) (min – max) 

16.5 

(2.8 – 30.9) 

Progression-free survival (based on BIRC)   

Number of events, n (%) 83 (72.2%) 89 (76.7%) 

Median, months (95% CI) 5.4 (4.1, 6.9) 1.6 (1.4, 2.8) 

HR (95% CI)a 0.49 (0.36, 0.67) 

p-valueb <0.001 

Overall survivalc   

Number of events, n (%) 48 (41.7%) 50 (43.1%) 

Median, months (95% CI) 18.1 (13.4, 23.9) 20.1 (11.9, 25.1) 

HR (95% CI)a 1.00 (0.67,1.49) 

p-valueb 0.496 

Tumour responses (based on BIRC)   

Objective response rate (95% CI) 39.1% (30.2, 48.7) 6.9% (3.0, 13.1) 

Duration of response   

Number of responders 45 8 

Median, monthsd (95% CI) 6.9 (5.4, 8.9) 8.3 (3.5, NE) 

Event-free probability estimate at 9 

monthsd (95% CI) 

31.5% (16.7%, 
47.3%) 

45.7% (6.9%, 79.5%) 

HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; 

NE=not estimable 
a Based on the stratified Cox proportional hazards analysis. 
b Based on the stratified log-rank test. 
c OS analysis was not adjusted for the potentially confounding effects of cross over. 
d Estimated using the Kaplan-Meier method.  

 



19 

 

Figure 3 ASCEND-5 (Study A2303) – Kaplan-Meier plot of progression-free survival as 

assessed by BIRC 

 

 

100 
 

   
 
 

80 
 

 

 
 
 

60 
 

 
 
 

40 
 

 
 
 

20 
 

 
 
0 

 

 

 
 
 
 
 
 

 No. of patients s till at risk 

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 

Ceritinib 750 mg 115 87 68 40 31 18 12 9 4 3 2 1 0 

Chemotherapy 116 45 26 12 9 6 2 2 2 0 0 0 0 

 

        0        2        4        6        8       10       12      14      16       18       20      22       24 

Time (Months) 

  
 

Censoring Times 

Ceritinib 750 mg (n/N = 83/115) 

  Chemotherapy (n/N = 89/116) 
 

 
Hazard Ratio = 0.49 

95% CI (0.36;0.67) 

 

Kaplan-Meier medians (95% CI) (Months) 

Ceritinib 750 mg: 5.4 (4.1;6.9) 

Chemotherapy: 1.6 (1.4;2.8) 

 

Log rank p-value = <0.001 

 

 

 

 

 

 
               

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Figure 4 ASCEND-5 (Study A2303) – Kaplan-Meier plot of overall survival by treatment 

arm 

 

100 
 
 
 
 

80 
 
 
 
 

60 
 
 
 
 

40 
 
 
 
 

20 
 
 

 

0 
 
 
 

0 2 4 6 

 
 
 

8 

 
 
 

10 

 
 
 

12 

 
 
 

14 16 

 
 
 
18 

 
 
 

20 

 
 
 

22 

 
 
 

24 

 
 
 

26 

 
 
 

28 

 
 
 

30 

  
No. of patients s till at risk 

   Time (Months)        

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 

Ceritinib 750 mg 115 107 92 83 71 61 52 37 28 23 13 8 2 2 0 0 

Chemotherapy 116 109 91 78 66 53 43 39 29 22 17 7 5 2 1 0 

 

Patient reported outcome questionnaires were collected using the EORTC QLQ C30/LC13, LCSS and 

EQ-5D-5L. 75% or more of patients in the ceritinib and chemotherapy arms completed the LCSS 

questionnaires at most of the time points during the course of the study. Significant improvements 

were reported for the majority of lung cancer specific symptoms for Zykadia compared to 

chemotherapy (four out of six LCSS and 10 out of 12 QLQ-LC13 symptom scores). Ceritinib 

significantly prolonged time to deterioration for the lung cancer specific symptoms of interest of 

cough, pain and dyspnoea (composite endpoint LCSS: HR=0.40; 95% CI: 0.25, 0.65, median Time to 

Deterioration [TTD] 18.0 months [95% CI: 13.4, NE] in the ceritinib arm versus 4.4 months [95% CI: 

1.6, 8.6] in the chemotherapy arm; LC13: HR=0.34; 95% CI: 0.22, 0. 52, median TTD 11.1 months 

[95% CI: 7.1, 14.2] in the ceritinib arm versus 2.1 months [95% CI: 1.0, 5.6] in the chemotherapy 

arm). The EQ-5D questionnaire showed a significant overall health status improvement for Zykadia in 

comparison to the chemotherapy. 

 

In Study A2303, 133 patients with baseline brain metastasis (66 patients in the Zykadia arm and 

67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-

radiologist (per modified RECIST 1.1 (i.e. up to 5 lesions in the brain). The OIRR in patients with 

measurable disease in the brain at baseline and at least one post-baseline assessment was higher in the 

ceritinib arm (35.3%, 95% CI: 14.2, 61.7) compared to the chemotherapy arm (5.0%, 95% CI: 0.1, 

24.9). The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the 

chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. 

The median PFS in patients with brain metastases was 4.4 months (95% CI: 3.4, 6.2) versus 

1.5 months (95% CI: 1.3, 1.8) in the ceritinib and chemotherapy arms, respectively with HR=0.54 

(95% CI: 0.36, 0.80). The median PFS in patients without brain metastases was 8.3 months (95% CI: 

4.1, 14.0) versus 2.8 months (95% CI: 1.4, 4.1) in the ceritinib and chemotherapy arms, respectively 

with HR=0.41 (95% CI: 0.24, 0.69). 

 

  
 
 
 
 
 
 
 
 

 
Censoring Times 

Ceritinib 750 mg (n/N = 48/115) 

              Chemotherapy (n/N = 50/116) 

 
Hazard Ratio = 1.00 

95% CI (0.67;1.49) 

 

Kaplan-Meier medians (95% CI) (Months) 

Ceritinib 750 mg: 18.1 (13.4;23.9) 

Chemotherapy: 20.1 (11.9;25.1) 

 

Log rank p-value = 0.496 

 

 

 

 

 

 
                  

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Dose optimisation Study A2112 (ASCEND-8) 

The efficacy of Zykadia 450 mg with food was evaluated in a multicentre, open-label dose 

optimisation study A2112 (ASCEND-8). A total of 81 previously untreated patients with 

ALK-positive locally advanced or metastatic NSCLC were randomised to receive Zykadia 450 mg 

once daily with food (N=41) or Zykadia 750 mg once daily under fasted conditions (N=40). A key 

secondary efficacy endpoint was ORR according to RECIST 1.1 as evaluated by BIRC. 

 

The population characteristics across the two arms were: mean age 53 years, age less than 65 (79%), 

female (57%), Caucasian (54%), Asian (33%), never or former smoker (95%), WHO PS 0 or 1 (93%), 

adenocarcinoma histology (94%), and metastases to the brain (33%). 

 

Efficacy results from ASCEND-8 are summarised in Table 5 below. 

 

Table 5 ASCEND-8 (Study A2112) - Efficacy results in patients with previously untreated 

ALK-positive locally advanced or metastatic NSCLC by BIRC 

 

Efficacy Parameter Ceritinib 450 mg with food 

(N=41) 

Ceritinib 750 mg fasted 

(N=40) 

Overall Response Rate (ORR: 

CR+PR), n (%) (95% CI)a 

32 (78.0) 

(62.4, 89.4) 

28 (70.0) 

(53.5, 83.4) 

CI: Confidence Interval 

Complete Response (CR), Partial Response (PR) confirmed by repeat assessments performed not 

less than 4 weeks after response criteria were first met 

Overall response rate determined based on BIRC assessment per RECIST 1.1 
aExact binomial 95% confidence interval 

 

Single arm studies X2101 and A2201 

The use of Zykadia in the treatment of ALK-positive NSCLC patients previously treated with an ALK 

inhibitor was investigated in two global, multicentre, open-label, single-arm phase 1/2 studies 

(Study X2101 and Study A2201). 

 

In study X2101 a total of 246 ALK-positive NSCLC patients were treated at a Zykadia dose of 750 mg 

once daily fasted: 163 who had received prior treatment with an ALK inhibitor and 83 who were ALK 

inhibitor naïve. Of the 163 ALK-positive NSCLC patients who had received prior treatment with an 

ALK inhibitor, the median age was 52 years (range: 24-80 years); 86.5% were younger than 65 years 

and 54% were female. The majority of patients were Caucasian (66.3%) or Asian (28.8%). 93.3% had 

adenocarcinoma and 96.9% had either never been or were former smokers. All of the patients were 

treated with at least one regimen prior to enrolment into the study and 84.0% with two or more 

regimens. 

 

Study A2201 involved 140 patients who had been previously treated with 1-3 lines of cytotoxic 

chemotherapy followed by treatment with crizotinib, and who had then progressed on crizotinib. The 

median age was 51 years (range: 29-80 years); 87.1% of patients were younger than 65 years and 

50.0% were female. The majority of patients were Caucasian (60.0%) or Asian (37.9%). 92.1% of 

patients had adenocarcinoma. 

 



22 

 

The main efficacy data for both studies are summarised in Table 6. Final overall survival (OS) data are 

presented for Study A2201. For Study X2101, OS data were not yet mature at the time of the analysis. 

 

Table 6 ALK-positive advanced NSCLC - overview of efficacy results from Studies X2101 

and A2201 

 

 Study X2101 

ceritinib 750 mg 

Study A2201 

ceritinib 750 mg 

 N=163 N=140 

Duration of follow-up 

Median (months) (min – max) 

10.2 

(0.1 – 24.1) 

14.1 

(0.1 – 35.5) 

Overall response rate   

Investigator (95% CI) 56.4% (48.5, 64.2) 40.7% (32.5, 49.3) 

BIRC (95% CI) 46.0% (38.2, 54.0) 35.7% (27.8, 44.2) 

Duration of response*   

Investigator (months, 95% CI) 8.3 (6.8, 9.7) 10.6 (7.4, 14.7) 

BIRC (months, 95% CI) 8.8 (6.0, 13.1) 12.9 (9.3, 18.4) 

Progression-free survival   

Investigator (months, 95% CI) 6.9 (5.6, 8.7) 5.8 (5.4, 7.6) 

BIRC (months, 95% CI) 7.0 (5.7, 8.7) 7.4 (5.6, 10.9) 

Overall survival (months, 95% 

CI) 

16.7 (14.8, NE) 15.6 (13.6, 24.2) 

NE = not estimable 

Study X2101: Responses assessed using RECIST 1.0 

Study A2201: Responses assessed using RECIST 1.1 

*Includes only patients with confirmed CR, PR 

 

In Studies X2101 and A2201, brain metastases were seen in 60.1% and 71.4% of patients, 

respectively. The ORR, DOR and PFS (by BIRC assessment) for patients with brain metastases at 

baseline were in line with those reported for the overall population of these studies. 

 

Non-adenocarcinoma histology 

 

Limited information is available in ALK-positive NSCLC patients with non-adenocarcinoma 

histology. 

 

Elderly 

 

Limited efficacy data are available in elderly patients. No efficacy data are available in patients over 

85 years of age. 

 

Paediatric population 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Zykadia in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell 

carcinoma) (see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Peak plasma levels (Cmax) of ceritinib are achieved approximately 4 to 6 hours after a single oral 

administration in patients. Oral absorption was estimated to be ≥25% based on metabolite percentages 

in the faeces. The absolute bioavailability of ceritinib has not been determined. 

 

  



23 

 

Systemic exposure of ceritinib was increased when administered with food. Ceritinib AUCinf values 

were approximately 58% and 73% higher (Cmax approximately 43% and 41% higher) in healthy 

subjects when a single 500 mg ceritinib dose was administered with a low fat meal (containing 

approximately 330 kcalories and 9 grams of fat) and a high fat meal (containing approximately 

1000 kcalories and 58 grams of fat), respectively, as compared with the fasted state. 

