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.

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.

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.

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.

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 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.

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 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.

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 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

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 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).

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no reported experience with overdose in humans. General supportive measures should be initiated in all cases of overdose.