Zykadia - summary of medicine characteristics

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, size 00 (approximate length: 23.3 mm), with “LDK 150MG” imprinted on the cap and “NVR” on the body, containing white to almost white powder.

4. CLINICAL PARTICULARS4.1 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 ceritinib 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 ceritinib therapy. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised.

Posology

The recommended dose of ceritinib is 450 mg taken orally once daily with food at the same time each day.

The maximum recommended dose with food is 450 mg taken orally once daily. Treatment should continue as long as clinical benefit is observed.

If a dose is missed, the patient should make up that dose, unless the next dose is due within 12 hours.

If vomiting occurs during the course of treatment, the patient should not take an additional dose, but should continue with the next scheduled dose.

Ceritinib should be discontinued in patients unable to tolerate 150 mg daily taken with food.

Dose adjustment due to adverse reactions

Temporary dose interruption and/or dose reduction of ceritinib may be required based on individual safety and tolerability. If dose reduction is required due to an adverse drug reaction (ADR) not listed in Table 1, then this should be achieved by decrements of 150 mg daily. Early identification and management of ADRs with standard supportive care measures should be considered.

In patients treated with ceritinib 450 mg with food, 24.1% of patients had an adverse event that required at least one dose reduction and 55.6% 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 9.7 weeks.

Table 1 summarises recommendations for dose interruption, reduction or discontinuation of ceritinib in the management of selected ADRs.

Table 1 Ceritinib dose adjustment and management recommendations for ADRs

Criteria	Ceritinib dosing
Severe or intolerable nausea, vomiting or diarrhoea despite optimal anti-emetic or anti-diarrhoeal therapy	Withhold ceritinib until improved, then reinitiate ceritinib with dose reduced by 150 mg.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation >5 times upper limit of normal (ULN) with concurrent total bilirubin <2 times ULN	Withhold ceritinib until recovery to baseline ALT/AST levels or to <3 times ULN, then reinitiate with dose reduced by 150 mg.
ALT or AST elevation >3 times ULN with concurrent total bilirubin elevation >2 times ULN (in the absence of cholestasis or haemolysis)	Permanently discontinue ceritinib.
Any grade treatment-related interstitial lung disease (ILD)/pneumonitis	Permanently discontinue ceritinib.
QT corrected for heart rate (QTc) >500 msec on at least 2 separate electrocardio­grams (ECGs)	Withhold ceritinib 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 ceritinib.

Bradycardia3 (symptomatic, may be severe and medically significant, medical intervention indicated)	Withhold ceritinib 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 ceritinib 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 ceritinib 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 ceritinib if no contributing concomitant medicinal product is identified. If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, reinitiate ceritinib 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 ceritinib until hyperglycaemia is adequately controlled, then reinitiate ceritinib with dose reduced by 150 mg. If adequate glucose control cannot be achieved with optimal medical management, permanently discontinue ceritinib.
Lipase or amylase elevation grade >3	Withhold ceritinib 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

Concomitant use of strong CYP3A inhibitors should be avoided (see section 4.5). If concomitant use of a strong CYP3A inhibitor is unavoidable, the dose of ceritinib should be reduced by approximately one third (dose not clinically verified), rounded to the nearest multiple of the 150 mg dose 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.

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 dose 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

Ceritinib is for oral use. The capsules should be administered orally once daily with food at the same time every day. It is important that ceritinib 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 ceritinib 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 ceritinib should be 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 ceritinib in patients with congenital long QT syndrome should be avoided. The benefits and potential risks of ceritinib should be considered before beginning therapy in patients who have pre-existing bradycardia (heart rate less than 60 beats per minute [bpm]), patients who have a history of or predisposition for QTc prolongation, patients who are taking anti-arrhythmics or other medicinal products that are known to prolong the QT interval and patients with relevant pre-existing cardiac disease and/or electrolyte disturbances. 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. Ceritinib should be permanently discontinued in patients who develop QTc >500 msec or >60 msec change from baseline and torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Ceritinib 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 ceritinib 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, ceritinib 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 ceritinib dose adjusted if necessary. In the event of life-threatening bradycardia ceritinib 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, ceritinib 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, ceritinib 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 76.9% of 108 patients treated with ceritinib at the recommended dose of 450 mg taken with food in a dose optimisation study and were mainly grade 1 (52.8%) and grade 2 (22.2%) events. Two patients (1.9%) experienced one grade 3 event each (diarrhoea and vomiting respectively). Nine patients (8.3%) required study drug interruption due to diarrhoea, nausea or vomiting. One patient (0.9%) required dose adjustment due to vomiting. In the same study, the incidence and severity of gastrointestinal adverse drug reactions were higher for patients treated with ceritinib 750 mg fasted (diarrhoea 80.0%, nausea 60.0%, vomiting 65.5%; 17.3% reported a grade 3 event) compared to 450 mg with food (diarrhoea 59.3%, nausea 42.6%, vomiting 38.0%; 1.9% reported a grade 3 event).