 

In a dose optimisation study A2112 (ASCEND-8) in patients comparing Zykadia 450 mg or 600 mg 

daily with food (approximately 100 to 500 kcalories and 1.5 to 15 grams of fat) to 750 mg daily under 

fasted conditions (dose and food condition of administration initially authorised), there was no 

clinically meaningful difference in the systemic steady-state exposure of ceritinib for the 450 mg with 

food arm (N=36) compared to the 750 mg fasted arm (N=31), with only small increases in steady-state 

AUC (90% CI) by 4% (-13%, 24%) and Cmax (90% CI) by 3% (-14%, 22%). In contrast, the 

steady-state AUC (90% CI) and Cmax (90% CI) for the 600 mg with food arm (N=30) increased by 

24% (3%, 49%) and 25% (4%, 49%), respectively, compared to the 750 mg fasted arm. The maximum 

recommended dose of Zykadia is 450 mg taken orally once daily with food (see section 4.2). 

 

After single oral administration of ceritinib in patients, plasma exposure to ceritinib, as represented by 

Cmax and AUClast, increased dose-proportionally over the 50 to 750 mg dose range under fasted 

conditions. In contrast with single-dose data, pre-dose concentration (Cmin) after repeated daily dosing 

appeared to increase in a greater than dose-proportional manner. 

 

Distribution 

 

Binding of ceritinib to human plasma proteins in vitro is approximately 97% in a concentration 

independent manner, from 50 ng/ml to 10,000 ng/ml. Ceritinib also has a slight preferential 

distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35. 

In vitro studies suggest that ceritinib is a substrate for P-glycoprotein (P-gp), but not of breast cancer 

resistance protein (BCRP) or multi-resistance protein 2 (MRP2). The in vitro apparent passive 

permeability of ceritinib was determined to be low. 

 

In rats, ceritinib crosses the intact blood brain barrier with a brain-to-blood exposure (AUCinf) ratio of 

about 15%. There are no data related to brain-to-blood exposure ratio in humans. 

 

Biotransformation 

 

In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance 

of ceritinib. 

 

Following a single oral administration of radioactive ceritinib dose at 750 mg fasted, ceritinib was the 

main circulating component in human plasma. A total of 11 metabolites were found circulating in 

plasma at low levels with mean contribution to the radioactivity AUC of ≤2.3% for each metabolite. 

Main biotransformation pathways identified in healthy subjects included mono-oxygenation, 

O-dealkylation, and N-formylation. Secondary biotransformation pathways involving the primary 

biotransformation products included glucuronidation and dehydrogenation. Addition of a thiol group 

to O-dealkylated ceritinib was also observed. 

 

Elimination 

 

Following single oral doses of ceritinib under fasted conditions, the geometric mean apparent plasma 

terminal half-life (T½) of ceritinib ranged from 31 to 41 hours in patients over the 400 to 750 mg dose 

range. Daily oral dosing of ceritinib results in achievement of steady-state by approximately 15 days 

and remains stable afterwards, with a geometric mean accumulation ratio of 6.2 after 3 weeks of daily 

dosing. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state 

(33.2 litres/hour) after 750 mg daily oral dosing than after a single 750 mg oral dose (88.5 litres/hour), 

suggesting that ceritinib demonstrates non-linear pharmacokinetics over time. 

 

  



24 

 

The primary route of excretion of ceritinib and its metabolites is in the faeces. Recovery of unchanged 

ceritinib in the faeces accounts for a mean 68% of an oral dose. Only 1.3% of the administered oral 

dose is recovered in the urine. 

 

Special populations 

 

Hepatic impairment 

The effect of hepatic impairment on the single-dose pharmacokinetics of ceritinib (750 mg under 
fasted conditions) was evaluated in subjects with mild (Child-Pugh class A; N=8), moderate (Child-

Pugh class B; N=7), or severe (Child-Pugh class C; N=7) hepatic impairment and in 8 healthy subjects 

with normal hepatic function. The geometric mean AUCinf (unbound AUCinf) of ceritinib was 

increased by 18% (35%) and 2% (22%) in subjects with mild and moderate hepatic impairment, 

respectively, compared to subjects with normal hepatic function. 

 

The geometric mean AUCinf (unbound AUCinf) of ceritinib was increased by 66% (108%) in subjects 

with severe hepatic impairment compared to subjects with normal hepatic function (see section 4.2). A 

dedicated pharmacokinetic study under steady-state in patients with hepatic impairment has not been 

conducted. 

 

Renal impairment 

A dedicated pharmacokinetic study in patients with renal impairment has not been conducted. Based 

on available data, ceritinib elimination via the kidney is negligible (1.3% of a single oral administered 

dose). 

 

Based on a population pharmacokinetic analysis of 345 patients with mild renal impairment (CLcr 60 

to <90 ml/min), 82 patients with moderate renal impairment (CLcr 30 to <60 ml/min) and 546 patients 

with normal renal function (≥90 ml/min), ceritinib exposures were similar in patients with mild and 

moderate renal impairment and normal renal function, suggesting that no dose adjustment is necessary 

in patients with mild to moderate renal impairment. Patients with severe renal impairment (CLcr 

<30 ml/min) were not included in the clinical studies of Zykadia (see section 4.2). 

 

Effects of age, gender, and race 

Population pharmacokinetic analyses showed that age, gender and race had no clinically meaningful 

influence on ceritinib exposure. 

 

Cardiac electrophysiology 

The potential for QT interval prolongation of ceritinib was assessed in seven clinical studies with 

Zykadia. Serial ECGs were collected following a single dose and at steady-state to evaluate the effect 

of ceritinib on the QT interval in 925 patients treated with Zykadia 750 mg once daily fasted. A 

categorical outlier analysis of ECG data demonstrated new QTc >500 msec in 12 patients (1.3%). 

There were 58 patients (6.3%) with a QTc increase from baseline >60 msec. A central tendency 

analysis of the QTc data at average steady-state concentration from Study A2301 demonstrated that 

the upper bound of the 2-sided 90% CI for QTc increase from baseline was 15.3 msec at Zykadia 

750 mg fasted. A pharmacokinetic analysis suggested that ceritinib causes concentration-dependent 

increases in QTc (see section 4.4). 

 

5.3 Preclinical safety data 

 

Safety pharmacology studies indicate that ceritinib is unlikely to interfere with vital functions of the 

respiratory and central nervous systems. In vitro data show that the IC50 for the inhibitory effect of 

ceritinib on the hERG potassium channel was 0.4 micromolar. An in vivo telemetry study in monkeys 

showed a modest QT prolongation in 1 of 4 animals after receiving the highest dose of ceritinib. ECG 

studies in monkeys after 4- or 13-weeks of dosing with ceritinib have not shown QT prolongation or 

abnormal ECGs. 

 

  



25 

 

The micronucleus test in TK6 cells was positive. No signs of mutagenicity or clastogenicity were 

observed in other in vitro and in vivo genotoxicity studies with ceritinib. Therefore, genotoxic risk is 

not expected in humans. 

 

Carcinogenicity studies have not been performed with ceritinib. 

 

Reproductive toxicology studies (i.e. embryo-foetal development studies) in pregnant rats and rabbits 

indicated no foetotoxicity or teratogenicity after dosing with ceritinib during organogenesis; however, 

maternal plasma exposure was less than that observed at the recommended human dose. Formal 

non-clinical studies on the potential effects of ceritinib on fertility have not been conducted. 

 

The principal toxicity related to ceritinib administration in rats and monkeys was inflammation of the 

extra-hepatic bile ducts accompanied by increased neutrophil counts in the peripheral blood. Mixed 

cell/neutrophilic inflammation of the extra-hepatic ducts extended to the pancreas and/or duodenum at 

higher doses. Gastrointestinal toxicity was observed in both species characterised by body weight loss, 

decreased food consumption, emesis (monkey), diarrhoea and, at high doses, by histopathological 

lesions including erosion, mucosal inflammation and foamy macrophages in the duodenal crypts and 

submucosa. The liver was also affected in both species, at exposures that approximate clinical 

exposures at the recommended human dose, and included minimal increases in liver transaminases in 

a few animals and vacuolation of the intra-hepatic bile duct epithelium. Alveolar foamy macrophages 

(confirmed phospholipidosis) were seen in the lungs of rats, but not in monkeys, and the lymph nodes 

of rats and monkeys had macrophage aggregates. Target organ effects showed partial to complete 

recovery. 

 

Effects on the thyroid were observed in both rat (mild increases in thyroid stimulating hormone and 

triiodothyronine/thyroxine T3/T4 concentrations with no microscopic correlate) and monkey 

(depletion of colloid in males in 4-week study, and one monkey at high dose with diffuse follicular 

cell hyperplasia and increased thyroid stimulating hormone in 13-week study). As these non-clinical 

effects were mild, variable and inconsistent, the relationship between ceritinib and thyroid gland 

changes in animals is unclear. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule content 

 

Cellulose, microcrystalline 

Hydroxypropylcellulose, low-substituted 

Sodium starch glycolate (type A) 

Magnesium stearate 

Silica, colloidal anhydrous 

 

Capsule shell 

 

Gelatin 

Indigotine (E132) 

Titanium dioxide (E171) 

 

Printing ink 

 

Shellac (bleached, de-waxed) glaze 45% 

Iron oxide black (E172) 

Propylene glycol 

Ammonium hydroxide 28% 



26 

 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

3 years 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

PVC/PCTFE (polyvinylchloride/polychlorotrifluoroethylene) – Aluminium blisters containing 10 hard 

capsules. 

 

Packs containing 40, 90 or 150 (3 packs of 50) hard capsules. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/999/001-003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 06 May 2015 

Date of latest renewal: 22 March 2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu 



27 

 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each film-coated tablet contains 150 mg ceritinib. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet (tablet) 

 

Light blue, round, biconvex film-coated tablet with bevelled edges, without score, debossed with 

“NVR” on one side and “ZY1” on the other side. Approximate diameter: 9.1 mm. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

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. 

 

4.2 Posology and method of administration 

 

Treatment with Zykadia should be initiated and supervised by a physician experienced in the use of 

anti-cancer medicinal products. 

 

ALK testing 

 

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. 

 

  



28 

 

Posology 

 

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. 

 

Dose adjustment due to adverse reactions 

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 2 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. 



29 

 

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 recovery to asymptomatic bradycardia or to a 

heart rate of 60 bpm or above, with frequent 

monitoringb. 

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 

 

Strong CYP3A inhibitors 

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. 

 

CYP3A substrates 

When ceritinib is co-administered with other medicinal products, the Summary of Product 

Characteristics (SmPC) for the other product must be consulted for the recommendations regarding 

co-administration with CYP3A4 inhibitors. 

 

  



30 

 

Co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substrates 

known to have narrow therapeutic indices (e.g. alfuzosin, amiodarone, cisapride, ciclosporin, 

dihydroergotamine, ergotamine, fentanyl, pimozide, quetiapine, quinidine, lovastatin, simvastatin, 

sildenafil, midazolam, triazolam, tacrolimus, alfentanil and sirolimus) should be avoided and 

alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible. 

If unavoidable, dose reduction for co-administered medicinal products that are CYP3A substrates with 

narrow therapeutic indices should be considered. 

 

Special populations 

 

Renal impairment 

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). 

 

Hepatic impairment 

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. 

 

Elderly (≥65 years) 

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. 

 

Paediatric population 

The safety and efficacy of ceritinib in children and adolescents aged up to 18 years have not been 

established. No data are available. 

 

Method of administration 

 

Zykadia is for oral use. The tablets 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). The tablets should be swallowed whole with 

water and should not be chewed or crushed. 

 

For patients who develop a concurrent medical condition and are unable to take Zykadia with food 

please refer to section 4.5. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

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. 

 



31 

 

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 sections 4.2 and 

4.8). Particular caution should be exercised when treating patients with severe hepatic impairment, and 

the dose should be adjusted (see section 4.2). Limited experience in these patients showed a worsening 

of the underlying condition (hepatic encephalopathy) in 2 out of 10 patients exposed to 750 mg single 

doses of ceritinib under fasted conditions (see sections 4.2, 4.8 and 5.2). 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. No dose adjustment is necessary in 

patients with mild or moderate hepatic impairment (see section 4.2). 

 

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. Other potential 

causes of ILD/pneumonitis should be excluded, and Zykadia permanently discontinued in patients 

diagnosed with any grade treatment-related ILD/pneumonitis (see sections 4.2 and 4.8). 

 

QT interval prolongation 

 

QTc prolongation has been observed in clinical studies in patients treated with ceritinib (see 

sections 4.8 and 5.2), 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 sections 4.2, 4.8 and 5.2). 

 

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 



32 

 

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 sections 4.2 and 4.8). 

 

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 section 4.8). 

 

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 sections 4.2 and 4.8). 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 sections 4.2 and 4.8). 

 

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 sections 4.2 and 4.8). Cases of pancreatitis have 

been reported in patients treated with ceritinib (see section 4.8). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Agents that may increase ceritinib plasma concentrations 

 

Strong CYP3A inhibitors 

In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole 

(200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold 

increase in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. The 

steady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mg 

twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib 

alone. Avoid concomitant use of strong CYP3A inhibitors during treatment with Zykadia. If it is not 

possible to avoid concomitant use with strong CYP3A inhibitors (including, but not limited to, 

ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and 

nefazodone), reduce the ceritinib dose by approximately one third, rounded to the nearest multiple of 

the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ceritinib 

dose that was taken prior to initiating the strong CYP3A inhibitor. 

 



33 

 

P-gp inhibitors 

Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If 

ceritinib is administered with medicinal products that inhibit P-gp, an increase in ceritinib 

concentration is likely. Caution should be exercised with concomitant use of P-gp inhibitors and 

ADRs carefully monitored. 

 

Agents that may decrease ceritinib plasma concentrations 

 

Strong CYP3A and P-gp inducers 

In healthy subjects, co-administration of a single 750 mg fasted ceritinib dose with rifampicin (600 mg 

daily for 14 days), a strong CYP3A/P-gp inducer, resulted in 70% and 44% decreases in ceritinib 

AUCinf and Cmax, respectively, compared to when ceritinib was given alone. Co-administration of 

ceritinib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Concomitant 

use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, 

phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum). Caution 

should be exercised with concomitant use of P-gp inducers. 

 

Agents that affect gastric pH 

Ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. 

Acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) can alter the 

solubility of ceritinib and reduce its bioavailability. Co-administration of a single 750 mg fasted 

ceritinib dose with a proton pump inhibitor (esomeprazole) 40 mg daily for 6 days in healthy, fasting 

subjects decreased ceritinib AUC by 76% and Cmax by 79%. The drug-drug interaction study was 

designed to observe the impact of proton pump inhibitor in the worst scenario, but in clinical use the 

impact of proton pump inhibitor on ceritinib exposure appears to be less pronounced. A dedicated 

study to evaluate the effect of gastric acid-reducing agents on the bioavailability of ceritinib under 

steady state has not been conducted. Caution is advised with concomitant use of proton pump 

inhibitors, as exposure of ceritinib may be reduced. There is no data with concomitant use of H2 

blockers or antacids. However, the risk for a clinically relevant decrease in bioavailability of ceritinib 

is possibly lower with concomitant use of H2 blockers if they are administered 10 hours before or 

2 hours after the ceritinib dose, and with antacids if they are administered 2 hours before or 2 hours 

after the ceritinib dose. 

 

Agents whose plasma concentration may be altered by ceritinib 

 

CYP3A and CYP2C9 substrates 

Based on in vitro data, ceritinib competitively inhibits the metabolism of a CYP3A substrate, 

midazolam, and a CYP2C9 substrate, diclofenac. Time-dependent inhibition of CYP3A was also 

observed. 

 

Ceritinib has been classified in vivo as a strong CYP3A4 inhibitor and has the potential to interact with 

medicinal products that are metabolised by CYP3A, which may lead to increased serum 

concentrations of the other product. Co-administration of a single dose of midazolam (a sensitive 

CYP3A substrate) following 3 weeks of ceritinib dosing in patients (750 mg daily fasted) increased 

the midazolam AUCinf (90% CI) by 5.4-fold (4.6, 6.3) compared to midazolam alone. 

Co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substrates 

known to have narrow therapeutic indices (e.g. alfuzosin, amiodarone, cisapride, ciclosporin, 

dihydroergotamine, ergotamine, fentanyl, pimozide, quetiapine, quinidine, lovastatin, simvastatin, 

sildenafil, midazolam, triazolam, tacrolimus, alfentanil and sirolimus) should be avoided and 

alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible. 

If unavoidable, dose reduction for co-administered medicinal products that are CYP3A substrates with 

narrow therapeutic indices should be considered. 

 

Ceritinib has been classified in vivo as a weak CYP2C9 inhibitor. Co-administration of a single dose 

of warfarin (a CYP2C9 substrate) following 3 weeks of ceritinib dosing in patients (750 mg daily 

fasted) increased the S-warfarin AUCinf (90% CI) by 54% (36%, 75%) compared to warfarin alone. 

Co-administration of ceritinib with substrates primarily metabolised by CYP2C9 or CYP2C9 



34 

 

substrates known to have narrow therapeutic indices (e.g. phenytoin and warfarin) should be avoided. 

If unavoidable, dose reduction for co-administered medicinal products that are CYP2C9 substrates 

with narrow therapeutic indices should be considered. Increasing the frequency of international 

normalised ratio (INR) monitoring may be considered if co-administration with warfarin is 

unavoidable. 

 

CYP2A6 and CYP2E1 substrates 

Based on in vitro data, ceritinib also inhibits CYP2A6 and CYP2E1 at clinically relevant 

concentrations. Therefore, ceritinib may have the potential to increase plasma concentrations of 

co-administered medicinal products that are predominantly metabolised by these enzymes. Caution 

should be exercised with concomitant use of CYP2A6 and CYP2E1 substrates and ADRs carefully 

monitored. 

 

A risk for induction of other PXR regulated enzymes apart from CYP3A4 cannot be completely 

excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced. 

 

Agents that are substrates of transporters 

 

Based on in vitro data, ceritinib does not inhibit apical efflux transporter MRP2, hepatic uptake 

transporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the 

organic cation uptake transporters OCT1 or OCT2 at clinically relevant concentrations. Therefore, 

clinical drug-drug interactions as a result of ceritinib-mediated inhibition of substrates for these 

transporters are unlikely to occur. Based on in vitro data, ceritinib is predicted to inhibit intestinal P-gp 

and BCRP at clinically relevant concentrations. Therefore, ceritinib may have the potential to increase 

plasma concentrations of co-administered medicinal products transported by these proteins. Caution 

should be exercised with concomitant use of BCRP substrates (e.g. rosuvastatin, topotecan, 

sulfasalazine) and P-gp substrates (digoxin, dabigatran, colchicine, pravastatin) and ADRs carefully 

monitored. 

 

Pharmacodynamic interactions 

 

In clinical studies, QT prolongation was observed with ceritinib. Therefore, ceritinib should be used 

with caution in patients who have or may develop prolongation of the QT interval, including those 

patients taking anti-arrhythmic medicinal products such as class I (e.g. quinidine, procainamide, 

disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) anti-arrhythmics or other 

medicinal products that may lead to QT prolongation such as domperidone, droperidol, chloroquine, 

halofantrine, clarithromycin, haloperidol, methadone, cisapride and moxifloxacin. Monitoring of the 

QT interval is indicated in the event of combinations of such medicinal products (see sections 4.2 and 

4.4). 

 

Food/drink interactions 

 

Zykadia should be taken with food. The bioavailability of ceritinib is increased in the presence of 

food. 

 

For patients who develop a concurrent medical condition and are unable to take Zykadia with food, 

Zykadia can be taken on an empty stomach as the alternate continued treatment regimen, in which no 

food should be eaten for at least two hours before and one hour after the dose. Patients should not 

alternate between fasted and fed dosing. Dose must be adjusted properly, i.e for patients treated with 

450 mg or 300 mg with food, the dose should be increased to 750 mg or 450 mg taken on an empty 

stomach, respectively (see section 5.2) and for patients treated with 150 mg with food treatment 

should be discontinued. For subsequent dose adjustment and management recommendations for 

ADRs, please follow table 1 (see section 4.2). The maximum allowable dose under fasted condition is 

750 mg (see section 5.2). 

 

Patients should be instructed to avoid grapefruit and grapefruit juice as they may inhibit CYP3A in the 

gut wall and may increase the bioavailability of ceritinib. 



35 

 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/Contraception 

 

Women of childbearing potential should be advised to use a highly effective method of contraception 

while taking Zykadia and for up to 3 months after discontinuing treatment (see section 4.5). 

 

Pregnancy 

 

There are no or limited amount of data from the use of ceritinib in pregnant women. 

 

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). 

 

Zykadia should not be used during pregnancy unless the clinical condition of the woman requires 

treatment with ceritinib. 

 

Breast-feeding 

 

It is unknown whether ceritinib/metabolites are excreted in human milk. A risk to the newborn/infant 

cannot be excluded. 

 

A decision must be made whether to discontinue breast-feeding or discontinue/abstain from Zykadia 

therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the 

woman (see section 5.3). 

 

Fertility 

 

The potential for Zykadia to cause infertility in male and female patients is unknown (see section 5.3). 

 

4.7 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. 
 

4.8 Undesirable effects 

 

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 



36 

 

reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure 

(see section 5.1 and subsection ‘Gastrointestinal adverse reactions’ below). 

 

Tabulated list of ADRs 

 

Table 2 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). 

 

Table 2 ADRs in patients treated with Zykadia 

 

System organ class 

Preferred term 

Zykadia 

N=925 

% 

Frequency category 

Blood and lymphatic system disorders 

Anaemia 15.2 Very common 

Metabolism and nutrition disorders 

Decreased appetite 39.5 Very common 

Hyperglycaemia 9.4 Common 

Hypophosphataemia 5.3 Common 

Eye disorders 

Vision disordera 7.0 Common 

Cardiac disorders 

Pericarditisb 5.8 Common 

Bradycardiac 2.3 Common 

Respiratory, thoracic and mediastinal disorders 

Pneumonitisd 2.1 Common 

Gastrointestinal disorders 

Diarrhoeae 56.2 Very common 

Nauseae 44.9 Very common 

Vomitinge 34.8 Very common 

Abdominal painf 46.1 Very common 

Constipation 24.0 Very common 

Oesophageal disorderg 14.1 Very common 

Pancreatitis 0.5 Uncommon 

Hepatobiliary disorders 

Abnormal liver function testsh 2.2 Common 

Hepatotoxicityi 1.1 Common 

Skin and subcutaneous tissue disorders 

Rashj 19.6 Very common 

Renal and urinary disorders 

Renal failurek 1.8 Common 

Renal impairmentl 1.0 Common 

General disorders and administration site conditions 

Fatiguem 48.4 Very common 



37 

 

Investigations 

Liver laboratory test abnormalitiesn 60.5 Very common 

Weight decreased 27.6 Very common 

Blood creatinine increased 22.1 Very common 

Electrocardiogram QT prolonged 9.7 Common 

Lipase increased 4.8 Common 

Amylase increased 7.0 Common 

Includes cases reported within the clustered terms: 
a Vision disorder (vision impairment, vision blurred, photopsia, vitreous floaters, visual acuity 

reduced, accommodation disorder, presbyopia) 
b Pericarditis (pericardial effusion, pericarditis) 
c Bradycardia (bradycardia, sinus bradycardia) 
d Pneumonitis (interstitial lung disease, pneumonitis) 
e The frequency of these selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) is based on 

patients treated with the recommended dose of ceritinib 450 mg with food (N=89) in the study A2112 

(ASCEND-8) (see subsection ‘Gastrointestinal adverse reactions’ below) 
f Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, epigastric 

discomfort) 
g Oesophageal disorder (dyspepsia, gastro-oesophageal reflux disease, dysphagia) 
h Abnormal liver function test (hepatic function abnormal, hyperbilirubinaemia) 
i Hepatotoxicity (drug-induced liver injury, hepatitis cholestatic, hepatocellular injury, hepatotoxicity) 
j Rash (rash, dermatitis acneiform, rash maculopapular) 
k Renal failure (acute renal injury, renal failure) 
l Renal impairment (azotaemia, renal impairment) 
m Fatigue (fatigue, asthenia) 
n Liver laboratory test abnormalities (alanine aminotransferase increased, aspartate aminotransferase 

increased, gamma-glutamyltransferase increased, blood bilirubin increased, transaminases increased, 

hepatic enzyme increased, liver function test abnormal, liver function test increased, blood alkaline 

phosphatase increased) 

 

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 section 4.2). 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. 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 sections 4.2 and 4.4). 

