ZYKADIA 150mg capsules medication leaflet

Zykadia 150 mg hard capsules

Each hard capsule contains 150 mg ceritinib.

For the full list of excipients, see section 6.1.

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 whitepowder.

Zykadia as monotherapy is indicated for the first-line treatment of adult patients with anaplasticlymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).

Zykadia as monotherapy is indicated for the treatment of adult patients with anaplastic lymphomakinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated withcrizotinib.

Treatment with ceritinib should be initiated and supervised by a physician experienced in the use ofanti-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. Assessmentfor ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in thespecific technology being utilised.

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

The maximum recommended dose with food is 450 mg taken orally once daily. Treatment shouldcontinue 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, butshould 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 individualsafety and tolerability. If dose reduction is required due to an adverse drug reaction (ADR) not listedin Table 1, then this should be achieved by decrements of 150 mg daily. Early identification andmanagement 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 thatrequired at least one dose reduction and 55.6% of patients had an adverse event that required at leastone 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 ceritinibin the management of selected ADRs.

Table 1 Ceritinib dose adjustment and management recommendations for ADRs

Criteria Ceritinib dosing

Severe or intolerable nausea, vomiting or Withhold ceritinib until improved, then reinitiatediarrhoea despite optimal anti-emetic or ceritinib with dose reduced by 150 mg.

anti-diarrhoeal therapy

Alanine aminotransferase (ALT) or Withhold ceritinib until recovery to baselineaspartate aminotransferase (AST) elevation ALT/AST levels or to ≤3 times ULN, then reinitiate>5 times upper limit of normal (ULN) with with dose reduced by 150 mg.

concurrent total bilirubin ≤2 times ULN

ALT or AST elevation >3 times ULN with Permanently discontinue ceritinib.

concurrent total bilirubin elevation >2 times

ULN (in the absence of cholestasis orhaemolysis)

Any grade treatment-related interstitial lung Permanently discontinue ceritinib.

disease (ILD)/pneumonitis

QT corrected for heart rate (QTc) Withhold ceritinib until recovery to baseline or to a>500 msec on at least 2 separate QTc ≤480 msec, check and if necessary correctelectrocardiograms (ECGs) electrolytes, then reinitiate with dose reduced by150 mg.

QTc >500 msec or >60 msec change from Permanently discontinue ceritinib.

baseline and torsade de pointes orpolymorphic ventricular tachycardia orsigns/symptoms of serious arrhythmia

Bradycardiaa (symptomatic, may be severe Withhold ceritinib until recovery to asymptomaticand medically significant, medical (grade ≤1) bradycardia or to a heart rate of 60 beatsintervention indicated) per minute (bpm) or above.

Evaluate concomitant medicinal products known tocause bradycardia, as well as anti-hypertensivemedicinal products.

If a contributing concomitant medicinal product isidentified and discontinued, or its dose is adjusted,reinitiate ceritinib at the previous dose uponrecovery to asymptomatic bradycardia or to a heartrate of 60 bpm or above.

If no contributing concomitant medicinal product isidentified, or if contributing concomitant medicinalproducts are not discontinued or dose modified,reinitiate ceritinib with dose reduced by 150 mgupon recovery to asymptomatic bradycardia or to aheart rate of 60 bpm or above.

Bradycardiaa (life-threatening Permanently discontinue ceritinib if no contributingconsequences, urgent intervention indicated) concomitant medicinal product is identified.

If a contributing concomitant medicinal product isidentified and discontinued, or its dose is adjusted,reinitiate ceritinib with dose reduced by 150 mgupon recovery to asymptomatic bradycardia or to aheart rate of 60 bpm or above, with frequentmonitoringb.

Persistent hyperglycaemia greater than Withhold ceritinib until hyperglycaemia is250 mg/dl despite optimal adequately controlled, then reinitiate ceritinib withanti-hyperglycaemic therapy dose reduced by 150 mg.

If adequate glucose control cannot be achieved withoptimal medical management, permanentlydiscontinue ceritinib.

Lipase or amylase elevation grade ≥3 Withhold ceritinib until lipase or amylase returns tograde ≤1, then reinitiate with dose reduced by150 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 useof a strong CYP3A inhibitor is unavoidable, the dose of ceritinib should be reduced by approximatelyone 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 patienttolerates the reduced dose well, the dose may be increased again with careful monitoring for safety, toavoid potential under-treatment.

After discontinuation of a strong CYP3A inhibitor, resume at the dose that was taken prior to initiatingthe strong CYP3A inhibitor.

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 regardingco-administration with CYP3A4 inhibitors.

Co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substratesknown 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 andalternative 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 withnarrow therapeutic indices should be considered.

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 doseadjustment is necessary in patients with mild to moderate renal impairment. Caution should be used inpatients with severe renal impairment, as there is no experience with ceritinib in this population (seesection 5.2).

Based on available data, ceritinib is eliminated primarily via the liver. Particular caution should beexercised when treating patients with severe hepatic impairment and the dose should be reduced byapproximately one third, rounded to the nearest multiple of the 150 mg dose strength (see sections 4.4and 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 notsuggest that a dose adjustment is required in elderly patients (see section 5.2). There are no availabledata on patients over 85 years of age.

The safety and efficacy of ceritinib in children and adolescents aged up to 18 years have not beenestablished. No data are available.

Ceritinib is for oral use. The capsules should be administered orally once daily with food at the sametime every day. It is important that ceritinib is taken with food to reach the appropriate exposure. Foodcan range from a light to a full meal (see section 5.2). The capsules should be swallowed whole withwater and should not be chewed or crushed.

For patients who develop a concurrent medical condition and are unable to take ceritinib with foodplease refer to section 4.5.

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

Cases of hepatotoxicity occurred in 1.1% of patients receiving ceritinib in clinical studies. Increases tograde 3 or 4 ALT elevations were observed in 25% of patients. The majority of cases weremanageable with dose interruption and/or dose reduction. Few events required discontinuation oftreatment.

Patients should be monitored with liver laboratory tests (including ALT, AST and total bilirubin) priorto the start of treatment, every 2 weeks during the first three months of treatment and monthlythereafter. In patients who develop transaminase elevations, more frequent monitoring of livertransaminases and total bilirubin should be carried out as clinically indicated (see sections 4.2 and4.8). Particular caution should be exercised when treating patients with severe hepatic impairment, andthe dose should be adjusted (see section 4.2). Limited experience in these patients showed a worseningof the underlying condition (hepatic encephalopathy) in 2 out of 10 patients exposed to 750 mg singledoses of ceritinib under fasted conditions (see sections 4.2, pct. 4.8 and 5.2). Other factors apart from studytreatment could have impacted on observed events of hepatic encephalopathy, however, the relationbetween study treatment and events cannot be fully ruled out. No dose adjustment is necessary inpatients 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 ceritinibin clinical studies. Most of these severe/life-threatening cases improved or resolved with interruptionof treatment.

Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potentialcauses of ILD/pneumonitis should be excluded, and ceritinib should be permanently discontinued inpatients 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 (seesections 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 andpotential risks of ceritinib should be considered before beginning therapy in patients who havepre-existing bradycardia (heart rate less than 60 beats per minute [bpm]), patients who have a historyof or predisposition for QTc prolongation, patients who are taking anti-arrhythmics or other medicinalproducts that are known to prolong the QT interval and patients with relevant pre-existing cardiacdisease and/or electrolyte disturbances. Periodic monitoring with ECGs and periodic monitoring ofelectrolytes (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 bepermanently discontinued in patients who develop QTc >500 msec or >60 msec change from baselineand torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of seriousarrhythmia. Ceritinib should be withheld in patients who develop QTc >500 msec on at least twoseparate ECGs until recovery to baseline or a QTc ≤480 msec, then reinitiated with dose reduced by150 mg (see sections 4.2, pct. 4.8 and 5.2).

Bradycardia

Asymptomatic cases of bradycardia (heart rate less than 60 bpm) have been observed in 21 out of925 (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 aspossible. Heart rate and blood pressure should be monitored regularly. In cases of symptomaticbradycardia that is not life-threatening, ceritinib should be withheld until recovery to asymptomaticbradycardia or to a heart rate of 60 bpm or above, the use of concomitant medicinal products should beevaluated and the ceritinib dose adjusted if necessary. In the event of life-threatening bradycardiaceritinib should be permanently discontinued if no contributing concomitant medicinal product isidentified; however, if associated with a concomitant medicinal product known to cause bradycardia orhypotension, ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rateof 60 bpm or above. If the concomitant medicinal product can be adjusted or discontinued, ceritinibshould be reinitiated with dose reduced by 150 mg on recovery to asymptomatic bradycardia or to aheart rate of 60 bpm or above, with frequent monitoring (see sections 4.2 and 4.8).

Diarrhoea, nausea, or vomiting occurred in 76.9% of 108 patients treated with ceritinib at therecommended 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 todiarrhoea, nausea or vomiting. One patient (0.9%) required dose adjustment due to vomiting. In thesame study, the incidence and severity of gastrointestinal adverse drug reactions were higher forpatients 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%, vomiting38.0%; 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 requireddiscontinuation 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 shouldbe 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.

Cases of hyperglycaemia (all grades) have been reported in less than 10% of patients treated withceritinib in clinical studies; grade 3-4 hyperglycaemia was reported in 5.4% of patients. The risk ofhyperglycaemia 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 andperiodically thereafter as clinically indicated. Anti-hyperglycaemic medicinal products should beinitiated 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 treatmentand periodically thereafter as clinically indicated (see sections 4.2 and 4.8). Cases of pancreatitis havebeen reported in patients treated with ceritinib (see section 4.8).

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

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-foldincrease in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. Thesteady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mgtwice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinibalone. 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 limitedto, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole andnefazodone), the dose of ceritinib should be reduced by approximately one third, rounded to thenearest 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.

Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). Ifceritinib is administered with medicinal products that inhibit P-gp, an increase in ceritinibconcentration 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 mgdaily 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 ofceritinib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Concomitantuse 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). Cautionshould 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 thesolubility of ceritinib and reduce its bioavailability. Co-administration of a single 750 mg fastedceritinib dose with a proton pump inhibitor (esomeprazole) 40 mg daily for 6 days in healthy, fastingsubjects decreased ceritinib AUC by 76% and Cmax by 79%. The drug-drug interaction study wasdesigned to observe the impact of proton pump inhibitor in the worst scenario, but in clinical use theimpact of proton pump inhibitor on ceritinib exposure appears to be less pronounced. A dedicatedstudy to evaluate the effect of gastric acid-reducing agents on the bioavailability of ceritinib understeady state has not been conducted. Caution is advised with concomitant use of proton pumpinhibitors, as exposure of ceritinib may be reduced. There is no data with concomitant use of H2blockers or antacids. However, the risk for a clinically relevant decrease in bioavailability of ceritinibis possibly lower with concomitant use of H2 blockers if they are administered 10 hours before or2 hours after the ceritinib dose, and with antacids if they are administered 2 hours before or 2 hoursafter 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 alsoobserved.

Ceritinib has been classified in vivo as a strong CYP3A4 inhibitor and has the potential to interact withmedicinal products that are metabolised by CYP3A, which may lead to increased serumconcentrations 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) increasedthe 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 substratesknown 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 andalternative 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 withnarrow therapeutic indices should be considered.

Ceritinib has been classified in vivo as a weak CYP2C9 inhibitor. Co-administration of a single doseof warfarin (a CYP2C9 substrate) following 3 weeks of ceritinib dosing in patients (750 mg dailyfasted) 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 CYP2C9substrates 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 substrateswith narrow therapeutic indices should be considered. Increasing the frequency of internationalnormalised ratio (INR) monitoring may be considered if co-administration with warfarin isunavoidable.

CYP2A6 and CYP2E1 substrates

Based on in vitro data, ceritinib also inhibits CYP2A6 and CYP2E1 at clinically relevantconcentrations. Therefore, ceritinib may have the potential to increase plasma concentrations ofco-administered medicinal products that are predominantly metabolised by these enzymes. Cautionshould be exercised with concomitant use of CYP2A6 and CYP2E1 substrates and ADRs carefullymonitored.

A risk for induction of other PXR regulated enzymes apart from CYP3A4 cannot be completelyexcluded. 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 uptaketransporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or theorganic 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 thesetransporters are unlikely to occur. Based on in vitro data, ceritinib is predicted to inhibit intestinal P-gpand BCRP at clinically relevant concentrations. Therefore, ceritinib may have the potential to increaseplasma concentrations of co-administered medicinal products transported by these proteins. Cautionshould be exercised with concomitant use of BCRP substrates (e.g. rosuvastatin, topotecan,sulfasalazine) and P-gp substrates (digoxin, dabigatran, colchicine, pravastatin) and ADRs carefullymonitored.

In clinical studies, QT prolongation was observed with ceritinib. Therefore, ceritinib should be usedwith caution in patients who have or may develop prolongation of the QT interval, including thosepatients 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 othermedicinal 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 and4.4).

Food/drink interactions

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

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 nofood should be eaten for at least two hours before and one hour after the dose. Patients should notalternate between fasted and fed dosing. Dose must be adjusted properly, i.e for patients treated with450 mg or 300 mg with food, the dose should be increased to 750 mg or 450 mg taken on an emptystomach, respectively (see section 5.2) and for patients treated with 150 mg with food treatmentshould 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 is750 mg (see section 5.2).

Patients should be instructed to avoid grapefruit and grapefruit juice as they may inhibit CYP3A in thegut wall and may increase the bioavailability of ceritinib.

Women of childbearing potential should be advised to use a highly effective method of contraceptionwhile taking ceritinib and for up to 3 months after discontinuing treatment (see section 4.5).

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 requirestreatment with ceritinib.

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

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain fromceritinib therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman (see section 5.3).

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

Zykadia has minor influence on the ability to drive or use machines. Caution should be exercisedwhen driving or using machines during treatment as patients may experience fatigue or visiondisorders.

Adverse drug reactions (ADRs) described below reflect exposure to ceritinib 750 mg once daily fastedin 925 patients with ALK-positive advanced NSCLC across a pool of seven clinical studies includingtwo 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 to200.1 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 liverlaboratory test abnormalities, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea.

In the dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patientswith ALK-positive advanced NSCLC, the overall safety profile of ceritinib at the recommended doseof 450 mg with food (N=108) was consistent with ceritinib 750 mg fasted (N=110), except for areduction 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 of750 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 withfood (N=108).

ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRsare ranked by frequency, with the most frequent reactions first. In addition, the correspondingfrequency category using the following convention (CIOMS III) is also provided for each ADR: verycommon (≥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). Withineach frequency grouping, ADRs are presented in the order of decreasing seriousness.

Table 2 ADRs in patients treated with ceritinib

System organ class Ceritinib Frequency category

N=925%

Anaemia 15.2 Very common

Decreased appetite 39.5 Very common

Hyperglycaemia 9.4 Common

Hypophosphataemia 5.3 Common

Vision disordera 7.0 Common

Pericarditisb 5.8 Common

Bradycardiac 2.3 Common

Pneumonitisd 2.1 Common

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

Abnormal liver function testsh 2.2 Common

Hepatotoxicityi 1.1 Common

Rashj 19.6 Very common

Renal failurek 1.8 Common

Renal impairmentl 1.0 Common

Fatiguem 48.4 Very common

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 acuityreduced, 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 onpatients 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)f Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, epigastricdiscomfort)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 aminotransferaseincreased, gamma-glutamyltransferase increased, blood bilirubin increased, transaminases increased,hepatic enzyme increased, liver function test abnormal, liver function test increased, blood alkalinephosphatase increased)

Elderly (≥65 years)

Across seven clinical studies, 168 out of 925 patients (18.2%) treated with ceritinib were aged65 years or older. The safety profile in patients aged 65 years or older was similar to that in patientsless than 65 years of age (see section 4.2). There are no safety data in patients older than 85 years ofage.

Concurrent elevations of ALT or AST greater than 3× ULN and total bilirubin greater than 2× ULNwithout elevated alkaline phosphatase have been observed in less than 1% of patients in clinicalstudies with ceritinib. Increases to grade 3 or 4 ALT elevations were observed in 25% of patientsreceiving ceritinib. Hepatotoxicity events were managed with dose interruptions or reductions in40.6% of patients. 1% of patients required permanent discontinuation of treatment in clinical studieswith ceritinib (see sections 4.2 and 4.4).

Liver laboratory tests including ALT, AST and total bilirubin should be performed prior to the start oftreatment, every 2 weeks during the first three months of treatment and monthly thereafter, with morefrequent testing for grade 2, 3 or 4 elevations. Patients should be monitored for liver laboratory testabnormalities and managed as recommended in sections 4.2 and 4.4.

Nausea, diarrhoea and vomiting were among the most commonly reported gastrointestinal events. Inthe dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patientswith 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 productsincluding anti-emetic/anti-diarrhoeal medicinal products. Nine patients (8.3%) required study druginterruption due to diarrhoea, nausea or vomiting. One patient (0.9%) required dose adjustment. In the450 mg with food and 750 mg fasted arms, no patients had diarrhoea, nausea, or vomiting thatrequired discontinuation of study drug. In the same study the incidence and severity of gastrointestinaladverse drug reactions were reduced for patients treated with ceritinib 450 mg with food (diarrhoea59.3%, 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 bemanaged 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 clinicalstudies, 9.7% of patients treated with ceritinib had events of QT prolongation (any grade), includinggrade 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 orwho 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 ofexperiencing 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 and4.4.

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 orinterruption in 0.2% of patients. None of these events led to discontinuation of ceritinib treatment. Theuse of concomitant medicinal products associated with bradycardia should be carefully evaluated.

Patients who develop symptomatic bradycardia should be managed as recommended in sections 4.2and 4.4.

Interstitial lung disease/Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis have been observed inpatients treated with ceritinib. Across the seven clinical studies, any grade ILD/pneumonitis has beenreported 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 todiscontinuation in 0.9% of patients. Patients with pulmonary symptoms indicative of ILD/pneumonitisshould be monitored. Other potential causes of ILD/pneumonitis should be excluded (see sections 4.2and 4.4).

Hyperglycaemia (all grades) was reported in 9.4% of patients treated with ceritinib across the sevenclinical studies; grade 3 or 4 events were reported in 5.4% of patients. These events required dosereduction or interruption in 1.4% of patients and led to discontinuation in 0.1% of patients. The risk ofhyperglycaemia 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 periodicallythereafter as clinically indicated. Administration of anti-hyperglycaemic medicinal products should beinitiated or optimised as indicated (see sections 4.2 and 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: antineoplastic agents, anaplastic lymphoma kinase (ALK) inhibitors,

ATC code: L01ED02.

Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylationof 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 ALKsignaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; thisgenerates 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 oftumours in H2228-derived xenografts in mouse and rat.

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 whohave not received previous systemic treatment anti-cancer therapy (including ALK inhibitor) with theexception 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, prioradjuvant/neoadjuvant chemotherapy and presence/absence of brain metastasis at screening) to receiveeither 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 diseasesubsequently received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days.

One hundred and eighty-nine (189) patients were randomised to ceritinib and one hundred eighty-seven (187) were randomised to chemotherapy.

The median age was 54 years (range: 22 to 81 years); 78.5% of patients were younger than 65 years. Atotal 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 eithernever 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 atbaseline. 59.5% of patients with brain metastasis at baseline received no prior radiotherapy to thebrain. Patients with symptomatic CNS (central nervous system) metastases who were neurologicallyunstable 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 ofcontinued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapyarm could cross-over to receive ceritinib upon RECIST-defined disease progression confirmed byblinded independent review committee (BIRC). One hundred and five (105) patients out of the145 patients (72.4%) that discontinued treatment in the chemotherapy arm received subsequent ALKinhibitor 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) at the primaryanalysis.

The study met its primary objective demonstrating a statistically significant improvement inprogression free survival (PFS) by BIRC (see Table 3 and Figure 1). The PFS benefit of ceritinib wasconsistent by investigator assessment and across various subgroups including age, gender, race,smoking class, ECOG performance status and disease burden.

At the time of the primary analysis, the overall survival (OS) data was not mature with 107 deathsrepresenting 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 (primary analysis)

Ceritinib Chemotherapy(N=189) (N=187)

Progression-free survival (based on BIRC)

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

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

HR (95% CI)a 0.55 (0.42, 0.73)p-valueb <0.001

Overall survivalc

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

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

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

HR (95% CI)a 0.73 (0.50,1.08)p-valueb 0.056

Tumour response (based on BIRC)

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

Duration of response (based on BIRC)

Number of responders 137 50

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

Event-free rate at 18 monthsd, % (95% 59.0 (49.3, 67.4) 30.4 (14.1, 48.6)

CI)

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

NE=not estimablea 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 asassessed by BIRC (primary analysis)

Hazard Ratio = 0.5595% CI (0.42, 0.73)80 Kaplan-Meier medians (95% CI) (Months)ceritinib 750 mg: 16.6 (12.6, 27.2)60 Chemotherapy: 8.1 (5.8, 11.1)

Logrank p-value = <0.00120 Censoring Timesceritinib 750 mg (n/N = 89/189)

Chemotherapy (n/N = 113/187)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

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 32 34ceritinib 750 mg 189 155 139 125 116 105 98 76 59 43 32 23 16 11 1 1 1 0

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

At the final OS analysis, 113 (59.8%) patients had died in the ceritinib arm and 122 (65.2%) in thechemotherapy arm. The median OS was 62.9 months (95% CI: 44.2, 77.6) and 40.7 months (95% CI:

28.5, 54.5) for the ceritinib arm and the chemotherapy arm, respectively. There was a statisticallysignificant 24% reduction in the risk of death in the ceritinib arm compared to the chemotherapy arm(HR 0.76; 95% CI: 0.59, 0.99; p=0.020). There was a high rate of crossover, with 61.5% of patients inthe chemotherapy arm switching to receive ceritinib. Additionally, patients in both arms received next-line antineoplastic therapies, including other ALK inhibitors, which influenced the OS outcome.

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

Censoring times

Ceritinib 750 mg (n/N = 113/189)

Chemotherapy (n/N = 122/187)

Hazard Ratio = 0.7695% CI (0.59, 0.99)

Kaplan Meier medians (95% CI) (months)

Ceritinib 750 mg: 62.9 (44.2, 77.6)

Chemotherapy: 40.7 (28.5, 54.5)

Logrank p-value = 0.020

No. of patients still at risk Time (months)

Time (months)

Ceritinib 750 mg

Chemotherapy

Probability (%) of event-free

Probability (%) of event-free

In Study A2301, 44 patients with measurable brain metastasis at baseline and at least one post-baselinebrain radiological assessment (22 patients in the ceritinib arm and 22 patients in the chemotherapyarm) 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 thechemotherapy 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) versus6.7 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 whohave 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 withcrizotinib and chemotherapy (one or two regimen including a platinum-based doublet) were includedin the analysis. One hundred fifteen (115) patients were randomised to ceritinib and one hundredsixteen (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 treatedwith 750 mg once daily fasted. The median age was 54.0 years (range: 28 to 84 years); 77.1% ofpatients were younger than 65 years. A total of 55.8% of patients were female. 64.5% of the studypopulation were Caucasian, 29.4% Asian, 0.4% Black and 2.6% other races. The majority of patientshad 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% hadbrain metastasis at baseline. All patients were treated with prior crizotinib. All except one patientreceived prior chemotherapy (including a platinum doublet) for advanced disease; 11.3% of thepatients in the ceritinib arm and 12.1% of the patients in the chemotherapy arm were treated with twoprior chemotherapy regimen for advanced disease.

Patients were allowed to continue the assigned study treatment beyond initial progression in case ofcontinued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapyarm could further crossover to receive ceritinib upon RECIST-defined disease progression confirmedby BIRC.

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

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 includingage, gender, race, smoking class, ECOG performance status, and presence of brain metastases or priorresponse to crizotinib. The PFS benefit was further supported by local investigator assessment, andanalysis of overall response rate (ORR) and disease control rate (DCR).

At the primary analysis 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 eventsfor the final OS analysis. In addition, 81 patients (69.8%) in the chemotherapy arm receivedsubsequent 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 (primary analysis)

Ceritinib Chemotherapy(N=115) (N=116)

Duration of follow-up 16.5

Median (months) (min - max) (2.8 - 30.9)

Progression-free survival (based on BIRC)

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

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

HR (95% CI)a 0.49 (0.36, 0.67)p-valueb <0.001

Overall survivalc

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

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

HR (95% CI)a 1.00 (0.67,1.49)p-valueb 0.496

Tumour responses (based on BIRC)

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

Duration of response

Number of responders 45 8

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

Event-free probability estimate at 9 31.5% (16.7%, 45.7% (6.9%, 79.5%)monthsd (95% CI) 47.3%)

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

NE=not estimablea 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 asassessed by BIRC (primary analysis)

Censoring Times

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

Chemotherapy (n/N = 89/116)

Hazard Ratio = 0.4995% CI (0.36;0.67)

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

Ceritinib 750 mg: 5.4 (4.1;6.9)

Chemotherapy: 1.6 (1.4;2.8)

Log rank p-value = <0.0010 2 4 6 8 10 12 14 16 18 20 22 24

Time (Months)

No. of patients s till at risk

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

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

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

At the final OS analysis, with a median duration of follow-up of 110 months, 102 (88.7%) patients haddied in the ceritinib arm and 88 (75.9%) in the chemotherapy arm. The median OS was 17.7 months(95% CI: 14.2, 23.7) and 20.1 months (95% CI: 11.9, 31.2) for the ceritinib arm and the chemotherapyarm, respectively. There was no statistically significant difference in OS between the two treatmentarms (HR 1.29; 95% CI: 0.96, 1.72; p=0.955). There was a high rate of early crossover, with 88 (76%)of patients in the chemotherapy arm switching to receive ceritinib. Additionally, patients in both armsreceived next-line antineoplastic therapies, including other ALK inhibitors. Overall, crossover andnext-line therapies were a major confounding factor that may have diluted any potential difference in

OS between the treatment arms.

Probability (%) of event-free

Figure 4 ASCEND-5 (Study A2303) - Kaplan-Meier plot of overall survival by treatmentarm (final OS analysis)

Censoring times

Ceritinib 750 mg (n/N = 102/115)

Chemotherapy (n/N = 88/116)

Hazard Ratio = 1.2995% CI (0.96, 1.72)

Kaplan Meier medians (95% CI) (months)

Ceritinib 750 mg: 17.7 (14.2, 23.7)

Chemotherapy: 20.1 (11.9, 31.2)

Logrank p-value = 0.955

Time (months)

No. of patients still at risk

Time (months)

Ceritinib 750 mg

Chemotherapy

In Study A2303, 133 patients with baseline brain metastasis (66 patients in the ceritinib arm and67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-radiologist (per modified RECIST 1.1 (i.e. up to 5 lesions in the brain). The OIRR in patients withmeasurable disease in the brain at baseline and at least one post-baseline assessment was higher in theceritinib 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 thechemotherapy 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) versus1.5 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, respectivelywith 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 doseoptimisation 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 mgonce daily with food (N=73) or ceritinib 750 mg once daily under fasted conditions (N=74). A keysecondary efficacy endpoint was ORR according to RECIST 1.1 as evaluated by BIRC.

The population characteristics of the previously untreated patients with ALK-positive locallyadvanced 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% and47.3%), 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%), andmetastases to the brain (32.9% and 28.4%), respectively.

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

Probability (%) of event-free

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 Ceritinib 750 mg fasted(N=73) (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 notless than 4 weeks after response criteria were first met

Overall response rate determined based on BIRC assessment per RECIST 1.1aExact 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 ALKinhibitor 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 of750 mg once daily fasted: 163 who had received prior treatment with an ALK inhibitor and 83 whowere ALK inhibitor naïve. Of the 163 ALK-positive NSCLC patients who had received priortreatment with an ALK inhibitor, the median age was 52 years (range: 24-80 years); 86.5% wereyounger 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 cytotoxicchemotherapy followed by treatment with crizotinib, and who had then progressed on crizotinib. Themedian age was 51 years (range: 29-80 years); 87.1% of patients were younger than 65 years and50.0% were female. The majority of patients were Caucasian (60.0%) or Asian (37.9%). 92.1% ofpatients had adenocarcinoma.

The main efficacy data for both studies are summarised in Table 6. Final overall survival (OS) data arepresented 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 X2101and A2201

Study X2101 Study A2201ceritinib 750 mg ceritinib 750 mg

N=163 N=140

Duration of follow-up 10.2 14.1

Median (months) (min - max) (0.1 - 24.1) (0.1 - 35.5)

Overall response rate

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

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

Duration of response*

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

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

Progression-free survival

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

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

Overall survival (months, 95% 16.7 (14.8, NE) 15.6 (13.6, 24.2)

CI)

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 atbaseline 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-adenocarcinomahistology.

Limited efficacy data are available in elderly patients. No efficacy data are available in patients over85 years of age.

The European Medicines Agency has waived the obligation to submit the results of studies withceritinib in all subsets of the paediatric population in lung carcinoma (small cell and non-small cellcarcinoma) (see section 4.2 for information on paediatric use).

Peak plasma levels (Cmax) of ceritinib are achieved approximately 4 to 6 hours after a single oraladministration in patients. Oral absorption was estimated to be ≥25% based on metabolite percentagesin the faeces. The absolute bioavailability of ceritinib has not been determined.

Systemic exposure of ceritinib was increased when administered with food. Ceritinib AUCinf valueswere approximately 58% and 73% higher (Cmax approximately 43% and 41% higher) in healthysubjects when a single 500 mg ceritinib dose was administered with a low fat meal (containingapproximately 330 kcalories and 9 grams of fat) and a high fat meal (containing approximately1000 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 mgdaily with food (approximately 100 to 500 kcalories and 1.5 to 15 grams of fat) to 750 mg daily underfasted conditions (dose and food condition of administration initially authorised), there was noclinically meaningful difference in the systemic steady-state exposure of ceritinib for the 450 mg withfood 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, thesteady-state AUC (90% CI) and Cmax (90% CI) for the 600 mg with food arm (N=30) increased by24% (3%, 49%) and 25% (4%, 49%), respectively, compared to the 750 mg fasted arm. The maximumrecommended 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 fastedconditions. In contrast with single-dose data, pre-dose concentration (Cmin) after repeated daily dosingappeared to increase in a greater than dose-proportional manner.

Binding of ceritinib to human plasma proteins in vitro is approximately 97% in a concentrationindependent manner, from 50 ng/ml to 10,000 ng/ml. Ceritinib also has a slight preferentialdistribution 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 cancerresistance protein (BCRP) or multi-resistance protein 2 (MRP2). The in vitro apparent passivepermeability of ceritinib was determined to be low.

In rats, ceritinib crosses the intact blood brain barrier with a brain-to-blood exposure (AUCinf) ratio ofabout 15%. There are no data related to brain-to-blood exposure ratio in humans.

In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearanceof ceritinib.

Following a single oral administration of radioactive ceritinib dose at 750 mg fasted, ceritinib was themain circulating component in human plasma. A total of 11 metabolites were found circulating inplasma 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 primarybiotransformation products included glucuronidation and dehydrogenation. Addition of a thiol groupto O-dealkylated ceritinib was also observed.

Following single oral doses of ceritinib under fasted conditions, the geometric mean apparent plasmaterminal half-life (T½) of ceritinib ranged from 31 to 41 hours in patients over the 400 to 750 mg doserange. Daily oral dosing of ceritinib results in achievement of steady-state by approximately 15 daysand remains stable afterwards, with a geometric mean accumulation ratio of 6.2 after 3 weeks of dailydosing. 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 unchangedceritinib in the faeces accounts for a mean 68% of an oral dose. Only 1.3% of the administered oraldose is recovered in the urine.

The effect of hepatic impairment on the single-dose pharmacokinetics of ceritinib (750 mg underfasted 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 subjectswith normal hepatic function. The geometric mean AUCinf (unbound AUCinf) of ceritinib wasincreased 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 subjectswith severe hepatic impairment compared to subjects with normal hepatic function (see section 4.2). Adedicated pharmacokinetic study under steady-state in patients with hepatic impairment has not beenconducted.

A dedicated pharmacokinetic study in patients with renal impairment has not been conducted. Basedon available data, ceritinib elimination via the kidney is negligible (1.3% of a single oral administereddose).

Based on a population pharmacokinetic analysis of 345 patients with mild renal impairment (CLcr 60to <90 ml/min), 82 patients with moderate renal impairment (CLcr 30 to <60 ml/min) and 546 patientswith normal renal function (≥90 ml/min), ceritinib exposures were similar in patients with mild andmoderate renal impairment and normal renal function, suggesting that no dose adjustment is necessaryin 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 meaningfulinfluence on ceritinib exposure.

The potential for QT interval prolongation of ceritinib was assessed in seven clinical studies withceritinib. Serial ECGs were collected following a single dose and at steady-state to evaluate the effectof ceritinib on the QT interval in 925 patients treated with ceritinib 750 mg once daily fasted. Acategorical 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 tendencyanalysis of the QTc data at average steady-state concentration from Study A2301 demonstrated thatthe upper bound of the 2-sided 90% CI for QTc increase from baseline was 15.3 msec at ceritinib750 mg fasted. A pharmacokinetic analysis suggested that ceritinib causes concentration-dependentincreases in QTc (see section 4.4).

Safety pharmacology studies indicate that ceritinib is unlikely to interfere with vital functions of therespiratory and central nervous systems. In vitro data show that the IC50 for the inhibitory effect ofceritinib on the hERG potassium channel was 0.4 micromolar. An in vivo telemetry study in monkeysshowed a modest QT prolongation in 1 of 4 animals after receiving the highest dose of ceritinib. ECGstudies in monkeys after 4- or 13-weeks of dosing with ceritinib have not shown QT prolongation orabnormal ECGs.

The micronucleus test in TK6 cells was positive. No signs of mutagenicity or clastogenicity wereobserved in other in vitro and in vivo genotoxicity studies with ceritinib. Therefore, genotoxic risk isnot expected in humans.

Carcinogenicity studies have not been performed with ceritinib.

Reproductive toxicology studies (i.e. embryo-foetal development studies) in pregnant rats and rabbitsindicated no foetotoxicity or teratogenicity after dosing with ceritinib during organogenesis; however,maternal plasma exposure was less than that observed at the recommended human dose. Formalnon-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 theextra-hepatic bile ducts accompanied by increased neutrophil counts in the peripheral blood. Mixedcell/neutrophilic inflammation of the extra-hepatic ducts extended to the pancreas and/or duodenum athigher doses. Gastrointestinal toxicity was observed in both species characterised by body weight loss,decreased food consumption, emesis (monkey), diarrhoea and, at high doses, by histopathologicallesions including erosion, mucosal inflammation and foamy macrophages in the duodenal crypts andsubmucosa. The liver was also affected in both species, at exposures that approximate clinicalexposures at the recommended human dose, and included minimal increases in liver transaminases ina 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 nodesof rats and monkeys had macrophage aggregates. Target organ effects showed partial to completerecovery.

Effects on the thyroid were observed in both rat (mild increases in thyroid stimulating hormone andtriiodothyronine/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 follicularcell hyperplasia and increased thyroid stimulating hormone in 13-week study). As these non-clinicaleffects were mild, variable and inconsistent, the relationship between ceritinib and thyroid glandchanges in animals is unclear.

Cellulose, microcrystalline

Hydroxypropylcellulose, low-substituted

Sodium starch glycolate (type A)

Magnesium stearate

Silica, colloidal anhydrous

Gelatin

Indigotine (E132)

Titanium dioxide (E171)

Shellac (bleached, de-waxed) glaze 45%

Iron oxide black (E172)

Ammonium hydroxide 28%

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

PVC/PCTFE (polyvinylchloride/polychlorotrifluoroethylene) - Aluminium blisters containing 10 hardcapsules.

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

PVC/PE/PVDC (polyvinylchloride/polyethylene/polyvinylidene chloride) - Aluminium blisterscontaining 10 hard capsules.

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

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/15/999/001-003

EU/1/15/999/005-006

Date of first authorisation: 06 May 2015

Date of latest renewal: 16 February 2022

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

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