In the 450 mg with food and 750 mg fasted arms of this dose optimisation study, no patients required discontinuation of ceritinib 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 ceritinib 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 ceritinib 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).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially “sodium-free”.

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. Concomitant use of strong CYP3A inhibitors should be avoided during treatment with ceritinib. 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), the dose of ceritinib should be reduced by approximately one third, rounded to the nearest multiple of the 150 mg dose strength. After discontinuation of a strong CYP3A inhibitor, ceritinib should be resumed at the 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

Ceritinib 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 ceritinib with food, ceritinib 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 ceritinib 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).

Ceritinib 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 to discontinue/abstain from ceritinib 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 ceritinib 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 ceritinib 750 mg once daily fasted in 925 patients with ALK-positive advanced NSCLC across a pool of seven clinical studies including two randomised, active-controlled, phase 3 studies (studies A2301 and A2303).

The median duration of exposure to ceritinib 750 mg fasted was 44.9 weeks (range: 0.1 to

200.1 weeks).

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

Grade 3–4 ADRs with an incidence of >5% in patients treated with ceritinib 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea.

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 ceritinib at the recommended dose of 450 mg with food (N=108) was consistent with ceritinib 750 mg fasted (N=110), 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 ceritinib in patients treated at a dose of 750 mg fasted (N=925) in seven clinical studies. The frequency of selected gastrointestinal ADRs (diarrhoea, nausea and vomiting) are based on patients treated with a dose of 450 mg once-daily with food (N=108).

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

Table 2 ADRs in patients treated with ceritinib

System organ class	Ceritinib 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 disorder1	7.0	Common
Cardiac disorders
Pericarditisb	5.8	Common
Bradycardiac	2.3	Common
Respiratory, thoracic and mediastinal c	isorders
Pneumonitisd	2.1	Common
Gastrointestinal disorders
Diarrhoeae	59.3	Very common
Nauseae	42.6	Very common
Vomitinge	38.0	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 impairment'	1.0	Common
General disorders and administration site conditions
Fatiguem	48.4	Very common

Investigations

Liver laboratory test abnormalities11	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)

Pericarditis (pericardial effusion, pericarditis)

Bradycardia (bradycardia, sinus bradycardia)

Pneumonitis (interstitial lung disease, pneumonitis)

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=108) in the study A2112 (ASCEND-8) (see subsection ‘Gastrointestinal adverse reactions’ below)

Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort)

Oesophageal disorder (dyspepsia, gastro-oesophageal reflux disease, dysphagia)

Abnormal liver function test (hepatic function abnormal, hyperbilirubi­naemia)

Hepatotoxicity (drug-induced liver injury, hepatitis cholestatic, hepatocellular injury, hepatotoxicity) Rash (rash, dermatitis acneiform, rash maculopapular)

Renal failure (acute renal injury, renal failure)

Renal impairment (azotaemia, renal impairment)

Fatigue (fatigue, asthenia)

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 ceritinib 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 x 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=108), adverse events of diarrhoea, nausea and vomiting were mainly grade 1 (52.8%) and grade 2 (22.2%). Grade 3 events of diarrhoea and vomiting were each reported in two different patients (1.9%). Gastrointestinal events were managed primarily with concomitant medicinal products including anti-emetic/anti-diarrhoeal medicinal products. Nine patients (8.3%) required study drug interruption due to diarrhoea, nausea or vomiting. One patient (0.9%) required dose adjustment. In the 450 mg with food and 750 mg fasted arms, no patients had diarrhoea, nausea, or vomiting that required discontinuation of study drug. In the same study the incidence and severity of gastrointestinal adverse drug reactions were reduced for patients treated with ceritinib 450 mg with food (diarrhoea 59.3%, nausea 42.6%, vomiting 38.0%; 1.9% reported a grade 3 event) compared to 750 mg fasted (diarrhoea 80.0%, nausea 60.0%, vomiting 65.5%; 17.3% reported a grade 3 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 national reporting system listed in

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 PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, anaplastic lymphoma kinase (ALK) inhibitors, ATC code: L01ED02.

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 ceritinib 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 eightyseven (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.

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 (%) Median, monthsd (95% CI) HR (95% CI)a p-valueb	89 (47.1) 16.6 (12.6, 27.2) 0.55	113 (60.4) 8.1 (5.8, 11.1) (0.42, 0.73) <0.001
Overall survivalc Number of events, n (%) Median, monthsd (95% CI) OS rate at 24 monthsd, % (95% CI) HR (95% CI)a p-valueb	48 (25.4) NE (29.3, NE) 70.6 (62.2, 77.5) 0.73	59 (31.6) 26.2 (22.8, NE) 58.2 (47.6, 67.5) (0.50,1.08) 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 Median, monthsd (95% CI) Event-free rate at 18 monthsd, % (95% CI)	137 23.9 (16.6, NE) 59.0 (49.3, 67.4)	50 11.1 (7.8, 16.4) 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.

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	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: 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 ceritinib 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 ceritinib 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 ceritinib 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 ceritinib 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).

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 ceritinib 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           Che­motherapy (N=115)            (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 (%) Median, months (95% CI) HR (95% CI)a p-valueb	83 (72.2%)           89 (76.7%) 5.4 (4.1, 6.9)            1.6 (1.4, 2.8) 0.49 (0.36, 0.67) <0.001
Overall survivalc Number of events, n (%) Median, months (95% CI) HR (95% CI)a p-valueb	48 (41.7%)           50 (43.1%) 18.1 (13.4, 23.9)       20.1 (11.9, 25.1) 1.00 (0.67,1.49) 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 Median, monthsd (95% CI) Event-free probability estimate at 9 monthsd (95% CI)	45                     8 6.9 (5.4, 8.9)           8.3 (3.5, NE) 31.5% (16.7%,    45.7% (6.9%, 79.5%) 47.3%)
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.

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

assessed by BIRC

Time (Months)

No. of patients still 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

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

Time (Months)

No. of patients still at risk

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 ceritinib 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 ceritinib in comparison to the chemotherapy.

In Study A2303, 133 patients with baseline brain metastasis (66 patients in the ceritinib arm and 67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuroradiologist (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).

Dose optimisation Study A2112 (ASCEND-8)

The efficacy of ceritinib 450 mg with food was evaluated in a multicentre, open-label dose optimisation study A2112 (ASCEND-8). A total of 147 previously untreated patients with ALK-positive locally advanced or metastatic NSCLC were randomised to receive ceritinib 450 mg once daily with food (N=73) or ceritinib 750 mg once daily under fasted conditions (N=74). A key secondary efficacy endpoint was ORR according to RECIST 1.1 as evaluated by BIRC.

The population characteristics of the previously untreated patients with ALK-positive locally advanced or metastatic NSCLC across the two arms, 450 mg with food (N=73) and 750 mg fasted (N=74), were: mean age 54.3 and 51.3 years, age less than 65 (78.1% and 83.8%), female (56.2% and 47.3%), Caucasian (49.3% and 54.1%), Asian (39.7% and 35.1%), never or former smoker (90.4% and 95.9%), WHO PS 0 or 1 (91.7% and 91.9%), adenocarcinoma histology (98.6% and 93.2%), and metastases to the brain (32.9% and 28.4%), respectively.

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=73)	Ceritinib 750 mg fasted (N=74)
Overall Response Rate (ORR:	57 (78.1)	56 (75.7)
CR+PR), n (%) (95% CI)a	(66.9, 86.9)	(64.3, 84.9)

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 ceritinib 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 ceritinib 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.

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 N=163	Study A2201 ceritinib 750 mg 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) BIRC (95% CI)	56.4% (48.5, 64.2) 46.0% (38.2, 54.0)	40.7% (32.5, 49.3) 35.7% (27.8, 44.2)
Duration of response* Investigator (months, 95% CI) BIRC (months, 95% CI)	8.3 (6.8, 9.7) 8.8 (6.0, 13.1)	10.6 (7.4, 14.7) 12.9 (9.3, 18.4)
Progression-free survival Investigator (months, 95% CI) BIRC (months, 95% CI)	6.9 (5.6, 8.7) 7.0 (5.7, 8.7)	5.8 (5.4, 7.6) 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 ceritinib 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.

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 ceritinib 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 ceritinib 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 (T/2) 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.

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 ceritinib (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 ceritinib. 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 ceritinib 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 ceritinib 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.

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 PARTICULARS6.1 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%

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 NUMBERS

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