 

Liver laboratory tests including ALT, AST and total bilirubin should be performed prior to the start of 

treatment, every 2 weeks during the first three months of treatment 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 sections 4.2 and 4.4. 

 

Gastrointestinal adverse reactions 

 

Nausea, diarrhoea and vomiting were among 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 



38 

 

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 sections 4.2 and 4.4. 

 

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 sections 4.4 and 4.5). 

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 sections 4.2 and 

4.4. 

 

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 sections 4.2 

and 4.4. 

 

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 sections 4.2 

and 4.4). 

 

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 sections 4.2 and 4.4). 

 



39 

 

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 

listed in Appendix V. 

 

4.9 Overdose 

 

There is no reported experience with overdose in humans. General supportive measures should be 

initiated in all cases of overdose. 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: antineoplasic and immunomodulating agents, ATC code: L01XE28. 

 

Mechanism of action 

 

Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation 

of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of 

ALK-dependent cancer cells both in vitro and in vivo. 

 

ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK 

signaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this 

generates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the 

N-terminal part of EML4. Ceritinib was demonstrated to be effective against EML4-ALK activity in a 

NSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of 

tumours in H2228-derived xenografts in mouse and rat. 

 

Clinical efficacy and safety 

 

Previously untreated ALK-positive advanced NSCLC - randomised phase 3 Study A2301 (ASCEND-4) 

The efficacy and safety of Zykadia for the treatment of advanced ALK-positive NSCLC patients who 

have not received previous systemic treatment anti-cancer therapy (including ALK inhibitor) with the 

exception of neo-adjuvant or adjuvant therapy, was demonstrated in a global multicentre, randomised, 

open-label phase 3 Study A2301. 

 

A total of 376 patients were randomised in a 1:1 ratio (stratified by WHO performance status, prior 

adjuvant/neoadjuvant chemotherapy and presence/absence of brain metastasis at screening) to receive 

either ceritinib (750 mg daily, fasted) or chemotherapy (based on investigator’s choice - pemetrexed 

[500 mg/m2] plus cisplatin [75 mg/m2] or carboplatin [AUC 5-6], administered every 21 days). 

Patients who completed 4 cycles of chemotherapy (induction) without progressive disease 

subsequently received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. 

One hundred and eighty-nine (189) patients were randomised to ceritinib and one hundred eighty-

seven (187) were randomised to chemotherapy. 

 

The median age was 54 years (range: 22 to 81 years); 78.5% of patients were younger than 65 years. A 

total of 57.4% of patients were female. 53.7% of the study population was Caucasian, 42.0% Asian, 

1.6% Black and 2.6% other races The majority of patients had adenocarcinoma (96.5%) and had either 

never smoked or were former smokers (92.0%). The Eastern Cooperative Oncology Group (ECOG) 

performance status was 0/1/2 in 37.0%/56.4%/6.4% of patients, and 32.2% had brain metastasis at 

baseline. 59.5% of patients with brain metastasis at baseline received no prior radiotherapy to the 

brain. Patients with symptomatic CNS (central nervous system) metastases who were neurologically 

unstable or had required increasing doses of steroids within the 2 weeks prior to screening to manage 

CNS symptoms, were excluded from the study. 



40 

 

 

Patients were allowed to continue the assigned study treatment beyond initial progression in case of 

continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy 

arm could cross-over to receive ceritinib upon RECIST-defined disease progression confirmed by 

blinded independent review committee (BIRC). One hundred and five (105) patients out of the 

145 patients (72.4%) that discontinued treatment in the chemotherapy arm received subsequent ALK 

inhibitor as first antineoplastic therapy. Of these patients 81 received ceritinib. 

 

The median duration of follow-up was 19.7 months (from randomisation to cut-off date). 

 

The study met its primary objective demonstrating a statistically significant improvement in 

progression free survival (PFS) by BIRC (see Table 3 and Figure 1). The PFS benefit of ceritinib was 

consistent by investigator assessment and across various subgroups including age, gender, race, 

smoking class, ECOG performance status and disease burden. 

 

The overall survival (OS) data was not mature with 107 deaths representing approximately 42.3% of 

the required events for the final OS analysis. 

 

Efficacy data from Study A2301 are summarised in Table 3, and the Kaplan-Meier curves for PFS and 

OS are shown in Figure 1 and Figure 2, respectively. 

 

Table 3 ASCEND-4 (Study A2301) - Efficacy results in patients with previously untreated 

ALK-positive advanced NSCLC 

 

 Ceritinib 

(N=189) 

Chemotherapy 

(N=187) 

Progression-free survival (based on BIRC)   

Number of events, n (%) 89 (47.1) 113 (60.4) 

Median, monthsd (95% CI) 16.6 (12.6, 27.2) 8.1 (5.8, 11.1) 

HR (95% CI)a 0.55 (0.42, 0.73) 

p-valueb <0.001 

Overall survivalc   

Number of events, n (%) 48 (25.4) 59 (31.6) 

Median, monthsd (95% CI) NE (29.3, NE) 26.2 (22.8, NE) 

OS rate at 24 monthsd, % (95% CI) 70.6 (62.2, 77.5) 58.2 (47.6, 67.5) 

HR (95% CI)a 0.73 (0.50,1.08) 

p-valueb 0.056 

Tumour response (based on BIRC)   

Overall response rate (95% CI) 72.5% (65.5, 78.7) 26.7% (20.5, 33.7) 

Duration of response (based on BIRC)   

Number of responders 137 50 

Median, monthsd (95% CI) 23.9 (16.6, NE) 11.1 (7.8, 16.4) 

Event-free rate at 18 monthsd, % (95% 

CI) 

59.0 (49.3, 67.4) 30.4 (14.1, 48.6) 

HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; 

NE=not estimable 
a Based on the Cox proportional hazards stratified analysis. 
b Based on the stratified log-rank test. 
c OS analysis was not adjusted for the effects of cross-over. 
d Estimated using the Kaplan-Meier method. 

 



41 

 

Figure 1 ASCEND-4 (Study A2301) - Kaplan-Meier curves of progression-free survival as 

assessed by BIRC 
 
 

 

 
 
 

 

 
 
 

 
 
 
 

 

 

 

 No. of patients still at risk 

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 

ceritinib 750 mg 189 155 139 125 116 105 98 76 59 43 32 23 16 11 1 1 1 0 

Chemotherapy 187 136 114 82 71 60 53 35 24 16 11 5 3 1 1 0 0 0 

 

Figure 2 ASCEND-4 (Study A2301)- Kaplan-Meier plot of overall survival by treatment arm 

 

 

 

 

 

 

 

 

 

 

 

 

 No. of patients still at risk 

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 

ceritinib 750 mg 189 180 175 171 165 155 150 138 103 77 56 39 26 18 6 3 2 0 

Chemotherapy 187 172 161 150 146 141 134 124 97 69 49 35 19 10 5 1 0 0 

 

Patient reported outcome questionnaires (Lung cancer symptom scale [LCSS], EORTC-QLQ-C30 

[C30], EORTC QLQ-LC13 [LC13] and EQ-5D-5L) were completed by 80% or more of patients in the 

ceritinib and chemotherapy arms for all questionnaires at most of the time-points during the course of 

the study. 

 

  

10 6 4 2 0 22 20 18 16 14 12 32

 

30 28 26 24 8 34

 

P
ro

b
a
b
ili

ty
 (

%
) 

o
f 

e
v
e
n
t-

fr
e
e

 

Hazard Ratio = 0.55 

95% CI (0.42, 0.73) 

Kaplan-Meier medians (95% CI) (Months) 

ceritinib 750 mg: 16.6 (12.6, 27.2) 

Chemotherapy: 8.1 (5.8, 11.1) 

Logrank p-value = <0.001 

Censoring Times 

ceritinib 750 mg (n/N = 89/189) 

Chemotherapy (n/N = 113/187) 

20 

100 

80 

60 

40 

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Time (Months) 

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80 

60 

40 

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10 8 6 4 2 0 22 20 18 16 14 12 32

 

30 28 26 24 34

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Hazard Ratio = 0.73 

95% CI (0.50, 1.08) 

 

Kaplan-Meier medians (95% CI) (Months) 

ceritinib 750 mg: NE (29.3, NE) 

Chemotherapy: 26.2 (22.8, NE) 

Logrank p-value = 0.056 

Censoring Times 

ceritinib 750 mg (n/N = 48/189) 

Chemotherapy (n/N = 59/187) 



42 

 

Ceritinib significantly prolonged time to deterioration for the pre-specified lung cancer specific 

symptoms of interest of cough, pain and dyspnoea (composite endpoint LCSS: HR=0.61, 95% CI: 

0.41, 0.90, median Time to Deterioration [TTD] NE [95% CI: 20.9, NE] in the ceritinib arm versus 

18.4 months [13.9, NE] in the chemotherapy arm; LC13: HR=0.48, 95% CI: 0.34, 0.69, median TTD 

23.6 months [95% CI: 20.7, NE] in the ceritinib arm versus 12.6 months [95% CI: 8.9, 14.9] in the 

chemotherapy arm). 

 

Patients receiving ceritinib showed significant improvements over chemotherapy in general Quality of 

Life and global Health Status measures (LCSS [p<0.001], QLQ-C30, [p<0.001] and EQ-5D-5L index 

[p<0.001]). 

 

In Study A2301, 44 patients with measurable brain metastasis at baseline and at least one post-baseline 

brain radiological assessment (22 patients in the ceritinib arm and 22 patients in the chemotherapy 

arm) were assessed for intracranial response by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. 

up to 5 lesions in the brain). The overall intracranial response rate (OIRR) was higher with ceritinib 
(72.7%, 95% CI: 49.8, 89.3) as compared to the chemotherapy arm (27.3%, 95% CI: 10.7, 50.2). 

 

The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the 

chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. 

The median PFS in patients with brain metastases was 10.7 months (95% CI: 8.1, 16.4) versus 

6.7 months (95% CI: 4.1, 10.6) in the ceritinib and chemotherapy arms, respectively, with HR=0.70 

(95% CI: 0.44, 1.12). The median PFS in patients without brain metastases was 26.3 months (95% CI: 

15.4, 27.7) versus 8.3 months (95% CI: 6.0, 13.7) in the ceritinib and chemotherapy arms, 

respectively, with HR=0.48 (95% CI: 0.33, 0.69). 

 

Previously treated ALK-positive advanced NSCLC - randomised phase 3 Study A2303 (ASCEND-5) 

The efficacy and safety of Zykadia for the treatment of ALK-positive advanced NSCLC patients who 

have received previous treatment with crizotinib, was demonstrated in a global multicentre, 

randomised, open-label phase 3 Study A2303. 

 

A total of 231 patients with advanced ALK positive NSCLC who have received prior treatment with 

crizotinib and chemotherapy (one or two regimen including a platinum-based doublet) were included 

in the analysis. One hundred fifteen (115) patients were randomised to Zykadia and one hundred 

sixteen (116) were randomised to chemotherapy (either pemetrexed or docetaxel). Seventy-three (73) 

patients received docetaxel and 40 received pemetrexed. In the ceritinib arm, 115 patients were treated 

with 750 mg once daily fasted. The median age was 54.0 years (range: 28 to 84 years); 77.1% of 

patients were younger than 65 years. A total of 55.8% of patients were female. 64.5% of the study 

population were Caucasian, 29.4% Asian, 0.4% Black and 2.6% other races. The majority of patients 

had adenocarcinoma (97.0%) and had either never smoked or were former smokers (96.1%). The 

ECOG performance status was 0/1/2 in 46.3%/47.6%/6.1% of patients respectively, and 58.0% had 

brain metastasis at baseline. All patients were treated with prior crizotinib. All except one patient 

received prior chemotherapy (including a platinum doublet) for advanced disease; 11.3% of the 

patients in the ceritinib arm and 12.1% of the patients in the chemotherapy arm were treated with two 

prior chemotherapy regimen for advanced disease. 

 

Patients were allowed to continue the assigned study treatment beyond initial progression in case of 

continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy 

arm could further crossover to receive Zykadia upon RECIST-defined disease progression confirmed 

by BIRC. 

 

The median duration of follow-up was 16.5 months (from randomisation to data cut-off date). 

 

The study met its primary objective demonstrating a statistically significant improvement in PFS by 

BIRC with an estimated 51% risk reduction in the ceritinib arm compared to chemotherapy arm (see 

Table 4 and Figure 3). The PFS benefit of Zykadia was consistent across various subgroups including 

age, gender, race, smoking class, ECOG performance status, and presence of brain metastases or prior 

response to crizotinib. The PFS benefit was further supported by local investigator assessment, and 



43 

 

analysis of overall response rate (ORR) and disease control rate (DCR). 

 

OS data was immature with 48 (41.7%) events in the ceritinib arm and 50 (43.1%) events in the 

chemotherapy arm, corresponding to approximately 50% of the required events for the final OS 

analysis. In addition, 81 patients (69.8%) in the chemotherapy arm received subsequent Zykadia as 

first antineoplastic therapy after study treatment discontinuation. 

 

Efficacy data from Study A2303 are summarised in Table 4, and the Kaplan-Meier curves for PFS and 

OS are shown in Figure 3 and 4, respectively. 

 

Table 4 ASCEND-5 (Study A2303) – Efficacy results in patients with previously treated 

ALK-positive metastatic/advanced NSCLC 

 

 Ceritinib 

(N=115) 

Chemotherapy 

(N=116) 

Duration of follow-up 

Median (months) (min – max) 

16.5 

(2.8 – 30.9) 

Progression-free survival (based on BIRC)   

Number of events, n (%) 83 (72.2%) 89 (76.7%) 

Median, months (95% CI) 5.4 (4.1, 6.9) 1.6 (1.4, 2.8) 

HR (95% CI)a 0.49 (0.36, 0.67) 

p-valueb <0.001 

Overall survivalc   

Number of events, n (%) 48 (41.7%) 50 (43.1%) 

Median, months (95% CI) 18.1 (13.4, 23.9) 20.1 (11.9, 25.1) 

HR (95% CI)a 1.00 (0.67,1.49) 

p-valueb 0.496 

Tumour responses (based on BIRC)   

Objective response rate (95% CI) 39.1% (30.2, 48.7) 6.9% (3.0, 13.1) 

Duration of response   

Number of responders 45 8 

Median, monthsd (95% CI) 6.9 (5.4, 8.9) 8.3 (3.5, NE) 

Event-free probability estimate at 9 

monthsd (95% CI) 

31.5% (16.7%, 
47.3%) 

45.7% (6.9%, 79.5%) 

HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; 

NE=not estimable 
a Based on the stratified Cox proportional hazards analysis. 
b Based on the stratified log-rank test. 
c OS analysis was not adjusted for the potentially confounding effects of cross over. 
d Estimated using the Kaplan-Meier method.  

 



44 

 

Figure 3 ASCEND-5 (Study A2303) – Kaplan-Meier plot of progression-free survival as 

assessed by BIRC 

 

 

100 
 

   
 
 

80 
 

 

 
 
 

60 
 

 
 
 

40 
 

 
 
 

20 
 

 
 
0 

 

 

 
 
 
 
 
 

 No. of patients s till at risk 

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 

Ceritinib 750 mg 115 87 68 40 31 18 12 9 4 3 2 1 0 

Chemotherapy 116 45 26 12 9 6 2 2 2 0 0 0 0 

 

        0        2        4        6        8       10       12      14      16       18       20      22       24 

Time (Months) 

  
 

Censoring Times 

Ceritinib 750 mg (n/N = 83/115) 

  Chemotherapy (n/N = 89/116) 
 

 
Hazard Ratio = 0.49 

95% CI (0.36;0.67) 

 

Kaplan-Meier medians (95% CI) (Months) 

Ceritinib 750 mg: 5.4 (4.1;6.9) 

Chemotherapy: 1.6 (1.4;2.8) 

 

Log rank p-value = <0.001 

 

 

 

 

 

 
               

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Figure 4 ASCEND-5 (Study A2303) – Kaplan-Meier plot of overall survival by treatment 

arm 

 

100 
 
 
 
 

80 
 
 
 
 

60 
 
 
 
 

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0 
 
 
 

0 2 4 6 

 
 
 

8 

 
 
 

10 

 
 
 

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18 

 
 
 

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26 

 
 
 

28 

 
 
 

30 

  
No. of patients s till at risk 

   Time (Months)        

Time (Months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 

Ceritinib 750 mg 115 107 92 83 71 61 52 37 28 23 13 8 2 2 0 0 

Chemotherapy 116 109 91 78 66 53 43 39 29 22 17 7 5 2 1 0 

 

Patient reported outcome questionnaires were collected using the EORTC QLQ C30/LC13, LCSS and 

EQ-5D-5L. 75% or more of patients in the ceritinib and chemotherapy arms completed the LCSS 

questionnaires at most of the time points during the course of the study. Significant improvements 

were reported for the majority of lung cancer specific symptoms for Zykadia compared to 

chemotherapy (four out of six LCSS and 10 out of 12 QLQ-LC13 symptom scores). Ceritinib 

significantly prolonged time to deterioration for the lung cancer specific symptoms of interest of 

cough, pain and dyspnoea (composite endpoint LCSS: HR=0.40; 95% CI: 0.25, 0.65, median Time to 

Deterioration [TTD] 18.0 months [95% CI: 13.4, NE] in the ceritinib arm versus 4.4 months [95% CI: 

1.6, 8.6] in the chemotherapy arm; LC13: HR=0.34; 95% CI: 0.22, 0. 52, median TTD 11.1 months 

[95% CI: 7.1, 14.2] in the ceritinib arm versus 2.1 months [95% CI: 1.0, 5.6] in the chemotherapy 

arm). The EQ-5D questionnaire showed a significant overall health status improvement for Zykadia in 

comparison to the chemotherapy. 

 

In Study A2303, 133 patients with baseline brain metastasis (66 patients in the Zykadia arm and 

67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-

radiologist (per modified RECIST 1.1 (i.e. up to 5 lesions in the brain). The OIRR in patients with 

measurable disease in the brain at baseline and at least one post-baseline assessment was higher in the 

ceritinib arm (35.3%, 95% CI: 14.2, 61.7) compared to the chemotherapy arm (5.0%, 95% CI: 0.1, 

24.9). The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the 

chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. 

The median PFS in patients with brain metastases was 4.4 months (95% CI: 3.4, 6.2) versus 

1.5 months (95% CI: 1.3, 1.8) in the ceritinib and chemotherapy arms, respectively with HR=0.54 

(95% CI: 0.36, 0.80). The median PFS in patients without brain metastases was 8.3 months (95% CI: 

4.1, 14.0) versus 2.8 months (95% CI: 1.4, 4.1) in the ceritinib and chemotherapy arms, respectively 

with HR=0.41 (95% CI: 0.24, 0.69). 

 

  
 
 
 
 
 
 
 
 

 
Censoring Times 

Ceritinib 750 mg (n/N = 48/115) 

              Chemotherapy (n/N = 50/116) 

 
Hazard Ratio = 1.00 

95% CI (0.67;1.49) 

 

Kaplan-Meier medians (95% CI) (Months) 

Ceritinib 750 mg: 18.1 (13.4;23.9) 

Chemotherapy: 20.1 (11.9;25.1) 

 

Log rank p-value = 0.496 

 

 

 

 

 

 
                  

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46 

 

Dose optimisation Study A2112 (ASCEND-8) 

The efficacy of Zykadia 450 mg with food was evaluated in a multicentre, open-label dose 

optimisation study A2112 (ASCEND-8). A total of 81 previously untreated patients with 

ALK-positive locally advanced or metastatic NSCLC were randomised to receive Zykadia 450 mg 

once daily with food (N=41) or Zykadia 750 mg once daily under fasted conditions (N=40). A key 

secondary efficacy endpoint was ORR according to RECIST 1.1 as evaluated by BIRC. 

 

The population characteristics across the two arms were: mean age 53 years, age less than 65 (79%), 

female (57%), Caucasian (54%), Asian (33%), never or former smoker (95%), WHO PS 0 or 1 (93%), 

adenocarcinoma histology (94%), and metastases to the brain (33%). 

 

Efficacy results from ASCEND-8 are summarised in Table 5 below. 

 

Table 5 ASCEND-8 (Study A2112) - Efficacy results in patients with previously untreated 

ALK-positive locally advanced or metastatic NSCLC by BIRC 

 

Efficacy Parameter Ceritinib 450 mg with food 

(N=41) 

Ceritinib 750 mg fasted 

(N=40) 

Overall Response Rate (ORR: 

CR+PR), n (%) (95% CI)a 

32 (78.0) 

(62.4, 89.4) 

28 (70.0) 

(53.5, 83.4) 

CI: Confidence Interval 

Complete Response (CR), Partial Response (PR) confirmed by repeat assessments performed not 

less than 4 weeks after response criteria were first met 

Overall response rate determined based on BIRC assessment per RECIST 1.1 
aExact binomial 95% confidence interval 

 

Single arm studies X2101 and A2201 

The use of Zykadia in the treatment of ALK-positive NSCLC patients previously treated with an ALK 

inhibitor was investigated in two global, multicentre, open-label, single-arm phase 1/2 studies 

(Study X2101 and Study A2201). 

 

In study X2101 a total of 246 ALK-positive NSCLC patients were treated at a Zykadia dose of 750 mg 

once daily fasted: 163 who had received prior treatment with an ALK inhibitor and 83 who were ALK 

inhibitor naïve. Of the 163 ALK-positive NSCLC patients who had received prior treatment with an 

ALK inhibitor, the median age was 52 years (range: 24-80 years); 86.5% were younger than 65 years 

and 54% were female. The majority of patients were Caucasian (66.3%) or Asian (28.8%). 93.3% had 

adenocarcinoma and 96.9% had either never been or were former smokers. All of the patients were 

treated with at least one regimen prior to enrolment into the study and 84.0% with two or more 

regimens. 

 

Study A2201 involved 140 patients who had been previously treated with 1-3 lines of cytotoxic 

chemotherapy followed by treatment with crizotinib, and who had then progressed on crizotinib. The 

median age was 51 years (range: 29-80 years); 87.1% of patients were younger than 65 years and 

50.0% were female. The majority of patients were Caucasian (60.0%) or Asian (37.9%). 92.1% of 

patients had adenocarcinoma. 

 



47 

 

The main efficacy data for both studies are summarised in Table 6. Final overall survival (OS) data are 

presented for Study A2201. For Study X2101, OS data were not yet mature at the time of the analysis. 

 

Table 6 ALK-positive advanced NSCLC - overview of efficacy results from Studies X2101 

and A2201 

 

 Study X2101 

ceritinib 750 mg 

Study A2201 

ceritinib 750 mg 

 N=163 N=140 

Duration of follow-up 

Median (months) (min – max) 

10.2 

(0.1 – 24.1) 

14.1 

(0.1 – 35.5) 

Overall response rate   

Investigator (95% CI) 56.4% (48.5, 64.2) 40.7% (32.5, 49.3) 

BIRC (95% CI) 46.0% (38.2, 54.0) 35.7% (27.8, 44.2) 

Duration of response*   

Investigator (months, 95% CI) 8.3 (6.8, 9.7) 10.6 (7.4, 14.7) 

BIRC (months, 95% CI) 8.8 (6.0, 13.1) 12.9 (9.3, 18.4) 

Progression-free survival   

Investigator (months, 95% CI) 6.9 (5.6, 8.7) 5.8 (5.4, 7.6) 

BIRC (months, 95% CI) 7.0 (5.7, 8.7) 7.4 (5.6, 10.9) 

Overall survival (months, 95% 

CI) 

16.7 (14.8, NE) 15.6 (13.6, 24.2) 

NE = not estimable 

Study X2101: Responses assessed using RECIST 1.0 

Study A2201: Responses assessed using RECIST 1.1 

*Includes only patients with confirmed CR, PR 

 

In Studies X2101 and A2201, brain metastases were seen in 60.1% and 71.4% of patients, 

respectively. The ORR, DOR and PFS (by BIRC assessment) for patients with brain metastases at 

baseline were in line with those reported for the overall population of these studies. 

 

Non-adenocarcinoma histology 

 

Limited information is available in ALK-positive NSCLC patients with non-adenocarcinoma 

histology. 

 

Elderly 

 

Limited efficacy data are available in elderly patients. No efficacy data are available in patients over 

85 years of age. 

 

Paediatric population 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Zykadia in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell 

carcinoma) (see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

 

Peak plasma levels (Cmax) of ceritinib are achieved approximately 4 to 6 hours after a single oral 

administration in patients. Oral absorption was estimated to be ≥25% based on metabolite percentages 

in the faeces. The absolute bioavailability of ceritinib has not been determined. 

 

  



48 

 

Systemic exposure of ceritinib was increased when administered with food. Ceritinib AUCinf values 

were approximately 39% and 64% higher (Cmax approximately 42% and 58% higher) in healthy 

subjects when a single 750 mg ceritinib dose (tablet) was administered with a low fat meal (containing 

approximately 330 kcalories and 9 grams of fat) and a high fat meal (containing approximately 

1000 kcalories and 58 grams of fat), respectively, as compared with the fasted state. 

 

In a dose optimisation study A2112 (ASCEND-8) in patients comparing Zykadia 450 mg or 600 mg 

daily with food (approximately 100 to 500 kcalories and 1.5 to 15 grams of fat) to 750 mg daily under 

fasted conditions (dose and food condition of administration initially authorised), there was no 

clinically meaningful difference in the systemic steady-state exposure of ceritinib for the 450 mg with 

food arm (N=36) compared to the 750 mg fasted arm (N=31), with only small increases in steady-state 

AUC (90% CI) by 4% (-13%, 24%) and Cmax (90% CI) by 3% (-14%, 22%). In contrast, the 

steady-state AUC (90% CI) and Cmax (90% CI) for the 600 mg with food arm (N=30) increased by 

24% (3%, 49%) and 25% (4%, 49%), respectively, compared to the 750 mg fasted arm. The maximum 

recommended dose of Zykadia is 450 mg taken orally once daily with food (see section 4.2). 

 

After single oral administration of ceritinib in patients, plasma exposure to ceritinib, as represented by 

Cmax and AUClast, increased dose-proportionally over the 50 to 750 mg dose range under fasted 

conditions. In contrast with single-dose data, pre-dose concentration (Cmin) after repeated daily dosing 

appeared to increase in a greater than dose-proportional manner. 

 

Distribution 

 

Binding of ceritinib to human plasma proteins in vitro is approximately 97% in a concentration 

independent manner, from 50 ng/ml to 10,000 ng/ml. Ceritinib also has a slight preferential 

distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35. 

In vitro studies suggest that ceritinib is a substrate for P-glycoprotein (P-gp), but not of breast cancer 

resistance protein (BCRP) or multi-resistance protein 2 (MRP2). The in vitro apparent passive 

permeability of ceritinib was determined to be low. 

 

In rats, ceritinib crosses the intact blood brain barrier with a brain-to-blood exposure (AUCinf) ratio of 

about 15%. There are no data related to brain-to-blood exposure ratio in humans. 

 

Biotransformation 

 

In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance 

of ceritinib. 

 

Following a single oral administration of radioactive ceritinib dose at 750 mg fasted, ceritinib was the 

main circulating component in human plasma. A total of 11 metabolites were found circulating in 

plasma at low levels with mean contribution to the radioactivity AUC of ≤2.3% for each metabolite. 

Main biotransformation pathways identified in healthy subjects included mono-oxygenation, 

O-dealkylation, and N-formylation. Secondary biotransformation pathways involving the primary 

biotransformation products included glucuronidation and dehydrogenation. Addition of a thiol group 

to O-dealkylated ceritinib was also observed. 

 

Elimination 

 

Following single oral doses of ceritinib under fasted conditions, the geometric mean apparent plasma 

terminal half-life (T½) of ceritinib ranged from 31 to 41 hours in patients over the 400 to 750 mg dose 

range. Daily oral dosing of ceritinib results in achievement of steady-state by approximately 15 days 

and remains stable afterwards, with a geometric mean accumulation ratio of 6.2 after 3 weeks of daily 

dosing. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state 

(33.2 litres/hour) after 750 mg daily oral dosing than after a single 750 mg oral dose (88.5 litres/hour), 

suggesting that ceritinib demonstrates non-linear pharmacokinetics over time. 

 

  



49 

 

The primary route of excretion of ceritinib and its metabolites is in the faeces. Recovery of unchanged 

ceritinib in the faeces accounts for a mean 68% of an oral dose. Only 1.3% of the administered oral 

dose is recovered in the urine. 

 

Special populations 

 

Hepatic impairment 

The effect of hepatic impairment on the single-dose pharmacokinetics of ceritinib (750 mg under 
fasted conditions) was evaluated in subjects with mild (Child-Pugh class A; N=8), moderate (Child-

Pugh class B; N=7), or severe (Child-Pugh class C; N=7) hepatic impairment and in 8 healthy subjects 

with normal hepatic function. The geometric mean AUCinf (unbound AUCinf) of ceritinib was 

increased by 18% (35%) and 2% (22%) in subjects with mild and moderate hepatic impairment, 

respectively, compared to subjects with normal hepatic function. 

 

The geometric mean AUCinf (unbound AUCinf) of ceritinib was increased by 66% (108%) in subjects 

with severe hepatic impairment compared to subjects with normal hepatic function (see section 4.2). A 

dedicated pharmacokinetic study under steady-state in patients with hepatic impairment has not been 

conducted. 

 

Renal impairment 

A dedicated pharmacokinetic study in patients with renal impairment has not been conducted. Based 

on available data, ceritinib elimination via the kidney is negligible (1.3% of a single oral administered 

dose). 

 

Based on a population pharmacokinetic analysis of 345 patients with mild renal impairment (CLcr 60 

to <90 ml/min), 82 patients with moderate renal impairment (CLcr 30 to <60 ml/min) and 546 patients 

with normal renal function (≥90 ml/min), ceritinib exposures were similar in patients with mild and 

moderate renal impairment and normal renal function, suggesting that no dose adjustment is necessary 

in patients with mild to moderate renal impairment. Patients with severe renal impairment (CLcr 

<30 ml/min) were not included in the clinical studies of Zykadia (see section 4.2). 

 

Effects of age, gender, and race 

Population pharmacokinetic analyses showed that age, gender and race had no clinically meaningful 

influence on ceritinib exposure. 

 

Cardiac electrophysiology 

The potential for QT interval prolongation of ceritinib was assessed in seven clinical studies with 

Zykadia. Serial ECGs were collected following a single dose and at steady-state to evaluate the effect 

of ceritinib on the QT interval in 925 patients treated with Zykadia 750 mg once daily fasted. A 

categorical outlier analysis of ECG data demonstrated new QTc >500 msec in 12 patients (1.3%). 

There were 58 patients (6.3%) with a QTc increase from baseline >60 msec. A central tendency 

analysis of the QTc data at average steady-state concentration from Study A2301 demonstrated that 

the upper bound of the 2-sided 90% CI for QTc increase from baseline was 15.3 msec at Zykadia 

750 mg fasted. A pharmacokinetic analysis suggested that ceritinib causes concentration-dependent 

increases in QTc (see section 4.4). 

 

5.3 Preclinical safety data 

 

Safety pharmacology studies indicate that ceritinib is unlikely to interfere with vital functions of the 

respiratory and central nervous systems. In vitro data show that the IC50 for the inhibitory effect of 

ceritinib on the hERG potassium channel was 0.4 micromolar. An in vivo telemetry study in monkeys 

showed a modest QT prolongation in 1 of 4 animals after receiving the highest dose of ceritinib. ECG 

studies in monkeys after 4- or 13-weeks of dosing with ceritinib have not shown QT prolongation or 

abnormal ECGs. 

 

  



50 

 

The micronucleus test in TK6 cells was positive. No signs of mutagenicity or clastogenicity were 

observed in other in vitro and in vivo genotoxicity studies with ceritinib. Therefore, genotoxic risk is 

not expected in humans. 

 

Carcinogenicity studies have not been performed with ceritinib. 

 

Reproductive toxicology studies (i.e. embryo-foetal development studies) in pregnant rats and rabbits 

indicated no foetotoxicity or teratogenicity after dosing with ceritinib during organogenesis; however, 

maternal plasma exposure was less than that observed at the recommended human dose. Formal 

non-clinical studies on the potential effects of ceritinib on fertility have not been conducted. 

 

The principal toxicity related to ceritinib administration in rats and monkeys was inflammation of the 

extra-hepatic bile ducts accompanied by increased neutrophil counts in the peripheral blood. Mixed 

cell/neutrophilic inflammation of the extra-hepatic ducts extended to the pancreas and/or duodenum at 

higher doses. Gastrointestinal toxicity was observed in both species characterised by body weight loss, 

decreased food consumption, emesis (monkey), diarrhoea and, at high doses, by histopathological 

lesions including erosion, mucosal inflammation and foamy macrophages in the duodenal crypts and 

submucosa. The liver was also affected in both species, at exposures that approximate clinical 

exposures at the recommended human dose, and included minimal increases in liver transaminases in 

a few animals and vacuolation of the intra-hepatic bile duct epithelium. Alveolar foamy macrophages 

(confirmed phospholipidosis) were seen in the lungs of rats, but not in monkeys, and the lymph nodes 

of rats and monkeys had macrophage aggregates. Target organ effects showed partial to complete 

recovery. 

 

Effects on the thyroid were observed in both rat (mild increases in thyroid stimulating hormone and 

triiodothyronine/thyroxine T3/T4 concentrations with no microscopic correlate) and monkey 

(depletion of colloid in males in 4-week study, and one monkey at high dose with diffuse follicular 

cell hyperplasia and increased thyroid stimulating hormone in 13-week study). As these non-clinical 

effects were mild, variable and inconsistent, the relationship between ceritinib and thyroid gland 

changes in animals is unclear. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

 

Cellulose, microcrystalline 

Hydroxypropylcellulose, low-substituted 

Povidone 

Croscarmellose sodium 

Magnesium stearate 

Silica, colloidal anhydrous 

 

Film-coating 
 

Hypromellose 

Titanium dioxide (E171) 

Macrogol 

Talc 

Indigo carmine aluminium lake (E132) 

 

6.2 Incompatibilities 

 

Not applicable. 



51 

 

 

6.3 Shelf life 

 

3 years 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

PVC/PCTFE (polyvinylchloride/polychlorotrifluoroethylene) – Aluminium blister containing 

21 film-coated tablets. 

 

Pack containing 84 film-coated tablets (4 blisters per pack). 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/999/004 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 06 May 2015 

Date of latest renewal: 22 March 2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu 

  



52 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



53 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

150 mg hard capsules 

Novartis Farmacéutica, S.A. 

Ronda de Santa María, 158 

08210 Barberà del Vallès (Barcelona) 

Spain 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

150 mg film-coated tablets 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports 
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed 

in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

  



54 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



55 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



56 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON OF UNIT PACK CONTAINING 40 OR 90 HARD CAPSULES 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg hard capsules 

ceritinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 150 mg ceritinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

40 hard capsules 

90 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



57 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/999/002 40 hard capsules 

EU/1/15/999/003 90 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Zykadia 150 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



58 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF PACK (INCLUDING BLUE BOX) CONTAINING 150 (3 PACKS OF 

50) HARD CAPSULES 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg hard capsules 

ceritinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 150 mg ceritinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

150 (3 packs of 50) hard capsules. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



59 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/999/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Zykadia 150 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



60 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF PACK (WITHOUT BLUE BOX) CONTAINING 50 HARD 

CAPSULES 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg hard capsules 

ceritinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 150 mg ceritinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

50 hard capsules. Cannot be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



61 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/999/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Zykadia 150 mg 

 

  



62 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg hard capsules 

ceritinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 

  



63 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg film-coated tablets 

ceritinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 150 mg ceritinib. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

84 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



64 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/999/004 84 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Zykadia 150 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



65 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Zykadia 150 mg tablets 

ceritinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 

  



66 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



67 

 

Package leaflet: Information for the patient 

 

Zykadia 150 mg hard capsules 

ceritinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Zykadia is and what it is used for 

2. What you need to know before you take Zykadia 

3. How to take Zykadia 

4. Possible side effects 

5. How to store Zykadia 

6. Contents of the pack and other information 

 

 

1. What Zykadia is and what it is used for 

 

What Zykadia is 

Zykadia is a cancer medicine that contains the active substance ceritinib. It is used to treat adults with 

advanced stages of a form of lung cancer called non-small cell lung cancer (NSCLC). Zykadia is only 

given to patients whose disease is due to a defect in a gene called ALK (anaplastic lymphoma kinase). 

 

How Zykadia works 

In patients with ALK defects, an abnormal protein is produced that stimulates the growth of the cancer 

cells. Zykadia blocks the action of this abnormal protein and thus slows down the growth and spread 

of NSCLC. 

 

If you have any questions about how Zykadia works or why this medicine has been prescribed for you, 

ask your doctor or pharmacist. 

 

 

2. What you need to know before you take Zykadia 

 

Do not take Zykadia: 

 if you are allergic to ceritinib or any of the other ingredients of this medicine (listed in 
section 6). 

 

  



68 

 

Warnings and precautions 

Talk to your doctor or pharmacist before taking Zykadia: 

 if you have problems with your liver. 

 if you have problems with your lungs or problems breathing. 

 if you have problems with your heart, including reduced heart rate, or if the results of an 
electrocardiogram (ECG) have shown that you have an abnormality of the electrical activity of 

your heart known as “prolonged QT interval”. 

 if you have diabetes (high level of sugar in your blood). 

 if you have problems with your pancreas. 

 if you are currently taking steroids. 
 

Tell your doctor or pharmacist immediately if you get any of the following signs or symptoms during 

treatment with Zykadia: 

 tiredness, itchy skin, yellowing of your skin or the whites of your eyes, nausea (feeling sick) or 
vomiting, decreased appetite, pain on the right side of your abdomen (belly), dark or brown 

urine, bleeding or bruising more easily than normal. These may be signs or symptoms of liver 

problems. 

 new or worsening cough with or without mucus, fever, chest pain, trouble breathing or shortness 
of breath. These may be symptoms of lung problems. 

 chest pain or discomfort, changes in your heartbeat (fast or slow), light-headedness, fainting, 
dizziness, blue discoloration of your lips, shortness of breath, swelling of your lower limbs or 

skin. These may be signs or symptoms of heart problems. 

 severe diarrhoea, nausea or vomiting. These are symptoms of digestive problems. 

 excessive thirst or increased frequency of urination. These may be symptoms of a high level of 
sugar in the blood. 

Your doctor may need to adjust your treatment or stop Zykadia temporarily or permanently. 

 

Blood tests during treatment with Zykadia 

Your doctor should perform blood tests before you start treatment, every 2 weeks during the first three 

months of treatment and monthly therafter. The purpose of these tests is to check your liver function. 

Your doctor should also perform blood tests to check the functioning of your pancreas and the level of 

sugar in your blood before you start treatment with Zykadia and regularly during treatment. 

 

Children and adolescents 

The use of Zykadia in children and adolescents up to 18 years of age is not recommended. 

 

Other medicines and Zykadia 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines, including medicines obtained without a prescription such as vitamins or herbal 

supplements, because they might interact with Zykadia. It is particularly important that you mention 

any of the following medicines. 

 

Medicines which may increase the risk of side effects with Zykadia: 

 medicines used to treat AIDS/HIV (e.g. ritonavir, saquinavir). 

 medicines used to treat infections. These include medicines that treat fungal infections 
(antifungals such as ketoconazole, itraconazole, voriconazole, posaconazole) and medicines that 

treat certain types of bacterial infection (antibiotics such as telithromycin). 

 

The following medicines may reduce the effectiveness of Zykadia: 

 St. John’s Wort, a herbal medicine used to treat depression. 

 medicines used to stop seizures or fits (anti-epileptics such as phenytoin, carbamazepine, or 
phenobarbital). 

 medicines used to treat tuberculosis (e.g. rifampicin, rifabutin). 
 

  



69 

 

Zykadia may increase the side effects associated with the following medicines: 

 medicines used to treat irregular heartbeat or other heart problems (e.g. amiodarone, 
disopyramide, procainamide, quinidine, sotalol, dofetilide, ibutilide and digoxin). 

 medicines used to treat stomach problems (e.g. cisapride). 

 medicines used to treat mental health problems (e.g. haloperidol, droperidol, pimozide). 

 medicines used to treat depression (e.g. nefazodone). 

 midazolam, a medicine used to treat acute seizures or as a sedative before or during surgery or 
medical procedures. 

 warfarin and dabigatran, medicines used to prevent blood clots. 

 diclofenac, a medicine used to treat joint pain and inflammation. 

 alfentanil and fentanyl, medicines used to treat severe pain. 

 ciclosporin, sirolimus and tacrolimus, medicines used in organ transplantation to prevent 
transplant organ rejection. 

 dihydroergotamine and ergotamine, medicines used to treat migraine. 

 domperidone, a medicine used to treat nausea and vomiting. 

 moxifloxacin and clarithromycin, medicines used to treat bacterial infections. 

 methadone, a medicine used to treat pain and for the treatment of opioid dependence. 

 chloroquine and halofantrine, medicines used to treat malaria. 

 topotecan, a medicine used to treat certain types of cancer. 

 colchicine, a medicine used to treat gout. 

 pravastatine and rosuvastatine, medicines used to reduce cholesterol levels. 

 sulfasalazine, a medicine used to treat inflammatory bowel disease or rheumatoid arthritis. 
 

Ask your doctor or pharmacist if you are not sure whether your medicine is one of the medicines listed 

above. 

 

These medicines should be used with care or may need to be avoided during your treatment with 

Zykadia. If you are taking any of these, your doctor might need to prescribe an alternative medicine 

for you. 

 

You should also tell your doctor if you are already taking Zykadia and you are prescribed a new 

medicine that you have not already taken at the same time as Zykadia. 

 

Oral contraceptives 

If you take Zykadia whilst using oral contraceptives, the oral contraceptives may become ineffective. 

 

Zykadia with food and drink 

You should not eat grapefruit or drink grapefruit juice during treatment. It may make the amount of 

Zykadia in your blood increase to a harmful level. 

 

Pregnancy and breast-feeding 

You must use a highly effective method of birth control during treatment with Zykadia and for 

3 months after stopping treatment. Talk to your doctor about the birth control methods that may be 

right for you. 

 

Zykadia is not recommended during pregnancy unless the potential benefit outweighs the potential 

risk to the baby. If you are pregnant, think you might be pregnant or plan to become pregnant, ask 

your doctor for advice. Your doctor will discuss with you the potential risks of taking Zykadia during 

pregnancy. 

 

Zykadia should not be used during breast-feeding. You and your doctor will decide together whether 

you should breast-feed or take Zykadia. You should not do both. 

 

  



70 

 

Driving and using machines 

You should take special care when driving and using machines when taking Zykadia as you may 

experience visual disturbances or tiredness. 

 

 

3. How to take Zykadia 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 

sure. 

 

How much to take 

The recommended dose is 450 mg (three capsules) taken once daily with food, although your doctor 

could modify this recommendation if needed. Your doctor will tell you exactly how many capsules 

you need to take. Do not change the dose without talking to your doctor. 

 Take Zykadia once a day at about the same time each day with food (for example a snack or a 
full meal). If you cannot eat food while taking Zykadia, talk to your doctor. 

 Swallow the capsules whole with water. Do not chew or crush them. 

 If you vomit after you swallow the Zykadia capsules, do not take any more capsules until your 
next scheduled dose. 

 

How long to take Zykadia 

 Continue taking Zykadia for as long as your doctor tells you. 

 This is a long-term treatment, possibly lasting for months. Your doctor will monitor your 
condition to see that the treatment is having the desired effect. 

 

If you have questions about how long to take Zykadia, talk to your doctor or pharmacist. 

 

If you take more Zykadia than you should 

If you accidentally take too many capsules, or if someone else accidentally takes your medicine, 

contact a doctor or hospital for advice immediately. Medical treatment may be necessary. 

 

If you forget to take Zykadia 

What to do if you forget to take a dose depends on how long it is until your next dose. 

- If your next dose is in 12 hours or more, take the missed capsules as soon as you remember. 

Then take the next capsules at the usual time. 

- If your next dose is in less than 12 hours, skip the missed capsules. Then take the next capsules 

at the usual time. 

Do not take a double dose to make up for a forgotten dose. 

 

If you stop taking Zykadia 

Do not stop taking this medicine before talking to your doctor. If you have any questions contact your 

doctor right away. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

STOP taking Zykadia and seek medical help immediately if you experience any of the following, 

which may be signs of an allergic reaction: 

 Difficulty in breathing or swallowing 

 Swelling of the face, lips, tongue or throat 

 Severe itching of the skin, with a red rash or raised bumps 

 



71 

 

Some side effects could be serious 

If you experience any of the following side effects, tell your doctor or pharmacist immediately: 

 Chest pain or discomfort, changes in your heartbeat (fast or slow), light-headedness, fainting, 
dizziness, blue discoloration of your lips, shortness of breath, swelling of your lower limbs or 

skin (potential signs or symptoms of heart problems) 

 New or worsening cough with or without mucus, fever, chest pain, trouble breathing or 
shortness of breath (potential signs of lung problems) 

 Tiredness, itchy skin, yellowing of your skin or the whites of your eyes, nausea (feeling sick) or 
vomiting, decreased appetite, pain on the right side of your abdomen (belly), dark or brown 

urine, bleeding or bruising more easily than normal (potential signs or symptoms of liver 

problems) 

 Severe diarrhoea, nausea or vomiting 

 Excessive thirst, increased frequency of urination (symptoms of high level of glucose in the 
blood) 

 Severe upper stomach pain (sign of inflammation of the pancreas, also known as pancreatitis) 

 
Other possible side effects 

Other side effects are listed below. If these side effects become severe, please tell your doctor or 

pharmacist. 

 

Very common (may affect more than 1 in 10 people): 

 Tiredness (fatigue and asthenia) 

 Abnormal results of blood tests to check liver function (high levels of enzymes called alanine 
aminotransferase and/or aspartate aminotransferase and/or gamma glutamyltransferase and/or 

blood alkaline phosphatase, high levels of bilirubin) 

 Abdominal pain 

 Decreased appetite 

 Weight decreased 

 Constipation 

 Rash 

 Abnormal results of blood tests to check kidney function (high level of creatinine) 

 Heartburn (potential sign of a disorder of the digestive tract) 

 Reduction in the number of red blood cells, known as anaemia 

 
Common (may affect up to 1 in 10 people): 

 Vision problems 

 Low level of phosphate in the blood (this would be detected during blood tests) 

 High level of enzymes called lipase and/or amylase in the blood (this would be detected during 
blood tests) 

 Significantly decreased urine flow (potential sign of a kidney problem) 

 
Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

  



72 

 

5. How to store Zykadia 

 

 Keep this medicine out of the sight and reach of children. 

 Do not use this medicine after the expiry date which is stated on the carton and blister after 
EXP. The expiry date refers to the last day of that month. 

 This medicine does not require any special storage conditions. 

 Do not use this medicine if you notice any damage to the packaging or if there are any signs of 
tampering. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Zykadia contains 

 The active substance of Zykadia is ceritinib. Each hard capsule contains 150 mg of ceritinib. 

 The other ingredients are: 

 Capsule contents: silica, colloidal anhydrous; hydroxypropylcellulose, low-substituted; 
sodium starch glycolate (type A); magnesium stearate; cellulose, microcrystalline. 

 Capsule shell: gelatin, indigotine (E132) and titanium dioxide (E171). 

 Printing ink: Shellac (bleached, de-waxed) glaze 45%, iron oxide black (E172), propylene 
glycol and ammonium hydroxide 28%. 

 

What Zykadia looks like and contents of the pack 

Zykadia hard capsules have a white opaque body and blue opaque cap, with “LDK 150MG” imprinted 

on the cap and “NVR” on the body. They contain white to almost white powder. 

 

The capsules are provided in blisters and are available in packs containing 40, 90 or 150 (3 packs of 

50) capsules. Not all pack sizes may be marketed in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Farmacéutica, S.A. 

Ronda de Santa María, 158 

08210 Barberà del Vallès (Barcelona) 

Spain 

 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

  



73 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



74 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 



75 

 

Package leaflet: Information for the patient 

 

Zykadia 150 mg film-coated tablets 

ceritinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Zykadia is and what it is used for 

2. What you need to know before you take Zykadia 

3. How to take Zykadia 

4. Possible side effects 

5. How to store Zykadia 

6. Contents of the pack and other information 

 

 

1. What Zykadia is and what it is used for 

 

What Zykadia is 

Zykadia is a cancer medicine that contains the active substance ceritinib. It is used to treat adults with 

advanced stages of a form of lung cancer called non-small cell lung cancer (NSCLC). Zykadia is only 

given to patients whose disease is due to a defect in a gene called ALK (anaplastic lymphoma kinase). 

 

How Zykadia works 

In patients with ALK defects, an abnormal protein is produced that stimulates the growth of the cancer 

cells. Zykadia blocks the action of this abnormal protein and thus slows down the growth and spread 

of NSCLC. 

 

If you have any questions about how Zykadia works or why this medicine has been prescribed for you, 

ask your doctor or pharmacist. 

 

 

2. What you need to know before you take Zykadia 

 

Do not take Zykadia: 

 if you are allergic to ceritinib or any of the other ingredients of this medicine (listed in 
section 6). 

 

  



76 

 

Warnings and precautions 

Talk to your doctor or pharmacist before taking Zykadia: 

 if you have problems with your liver. 

 if you have problems with your lungs or problems breathing. 

 if you have problems with your heart, including reduced heart rate, or if the results of an 
electrocardiogram (ECG) have shown that you have an abnormality of the electrical activity of 

your heart known as “prolonged QT interval”. 

 if you have diabetes (high level of sugar in your blood). 

 if you have problems with your pancreas. 

 if you are currently taking steroids. 
 

Tell your doctor or pharmacist immediately if you get any of the following signs or symptoms during 

treatment with Zykadia: 

 tiredness, itchy skin, yellowing of your skin or the whites of your eyes, nausea (feeling sick) or 
vomiting, decreased appetite, pain on the right side of your abdomen (belly), dark or brown 

urine, bleeding or bruising more easily than normal. These may be signs or symptoms of liver 

problems. 

 new or worsening cough with or without mucus, fever, chest pain, trouble breathing or shortness 
of breath. These may be symptoms of lung problems. 

 chest pain or discomfort, changes in your heartbeat (fast or slow), light-headedness, fainting, 
dizziness, blue discoloration of your lips, shortness of breath, swelling of your lower limbs or 

skin. These may be signs or symptoms of heart problems. 

 severe diarrhoea, nausea or vomiting. These are symptoms of digestive problems. 

 excessive thirst or increased frequency of urination. These may be symptoms of a high level of 
sugar in the blood. 

Your doctor may need to adjust your treatment or stop Zykadia temporarily or permanently. 

 

Blood tests during treatment with Zykadia 

Your doctor should perform blood tests before you start treatment, every 2 weeks during the first three 

months of treatment and monthly therafter. The purpose of these tests is to check your liver function. 

Your doctor should also perform blood tests to check the functioning of your pancreas and the level of 

sugar in your blood before you start treatment with Zykadia and regularly during treatment. 

 

Children and adolescents 

The use of Zykadia in children and adolescents up to 18 years of age is not recommended. 

 

Other medicines and Zykadia 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines, including medicines obtained without a prescription such as vitamins or herbal 

supplements, because they might interact with Zykadia. It is particularly important that you mention 

any of the following medicines. 

 

Medicines which may increase the risk of side effects with Zykadia: 

 medicines used to treat AIDS/HIV (e.g. ritonavir, saquinavir). 

 medicines used to treat infections. These include medicines that treat fungal infections 
(antifungals such as ketoconazole, itraconazole, voriconazole, posaconazole) and medicines that 

treat certain types of bacterial infection (antibiotics such as telithromycin). 

 

The following medicines may reduce the effectiveness of Zykadia: 

 St. John’s Wort, a herbal medicine used to treat depression. 

 medicines used to stop seizures or fits (anti-epileptics such as phenytoin, carbamazepine, or 
phenobarbital). 

 medicines used to treat tuberculosis (e.g. rifampicin, rifabutin). 
 

  



77 

 

Zykadia may increase the side effects associated with the following medicines: 

 medicines used to treat irregular heartbeat or other heart problems (e.g. amiodarone, 
disopyramide, procainamide, quinidine, sotalol, dofetilide, ibutilide and digoxin). 

 medicines used to treat stomach problems (e.g. cisapride). 

 medicines used to treat mental health problems (e.g. haloperidol, droperidol, pimozide). 

 medicines used to treat depression (e.g. nefazodone). 

 midazolam, a medicine used to treat acute seizures or as a sedative before or during surgery or 
medical procedures. 

 warfarin and dabigatran, medicines used to prevent blood clots. 

 diclofenac, a medicine used to treat joint pain and inflammation. 

 alfentanil and fentanyl, medicines used to treat severe pain. 

 ciclosporin, sirolimus and tacrolimus, medicines used in organ transplantation to prevent 
transplant organ rejection. 

 dihydroergotamine and ergotamine, medicines used to treat migraine. 

 domperidone, a medicine used to treat nausea and vomiting. 

 moxifloxacin and clarithromycin, medicines used to treat bacterial infections. 

 methadone, a medicine used to treat pain and for the treatment of opioid dependence. 

 chloroquine and halofantrine, medicines used to treat malaria. 

 topotecan, a medicine used to treat certain types of cancer. 

 colchicine, a medicine used to treat gout. 

 pravastatine and rosuvastatine, medicines used to reduce cholesterol levels. 

 sulfasalazine, a medicine used to treat inflammatory bowel disease or rheumatoid arthritis. 
 

Ask your doctor or pharmacist if you are not sure whether your medicine is one of the medicines listed 

above. 

 

These medicines should be used with care or may need to be avoided during your treatment with 

Zykadia. If you are taking any of these, your doctor might need to prescribe an alternative medicine 

for you. 

 

You should also tell your doctor if you are already taking Zykadia and you are prescribed a new 

medicine that you have not already taken at the same time as Zykadia. 

 

Oral contraceptives 

If you take Zykadia whilst using oral contraceptives, the oral contraceptives may become ineffective. 

 

Zykadia with food and drink 

You should not eat grapefruit or drink grapefruit juice during treatment. It may make the amount of 

Zykadia in your blood increase to a harmful level. 

 

Pregnancy and breast-feeding 

You must use a highly effective method of birth control during treatment with Zykadia and for 

3 months after stopping treatment. Talk to your doctor about the birth control methods that may be 

right for you. 

 

Zykadia is not recommended during pregnancy unless the potential benefit outweighs the potential 

risk to the baby. If you are pregnant, think you might be pregnant or plan to become pregnant, ask 

your doctor for advice. Your doctor will discuss with you the potential risks of taking Zykadia during 

pregnancy. 

 

Zykadia should not be used during breast-feeding. You and your doctor will decide together whether 

you should breast-feed or take Zykadia. You should not do both. 

 

  



78 

 

Driving and using machines 

You should take special care when driving and using machines when taking Zykadia as you may 

experience visual disturbances or tiredness. 

 

 

3. How to take Zykadia 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 

sure. 

 

How much to take 

The recommended dose is 450 mg (three tablets) taken once daily with food, although your doctor 

could modify this recommendation if needed. Your doctor will tell you exactly how many tablets you 

need to take. Do not change the dose without talking to your doctor. 

 Take Zykadia once a day at about the same time each day with food (for example a snack or a 
full meal). If you cannot eat food while taking Zykadia, talk to your doctor. 

 Swallow the tablets whole with water. Do not chew or crush them. 

 If you vomit after you swallow the Zykadia tablets, do not take any more tablets until your next 
scheduled dose. 

 

How long to take Zykadia 

 Continue taking Zykadia for as long as your doctor tells you. 

 This is a long-term treatment, possibly lasting for months. Your doctor will monitor your 
condition to see that the treatment is having the desired effect. 

 

If you have questions about how long to take Zykadia, talk to your doctor or pharmacist. 

 

If you take more Zykadia than you should 

If you accidentally take too many tablets, or if someone else accidentally takes your medicine, contact 

a doctor or hospital for advice immediately. Medical treatment may be necessary. 

 

If you forget to take Zykadia 

What to do if you forget to take a dose depends on how long it is until your next dose. 

- If your next dose is in 12 hours or more, take the missed tablets as soon as you remember. Then 

take the next tablets at the usual time. 

- If your next dose is in less than 12 hours, skip the missed tablets. Then take the next tablets at 

the usual time. 

Do not take a double dose to make up for a forgotten dose. 

 

If you stop taking Zykadia 

Do not stop taking this medicine before talking to your doctor. If you have any questions contact your 

doctor right away. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

STOP taking Zykadia and seek medical help immediately if you experience any of the following, 

which may be signs of an allergic reaction: 

 Difficulty in breathing or swallowing 

 Swelling of the face, lips, tongue or throat 

 Severe itching of the skin, with a red rash or raised bumps 

 



79 

 

Some side effects could be serious 

If you experience any of the following side effects, tell your doctor or pharmacist immediately: 

 Chest pain or discomfort, changes in your heartbeat (fast or slow), light-headedness, fainting, 
dizziness, blue discoloration of your lips, shortness of breath, swelling of your lower limbs or 

skin (potential signs or symptoms of heart problems) 

 New or worsening cough with or without mucus, fever, chest pain, trouble breathing or 
shortness of breath (potential signs of lung problems) 

 Tiredness, itchy skin, yellowing of your skin or the whites of your eyes, nausea (feeling sick) or 
vomiting, decreased appetite, pain on the right side of your abdomen (belly), dark or brown 

urine, bleeding or bruising more easily than normal (potential signs or symptoms of liver 

problems) 

 Severe diarrhoea, nausea or vomiting 

 Excessive thirst, increased frequency of urination (symptoms of high level of glucose in the 
blood) 

 Severe upper stomach pain (sign of inflammation of the pancreas, also known as pancreatitis) 

 
Other possible side effects 

Other side effects are listed below. If these side effects become severe, please tell your doctor or 

pharmacist. 

 

Very common (may affect more than 1 in 10 people): 

 Tiredness (fatigue and asthenia) 

 Abnormal results of blood tests to check liver function (high levels of enzymes called alanine 
aminotransferase and/or aspartate aminotransferase and/or gamma glutamyltransferase and/or 

blood alkaline phosphatase, high levels of bilirubin) 

 Abdominal pain 

 Decreased appetite 

 Weight decreased 

 Constipation 

 Rash 

 Abnormal results of blood tests to check kidney function (high level of creatinine) 

 Heartburn (potential sign of a disorder of the digestive tract) 

 Reduction in the number of red blood cells, known as anaemia 

 
Common (may affect up to 1 in 10 people): 

 Vision problems 

 Low level of phosphate in the blood (this would be detected during blood tests) 

 High level of enzymes called lipase and/or amylase in the blood (this would be detected during 
blood tests) 

 Significantly decreased urine flow (potential sign of a kidney problem) 

 
Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

  



80 

 

5. How to store Zykadia 

 

 Keep this medicine out of the sight and reach of children. 

 Do not use this medicine after the expiry date which is stated on the carton and blister after 
EXP. The expiry date refers to the last day of that month. 

 This medicine does not require any special storage conditions. 

 Do not use this medicine if you notice any damage to the packaging or if there are any signs of 
tampering. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Zykadia contains 

 The active substance of Zykadia is ceritinib. Each film-coated tablet contains 150 mg of 
ceritinib. 

 The other ingredients are: 

 Tablet core: cellulose, microcrystalline; hydroxypropylcellulose, low-substituted; 
povidone; croscarmellose sodium; magnesium stearate; silica, colloidal anhydrous. 

 Film-coating: hypromellose; titanium dioxide (E171); macrogol; talc; indigo carmine 
aluminium lake (E132). 

 

What Zykadia looks like and contents of the pack 

Zykadia film-coated tablets are light blue, round, biconvex with bevelled edges, without score, 

debossed with “NVR” on one side and “ZY1” on the other side. 

 

The tablets are provided in blisters and are available in a pack containing 84 tablets (4 blisters of 

21 tablets). 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstraße 25 

D-90429 Nuremberg 

Germany 

 

  



81 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



82 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET