Consumer medicine information

Zykadia

Ceritinib

BRAND INFORMATION

Brand name

Zykadia

Active ingredient

Ceritinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zykadia.

SUMMARY CMI

Zykadia®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before taking this medicine.

1. Why am I taking Zykadia?

Zykadia contains the active ingredient ceritinib. Zykadia is used to treat advanced non-small cell lung cancer (NSCLC) that may have spread to other parts of the body and is caused by a defect in a gene called ALK (anaplastic lymphoma kinase). For more information, see Section 1. Why am I taking Zykadia? in the full CMI.

2. What should I know before I take Zykadia?

Do not take if you have ever had an allergic reaction to ceritinib or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take Zykadia? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zykadia and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Zykadia?

  • The usual dose is three (3) capsules once a day with food. Take your capsules at the about the same time each day. Do not take Zykadia with grapefruit juice. More instructions can be found in Section 4. How do I take Zykadia? in the full CMI.

5. What should I know while taking Zykadia?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking Zykadia.
  • Call your doctor straight away if you experience any of the serious side effects listed.
  • Keep all of your doctor's appointments and do the blood tests so your progress can be checked.
  • Tell your doctor if you become pregnant.
Things you should not do
  • Do not stop taking this medicine unless advised by your doctor.
  • Do not take Zykadia for any other complaints unless your doctor tells you to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Zykadia affects you.
Looking after your medicine
  • Store Zykadia in a cool dry place where the temperature stays below 30°C. Store it away from moisture, heat or sunlight.

For more information, see Section 5. What should I know while taking Zykadia? in the full CMI.

6. Are there any side effects?

  • Common side effects include diarrhoea, tiredness, nausea, vomiting, abdominal pain, heartburn, rash, vision problems, excessive thirst, high urine flow, increased appetite with weight loss, significantly decreased urine flow.
  • Other serious side effects are irregular or slow heartbeat, pain in the chest, cough, difficult or painful breathing, wheezing, pain in chest when breathing in, fever, yellow skin and eyes, nausea, loss of appetite, dark urine, severe upper stomach pain.

For more information, including what to do if you have any side effects See Section 6. Are there any side effects? in the full CMI.

WARNING: Zykadia may cause QT prolongation, a heart rhythm condition. Your healthcare provider will do an electrocardiogram (ECG) test periodically during treatment with Zykadia. REPORT: new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, light-headedness, discomfort, fainting, and changes in or new use of heart or blood pressure medications.



FULL CMI

Zykadia®

Active ingredient(s): Ceritinib

Consumer Medicine Information (CMI)

This leaflet provides important information about taking Zykadia. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking Zykadia.

Where to find information in this leaflet:

1. Why am I taking Zykadia?
2. What should I know before I take Zykadia?
3. What if I am taking other medicines?
4. How do I take Zykadia?
5. What should I know while taking Zykadia?
6. Are there any side effects?
7. Product details

1. Why am I taking Zykadia?

Zykadia contains the active ingredient ceritinib.

Zykadia is used to treat a type of a cancer called non-small cell lung cancer (NSCLC) that is either advanced or has spread to other parts of the body. This type of cancer is caused by a defect in a gene called ALK (anaplastic lymphoma kinase). This medicine belongs to a type of medicine called an ALK inhibitor.

2. What should I know before I take Zykadia?

Warnings

Do not take Zykadia if:

  • You are allergic to ceritinib, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take Zykadia.

Check with your doctor if you have/have had:

  • Problems with your liver.
  • Problems with your lungs or problems breathing.
  • Problems with your heart including a condition called long QT syndrome.
  • Diabetes.
  • Problems with your pancreas.

Tell your doctor or pharmacist if you are currently taking steroids.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant before taking Zykadia. This medicine should not be used during pregnancy unless the potential benefit outweighs the potential risk to the baby. Your doctor will discuss with you the potential risks of taking Zykadia during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed because Zykadia should not be used during breast-feeding. You and your doctor will decide together whether you should breast-feed or take Zykadia. You should not do both.

Use in Children

Zykadia is not to be used in children or adolescents under 18 years of age.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Zykadia and affect how it works.

Medicines, foods & drink that may increase the effect of Zykadia include:

  • Antifungals such ketoconazole, itraconazole, voriconazole and posaconazole.
  • Medicines used to treat AIDS or HIV such as ritonavir, saquinavir.
  • Antibiotics such as telithromycin.
  • Antidepressants such as nefazodone.
  • Grapefruit & grapefruit juice.

Medicines that may reduce the effect of Zykadia include:

  • Medicines which stop seizures or fits (anti-epileptics such as carbamazepine, phenobarbitone and phenytoin.
  • Medicines that are used to treat tuberculosis (TB) such as rifabutin, rifampicin.
  • St John's Wort (Hypericum perforatum), available in health food stores to treat depression, anxiety and insomnia.
  • Medicines used to treat heartburn (gastric reflux). These include proton pump inhibitors such as esomeprazole, H2 antagonists or antacids.

Other medicines to be careful of:

  • Midazolam, a medicine used to treat acute seizures, or as a sedative before or during surgery or medical procedures.
  • Fentanyl and alfentanil which is used to treat severe pain.
  • Migraine medications such dihydroergotamine, ergotamine.
  • Diclofenac, a medicine used to treat joint pain and inflammation.
  • Cyclosporin, tacrolimus and sirolimus, used to prevent organ rejection in transplant patients.
  • Warfarin, a blood thinner.
  • Birth control pills (oral contraceptives.)
  • Medicines used to treat irregular heartbeat such as quinidine.
  • Medicines used for increasing motility in the upper gastrointestinal tract such as cisapride.
  • Medicine used to treat psychosis such as pimozide.

Check with your doctor or pharmacist about what medicines, vitamins or supplements you are taking and if these affect Zykadia.

4. How do I take Zykadia?

How much to take

Follow the instructions provided and use Zykadia until your doctor tells you to stop.

The usual dose is three (3) capsules once a day with food.

The capsules should be swallowed whole with water. Do not chew or crush the capsules.

When to take Zykadia

Take your capsules at about the same time every day.

If you forget to take Zykadia

If you miss a dose of Zykadia do not take the missed dose. Take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you take too much Zykadia

If you think that you have taken too much Zykadia, or anyone else has taken your medicine you / they must seek urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre by calling 13 11 26, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking Zykadia?

Things you should do

Call your doctor straight away if you:

  • Experience any side effects. Your doctor may need to adjust the amount of Zykadia you are taking or stop the medication altogether. Some of the symptoms include:
    - tiredness, itchy skin, yellow skin or the whites of your eyes turn yellow, nausea or vomiting, decreased appetite, pain on the right side of your stomach, dark or brown urine, or you bleed or bruise more easily than normal because these may be signs of liver problems.
    - new or worsening symptoms such as cough with or without mucous, fever, chest pain, trouble breathing or shortness of breath because these may be signs of lung problems.
    - chest pain or discomfort, changes in your heartbeat (fast or slow), light-headedness, fainting, dizziness, blue discoloration of your lips, shortness of breath, or swelling of your lower limbs (oedema) or skin because these may be signs of heart problems.
    - diarrhoea, nausea or vomiting because they may be signs of gastrointestinal problems.
    - excessive thirst or increased frequency of urination because they may be signs of a high level of sugar in the blood.

Your doctor may need to adjust, temporarily stop or completely discontinue your treatment with Zykadia.

Keep all of your doctor's APPOINTMENTS so that your progress can be checked.

  • Your doctor should do blood tests before you start treatment with Zykadia to check your liver and pancreas and to check the level of sugar in your blood.
  • Your doctor should do blood tests every month thereafter to check your liver while you are taking Zykadia.
  • Your doctor should also do blood tests to check your pancreas and the level of sugar in your blood regularly while you are taking Zykadia.
  • If you are a women who can still have children you need to be on an effective method of birth control. You must continue using birth control measures for 3 months after you stop taking Zykadia. Remember that Zykadia may affect the oral contraceptive so you should discuss effective birth control with your doctor.
  • If you are pregnant or think you might be pregnant or plan to become pregnant, your doctor will discuss the risk of Zykadia on your pregnancy and your developing baby.

Remind any doctor, dentist or pharmacist that you visit that you are taking Zykadia.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Things you should not do

  • This medicine has been prescribed for you only. Do not use it for any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if their condition seems similar to yours. It may harm them.
  • Do not stop taking this medicine suddenly unless advised by your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Zykadia affects you.

There is no specific information on Zykadia and driving or operating machines.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly. Store it in a cool dry place, where the temperature stays below 30°C. Store it away from moisture, heat or sunlight. Keep your Zykadia in the original blister container until it is time to take it.

Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep this medicine where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Diarrhoea.
  • Nausea.
  • Vomiting.
  • Abdominal pain.
  • Tiredness (fatigue).
  • Decreased appetite.
  • Weight decreased.
  • Constipation.
  • Heartburn.
  • Rash.
  • Vision problems.
  • Excessive thirst, high urine flow.
  • Weight loss whilst eating more.
  • Significantly decreased urine flow.
Speak to your doctor, pharmacist or healthcare provider if these side effects become severe or they worry you.

Serious side effects

Serious side effectsWhat to do
Heart:
  • Irregular or slow heartbeat.
  • Pain in the chest.
Lung:
  • Cough, difficult or painful breathing, wheezing, pain in chest when breathing in, fever.
Liver:
  • Yellow skin and eyes, nausea, loss of appetite, dark urine.
Pancreas:
  • Severe upper stomach pain.
Allergic reactions:
  • Difficulty breathing, swallowing, swelling of the face, lips, tongue or throat, severe itching of the skin with a red rash or raised bumps.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some side effects, for example, changes in kidney and liver function or abnormal blood test results, can only be found when your doctor does tests from time to time to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Zykadia contains

Active ingredient
(main ingredient)		Ceritinib
Other ingredients
(inactive ingredients)		Capsule contents:
Microcrystalline cellulose
Hyprolose
Sodium starch glycolate type A
Magnesium stearate
Colloidal anhydrous silica
Capsule shell:
Gelatin
Indigo carmine
Titanium dioxide
The printing ink used to mark the capsule is:
OPACODE monogramming ink S-1-277002 BLACK
Potential allergensSulfites

Do not take this medicine if you are allergic to any of the above ingredients.

What Zykadia looks like

Zykadia is supplied as hard capsules. Each capsule has an opaque white body and opaque blue cap. The cap is marked with black ink “LDK 150MG” and the body is marked with black ink “NVR”. The capsule contains a white to almost white powder. One blister strip contains 10 hard capsules. Multipacks contain 150 (3 packs of 50) hard capsules.

Australian Registration Number AUST R 235737.

Who distributes Zykadia

This medicine is distributed by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Web site: www.novartis.com.au

This leaflet was prepared in March 2022.

®Registered trademark.

© Copyright 2022.

(zyk230322c.doc) based on PI (zyk230322i.doc)

Published by MIMS May 2022

BRAND INFORMATION

Brand name

Zykadia

Active ingredient

Ceritinib

Schedule

S4

 

1 Name of Medicine

Ceritinib.

2 Qualitative and Quantitative Composition

Zykadia 150 mg hard capsules.

The active ingredient in Zykadia 150 mg hard capsules is ceritinib. Ceritinib is white to almost white or light yellow or light brown powder that has good solubility in very acidic aqueous medium. The solubility decreases significantly with increasing pH. The pH of a 1% aqueous suspension of ceritinib in water is 6.86 and melting point 174.0°C.

Excipients with known effect.

Contains sulfites. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsule.
Zykadia ceritinib 150 mg hard capsules are opaque white and opaque blue capsule. The opaque blue cap is marked with black ink "LDK 150MG" and the opaque white body is marked with black ink "NVR". The capsule contains a white to almost white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Zykadia is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive.

4.2 Dose and Method of Administration

The recommended dose of Zykadia is 450 mg taken orally once daily with food at the same time each day. Food can range from a snack to a full meal. Continue treatment as long as the patient is deriving clinical benefit from therapy. The maximum recommended dose is 450 mg taken orally once daily with food.
Zykadia capsules should be swallowed whole with water. The capsules should not be chewed or crushed.
If a dose is missed, the patient should not take the missed dose, but take the next prescribed dose.

Dosage adjustment.

Temporary dose interruption and/or dose reduction of Zykadia therapy may be required based on individual safety and tolerability. If dose reduction is required due to an adverse drug reaction not listed in Table 1, then the daily dose of Zykadia should be reduced by decrements of 150 mg. Early identification and management of adverse drug reactions with standard supportive care measures should be considered.
Zykadia should be discontinued in patients unable to tolerate 150 mg taken daily with food.
Table 1 summarises recommendations for dose interruption, reduction, or discontinuation of Zykadia in the management of select adverse drug reactions (ADRs).
Avoid concurrent use of strong CYP3A inhibitors during treatment with Zykadia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the Zykadia dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. Patients should be carefully monitored for safety. If long-term concomitant treatment with a strong CYP3A inhibitor is necessary and the patient tolerates the reduced dose well, the dose may be increased again with careful monitoring for safety, to avoid potential under-treatment. After discontinuation of a strong CYP3A inhibitor, resume the Zykadia dose that was taken prior to initiating the strong CYP3A inhibitor.

Patients with renal impairment.

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 Zykadia in this population (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups).

Patients with hepatic impairment.

For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of Zykadia by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength (see Section 5.2 Pharmacokinetic Properties). No dose adjustment is recommended in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Paediatric patients.

The safety and efficacy of Zykadia have not been established in paediatric patients.

Elderly patients (≥ 65 years).

The limited data on the safety and efficacy of Zykadia in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Data in the Precautions section below reflects the safety of Zykadia 750 mg daily under fasted conditions in 925 patients with ALK-positive NSCLC across a pool of seven clinical studies at systemic exposures similar to the recommended dose of 450 mg with food. In a dose optimisation study (ASCEND-8), there were no clinically meaningful differences observed in the incidence of toxicities described in Special Warnings and Precautions for Use between patients receiving 750 mg daily under fasted conditions and 450 mg with food, except for a reduction in gastrointestinal adverse reactions as described (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hepatotoxicity.

Drug-induced hepatotoxicity occurred in patients treated with Zykadia. Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 28% and elevations in aspartate aminotransferase (AST) greater than 5 times ULN occurred in 16% of 925 patients across clinical studies. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN, with alkaline phosphatase less than 2 times the ULN occurred in 0.3% of patients across clinical studies. Approximately 1.0% of patients required permanent discontinuation due to hepatotoxicity.
Monitor with liver laboratory tests including ALT, AST, and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold Zykadia with resumption at a reduced dose, or permanently discontinue Zykadia as described in Table 1 (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Interstitial lung disease/pneumonitis.

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis have been observed in patients treated with Zykadia in clinical studies. In clinical studies, ILD events (including 'pneumonitis', 'ILD', 'Lung Infiltration' and 'Alveolitis Allergic') occurred in 2.4% of patients, and in 1.3% these were grade 3 or 4. ILD events that required dose reduction/interruptions were reported in 1.2% and those that led to discontinuation were reported in 1.1%. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other potential causes of pneumonitis, and discontinue Zykadia in patients diagnosed with treatment-related pneumonitis, any grade (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

QT interval prolongation.

QTc prolongation has been observed in clinical studies in patients treated with Zykadia, which may lead to an increased risk for ventricular tachyarrhythmias (e.g. Torsade de pointes) or sudden death. In clinical studies, 9.7% of patients treated with Zykadia 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.
A categorical outlier analysis of ECG data demonstrated new QTc > 500 msec in 12 patients (1.3%) among which six had elevated QTc > 450 msec at baseline. There were 58 patients (6.3%) with a QTc increase from baseline > 60 msec. A pharmacokinetic/pharmacodynamic analysis indicates that ceritinib causes concentration-dependent increases in QTc.
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. Periodic monitoring with ECGs and periodic monitoring of electrolytes (e.g. potassium) is recommended in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in patients who are taking medications that are known to prolong the QT interval. Particular care should be exercised when administering Zykadia to patients with an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging medicinal product. In case of vomiting, diarrhoea, dehydration, or impaired renal function, correct electrolytes as clinically indicated. Permanently discontinue Zykadia in patients who develop QTc greater than 500 msec or greater than 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold Zykadia in patients who develop QTc greater than 500 msec on at least 2 separate ECGs until recovery to baseline or a QTc less than 481 msec, then reinitiate Zykadia by reducing dose by 150 mg (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups).

Bradycardia.

In clinical studies, events of bradycardia and sinus bradycardia were reported in 1.2% and 1.1% of patients respectively, with 0.2% requiring dose adjustment or interruption for bradycardia, but none requiring treatment discontinuation. Asymptomatic cases of bradycardia have been observed in 11 out of 925 (1.2%) patients treated with Zykadia in clinical studies. Use of Zykadia in combination with other agents known to cause bradycardia (e.g. beta-blockers, nondihydropyridine calcium channel blockers, clonidine, and digoxin) should be avoided as far as possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold Zykadia until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Zykadia if necessary. Permanently discontinue Zykadia for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with concomitant medication known to cause bradycardia or hypotension, withhold Zykadia until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If concomitant medication can be adjusted or discontinued, reinitiate Zykadia by reducing dose by 150 mg upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Gastrointestinal adverse reactions.

In clinical studies, gastrointestinal adverse reactions (all grades) occurred in 94.8% of patients treated at a dose of 750 mg under fasted conditions. Diarrhoea, nausea and vomiting occurred in 82.1%, 74.7% and 63.2% of patients, respectively. Persistent grade 1-2 nausea, vomiting and diarrhoea requiring dose reduction have been observed. Grade 3-4 (severe) diarrhoea, nausea and vomiting occurred in 5.2%, 5.3% and 5.6% of patients, respectively. Nausea led to dose discontinuation in 5 patients (0.5%) and nausea and vomiting led to dose discontinuation in 7 patients (0.8%). Nausea, vomiting, and diarrhoea led to dose adjustments or interruptions in 16.8%, 19.2%, and 15.0%, respectively.
Gastrointestinal events were managed primarily with concomitant medicinal products including anti-emetic/anti-diarrhoeal medicinal products (in 81.0% of patients) and/or with dose reduction or interruption (in 32.2% of patients). Gastrointestinal events led to discontinuation in 0.6% of patients.
Diarrhoea, nausea, or vomiting occurred in 76.9% of 108 patients treated with Zykadia at the recommended dose of 450 mg taken with food in a dose optimisation study A2112 (ASCEND-8) and were mainly grade 1 events (52.8%) and grade 2 events (22.2%). Two patients (1.9%) experienced one grade 3 event each (diarrhoea n = 1 (0.9%) and vomiting n = 1 (0.9%)). Nine patients (8.3%) required study drug interruption due to diarrhoea or nausea or vomiting. One patient (0.9%) required dose adjustment due to vomiting. No patients required discontinuation of Zykadia due to diarrhoea, nausea or vomiting, (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor and manage patients using standards of care, including anti-diarrhoeals, anti-emetics, or fluid replacement, as indicated. Dose interruption and dose reduction may be employed as necessary (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). 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.

Hyperglycaemia occurred in patients receiving Zykadia. Across clinical studies, hyperglycaemia AEs occurred in 13% of which CTCAE Grade 3 or 4 hyperglycaemia AEs occurred in 6.5% of 925 patients. Monitor fasting serum glucose prior to the start of Zykadia treatment and periodically thereafter as clinically indicated. Initiate or optimise anti-hyperglycaemic medications as indicated. Based on the severity of the adverse drug reaction withhold Zykadia until hyperglycaemia is adequately controlled, then resume Zykadia at a reduced dose as described in Table 1. If adequate hyperglycaemic control cannot be achieved with optimal medical management, permanently discontinue Zykadia (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Pancreatic toxicity.

Pancreatitis occurred in patients receiving Zykadia. Pancreatitis, including one fatality, occurred in less than 1% of patients receiving Zykadia in clinical studies. CTCAE Grade 3 or 4 elevations of amylase occurred in 7% of patients receiving Zykadia across clinical studies. CTCAE Grade 3 or 4 elevations of lipase occurred in 14% of patients. Monitor lipase and amylase prior to the start of Zykadia treatment and periodically thereafter as clinically indicated. Based on the severity of the laboratory abnormalities, withhold Zykadia with resumption at a reduced dose as described in Table 1 (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

Across seven clinical studies, 168 of 925 patients (18.2%) treated with Zykadia were aged 65 years and older. The safety profile in patients aged 65 years and older was similar to that in patients less than 65 years of age (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special patient groups). There are no available data on patients over 85 years of age.

Paediatric use.

The safety and effectiveness of Zykadia in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Agents that may increase ceritinib plasma concentrations.

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. If concomitant use of strong CYP3A inhibitors, including but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, and nefazodone is unavoidable, reduce the ceritinib dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ceritinib dose that was taken prior to initiating the strong CYP3A inhibitor.
Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If ceritinib is administered with drugs that inhibit P-gp, an increase in ceritinib concentration is likely. Exercise caution with concomitant use of P-gp inhibitors and carefully monitor adverse drug reactions.

Agents that may decrease ceritinib plasma concentrations.

In healthy subjects, co-administration of a single 750 mg ceritinib dose under fasted conditions with rifampin (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. Avoid concomitant use of strong CYP3A inducers, including but not limited to, carbamazepine, phenobarbitone, phenytoin, rifabutin, rifampin, and St. John's wort (Hypericum perforatum). Exercise caution with concomitant use of P-gp inducers.
Gastric acid-reducing agents (e.g. proton pump inhibitors [PPIs], H2-receptor antagonists, antacids) may reduce the bioavailability of ceritinib as it demonstrates reduced solubility with increased pH in vitro. In healthy subjects (N = 22), administration of esomeprazole (a PPI) at 40 mg daily for six days resulted in decreased exposure to a single dose of 750 mg ceritinib under fasted conditions co-administered on the sixth day (ceritinib AUCinf and Cmax were decreased by 76% and 79%, respectively). A dedicated study to evaluate the effect of gastric acid-reducing agents on ceritinib exposure in patients under recommended dosing and steady-state conditions has not been conducted, and data for H2 receptor antagonists and antacids is lacking. Caution is advised with concomitant use of gastric acid-reducing agents, particularly PPIs.

Agents whose plasma concentration may be altered by ceritinib.

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. 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. Avoid co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substrates known to have narrow therapeutic indices (e.g. astemizole, cisapride, cyclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus). If unavoidable, consider dose reduction for co-administered medicines that are CYP3A substrates with narrow therapeutic indices.
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. Avoid co-administration of ceritinib with substrates primarily metabolised by CYP2C9 or CYP2C9 substrates known to have narrow therapeutic indices (e.g. phenytoin and warfarin). If unavoidable, consider dose reduction for co-administered medicines that are CYP2C9 substrates with narrow therapeutic indices. Increase the frequency of international normalised ratio (INR) monitoring if co-administration with warfarin is unavoidable as the anti-coagulant effect of warfarin may be enhanced.
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 drugs that are predominantly metabolised by these enzymes. Exercise caution with concomitant use of CYP2A6 and CYP2E1 substrates and carefully monitor adverse drug reactions.
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 transporters, BCRP, P-gp or 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.

Drug-food/drink interactions.

Zykadia should be taken with food. The bioavailability of ceritinib is increased in the presence of food (see Section 5.2 Pharmacokinetic Properties, Absorption). Patients should be instructed to avoid grapefruit or grapefruit juice as they may inhibit CYP3A in the gut wall and may increase the bioavailability of ceritinib.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The potential for Zykadia to cause infertility in male and female patients is unknown. The potential effects on fertility have not been assessed in animal studies. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving Zykadia and for up to 3 months after discontinuing treatment. The effectiveness of concomitant administration of oral contraceptives may be reduced (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
(Category D)
There are no data regarding the use of Zykadia in pregnant women. Based on its mechanism of action, Zykadia may cause fetal harm when administered to a pregnant woman. Zykadia should not be given to a pregnant woman unless the potential benefits for her outweigh the potential risk to the fetus.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Women of childbearing potential should be advised to use a highly effective method of contraception noting the potential for ceritinib to decrease the effectiveness of the oral contraceptive (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) while receiving Zykadia and for up to 3 months after discontinuing treatment.
In an embryofetal development study in which pregnant rats were administered daily doses of ceritinib during organogenesis, dose-related skeletal anomalies were observed at doses as low as 50 mg/kg (0.6-fold the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations (wavy ribs).
In pregnant rabbits administered ceritinib daily during organogenesis, dose-related skeletal anomalies, including incomplete ossification, were observed at doses equal to or greater than 2 mg/kg/day (approximately 0.02-fold the human exposure by AUC at the recommended dose). A low incidence of visceral anomalies, including absent or malpositioned gallbladder and retro-oesophageal subclavian cardiac artery, was observed at doses equal to or greater than 10 mg/kg/day (approximately 0.1-fold the human exposure by AUC at the recommended dose). Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or greater. In addition, embryolethality was observed in rabbits at a dose of 50 mg/kg.
 It is unknown whether ceritinib is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse drug reactions in breastfed newborns/infants, a decision should be made whether to abstain from breast-feeding or abstain from using Zykadia, taking into account the importance of Zykadia to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The data described below reflect exposure to Zykadia 750 mg orally once daily fasted in 925 patients with ALK-positive advanced NSCLC in seven clinical studies including two randomised, active controlled, phase 3 studies (A2301 and A2303).
The median duration of exposure to Zykadia 750 mg under fasted conditions was 44.9 weeks (range 0.1 to 200.1 weeks). Dose reductions occurred in 62.2% of patients and dose interruptions in 74.8% of patients.
The rate of adverse events (AEs) resulting in permanent discontinuation of Zykadia was 12.1%. The most frequent AEs (> 0.5%) leading to discontinuation of Zykadia were pneumonia (0.6%) and respiratory failure (0.6%).
The most frequently (> 10%) reported AEs for study A2301 regardless of study drug relationship in either treatment group are reported in Table 2.
The most frequently (> 10%) reported AEs for study A2303 regardless of study drug relationship in either treatment group are reported in Table 3.

Adverse drug reactions (ADR).

Adverse drug reactions (ADRs) with an incidence of ≥ 10% in patients treated with Zykadia 750 mg fasted were diarrhoea, nausea, vomiting, fatigue, liver laboratory test abnormalities, abdominal pain, decreased appetite, weight decreased, constipation, rash, blood creatinine increased, oesophageal disorder and anaemia.
Grade 3/4 ADRs with an incidence of ≥ 5% in patients treated with Zykadia 750 mg fasted were liver laboratory test abnormalities, fatigue, vomiting, diarrhoea, nausea and hyperglycaemia.
Table 4 presents the frequency category of ADRs reported for Zykadia in patients treated at a dose of 750 mg under fasted conditions (n = 925) in 7 clinical studies*.
ADRs are listed according to MedDRA system organ class. Within each system organ class, the adverse drug reactions 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 adverse drug reaction: 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).
In the dose optimisation study A2112 (ASCEND-8) in both previously treated and untreated patients with ALK-positive advanced NSCLC, the overall safety profile of Zykadia at the recommended dose of 450 mg with food (N = 108) was consistent with Zykadia 750 mg fasted (N = 110), except for a reduction in gastrointestinal adverse drug reactions, while achieving comparable steady-state exposure (see Section 5.2 Pharmacokinetic Properties). The incidence and severity of gastrointestinal adverse drug reactions (diarrhoea 59.3%, nausea 42.6%, vomiting 38.0%; 1.9% reported a grade 3/4 event) were reduced for patients treated with Zykadia 450 mg with food compared to 750 mg fasted (diarrhoea 80%, nausea 60%, vomiting 65.5%; 17.3% reported a grade 3/4 event). In patients treated with Zykadia 450 mg with food, 24.1% of patients had at least one adverse event that required dose reduction and 55.6% of patients had at least one adverse event that required study drug interruption.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no reported experience with overdose in humans. General supportive measures should be initiated in all cases of overdose. For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

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

5.1 Pharmacodynamic Properties

Mechanism of action.

Ceritinib is an 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 signalling 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 effective against EML4-ALK kinase 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 trials.

Previously untreated ALK-positive locally advanced or metastatic NSCLC.

The efficacy and safety of Zykadia for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who have not received previous systemic anti-cancer therapy for their metastatic disease was demonstrated in an open-label, randomised, active-controlled, multicentre study (ASCEND-4/Study A2301). Patients were required to have ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx Assay. Neurologically stable patients with central nervous system (CNS) metastases that did not require increasing doses of steroids to manage CNS symptoms were permitted to enrol.
The primary efficacy endpoint was progression free survival (PFS), as determined by a Blinded Independent Review Committee (BIRC), according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Additional efficacy endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate (DCR), time to response (TTR) and patient reported outcomes.
Intracranial ORR (OIRR), intracranial DCR (IDCR) and duration of intracranial response (DOIR) were determined by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. up to 5 lesions in the brain).
Patients were randomised 1:1 to receive Zykadia 750 mg orally once daily under fasted conditions or chemotherapy plus maintenance chemotherapy. Randomisation was stratified by World Health Organization (WHO) performance status, prior adjuvant/neoadjuvant chemotherapy and presence or absence of CNS metastases. Patients randomised to chemotherapy received pemetrexed (500 mg/m2) and investigator's choice of cisplatin (75 mg/m2) or carboplatin (AUC of 5 - 6 mg*min/mL) administered on day 1 of each 21-day cycle for a maximum of 4 cycles followed by pemetrexed (500 mg/m2) every 21 days. Treatment in both arms was continued until disease progression or unacceptable toxicity. Patients randomised to the chemotherapy arm could crossover to receive Zykadia upon RECIST-defined disease progression by BIRC.
A total of 376 patients were randomised to receive Zykadia (n = 189) or chemotherapy (n = 187). The demographic characteristics of the study population were 57% female, median age 54 years (range: 22 to 81 years), 22% age 65 years or older, 54% Caucasian, 42% Asian, 2% Black, and 2% other races. The WHO performance status was 0/1/2 in 37%/56%/6% of patients, respectively. The majority of patients had adenocarcinoma (97%) and never smoked (61%). CNS metastases were present in 32% (n = 121) of patients. Approximately half (n = 55) had measurable CNS metastases as determined by BIRC neuro-radiologist and 71% (n = 39) of these patients received no prior intracranial radiotherapy. Of those randomised to chemotherapy, 43% received Zykadia as the next antineoplastic therapy after platinum-based chemotherapy.
The median duration of follow-up was 19.7 months (from randomisation to data cut-off date).
Efficacy data from Study A2301 are summarised in Table 5 and the Kaplan-Meier curves for PFS is shown in Figure 1.
There was no significant difference in OS in a pre-specified interim analysis conducted at 42% of the events required for the final analysis.
Analyses of patient-reported outcome measures suggested ceritinib prolonged time to deterioration for the lung cancer specific symptoms cough, pain and dyspnoea compared to chemotherapy. The patient-reported delay to deterioration may be an overestimation, because patients were not blinded to treatment assignment.
Anti-tumour activity of Zykadia in the brain was assessed in patients with measurable disease at baseline with at least one post baseline assessment as determined by the BIRC neuro-radiologist at baseline (N = 44) according to RECIST 1.1 (see Table 6).

Previously treated ALK-positive locally advanced or metastatic NSCLC.

The efficacy and safety of Zykadia for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC, who have received previous treatment with crizotinib was demonstrated in an open-label, randomised, active-controlled, multicentre study (ASCEND-5/Study A2303). Patients were required to have ALK-positive NSCLC as identified by the VYSIS ALK Break Apart FISH test. Neurologically stable patients with CNS metastases that did not require increasing doses of steroids to manage CNS symptoms were permitted to enrol.
The primary efficacy endpoint was PFS, as determined by BIRC, according to RECIST 1.1. Additional efficacy endpoints included OS, ORR, DOR, DCR, TTR and patient reported outcomes.
OIRR, IDCR and DOIR were determined by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. up to 5 lesions in the brain).
Patients were randomised 1:1 to receive Zykadia 750 mg orally once daily under fasted conditions or chemotherapy. Randomisation was stratified by WHO performance status and presence or absence of CNS metastases. Patients randomised to chemotherapy received investigator's choice of pemetrexed (500 mg/m2) or docetaxel (75 mg/m2) administered on day 1 of each 21-day cycle. Treatment in both arms was continued until disease progression or unacceptable toxicity. Patients randomised to the chemotherapy arm could crossover to receive Zykadia upon RECIST-defined disease progression by BIRC.
A total of 231 patients were randomised to receive Zykadia (n = 115) or chemotherapy (n = 116); in the chemotherapy arm, 73 patients received docetaxel and 40 received pemetrexed.
The demographic characteristics of the study population were 56% female, median age 54 years (range: 28 to 84 years), 23% age 65 years or older, 65% Caucasian, 29% Asian, < 1% Black, and 3% other races. The WHO performance status was 0/1/2 in 46%/48%/6% of patients respectively, and 58% had CNS metastasis at baseline.
All patients had been treated previously with crizotinib, and in 82% of both arms it was their most recent treatment. All except one patient had received prior chemotherapy (including a platinum doublet) for advanced disease; 11% of the patients in the Zykadia arm and 12% of the patients in the chemotherapy arm had received two prior chemotherapy regimens for advanced disease.
The median duration of follow-up was 16.5 months.
Efficacy data from Study A2303 are summarised in Table 7 and the Kaplan-Meier curve for PFS in Figure 2.
There was no significant difference in OS in a pre-specified interim analysis conducted at approximately 50% of the events required for the final analysis.
Analyses of patient-reported outcome measures suggested ceritinib prolonged time to deterioration for the lung cancer specific symptoms cough, pain and dyspnoea compared to chemotherapy. The patient-reported delay to deterioration may be an overestimation, because patients were not blinded to treatment assignment.
Anti-tumour activity of Zykadia in the brain was assessed in patients with measurable disease at baseline with at least one post baseline assessment as determined by the BIRC neuro-radiologist at baseline (N = 37) according to RECIST 1.1 (see Table 8).

Dose optimisation study A2112 (ASCEND-8).

The efficacy of Zykadia 450 mg with food was evaluated in a multicentre open-label dose optimisation Study A2112 (ASCEND-8). A total of 147 previously untreated patients with ALK-positive locally advanced or metastatic NSCLC were randomised to receive Zykadia 450 mg once daily with food (N = 73) or Zykadia 750 mg once daily under fasted conditions (N = 74). ALK-positivity was identified by VENTANA IHC. A key secondary efficacy endpoint was overall response rate (ORR) according to RECIST 1.1 as evaluated by a Blinded Independent Review Committee (BIRC).
The population characteristics across the 450 mg with food arm and 750 mg fasted arm 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 Performance Status 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 9.

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 under fasted conditions. Oral absorption was estimated to be ≥ 25% based on metabolite percentages in the faeces. The maximum possible absolute oral bioavailability of ceritinib from the capsules is estimated at approximately ≤ 58%.
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.
After a single oral administration of ceritinib in patients, plasma exposure to ceritinib, as represented by Cmax and AUClast, increased dose-proportionally over 50 to 750 mg under fasting conditions. In contrast with single-dose data, pre-dose concentration (Cmin) after repeated daily dosing under fasting conditions appeared to increase in a greater than dose-proportional manner.

Food effect.

Systemic exposure to ceritinib is increased when administered with food. A food effect study conducted in healthy subjects with a single 500 mg ceritinib dose showed that a high-fat meal increased ceritinib AUC by 73% and Cmax by 41% and a low-fat meal increased ceritinib AUC by 58% and Cmax by 43% as compared with the fasted state.
In a dose optimisation study A2112 (ASCEND-8) in patients receiving Zykadia 450 mg or 600 mg daily with food (approximately 100 to 500 calories and 1.5 to 15 grams of fat) or 750 mg daily under fasted conditions, there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib (AUC) for the 450 mg with food arm (n = 36) compared to the 750 mg fasted arm (n = 31). The steady-state AUC increased by 24% and Cmax increased by 25% in the 600 mg with food arm (n = 30) compared to the 750 mg fasted arm (n = 31). The maximum recommended dose of Zykadia is 450 mg taken orally once daily with food.

Distribution.

Binding of ceritinib to human plasma proteins in vitro is approximately 97% in a concentration independent manner, from 50 nanogram/mL to 10,000 nanogram/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.

Metabolism.

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 under fasted conditions, 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.

Excretion.

Following single oral doses of ceritinib under fasted conditions, the geometric mean apparent plasma terminal half-life (T1/2) of ceritinib ranged from 31 to 41 hours in patients over the 400 to 750 mg dose range. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/hr) after 750 mg daily oral dosing than after a single 750 mg oral dose (88.5 L/hr) suggesting that ceritinib demonstrates non-linear PK 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.

Pharmacokinetics in special patient groups.

Patients with hepatic impairment.

Following a single 750 mg Zykadia dose under fasted conditions, the geometric mean systemic exposure (AUCinf) of ceritinib was increased by 66% and unbound ceritinib AUCinf was increased by 108% in subjects with severe (Child-Pugh C) hepatic impairment compared to healthy subjects with normal hepatic function (see Section 4.2 Dose and Method of Administration). Total and unbound systemic exposure of ceritinib were similar in subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment compared to healthy subjects with normal hepatic function.

Patients with 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 (CrCl 60 to < 90 mL/min), 82 patients with moderate renal impairment (CrCl 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 (CrCl < 30 mL/min) were not included in the clinical studies with Zykadia (see Section 4.2 Dose and Method of Administration).

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.

Ceritinib inhibited hERG channel activity in an in vitro assay (IC50 0.4 microM). The potential for QT interval prolongation of ceritinib was assessed in 7 clinical studies with Zykadia. Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of ceritinib on the QT interval in 925 patients treated with ceritinib 750 mg once daily under fasted conditions. 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 concentrations from a global phase 3 study (A2301) demonstrated that the upper bound of the 2-sided 90% CI for QTc was 15.3 msec at ceritinib 750 mg once daily under fasted conditions. A pharmacokinetic/pharmacodynamic analysis suggested that ceritinib causes concentration-dependent increases in QTc (see Boxed Warnings; see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

5.3 Preclinical Safety Data

Genotoxicity.

Ceritinib induced polyploidy in human lymphocytes and a small increase in micronuclei in TK6 cells in vitro. However, it was not mutagenic in vitro in the bacterial gene mutation assay and not clastogenic in human lymphocytes in vitro and in a rat micronucleus assay in vivo. Ceritinib has a low risk of genotoxicity in patients.

Carcinogenicity.

Carcinogenicity studies have not been performed with ceritinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, hyprolose, sodium starch glycolate type A, magnesium stearate, colloidal anhydrous silica.
The hard gelatin capsule shell contains gelatin, titanium dioxide, indigo carmine. The printing ink is Opacode monogramming ink S-1-277002 Black.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Zykadia 150 mg capsules should be stored below 30°C. Store in original container.

6.5 Nature and Contents of Container

The blister packaging is made from PCTFE/PVC backed with a heat sealable lacquered aluminium foil. One blister strip contains 10 hard capsules. Multipacks containing 150 (3 packs of 50) hard capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


INN: ceritinib (free base).

CAS number.

CAS: 1032900-25-6.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes