Consumer medicine information

Xalkori

Crizotinib

BRAND INFORMATION

Brand name

Xalkori

Active ingredient

Crizotinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xalkori.

What is in this leaflet

This leaflet answers some common questions about XALKORI.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking XALKORI against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What XALKORI is used for

XALKORI is used to treat rare types of lung cancer caused by defects in a gene called anaplastic lymphoma kinase (ALK) or a gene called ROS1.

XALKORI may slow or stop the growth of these types of lung cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

XALKORI is only available with a doctor's prescription.

It is not addictive.

Use in Children

The safety and efficacy of XALKORI in children have not been established.

Before you take XALKORI

When you must not take it

Do not take XALKORI if you have an allergy to:

  • crizotinib (the active ingredient in XALKORI)
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take XALKORI after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have ever had any of the following medical conditions:

  • any other lung problems
  • problems with your heart rate or heart rhythm, including prolonged QT interval
  • liver problems
  • kidney problems
  • inflammation of the gastrointestinal tract
  • cancer that has spread to the stomach or intestines

Tell your doctor if you are pregnant, plan to become pregnant or plan to father a child. XALKORI may affect the developing baby.

Tell your doctor if you are breast-feeding. You should not breastfeed if you are being treated with XALKORI.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by XALKORI or may affect how well it works.

Tell your doctor or pharmacist if you are taking any of the following medicines:

  • itraconazole, ketoconazole or voriconazole, medicines to treat fungal infections
  • atazanavir, efavirenz, indinavir, ritonavir or saquinavir, medicines to treat HIV infection/AIDS
  • clarithromycin, troleandomycin, moxifloxacin or ciprofloxacin, medicines to treat bacterial infections
  • carbamazepine, phenobarbital or phenytoin, medicines to treat epilepsy, seizures or fits
  • rifabutin or rifampicin, medicines to treat tuberculosis and some other infections
  • St. John's wort, a herbal medicine to treat anxiety or depression
  • ergotamine, a medicine to treat migraine and some other types of headache
  • chlorpromazine, amisulpride, droperidol, haloperidol or ziprasidone, medicines to treat mental illness
  • amitriptyline, citalopram, escitalopram, fluoxetine, imipramine or other medicines to treat depression
  • midazolam, a medicine used for sedation or to cause sleepiness
  • alfentanil, fentanyl or methadone, medicines to treat pain
  • ciclosporin, sirolimus or tacrolimus, medicines used in transplant patients
  • amiodarone, digoxin, diltiazem, disopyramide, verapamil, bisoprolol, carvedilol or sotalol, medicines to treat heart problems and/or high blood pressure
  • clonidine, atenolol, labetalol, metoprolol, nebivolol, oxprenolol, pindolol or propranolol, medicines to treat high blood pressure and/or other heart problems
  • colchicine, a medicine to treat gout
  • dabigatran, a medicine to prevent blood clots
  • bupropion, a medicine to help people stop smoking
  • pravastatin, a medicine to treat high cholesterol
  • metformin, a medicine to treat diabetes
  • mefloquine or quinine, medicines to prevent or treat malaria

You may need to take different amounts of your medicines or you may need to use different medicines. Your doctor will advise you.

How to take XALKORI

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many capsules you need to take each day. This may depend on your condition and whether you are taking any other medicines.

The usual dose of XALKORI is one capsule of 250 mg taken twice a day.

Your doctor may change your dose during treatment.

How to take it

Swallow the capsule whole with a glass of water.

When to take it

Take the capsules at about the same time each day.

If your doctor has told you to take the capsules twice a day, take one capsule in the morning and one capsule in the evening, about 12 hours apart.

Taking them at the same time each day will help you to remember when to take them.

It does not matter if you take XALKORI before or after food.

If you vomit after taking a dose of XALKORI, do not take an extra dose, just take your next dose at the usual time.

How long to take it

Continue taking XALKORI for as long as your doctor tells you.

If you forget to take it

If it is less than 6 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking XALKORI as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (Phone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much XALKORI.

Do this even if there are no signs of discomfort or poisoning.

While you are using XALKORI

Things you must do

Make sure you follow your doctor's instructions and keep all appointments. Your doctor will check your progress. You will also have blood tests and other tests to check for side effects.

Tell your doctor immediately if you or your partner become pregnant while taking XALKORI.

Use contraception (birth control) to prevent pregnancy while you are being treated with XALKORI. Women who could become pregnant or men who could father a child must use a reliable method of contraception during treatment with XALKORI and for at least 90 days after taking the last dose.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Tell any doctor, dentist or pharmacist who treats you that you are taking XALKORI.

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

Things you must not do

Do not take XALKORI to treat any other complaints unless your doctor tells you to.

Do not give XALKORI to anyone else, even if their condition seems similar to yours.

Do not stop taking XALKORI or change the dosage without checking with your doctor.

Things to be careful of

Avoid eating grapefruit or drinking grapefruit juice while you are being treated with XALKORI. Grapefruit and grapefruit juice may change the amount of XALKORI in your body.

Be careful driving or operating machinery until you know how XALKORI affects you. XALKORI may cause dizziness and tiredness and changes in vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking XALKORI.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking XALKORI, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

Medicines can affect people in different ways.

Ask your doctor or pharmacist to answer any questions you may have.

Do not be alarmed by the list of possible side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following:

  • blurred vision, flashes of light, floaters in eye, double vision
  • nausea (feeling sick) or vomiting
  • diarrhoea, constipation
  • swelling of hands, feet or legs
  • tiredness
  • loss of appetite
  • dizziness
  • tingling or numbness of hands or feet; pins and needles
  • change in sense of taste
  • soreness or redness of mouth, lips or tongue
  • skin rash
  • slow heart rate
  • pain in back, side or upper stomach.
  • heartburn, belching, indigestion
  • reduced sex drive in men, difficulty in getting an erection

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • difficulty breathing, shortness of breath, cough, coughing up pinkish mucus or blood, rapid weight gain, fluid retention, swollen ankles
  • infection, fever
  • dizziness, fainting, chest pain, rapid or irregular heartbeat
  • pain on right side of stomach, feeling more tired than usual, weakness, dark urine, itchy skin, yellowing of the skin or eyes, bleeding or bruising more easily than usual
  • severe stomach pain
  • loss of vision

The above side effects may be serious. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Some side effects might only be found when your doctor does blood tests or other tests. These tests could show a change in the liver, kidney, levels of blood cells or changes in heart rhythm.

After using XALKORI

Storage

Keep XALKORI capsules in the original container until it is time to take them.

Store XALKORI in a cool dry place where the temperature stays below 30°C.

Do not leave XALKORI or any other medicine in the car or on window sills.

Do not store XALKORI or any other medicine in the bathroom or near a sink. Heat and dampness can destroy some medicines.

Keep the capsules where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any capsules that are left over.

Product description

What it looks like

XALKORI 200 mg capsules have a pink cap and white body and are printed with "Pfizer" on the cap and "CRZ 200" on the body in black ink.

XALKORI 250 mg capsules have a pink cap and body and are printed with "Pfizer" on the cap and "CRZ 250" on the body in black ink.

XALKORI is supplied in blister packs containing 60 capsules.

Ingredients

XALKORI capsules contain 200 mg or 250 mg of crizotinib as the active ingredient.

The capsules also contain:

  • microcrystalline cellulose
  • calcium hydrogen phosphate
  • sodium starch glycollate
  • magnesium stearate
  • colloidal anhydrous silica
  • gelatin
  • titanium dioxide (E171)
  • red iron oxide (E172)

XALKORI capsules do not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

XALKORI is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free number: 1800 675 229

Australian registration numbers

XALKORI 200 mg:
AUST R 190964 (blister pack)

XALKORI 250 mg:
AUST R 190965 (blister pack)

Date of preparation

This leaflet was prepared in April 2019.

® = Registered Trademark

© Pfizer Australia Pty Ltd

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Xalkori

Active ingredient

Crizotinib

Schedule

S4

 

1 Name of Medicine

Australian Approved Name (AAN): Crizotinib.

6.7 Physicochemical Properties

Chemical name: (R)-3-[1- (2,6-Dichloro-3-fluorophenyl) ethoxy]- 5-[1-(piperidin-4-yl)- 1H-pyrazol-4-yl] pyridin-2-amine.
Molecular Formula: C21H22Cl2FN5O.
Molecular Weight: 450.34 Daltons.
Crizotinib is a white to pale yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation). The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.

Chemical structure.


CAS number.

877399-52-5.

2 Qualitative and Quantitative Composition

Xalkori is supplied as hard gelatin capsules containing 200 mg or 250 mg of crizotinib.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The capsules are differentiated by size, colour and printing.

200 mg strength.

Hard gelatin capsule with white opaque body and pink opaque cap containing a white to pale yellow powder, printed with black ink "Pfizer" on the cap and "CRZ 200" on the body.

250 mg strength.

Hard gelatin capsule with pink opaque cap and body containing a white to pale yellow powder, printed with black ink "Pfizer" on the cap and "CRZ 250" on the body.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Crizotinib is an inhibitor of the ALK receptor tyrosine kinase (RTK) and its oncogenic variants (i.e. ALK fusion events). Crizotinib is also an inhibitor of the Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros) and Recepteur d'Origine Nantais (RON) RTKs. Crizotinib demonstrated concentration dependent inhibition of the kinase activity of ALK, ROS1 and c-Met in biochemical assays and inhibited phosphorylation and modulated kinase dependent phenotypes in cell based assays. Crizotinib demonstrated growth inhibitory activity and induced apoptosis in tumour cell lines exhibiting ALK fusion events (including echinoderm microtubule associated protein like 4 [EML4]-ALK and nucleophosmin [NPM]-ALK) or ROS1 fusion events.
Crizotinib demonstrated antitumour activity in mice bearing tumour xenografts that expressed ALK fusion proteins. The antitumour efficacy of crizotinib was dose dependent and correlated to pharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and NPM-ALK) in tumours in vivo. Crizotinib also produced marked, dose-dependent regression of tumours in athymic mice with NIH-3T3 cell implants expressing human oncogenic ROS fusion proteins, and the antitumour efficacy of crizotinib was correlated with inhibition of ROS1 phosphorylation.

Clinical trials.

Previously untreated ALK positive advanced NSCLC.

Randomised phase 3 study 1014.

The use of single-agent crizotinib for the first-line treatment of ALK-positive advanced NSCLC in patients with or without brain metastases was investigated in a multicentre, multinational, randomised, open-label phase 3 Study 1014. The primary objective of this study was to demonstrate that crizotinib was superior to first-line standard-of-care platinum-based chemotherapy (pemetrexed-cisplatin or pemetrexed-carboplatin) in prolonging ProgressionFree Survival (PFS) as assessed by independent radiology review (IRR) in patients with ALK-positive advanced NSCLC who had not received previous systemic treatment for advanced disease. Secondary objectives were to compare measures of clinical efficacy including Objective Response Rate (ORR) as assessed by IRR, Duration of Response (DR), Overall Survival (OS), Intracranial Time to Progression (IC-TTP) as assessed by IRR and Patient Reported Outcomes (PRO).
The full analysis population for study 1014 included 343 patients with ALK positive advanced NSCLC as identified by Fluorescence In Situ Hybridisation (FISH) prior to randomisation. One hundred seventy two (172) patients were randomised to the crizotinib arm (171 patients received crizotinib 250 mg orally twice daily) and 171 patients were randomised to the chemotherapy arm (169 patients received chemotherapy; 91 patients were treated with pemetrexed/ cisplatin and 78 patients were treated with pemetrexed/ carboplatin). Chemotherapy consisted of pemetrexed 500 mg/m2 in combination with cisplatin 75 mg/m2 or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg.min/mL. Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles. The median duration of study treatment was 47 weeks in the crizotinib arm and 18 weeks in the chemotherapy arm. Patients could continue crizotinib treatment beyond the time of Response Evaluation Criteria in Solid Tumours (RECIST) defined disease progression, as assessed by IRR, at the discretion of the investigator if the patient was still experiencing clinical benefit. Patients in the chemotherapy arm who completed 6 cycles were to continue in the study without further treatment, but have ongoing tumour assessments until RECIST-defined disease progression as determined by IRR. Patients randomised to chemotherapy could cross over to receive crizotinib upon RECIST defined disease progression confirmed by IRR. One hundred forty four (84%) patients in the chemotherapy arm received subsequent crizotinib treatment.
Randomisation was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2), race (Asian vs non-Asian), and brain metastases (present vs absent).
Baseline demographic and disease characteristics were similar between the crizotinib and chemotherapy treatment arms with regard to gender (female: 61% vs 63% for crizotinib vs chemotherapy, respectively), median age (52 years vs 54 years), race (White: 53% vs 50%, and Asian: 45% vs 47%); smoking status (current smokers: 6% vs 3%, former smokers: 33% vs 32%, and never smokers: 62% vs 65%), metastatic disease (98% in both treatment arms), tumour histology (adenocarcinoma: 92% vs 93%), performance status (ECOG 0 or 1: 94% vs 95%, and ECOG 2: 6% vs 5%) and brain metastases (present 26% vs 28%).
Crizotinib significantly prolonged PFS compared to chemotherapy as assessed by IRR. The PFS benefit of crizotinib was consistent across subgroups of baseline patient characteristics such as age, gender, race, smoking class, time since diagnosis, ECOG performance status and presence of brain metastases. There was a numerical improvement in OS in the patients treated with crizotinib, although this improvement was not statistically significant. OS analysis was not adjusted for the potentially confounding effects of cross over. Efficacy data from Study 1014 are summarised in Table 6 and the Kaplan-Meier curves for PFS and OS are shown in Figures 1 and 2, respectively.
Based on IRR assessment, a total of 9 (23.1%) of the 39 patients in the crizotinib arm and 12 (30.0%) of the 40 patients in the chemotherapy arm with previously treated baseline brain metastases experienced progression of intracranial lesions or developed new intracranial lesions. For patients with previously treated baseline brain metastases, the median intracranial TTP (IC-TTP) was 15.7 months in the crizotinib arm and 12.5 months in the chemotherapy arm (HR = 0.45 [95% CI: 0.19, 1.07]; 1 sided p-value = 0.0315). A total of 16 (12.1%) of the 132 patients in the crizotinib arm and 14 (10.7%) of the 131 patients in the chemotherapy arm without baseline brain metastases developed new intracranial lesions. For patients without baseline brain metastases, the median IC-TTP was not reached in either the crizotinib or the chemotherapy arms (HR = 0.69 [95% CI: 0.33, 1.45]; 1 sided p-value = 0.1617).
Patient reported symptoms and global QOL was collected using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13) at baseline (day 1), day 7 and day 15 of cycle 1, and day 1 of each subsequent treatment cycle. A total of 166 patients in the crizotinib arm and 163 patients in the chemotherapy arm had completed the EORTC QLQ-C30 and LC-13 questionnaires at baseline and at least 1 post-baseline visit.
Time to Deterioration (TTD) was pre-specified as the time from randomisation to the first occurrence of a ≥ 10 point increase in scores from baseline in symptoms of pain (EORTC QLQ-LC13 pain in chest), cough (EORTC QLQ-LC13 cough) or dyspnoea (EORTC QLQ-LC13 dyspnoea). The median TTD in patient reported pain in chest, dyspnoea or cough as a composite endpoint was 2.1 months (95% CI: 0.8 months, 4.2 months) in the crizotinib arm compared to 0.5 months (95% CI: 0.4 months, 0.7 months) in the chemotherapy arm. Treatment with crizotinib was associated with a significantly longer TTD in the symptoms of pain in chest, dyspnoea or cough compared to chemotherapy (hazard ratio 0.59; 95% CI: 0.45, 0.77; Hochberg adjusted logrank 2 sided p-value = 0.0005). See Figure 3.
The change from baseline scores was found to be significantly different between the 2 treatment arms, with a significantly greater improvement observed in global quality of life in the crizotinib arm compared to the chemotherapy arm (overall difference in change from baseline scores 13.8; p-value < 0.0001).

Previously treated ALK positive advanced NSCLC.

Randomised phase 3 study 1007.

The use of single-agent crizotinib in the treatment of ALK-positive advanced NSCLC with or without brain metastases was investigated in a multicentre, multinational, randomised, openlabel phase 3 study (Study 1007). The primary objective of this study was to demonstrate that crizotinib 250 mg orally twice daily was superior to standard-of-care chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2) intravenously (IV) every 21 days in prolonging Progression-Free Survival (PFS) in patients with ALK-positive advanced NSCLC who had received one prior chemotherapy regimen. Patients were required to have ALK-positive NSCLC as identified by FISH prior to randomisation. Patients randomised to chemotherapy could cross over to receive crizotinib in Study 1005 upon RECIST-defined disease progression confirmed by independent radiology review (IRR). The primary efficacy endpoint was PFS with disease progression events determined by IRR. Secondary endpoints included ORR as determined by IRR, DR, OS and PRO.
The full analysis population for study 1007 included 347 patients with ALK positive advanced NSCLC. One hundred seventy three (173) patients were randomised to the crizotinib arm (172 patients received crizotinib) and 174 patients were randomised to the chemotherapy arm, (99 [58%] patients received pemetrexed and 72 [42%] patients received docetaxel). Randomisation was stratified by ECOG performance status (PS) (0-1, 2), brain metastases (present, absent) and prior EGFR tyrosine kinase inhibitor treatment (yes, no). The median duration of study treatment was 31 weeks in the crizotinib arm as compared to 12 weeks in the chemotherapy arm.
Patients could continue treatment as assigned beyond the time of RECIST defined disease progression, as assessed by IRR, at the discretion of the investigator if the patient was still experiencing clinical benefit. Fifty eight of 84 (69%) patients treated with crizotinib and 17 of 119 (14%) patients treated with chemotherapy continued treatment for at least 3 weeks after objective disease progression.
Baseline demographic and disease characteristics for patients in this study were similar between the crizotinib and chemotherapy arms with regard to gender (female: 57% vs 55% for crizotinib vs chemotherapy, respectively), median age (51 years vs 49 years), race (white: 52% in both treatment arms, and Asian: 46% vs 45%), smoking status (current smokers: 3% vs 5%, former smokers: 34% vs 31%, and never smokers: 62% vs 64%), metastatic disease (95% vs 91%), tumour histology (adenocarcinoma: 94% vs 92%), performance status (ECOG 0 or 1: 89% vs 91%, ECOG 2: 11% vs 9%) and brain metastases (present: 35% in both treatment arms).
Crizotinib significantly prolonged PFS compared to chemotherapy as assessed by IRR.
Efficacy data from study 1007 are summarised in Table 7 and the Kaplan-Meier curve for PFS is shown in Figure 4.
Patient reported symptoms and global QOL were collected using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13) at baseline (day 1 cycle 1) and day 1 of each subsequent treatment cycle. A total of 162 patients in the crizotinib arm and 151 patients in the chemotherapy arm had completed the EORTC QLQ-C30 and LC13 questionnaires at baseline and at least 1 postbaseline visit.
TTD was prespecified as the time from randomisation to the first occurrence of a ≥ 10 point increase in scores from baseline in symptoms of pain (EORTC QLQ-LC13 pain in chest), cough (EORTC QLQ-LC13 cough) or dyspnoea (EORTC QLQ-LC13 dyspnoea). The median TTD in patient reported pain in chest, dyspnoea or cough as a composite endpoint was 4.5 months (95% CI: 3.0 months, 6.9 months) in the crizotinib arm compared to 1.4 months (95% CI: 1.0 months, 1.6 months) in the chemotherapy arm. Treatment with crizotinib was associated with a significantly longer TTD in the symptoms of pain in chest, dyspnoea or cough compared to chemotherapy (hazard ratio 0.50; 95% CI: 0.37, 0.66; Hochberg adjusted logrank p-value < 0.0001). The Kaplan-Meier plot of TTD in pain in chest, dyspnoea or cough as a composite endpoint by arm for the patient reported outcome evaluable population is shown in Figure 5.
The change from baseline scores was found to be significantly different between the 2 treatment arms, with a significantly greater improvement observed in global quality of life in the crizotinib arm compared to the chemotherapy arm (overall difference in change from baseline scores 9.84; p-value < 0.0001).

Single arm studies in ALK positive advanced NSCLC.

The use of single agent crizotinib in the treatment of ALK positive advanced NSCLC with or without brain metastases was investigated in two multicentre, multinational, single arm studies (studies 1001 and 1005). Patients enrolled into these studies had received prior systemic therapy, with the exception of 22 patients in study 1001 and 3 patients in study 1005 who had no prior systemic treatment for locally advanced or metastatic disease. The primary efficacy endpoint in both studies was ORR according to RECIST. Secondary endpoints included Time to Tumour Response (TTR), DR, Disease Control Rate (DCR), PFS and OS. Patients received 250 mg of crizotinib orally twice daily.
In study 1001 (N = 149), the demographic characteristics were 49% female; median age 52 years; baseline ECOG performance status of 0 or 1 (88%) and 2 or 3 (12%), 64% White and 28% Asian; < 1% current smokers, 28% former smokers and 71% never smokers. The disease characteristics were 94% metastatic, 97% adenocarcinoma histology and 15% with no prior systemic therapy for metastatic disease.
In study 1005 (N = 934), the demographic characteristics were 57% female; median age 53 years; baseline ECOG performance status of 0/1 (82%) or 2/3 (18%), 52% White and 44% Asian; and 4% current smokers, 30% former smokers and 66% never smokers. The disease characteristics were 92% metastatic, 94% adenocarcinoma histology.
In study 1001, patients with advanced NSCLC were required to have ALK positive tumours prior to entering the clinical trial. ALK positive NSCLC was identified using a number of local clinical trial assays. One hundred forty nine patients with ALK positive advanced NSCLC were enrolled into study 1001 at the time of data cutoff for the PFS and ORR analyses. The median duration of treatment was 43 weeks. There were 3 complete responses and 85 partial responses for an ORR of 62%. The median response duration was 49.1 weeks. There were an additional 30 patients who had stable disease for a DCR at 8 weeks of 83%. Fifty one percent of objective tumour responses were achieved during the first 8 weeks of treatment. Study 1001 OS data were updated based on 154 ALK positive advanced NSCLC patients. The median OS at the time of data cutoff was 28.9 months (95% CI: 21.1, 40.1).
In study 1005, patients with advanced NSCLC were required to have ALK positive tumours prior to entering the clinical trial. For most patients, ALK positive NSCLC was identified by FISH. Nine hundred thirty four patients with ALK positive advanced NSCLC were treated with crizotinib in study 1005 at the time of data cutoff for the PFS and ORR analyses. The median duration of treatment for these patients was 23 weeks. Patients could continue treatment as assigned beyond the time of RECIST defined disease progression at the discretion of the investigator if the benefit/ risk assessment justified continuation of treatment. Seventy seven of 106 patients (73%) continued crizotinib treatment for at least 3 weeks after objective disease progression.
Seven hundred sixty five patients with ALK positive advanced NSCLC from study 1005 were both evaluable for response and identified by the same FISH assay used in randomised phase 3 study 1007. There were 8 complete responses and 357 partial responses for an ORR of 48%. The median DR was 47 weeks. Eighty three percent of objective tumour responses were achieved within the first 12 weeks of treatment. Study 1005 OS data were updated based on 905 ALK positive advanced NSCLC patients identified by the same FISH assay used in randomised phase 3 study 1007. The median OS at the time of data cutoff was 21.5 months (95% CI: 19.3, 23.6).
Efficacy data from studies 1001 and 1005 are provided in Table 8.

ROS1-positive advanced NSCLC.

The use of single-agent crizotinib in the treatment of ROS1-positive advanced NSCLC was investigated in multicentre, multinational, single-arm Study 1001. A total of 53 ROS1-positive advanced NSCLC patients were enrolled in the study at the time of data cutoff, including 46 patients with previously treated ROS1-positive advanced NSCLC and 7 patients who had no prior systemic treatment. The primary efficacy endpoint was ORR according to RECIST as assessed by investigator. Secondary endpoints included ORR as assessed by IRR, TTR, DR, PFS and OS. Patients received crizotinib 250 mg orally twice daily.
The demographic characteristics were 57% female; median age 55 years; baseline ECOG performance status of 0 or 1 (98%) or 2 (2%), 57% White and 40% Asian; 25% former smokers, and 75% never smokers. The disease characteristics were 91% metastatic, 96% adenocarcinoma histology and 13% with no prior systemic therapy for metastatic disease.
In Study 1001, patients were required to have ROS1-positive advanced NSCLC prior to entering the clinical trial. For most patients, ROS1-positive NSCLC was identified by FISH. The median duration of treatment was 101 weeks. There were 5 complete responses and 32 partial responses for an ORR of 70% (95% CI: 56%, 82%). The median DR was not reached (95% CI: 15.2 months, NR). Fifty-one percent of objective tumour responses were achieved during the first 8 weeks of treatment. The median PFS at the time of data cutoff was 19.3 months (95% CI: 14.8, NR). Overall survival data were not mature at the time of data cutoff. Efficacy data from ROS1-positive advanced NSCLC patients from Study 1001 are provided in Table 9.

Elderly.

Of 171 ALK-positive NSCLC patients treated with crizotinib in randomised phase 3 Study 1014, 22 (13%) were 65 years or older, and of 109 ALK-positive patients treated with crizotinib who crossed over from the chemotherapy arm, 26 (24%) were 65 years or older. Of 172 ALK-positive patients treated with crizotinib in phase 3 Study 1007, 27 (16%) were 65 years or older. Of 154 and 1063 ALK-positive NSCLC patients in single arm studies 1001 and 1005, 22 (14%) and 173 (16%) were 65 years or older, respectively. In ALK-positive NSCLC patients, the frequency of adverse reactions was generally similar for patients < 65 years of age and patients ≥ 65 years of age with the exception of oedema and constipation, which were reported with greater frequency in Study 1014 among patients treated with crizotinib ≥ 65 years of age. No overall differences in safety or efficacy were observed in comparison with younger patients. Of the 53 ROS1-positive NSCLC patients in single arm Study 1001, 15 (28%) were 65 years or older.

5.2 Pharmacokinetic Properties

Absorption.

Following oral single dose administration in the fasted state, crizotinib is absorbed with median time to achieve peak concentrations of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable with a median accumulation ratio of 4.8. The absolute bioavailability of crizotinib was determined to be 43% (range 32% to 66%) following the administration of a single 250 mg oral dose.
A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14% when a 250 mg single dose was given to healthy volunteers. Crizotinib can be administered with or without food.

Distribution.

The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.
Binding of crizotinib to human plasma proteins in vitro is 91%; in the in vitro study, there was variability in the fraction of unbound crizotinib at a clinically relevant concentration. In vitro studies suggest that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.

Metabolism.

In vitro studies demonstrated that CYP3A4/5 were the major enzymes involved in the metabolic clearance of crizotinib. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent phase 2 conjugation of O-dealkylated metabolites.
In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP2B6 and CYP3A.

Excretion.

Following single doses of crizotinib, the apparent plasma terminal half-life of crizotinib was 42 hours in patients.
Following the administration of a single 250 mg radiolabelled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in faeces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in faeces and urine, respectively.
The mean apparent clearance (CL/F) of crizotinib was lower at steady-state (60 L/hr) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.

Pharmacokinetics in special patient groups.

Hepatic impairment.

As crizotinib is extensively metabolised in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies relevant to the indications excluded patients with ALT or AST > 2.5 x ULN or, if due to underlying malignancy, > 5.0 x ULN or with total bilirubin > 1.5 x ULN. Study 1012 was an open-label, non-randomised clinical study of patients with advanced cancer (including mostly patients with hepatic and colon cancer in groups with hepatic impairment). Based on NCI classification, patients had either mild (either AST > ULN and total bilirubin ≤ ULN or any AST and total bilirubin > ULN but ≤ 1.5 x ULN), moderate (any AST and total bilirubin > 1.5 x ULN and ≤ 3 x ULN) or severe (any AST and total bilirubin > 3 x ULN) hepatic impairment. Patients with advanced cancer with normal (AST and total bilirubin ≤ ULN) hepatic function were matched controls for mild or moderate hepatic impairment.
Following crizotinib 250 mg twice daily dosing, patients with mild hepatic impairment (N=10) showed similar systemic crizotinib exposure at steady state compared to patients with normal hepatic function (N=8), with geometric mean ratios for area under the plasma concentration-time curve as daily exposure at steady state (AUCdaily) and Cmax of 91.1% (90% CI: 56.6%, 146.8%) and 91.2% (90% CI: 57.5%, 144.7%), respectively.
Following crizotinib 200 mg twice daily dosing, patients with moderate hepatic impairment (N=8) showed higher systemic crizotinib exposure compared to patients with normal hepatic function (N=9) at the same dose level, with geometric mean ratios for AUCdaily and Cmax of 150% (90% CI: 91.8%, 243.5%) and 144% (90% CI: 89.1%, 232.1%), respectively. However, the systemic crizotinib exposure in patients with moderate hepatic impairment at the dose of 200 mg twice daily was comparable to that observed from patients with normal hepatic function at a dose of 250 mg twice daily, with geometric mean ratios for AUCdaily and Cmax of 114% (90% CI: 73.6%, 176.9%) and 109% (90% CI: 70.1%, 169%), respectively.
The systemic crizotinib exposure parameters AUCdaily and Cmax in patients with severe hepatic impairment (N=6) receiving a crizotinib dose of 250 mg once daily were approximately 64.7% (90% CI: 39.5%, 105.9%) and 72.6% (90% CI: 49.1%, 107.5%), respectively, of those from patients with normal hepatic function receiving a dose of 250 mg twice daily (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).

Renal impairment.

Patients with mild (CLcr 60 to < 90 mL/min) and moderate (CLcr 30 to < 60 mL/min) renal impairment were enrolled in single arm studies 1001 and 1005. The effect of renal function, as measured by baseline CLcr on observed crizotinib steady-state trough concentrations (Ctrough, ss) was evaluated. In study 1001, the adjusted geometric mean of plasma Ctrough, ss in mild (N = 35) and moderate (N = 8) renal impairment patients were 5.1% and 11% higher, respectively, than those in patients with normal renal function. In study 1005, the adjusted geometric mean Ctrough, ss of crizotinib in mild (N = 191) and moderate (N = 65) renal impairment groups were 9.1% and 15% higher, respectively, than those in patients with normal renal function. In addition, the population pharmacokinetic analysis from studies 1001, 1005 and 1007 indicated CLcr did not have a clinically meaningful effect on the pharmacokinetics of crizotinib. Due to the small size of the increases in crizotinib exposure (5%-15%), no starting dose adjustment is recommended for patients with mild or moderate renal impairment.
After a single 250 mg dose in subjects with severe renal impairment (CLcr < 30 mL/min) not requiring peritoneal dialysis or haemodialysis, crizotinib AUCinf and Cmax increased by 79% and 34%, respectively, compared to those with normal renal function. An adjustment of the dose of crizotinib is recommended when administering crizotinib to patients with severe renal impairment not requiring peritoneal dialysis or haemodialysis (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment).

Age.

Based on the population pharmacokinetic analyses from studies 1001, 1005 and 1007, age has no effect on crizotinib pharmacokinetics (see Section 4.2 Dose and Method of Administration, Elderly; Section 5.1 Pharmacodynamic Properties, Clinical trials, Elderly).

Body weight and gender.

Based on the population pharmacokinetic analyses from studies 1001, 1005 and 1007, there was no clinically meaningful effect of body weight or gender on crizotinib pharmacokinetics. No starting dose adjustment is required.

Ethnicity.

Based on the population pharmacokinetic analyses form Studies 1001, 1005 and 1007, the predicted area under the plasma concentration-time curve at steady-state (AUCss) (95% CI) was 23%-37% higher in Asian patients (n = 523) than in non-Asian patients (n = 691).

Cardiac electrophysiology.

The QT interval prolongation potential of crizotinib was assessed in patients with either ALK-positive or ROS1-positive NSCLC who received crizotinib 250 mg twice daily. Serial ECGs in triplicate were collected following a single dose and at steady-state to evaluate the effect of crizotinib on QT intervals. Thirty four of 1619 patients (2.1%) with at least 1 post-baseline ECG assessment were found to have QTcF (corrected QT by the Fridericia method) ≥ 500 msec and 79 of 1585 patients (5.0%) with a baseline and at least 1 post-baseline ECG assessment had an increase from baseline QTcF ≥ 60 msec by automated machine-read evaluation of ECG (see Section 4.4 Special Warnings and Precautions for Use, QT interval prolongation).
An ECG substudy using blinded manual ECG measurements was conducted in 52 ALK positive NSCLC patients who received crizotinib 250 mg twice daily. A central tendency analysis indicated that a QTc effect ≥ 20 msec can be excluded. A pharmacokinetic/ pharmacodynamic analysis suggested a relationship between crizotinib plasma concentration and QTc. In addition, a decrease in heart rate was found to be associated with increasing crizotinib plasma concentration (see Section 4.4 Special Warnings and Precautions for Use, QT interval prolongation).

5.3 Preclinical Safety Data

Genotoxicity.

Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese hamster ovary cells, in an in vitro human lymphocyte chromosome aberration assay and in an in vivo rat bone marrow micronucleus assay. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

Carcinogenicity.

Carcinogenicity studies with crizotinib have not been performed.

In vitro phototoxicity.

The results of an in vitro phototoxicity study demonstrated that crizotinib may have phototoxic potential.

4 Clinical Particulars

4.1 Therapeutic Indications

Xalkori is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC).
Xalkori is indicated for the treatment of patients with ROS1-positive advanced non-small cell lung cancer (NSCLC).

4.3 Contraindications

Use of Xalkori is contraindicated in patients with hypersensitivity to crizotinib or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Assessment of ALK and ROS1 status.

When assessing either ALK or ROS1 status of a patient, it is important that a well validated and robust methodology is chosen to avoid false negative or false positive determinations.

Hepatotoxicity.

Drug induced hepatotoxicity with fatal outcome occurred in 0.1% of 1722 patients treated with crizotinib across clinical trials. Concurrent elevations in ALT and/or AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN without significant elevations of alkaline phosphatase (< 2 x ULN) have been observed in less than 1% patients treated with crizotinib.
Transaminase elevations generally occurred within the first 2 months of treatment. Across studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC, median time to onset of increased Grade 1 or 2 transaminases was 23 days. Median time to onset of increased Grade 3 or 4 transaminases was 43 days. Increases to grade 3 or 4 ALT or AST elevations were observed in 187 (11%) and 95 (6%) of patients, respectively.
Grades 3 and 4 transaminase elevations were generally reversible upon dosing interruption. Across studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC (N=1722), dose reductions associated with transaminase elevations occurred in 76 (4%) patients. Seventeen (1%) patients required permanent discontinuation from treatment associated with elevated transaminases, suggesting that these events were generally manageable by dosing modifications as defined in Table 2 (see Section 4.2 Dose and Method of Administration, Dosage adjustment).
Liver function tests including ALT, AST and total bilirubin should be monitored every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for grades 2, 3 or 4 elevations. For patients with hepatic impairment at commencement, monitoring once a week is recommended for the first 4 weeks, every 2 weeks for the next 4 weeks and then monthly, with appropriate dose interruptions or modifications (see Section 4.2 Dose and Method of Administration, Dosage adjustment). For patients who develop transaminase elevations, see Section 4.2 Dose and Method of Administration, Dosage adjustment.

Interstitial lung disease (pneumonitis).

Crizotinib has been associated with severe, life threatening or fatal interstitial lung disease (ILD)/ pneumonitis in clinical trials with a frequency of 26 (2%) of 1722 patients treated with crizotinib. These cases generally occurred within 90 days (range 5 days to 790 days) after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/ pneumonitis. Other potential causes of pneumonitis should be excluded. Crizotinib should be permanently discontinued in patients diagnosed with treatment related ILD/ pneumonitis (see Section 4.2 Dose and Method of Administration, Dosage adjustment).

QT interval prolongation.

Automated machine read QTc prolongation without accompanying arrhythmia has been observed (see Section 5.2 Pharmacokinetic Properties, Cardiac electrophysiology). Crizotinib should be administered with caution to patients who have a history of or predisposition for QTc prolongation, or who are taking medications that are known to prolong the QT interval. When using crizotinib in these patients, periodic monitoring with electrocardiograms and electrolytes should be considered. For patients who develop QTc prolongation, see Section 4.2 Dose and Method of Administration, Dosage adjustment.

Bradycardia.

Bradycardia has been reported in clinical studies and it was usually asymptomatic. The full effect of crizotinib on pulse rate may not develop until several weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (e.g. beta-blockers, nondihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia (syncope, dizziness, hypotension). Monthly monitoring of pulse rate and blood pressure is recommended. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia, crizotinib should be withheld and the use of concomitant medications should be re-evaluated. For management of patients who develop symptomatic bradycardia, see Section 4.2 Dose and Method of Administration, Dosage adjustment; Section 4.8 Adverse Effects (Undesirable Effects).

Cardiac failure.

In clinical studies with crizotinib and during post-marketing surveillance, severe, life threatening or fatal adverse events of cardiac failure were reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with or without pre-existing cardiac disorders receiving crizotinib should be monitored for signs and symptoms of heart failure. Dosing interruption, dose reduction or discontinuation should be considered as appropriate if such symptoms are observed.

Leucopenia.

Crizotinib has been associated with neutropenia and, less commonly, febrile neutropenia. Dosing interruption is recommended in patients with grade 3-4 neutropenia (see Section 4.2 Dose and Method of Administration, Dosage adjustment). Onset of neutropenia may occur after many months of exposure to crizotinib. Lymphopenia has also been observed. Monitor white blood cell count (including differential count) monthly and additionally as clinically indicated (e.g. if grade 3-4 abnormalities are observed, or if fever or infection occurs).

Gastrointestinal perforation.

Crizotinib should be used with caution in patients at risk for gastrointestinal perforation (e.g. history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medications with a recognised risk of gastrointestinal perforation).
Crizotinib should be discontinued in patients who develop gastrointestinal perforation. Patients should be informed of the signs of gastrointestinal perforation and be advised to consult their doctor immediately if these signs are experienced.

Visual effects.

In clinical studies with crizotinib in patients with either ALK positive or ROS1-positive NSCLC (N = 1722), grade 4 visual field defect with vision loss has been reported in 4 (0.2%) patients. Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss.
In patients with new onset of severe visual loss (best corrected visual acuity less than 6/60 in one or both eyes), crizotinib treatment should be discontinued. Ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss should be performed. There is insufficient information to characterise the risks of resumption of crizotinib in patients with a severe visual loss. A decision to resume crizotinib should consider the potential benefit to the patient.
Ophthalmological evaluation is recommended if vision disorder persists or worsens in severity.

Use in hepatic impairment.

Crizotinib should be used with caution in patients with hepatic impairment (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Use in renal impairment.

No starting dose adjustment is needed for patients with mild or moderate renal impairment, since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients (see Section 5.2 Pharmacokinetic Properties, Renal impairment). If patients have severe renal impairment not requiring peritoneal dialysis or haemodialysis, the dose of crizotinib should be adjusted (see Section 4.2 Dose and Method of Administration, Renal impairment).

Use in the elderly.

No overall differences in safety or efficacy were observed in comparison with younger patients, and no starting dose adjustment is required (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Elderly; Section 5.1 Pharmacodynamic Properties, Clinical trials, Elderly; Section 5.2 Pharmacokinetic Properties, Age).

Paediatric use.

The safety and efficacy of Xalkori in paediatric patients have not been established.
Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 5 times human clinical exposure based on area under the plasma concentration-time curve (AUC) in adult patients). Exposure at the no effect level was approximately 2 times the AUC in adult patients at the recommended human dose. Other toxicities of potential concern to paediatric patients have not been evaluated in juvenile animals.

Effects on laboratory tests.

No data are available. For laboratory abnormalities reported during use with crizotinib, see Section 4.8 Adverse Effects (Undesirable Effects), Laboratory abnormalities/testing.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Crizotinib is a substrate of CYP3A4/5 and also a moderate inhibitor of CYP3A. In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP3A.

Agents that may increase crizotinib plasma concentrations.

Coadministration of crizotinib and CYP3A inhibitors.

Coadministration of crizotinib with strong CYP3A inhibitors may increase crizotinib plasma concentrations. Coadministration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib area under the plasma concentration-time curve from time zero to infinity (AUCinf) and maximum observed plasma concentration (Cmax) values that were approximately 3.2-fold and 1.4-fold, respectively, of those seen when crizotinib was administered alone. Coadministration of crizotinib (250 mg once daily) with itraconazole (200 mg once daily), a strong CYP3A inhibitor, resulted in 57% and 33% increases in crizotinib steady-state area under the plasma concentration-time curve from 0 hour to time tau, the dosing interval (AUCtau) and Cmax, respectively, compared to when crizotinib was given alone.
Therefore, the concomitant use of strong CYP3A inhibitors (certain protease inhibitors such as atazanavir, indinavir, ritonavir and saquinavir, certain azole antifungals such as itraconazole, ketoconazole and voriconazole, certain macrolides such as clarithromycin and troleandomycin) should be avoided. Grapefruit or grapefruit juice may also increase plasma concentrations of crizotinib and should be avoided.

Agents that may decrease crizotinib plasma concentrations.

Coadministration of crizotinib and CYP3A inducers.

Coadministration of crizotinib (250 mg twice daily) with rifampicin (600 mg once daily), a strong CYP3A4 inducer, resulted in 84% and 79% decreases in crizotinib steady-state AUCtau and Cmax, respectively, compared to when crizotinib was given alone. Coadministration of crizotinib with strong CYP3A inducers may decrease crizotinib plasma concentrations. The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's wort, should be avoided.

Agents whose plasma concentrations may be altered by crizotinib.

Crizotinib has been identified as an inhibitor of CYP3A both in vitro and in vivo. Caution should be exercised in administering crizotinib in combination with drugs that are predominantly metabolised by CYP3A, particularly those CYP3A substrates that have narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, fentanyl, sirolimus and tacrolimus.
Coadministration of crizotinib should be avoided with CYP3A substrates that have narrow therapeutic indices and are associated with life-threatening arrhythmias, including but not limited to ergotamine.

Coadministration of crizotinib and CYP3A substrates.

Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUCinf was 3.7-fold (90% CI: 2.63-5.07) those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A.

Coadministration with other CYP substrates.

In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.
Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are predominantly metabolised by CYP2B6. In vitro studies in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A.

Coadministration with UGT substrates.

In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for uridine diphosphate glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.

Coadministration with drugs that are substrates of transporters.

Crizotinib is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp.
Crizotinib is an inhibitor of hepatic uptake transporter, organic cation transporter 1 (OCT1) and renal uptake transporter, organic cation transporter 2 (OCT2) in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2.
In vitro, crizotinib did not inhibit the human hepatic uptake transport proteins organic anion transporting polypeptide (OATP)1B1 or OATP1B3, or the renal uptake transport proteins organic anion transporter (OAT)1 or OAT3 at clinically relevant concentrations. Therefore, clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the hepatic or renal uptake of drugs that are substrates for these transporters.

Effect on other transport proteins.

In vitro, crizotinib is not an inhibitor of hepatic efflux bile salt export pump transporter (BSEP) at clinically relevant concentrations.

Coadministration of crizotinib with agents that increase gastric pH.

The aqueous solubility of crizotinib is pH dependent, with low (acidic) pH resulting in higher solubility. Administration of a single 250 mg crizotinib dose following treatment with esomeprazole 40 mg once daily for 5 days resulted in an approximately 10% decrease in crizotinib total exposure (AUCinf) and no change in peak exposure (Cmax); the extent of the change in total exposure was not clinically meaningful. Therefore, starting dose adjustment is not required when crizotinib is coadministered with agents that increase gastric pH (such as proton-pump inhibitors, H2 blockers or antacids).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥ 50 mg/kg/day for 28 days (approximately 2-fold human clinical exposure based on AUC). Findings observed in the female reproductive tract included single cell necrosis of ovarian follicles of a rat given 500 mg/kg/day for 3 days. Exposure at the no effect level for male reproductive organ effects was less than the clinical AUC and 4 times the clinical AUC for female reproductive organ effects.
Based on nonclinical safety findings, male and female fertility may be compromised by treatment with crizotinib.
(Category D)
Crizotinib may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using crizotinib. Crizotinib was not shown to be teratogenic in pregnant rats or rabbits, but the maximum doses (200 and 60 mg/kg/day, respectively) were low, resulting in maximum exposures of only 3 and 2 times the human clinical exposure based on AUC in rats and rabbits, respectively. Reduced fetal body weights were observed in both species at 200 and 60 mg/kg/day in the rat and rabbit, respectively and were considered adverse effects. Exposure at the no effect level was similar to or below the human clinical exposure based on AUC.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib. Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy.
Female patients taking crizotinib during pregnancy or who become pregnant while taking crizotinib should be apprised of the potential hazard to a fetus. Male patients taking crizotinib should also be apprised of the potential hazard to a fetus if their partner is or should become pregnant.
It is not known whether crizotinib and its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from exposure to crizotinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The data described below reflect exposure to crizotinib in 1669 patients with ALK positive advanced NSCLC who participated in randomised Phase 3 studies 1007 and 1014 or in single arm studies 1001 and 1005 with the data cutoff date of 30 November 2013, and in 53 patients with ROS1-positive advanced NSCLC who participated in single-arm study 1001 with the data cutoff date of 30 November 2014, for a total of 1722 patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials). These patients received a starting oral dose of 250 mg taken twice daily continuously. In study 1014, the median duration of study treatment was 47 weeks for patients in the crizotinib arm (N = 171); the median duration of treatment was 23 weeks for patients who crossed over from the chemotherapy arm to receive crizotinib treatment (N = 109). In study 1007, the median duration of treatment was 48 weeks for patients in the crizotinib arm (N = 172). For ALK-positive NSCLC patients in Studies 1001 (N = 154) and 1005 (N = 1063), the median duration of treatment was 57 and 45 weeks, respectively. For ROS1-positive NSCLC patients in study 1001 (N = 53), the median duration of treatment was 101 weeks.

Clinical trials experience.

The most serious adverse reactions in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC were hepatotoxicity, ILD/pneumonitis and QT interval prolongation (see Section 4.4 Special Warnings and Precautions for Use). The most common adverse reactions (≥ 25%) in patients with either ALK-positive or ROS1-positive NSCLC were vision disorder, nausea, diarrhoea, vomiting, oedema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness and neuropathy.
In 1722 patients with either ALK-positive or ROS1-positive NSCLC treated with crizotinib, all-causality adverse events associated with dosing interruptions or dose reductions occurred in 763 (44%) and 259 (15%) patients, respectively. All-causality adverse events associated with permanent treatment discontinuation occurred in 302 (18%) patients.

ADR frequency and category overview.

Table 3 presents adverse drug reactions experienced by ALK-positive NSCLC patients who participated in randomised phase 3 studies 1007 or 1014 or in single-arm studies 1001 or 1005 (N = 1669) and in ROS1-positive NSCLC patients who participated in single-arm study 1001 (N=53) for a total dataset of 1722 patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Note.

The adverse drug reactions are listed by system organ class (SOC) and frequency categories, defined using the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). The adverse drug reactions are listed in order of decreasing medical seriousness or clinical importance within each frequency category and SOC.

Previously untreated ALK positive advanced NSCLC.

Randomised phase 3 study 1014.

The safety analysis population in randomised phase 3 study 1014 included 171 patients who received crizotinib and 169 patients who received chemotherapy (91 pemetrexed in combination with cisplatin, 78 pemetrexed in combination with carboplatin). The median duration of study treatment was 47 weeks for patients on crizotinib and 18 weeks for patients on chemotherapy for which a maximum of 6 cycles was permitted.
All-causality adverse events associated with dosing interruptions occurred in 70 (41%) patients on crizotinib and 58 (34%) patients on chemotherapy. All-causality adverse events associated with dose reductions occurred in 11 (6%) patients on crizotinib and 14 (8%) patients on chemotherapy. All-causality adverse events associated with permanent discontinuation from treatment occurred in 21 (12%) patients on crizotinib and 24 (14%) patients on chemotherapy.
Table 4 presents adverse drug reactions experienced by patients in both the crizotinib and chemotherapy arms of randomised phase 3 study 1014. The conventions for adverse reactions listed by SOC and frequency categories are defined above. The adverse drug reactions are listed in order of decreasing medical seriousness or clinical importance within each frequency category and SOC.

Previously treated ALK positive advanced NSCLC.

Randomised phase 3 study 1007.

The safety analysis population in study 1007 included 172 patients who received crizotinib and 171 patients who received chemotherapy (99 pemetrexed, 72 docetaxel). The median duration of study treatment was 48 weeks for patients on crizotinib and 13 weeks for patients on chemotherapy.
All-causality adverse events associated with dosing interruptions occurred in 76 (44%) patients on crizotinib and 28 (16%) patients on chemotherapy. All-causality adverse events associated with dose reductions occurred in 30 (17%) patients on crizotinib and 25 (15%) patients on chemotherapy. All-causality adverse events associated with permanent discontinuation from treatment occurred in 34 (20%) patients on crizotinib and 34 (20%) patients on chemotherapy.
Table 5 presents adverse drug reactions experienced by patients in both the crizotinib and chemotherapy arms of study 1007. The conventions for adverse reactions listed by SOC and frequency categories are defined above. The adverse drug reactions are listed in order of decreasing medical seriousness or clinical importance within each frequency category and SOC.

Single arm studies in ALK positive advanced NSCLC.

The safety analysis population in study 1005 included 1063 patients who received crizotinib. The median duration of treatment was 45 weeks. All-causality adverse events associated with dosing interruptions and dose reductions occurred in 476 (45%) patients and 192 (18%) patients in study 1005, respectively. All-causality adverse events associated with permanent discontinuation from treatment occurred in 202 (19%) patients in study 1005. The most common adverse reactions (≥ 25%) in study 1005 were vision disorder, nausea, vomiting, diarrhoea, oedema, constipation, elevated transaminases, decreased appetite, fatigue, and neuropathy. The most common grade 3 or 4 adverse reactions (≥ 3%) in study 1005 were neutropenia, elevated transaminases, fatigue and leucopenia.
The safety analysis population in study 1001 included 154 patients who received crizotinib. The median duration of treatment was 57 weeks. All-causality adverse events associated with dosing interruptions and dose reductions occurred in 73 (47%) patients and 18 (12%) patients in study 1001, respectively. All-causality adverse events associated with permanent discontinuation occurred in 24 (16%) patients in study 1001. The most common adverse reactions (≥ 25%) in study 1001 were consistent with those in randomised phase 3 study 1007 and single arm study 1005 and were vision disorder, nausea, diarrhoea, oedema, vomiting, constipation, dizziness, fatigue, neuropathy, decreased appetite and rash. The most common grade 3 or 4 adverse reactions (≥ 3%) in study 1001 were elevated transaminases, neutropenia, syncope, nausea, vomiting, oedema, fatigue, and neuropathy.

Single arm study of ROS1-positive advanced NSCLC.

The safety analysis population in study 1001 included 53 patients with ROS1-positive NSCLC who received crizotinib. The median duration of treatment was 101 weeks. All-causality adverse events associated with dosing interruptions and dose reductions occurred in 24 (45%) patients and 6 (11%) patients, respectively. All-causality adverse events associated with permanent discontinuation from treatment occurred in 4 (8%) patients in study 1001.
The most common adverse reactions (≥ 10%) in study 1001 were consistent with those seen in patients with ALK-positive advanced NSCLC and were vision disorder (87%), nausea (58%), oedema (55%), vomiting (51%), diarrhoea (45%), constipation (43%), dizziness (40%), elevated transaminases (36%), fatigue (32%), neuropathy (30%), bradycardia (26%), rash (26%), decreased appetite (25%), dysgeusia (23%), neutropenia (17%) and increased blood creatinine (11%). The most common Grade 3 adverse reactions (≥ 2%) were neutropenia (9%), syncope (6%), vomiting (6%), elevated transaminases (4%) and prolonged electrocardiogram QT (4%). No Grade 4 adverse reactions were reported. There were 9 (17.0%) patient deaths within 28 days after the last dose of crizotinib, all of which were due to disease progression.

Description of selected adverse effects.

Visual effects.

In clinical trials of patients with either ALK-positive or ROS1-positive advanced NSCLC, all-causality vision disorder, most commonly visual impairment, photopsia, blurred vision and vitreous floaters, was experienced by 1084 (63%) of 1722 patients treated with crizotinib. Of the 1084 patients who experienced vision disorder, 95% had events that were mild in severity. Ophthalmological evaluation should be considered if vision disorder persists or worsens in severity. Seven (0.4%) patients had temporary treatment discontinuation and 2 (0.1%) patients had a dose reduction associated with vision disorder. There were no permanent discontinuations associated with vision disorder for any of the 1722 patients treated with crizotinib.
Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with crizotinib in study 1007 and study 1014 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally occurred within 8 days (range 1 day to 984 days) after the initiation of treatment. The majority of patients in the crizotinib arms in study 1007 and study 1014 (> 50%) reported visual disturbances, which occurred at a frequency of 4 to 7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured by the VSAQ-ALK questionnaire.

Gastrointestinal effects.

Nausea (57%), diarrhoea (54%), vomiting (51%) and constipation (43%) were the most commonly reported gastrointestinal events. Most events were mild to moderate in severity. The median time to onset for nausea or vomiting was 3 days and these events declined in frequency after 3 weeks of treatment. Supportive care should include the use of antiemetic medications. In clinical trials, the most commonly used antiemetic medications were ondansetron and prochlorperazine. Median times to onset for diarrhoea and constipation were 13 and 17 days, respectively. Supportive care for diarrhoea and constipation should include the use of standard antidiarrhoeal and laxative medications, respectively.

Nervous system effects.

All-causality neuropathy as defined in Table 3 was experienced by 435 (25%) of 1722 patients treated with crizotinib and was primarily grade 1 or 2 in severity. Dizziness and dysgeusia were also very commonly reported and were primarily grade 1 in severity.

Bradycardia.

In clinical trials of patients with either ALK-positive or ROS1-positive advanced NSCLC, all-causality bradycardia was experienced by 219 (13%) of 1722 patients treated with crizotinib. Most events were mild in severity. A total of 259 (16%) of 1666 patients with at least 1 post-baseline vital sign assessment had a pulse rate < 50 bpm. The use of concomitant medications associated with bradycardia should be carefully evaluated. Patients who develop symptomatic bradycardia should be managed as recommended (see Section 4.2 Dose and Method of Administration, Dosage adjustment; Section 4.4 Special Warnings and Precautions for Use).

Renal cyst.

All-causality complex renal cysts were experienced by 52 (3%) of 1722 patients treated with crizotinib. There were no reports of clinically relevant abnormal urinalyses or renal impairment in these cases, although local cystic invasion beyond the kidney was observed in some patients. Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts.

Laboratory abnormalities/testing.

Haematological laboratory abnormalities.

In clinical studies of crizotinib in patients with either ALK-positive or ROS1-positive advanced NSCLC, shifts to grade 3 or 4 decreases in leucocytes and neutrophils were observed in 64 (4%) and 226 (13%) patients, respectively. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if grade 3 or 4 abnormalities are observed, or if fever or infection occurs. In patients who develop haematologic laboratory abnormalities, see Section 4.2 Dose and Method of Administration, Dosage adjustment.

Hepatic laboratory abnormalities.

In clinical studies of crizotinib in patients with either ALK-positive or ROS1-positive advanced NSCLC, shifts to grade 3 or 4 ALT, AST, and alkaline phosphatase were observed in 187 (11%), 95 (6%) and 33 (2%) patients, respectively. Patients should be monitored for hepatotoxicity and managed as recommended (see Section 4.2 Dose and Method of Administration, Dosage adjustment; Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).

Renal laboratory abnormalities.

In clinical studies of crizotinib in patients with ALK positive advanced NSCLC, the estimated glomerular filtration rate (eGFR) decreased from a baseline median of 96.42 mL/min/1.73 m2 (n = 1681) to a median of 80.23 mL/min/1.73 m2 at 2 weeks of treatment (n = 1499). Median eGFR appeared to be relatively stable from 12 weeks of treatment (78.06 mL/min/1.73 m2, n = 1338) through 104 weeks of treatment (75.45 mL/min/1.73 m2, n = 315) and increased to 83.02 mL/min/1.73 m2 at 28 days after the last dose of crizotinib (n = 123).
Shifts to eGFR grade 4 (15 to < 30 mL/min/1.73 m2) or to eGFR grade 5 (< 15 mL/min/1.73 m2) were observed in 3% and < 1% of patients, respectively.

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.

4.2 Dose and Method of Administration

ALK and ROS1 testing.

An accurate and validated assay for either ALK or ROS1 is necessary for the selection of patients for treatment with Xalkori. Either ALK-positive or ROS1-positive NSCLC status needs to be established to select patients for treatment with crizotinib because these are the only patients for whom benefit has been shown (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Assessment for either ALK-positive or ROS1-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised. Improper assay performance can lead to unreliable test results.

Dosage and method of administration.

The recommended dose schedule of Xalkori is 250 mg taken orally twice daily. Continue treatment as long as the patient is deriving clinical benefit from therapy.
Xalkori may be taken with or without food (see Section 5.2 Pharmacokinetic Properties, Absorption). Capsules should be swallowed whole.

Missed dose.

If a dose of Xalkori is missed, then it should be taken as soon as the patient remembers unless it is less than 6 hours until the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.

Dosage adjustment.

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary for patients treated with crizotinib 250 mg orally twice daily, then the dose of Xalkori should be reduced as below.
First dose reduction: Xalkori 200 mg taken orally twice daily.
Second dose reduction: Xalkori 250 mg taken orally once daily.
Permanently discontinue if unable to tolerate Xalkori 250 mg taken orally once daily.
Dose reduction guidelines for haematologic and non-haematologic toxicities are provided in Tables 1 and 2. For patients treated with a lower dose of crizotinib than 250 mg twice daily, use the recommendations in Table 1 and Table 2 accordingly.

Hepatic impairment.

As crizotinib is extensively metabolised in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Crizotinib should be used with caution if treatment is contemplated in patients with hepatic impairment. Patients should be closely monitored for liver function and adverse events (see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity; Section 5.2 Pharmacokinetic Properties, Hepatic impairment). For patients who develop transaminase elevations, see Table 2 Xalkori dose modification, Non-haematologic toxicities.
A clinical study was conducted in patients with advanced cancer and varying degrees of hepatic impairment, based on NCI classification, who received multiple doses of crizotinib to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of crizotinib (see Section 5.2 Pharmacokinetic Properties, Hepatic impairment). The pharmacokinetic data from this study suggest that dosage adjustment might not be needed in mild hepatic impairment (either AST > Upper Limit of Normal (ULN) and total bilirubin ≤ ULN or any AST and total bilirubin > ULN but ≤ 1.5 x ULN).
For patients with moderate hepatic impairment (any AST and total bilirubin > 1.5 x ULN and ≤ 3 x ULN), the pharmacokinetic data suggest the use of a reduced starting dose of 200 mg twice daily should be considered, because the systemic crizotinib exposure increased compared to that from patients with normal hepatic function receiving the same dose of 200 mg twice daily, but was comparable to that from patients with normal hepatic function receiving 250 mg twice daily.
The starting crizotinib dose for patients with severe hepatic impairment (any AST and total bilirubin > 3 x ULN) should not be greater than 250 mg once daily, as crizotinib doses greater than 250 mg once daily have not been studied in patients with severe hepatic impairment and may result in increases of systemic crizotinib exposure to supra-therapeutic levels.
Crizotinib dose adjustment according to Child-Pugh classification has not been studied in patients with hepatic impairment.

Renal impairment.

No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60 to < 90 mL/min) or moderate (CLcr 30 to < 60 mL/min) renal impairment. The crizotinib dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or haemodialysis. The dose may be increased to 200 mg twice daily based on individual safety and tolerability after at least 4 weeks of treatment (see Section 5.2 Pharmacokinetic Properties, Renal impairment).

Elderly.

No starting dose adjustment is required (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Elderly; Section 5.2 Pharmacokinetic Properties, Age).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effect of crizotinib on the ability to drive and use machines have been performed. However, caution should be exercised when driving or operating machinery by patients who experience vision disorder, dizziness or fatigue while taking Xalkori.

4.9 Overdose

There have been no known cases of crizotinib overdose. Treatment of overdose with crizotinib should consist of general supportive measures. There is no antidote for crizotinib.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content.

Microcrystalline cellulose, Calcium hydrogen phosphate, Sodium starch glycollate, Magnesium stearate, Colloidal anhydrous silica.

Capsule shell (pink).

Gelatin,Titanium dioxide, Red iron oxide.

Capsule shell (white).

Gelatin, Titanium dioxide.

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

Store below 30°C.

6.5 Nature and Contents of Container

Polyvinyl chloride (PVC)/aluminium foil blister packs containing 60 capsules.
HDPE bottles with child-resistant polypropylene closures containing 60 capsules.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes