4.1. Therapeutic indications

XALKORI as monotherapy is indicated for:

• The first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)

• The treatment of adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)

• The treatment of adults with ROS1-positive advanced non-small cell lung cancer (NSCLC)

• The treatment of paediatric patients (age ≥1 to <18 years) with relapsed or refractory systemic anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL)

• The treatment of paediatric patients (age ≥1 to <18 years) with recurrent or refractory anaplastic lymphoma kinase (ALK)-positive unresectable inflammatory myofibroblastic tumour (IMT)

4.2. Posology and method of administration

Treatment with XALKORI should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

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 (see section 5.1 for information on assays used in the clinical studies).

ALK-positive NSCLC, ROS1-positive NSCLC, ALK-positive ALCL or ALK-positive IMT status should be established prior to initiation of crizotinib therapy. Assessment should be performed by laboratories with demonstrated proficiency in the specific technology being utilised (see section 4.4).

Posology

Adult patients with ALK-positive or ROS1-positive advanced NSCLC

The recommended dose schedule of crizotinib is 250 mg twice daily (500 mg daily) taken continuously.

Paediatric patients with ALK-positive ALCL or ALK-positive IMT

The recommended starting dose schedule of crizotinib in paediatric patients is based on body surface area (BSA). The recommended dosage of crizotinib for paediatric patients with ALCL or IMT is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity.

The recommended dosage for paediatric patients with BSA ≥1.34 m2 is provided in Table 1. If needed, attain the desired dose by combining different strengths of crizotinib capsules.

Table 1. Paediatric patients with body surface area (BSA) ≥1.34 m2: Recommended crizotinib capsules* starting dosage

Body Surface Area (BSA)**

Dose (Twice Daily)

Total Daily Dose

1.34 – 1.51 m2

400 mg

(2×200 mg capsule)

800 mg

1.52 – 1.69 m2

450 mg

(1×200 mg capsule + 1×250 mg capsule)

900 mg

≥1.70 m2

500 mg

(2×250 mg capsule)

1000 mg

* Refers to the XALKORI 200 mg and 250 mg hard capsules.

** For paediatric patients with BSA <1.34 m2, refer to Table 2.

For paediatric patients with BSA <1.34 m2, the granules in capsules for opening formulation of XALKORI should be used. The recommended dosage for paediatric patients with BSA <1.34 m2 is provided in Table 2.

The granules are encapsulated into 3 dosage strengths: 20 mg, 50 mg and 150 mg crizotinib. If needed, attain the desired dose by combining different strengths of crizotinib granules in capsules for opening. No more than 4 capsules will be required for a single dose (see Table 2).

Table 2. Paediatric patients with body surface area (BSA) of 0.38 m2 to 1.33 m2: Recommended crizotinib granules* starting dosage

Body Surface Area (BSA)**

Dose (Twice Daily)

Total Daily Dose

0.38 to 0.46 m2

120 mg

(1 × 20 mg + 2 × 50 mg)

240 mg

0.47 to 0.51 m2

140 mg

(2× 20 mg + 2 × 50 mg)

280 mg

0.52 to 0.61 m2

150 mg

(1 × 150 mg)

300 mg

0.62 to 0.80 m2

200 mg

(1 × 50 mg + 1 × 150 mg)

400 mg

0.81 to 0.97 m2

250 mg

(2 × 50 mg + 1 × 150 mg)

500 mg

0.98 to 1.16 m2

300 mg

(2 × 150 mg)

600 mg

1.17 to 1.33 m2

350 mg

(1 × 50 mg + 2 × 150 mg)

700 mg

* Refers to the 20 mg, 50 mg and 150 mg crizotinib granules in capsules for opening.

** The recommended dosage for patients with a BSA less than 0.38 m2 has not been established. For paediatric patients with BSA ≥1.34 m2, refer to Table 1.

Administer crizotinib to paediatric patients under adult supervision.

Dose adjustments

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.

Adult patients with ALK-positive or ROS1-positive advanced NSCLC

In 1722 adult patients treated with crizotinib with either ALK-positive or ROS1-positive NSCLC across clinical studies, the most frequent adverse reactions (≥3%) associated with dosing interruptions were neutropenia, elevated transaminases, vomiting, and nausea. The most frequent adverse reactions (≥3%) associated with dose reductions were elevated transaminases and neutropenia. If dose reduction is necessary for patients treated with crizotinib 250 mg orally twice daily, then the dose of crizotinib 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 haematological and non-haematological toxicities are provided in Tables 3 and 4. For patients treated with a lower dose of crizotinib than 250 mg twice daily, then follow the dose reduction guidelines provided in Tables 3 and 4 accordingly.

Table 3. Adult patients: XALKORI dose modification – haematological toxicitiesa,b

CTCAEc Grade

XALKORI treatment

Grade 3

Withhold until recovery to Grade ≤2, then resume at the same dose schedule

Grade 4

Withhold until recovery to Grade ≤2, then resume at the next lower dosed,e

a. Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

b. For patients who develop neutropenia and leukopenia, see also sections 4.4 and 4.8.

c. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events

d. In case of recurrence, dosing should be withheld until recovery to Grade ≤2, then dosing should be resumed at 250 mg once daily. XALKORI must be permanently discontinued in case of further Grade 4 recurrence.

e. For patients treated with 250 mg once daily or whose dose was reduced to 250 mg once daily, discontinue during evaluation.

Table 4. Adult patients: XALKORI dose modification – non-haematological toxicities

CTCAEa Grade

XALKORI treatment

Grade 3 or 4 Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) elevation with Grade ≤1 total bilirubin

Withhold until recovery to Grade ≤1 or baseline, then resume at 250 mg once daily and escalate to 200 mg twice daily if clinically toleratedb,c

Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or haemolysis)

Permanently discontinue

Any Grade Interstitial lung disease (ILD)/pneumonitis

Withhold if ILD/pneumonitis is suspected, and permanently discontinue if treatment-related ILD/pneumonitis is diagnosedd

Grade 3 QTc prolongation

Withhold until recovery to Grade ≤1, check and if necessary correct electrolytes, then resume at the next lower doseb,c

Grade 4 QTc prolongation

Permanently discontinue

Grade 2, 3 Bradycardiad,e

Symptomatic, may be severe and medically significant, medical intervention indicated

Withhold until recovery to Grade ≤1 or to heart rate 60 or above

Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products

If contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to Grade ≤1 or to heart rate 60 or above

If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dosec upon recovery to Grade ≤1 or to heart rate 60 or above

Grade 4 Bradycardiad,e,f

Life-threatening consequences, urgent intervention indicated

Permanently discontinue if no contributing concomitant medicinal product is identified

If contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at 250 mg once dailyc upon recovery to Grade ≤1 or to heart rate 60 or above, with frequent monitoring

Grade 4 Ocular disorder (Visual loss)

Discontinue during evaluation of severe vision loss

a. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events

b. XALKORI must be permanently discontinued in case of further Grade ≥3 recurrence. See sections 4.4 and 4.8.

c. For patients treated with 250 mg once daily or whose dose was reduced to 250 mg once daily, discontinue during evaluation.

d. See sections 4.4 and 4.8.

e. Heart rate less than 60 beats per minute (bpm).

f. Permanently discontinue for recurrence.

Paediatric patients with ALK-positive ALCL or ALK-positive IMT

If a dose reduction is necessary for paediatric patients treated at the recommended starting dose, then the dose of XALKORI for paediatric patients with BSA ≥1.34 m2 should be reduced as shown in Table 5.

Table 5. Paediatric patients with body surface area (BSA) ≥1.34 m2: Recommended XALKORI capsules*dose reductions

Body Surface Area

(BSA)**

First Dose Reduction

Second Dose Reduction***

Dose

(Twice daily*)

Total Daily Dose

Dose

(Twice daily*)

Total Daily Dose

1.34 – 1.69 m2

250 mg

500 mg

200 mg

400 mg

≥1.70 m2

400 mg

800 mg

250 mg

500 mg

Refers to the XALKORI 200 mg and 250 mg hard capsules.

** For paediatric patients with BSA <1.34 m2, refer to Table 6.

*** Permanently discontinue in patients who are unable to tolerate crizotinib after 2 dose reductions.

If a dose reduction is necessary for paediatric patients treated at the recommended starting dose, then the dose of XALKORI for paediatric patients with BSA <1.34 m2 should be reduced as shown in Table 6.

Table 6. Paediatric patients with body surface area (BSA) of 0.38 m2 to 1.33 m2: Recommended XALKORI granules * dose reductions

Body Surface Area (BSA)**

First Dose Reduction

Second Dose Reduction***

Dose

(Twice Daily)

Total Daily Dose

Dose

(Twice Daily)

Total Daily Dose

0.38 to 0.46 m2

90 mg

(2 × 20 mg + 1 × 50 mg)

180 mg

70 mg

(1 × 20 mg + 1 × 50 mg)

140 mg

0.47 to 0.51 m2

100 mg

(2 × 50 mg)

200 mg

80 mg

(4 × 20 mg)

160 mg

0.52 to 0.61 m2

120 mg

(1 × 20 mg + 2 × 50 mg)

240 mg

90 mg

(2 × 20 mg + 1 × 50 mg)

180 mg

0.62 to 0.80 m2

150 mg

(1 × 150 mg)

300 mg

120 mg

(1 × 20 mg + 2 × 50 mg)

240 mg

0.81 to 0.97 m2

200 mg

(1 × 50 mg + 1 × 150 mg)

400 mg

150 mg

(1 × 150 mg)

300 mg

0.98 to 1.16 m2

220 mg

(1 × 20 mg + 1 × 50 mg + 1 × 150 mg)

440 mg

170 mg

(1 × 20 mg + 1 × 150 mg)

340 mg

1.17 to 1.33 m2

250 mg

(2 × 50 mg + 1 × 150 mg)

500 mg

200 mg

(1 × 50 mg + 1 × 150 mg)

400 mg

* Refers to the 20 mg, 50 mg, and 150 mg crizotinib as granules in capsules for opening.

** For paediatric patients with BSA ≥1.34 m2, refer to Table 5.

*** Permanently discontinue in patients who are unable to tolerate crizotinib after 2 dose reductions.

Recommended dosage modifications for haematologic and non-haematologic adverse reactions for paediatric patients with ALK-positive ALCL or ALK-positive IMT are provided in Tables 7 and 8, respectively.

Table 7. Paediatric patients: XALKORI dosage modification for haematologic adverse reactions

CTCAEa Grade

XALKORI Dosing

Absolute Neutrophil Count (ANC)

Grade 4 Neutrophil count decreased

First occurrence: Withhold until recovery to Grade ≤2, then resume at the next lower dosage.

Second occurrence:

• Permanently discontinue for recurrence complicated by febrile neutropenia or infection.

• For uncomplicated Grade 4 neutropenia, either permanently discontinue, or withhold until recovery to Grade ≤2, then resume at the next lower dosage.b

Platelet Count

Grade 3 platelet count decreased (with concurrent bleeding)

Withhold until recovery to Grade ≤2, then resume at the same dosage.

Grade 4 platelet count decreased

Withhold until recovery to Grade ≤2, then resume at the next lower dosage. Permanently discontinue for recurrence.

Anaemia

Grade 3

Withhold until recovery to Grade ≤2, then resume at the same dosage.

Grade 4

Withhold until recovery to Grade ≤2, then resume at the next lower dosage. Permanently discontinue for recurrence.

a. Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

b. Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise indicated in Tables 5 and 6.

It is recommended to monitor complete blood counts, including differential counts, weekly for the first month of therapy and then at least monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur.

Table 8. Paediatric patients: XALKORI dosage modification for non-haematologic adverse reactions

CTCAEa Grade

XALKORI Dosing

Grade 3 or 4 ALT or AST elevation with Grade ≤1 total bilirubin

Withhold until recovery to Grade ≤1, then resume at next lower dose.

Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or haemolysis)

Permanently discontinue.

Any Grade drug-related Interstitial lung disease/pneumonitis

Permanently discontinue.

Grade 3 QTc prolongation

Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage.

Grade 4 QTc prolongation

Permanently discontinue.

Grade 2, 3 Bradycardiab

Symptomatic, may be severe and medically significant, medical intervention indicated

Withhold until recovery to a resting heart rate according to the patient's age (based on the 2.5th percentile per age-specific norms) as follows:

1 to <2 years: 91 bpm or above

2 to 3 years: 82 bpm or above

4 to 5 years: 72 bpm or above

6 to 8 years: 64 bpm or above

>8 years: 60 bpm or above

Grade 4 Bradycardiab,c

Life-threatening consequences, urgent intervention indicated

Permanently discontinue if no contributing concomitant medication is identified.

If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at the second dose reduction level in Table 5c upon recovery to Grade ≤1 or to the heart rate criteria listed for management of symptomatic or severe, medically significant bradycardia, with frequent monitoring.

Grade 3 Nausea

Inadequate oral intake for more than 3 days, medical intervention required

Grade 3 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.d

Grade 3, 4 Vomiting

More than 6 episodes in 24 hours for more than 3 days, medical intervention required, i.e., tube feeding or hospitalisation; life-threatening consequences, urgent intervention indicated

Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.d

Grade 3, 4 Diarrhoea

Increase of 7 or more stools per day over baseline, incontinence, hospitalisation indicated; life-threatening consequences, urgent intervention indicated

Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.d

Grade 1 (mild symptoms), 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living) Ocular disorder

Grade 1 or 2: Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders.

Grade 3, 4 Ocular disorder (visual loss, marked decrease in vision)

Grade 3 or 4: Withhold pending evaluation of severe visual loss. Permanently discontinue, if no other cause found on evaluation.

a. Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

b. Resting heart rate less than the 2.5th percentile per age-specific norms.

c. Permanently discontinue for recurrence.

d. Permanently discontinue in patients who are unable to tolerate crizotinib after 2 dose reductions, unless otherwise indicated in Tables 5 and 6.

Hepatic impairment

Crizotinib is extensively metabolised in the liver. Treatment with crizotinib should be used with caution in patients with hepatic impairment (see Tables 4 and 8, and sections 4.4, 4.8 and 5.2).

Adjustments for adult patients with ALK-positive or ROS1-positive advanced NSCLC

Based on the National Cancer Institute (NCI) classification, no starting dose adjustment of crizotinib is recommended for patients with mild hepatic impairment (either AST >Upper Limit of Normal (ULN) and total bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5 × ULN). The starting crizotinib dose for patients with moderate hepatic impairment (any AST and total bilirubin >1.5 × ULN and ≤ 3 × ULN) is recommended to be 200 mg twice daily. The starting crizotinib dose for patients with severe hepatic impairment (any AST and total bilirubin >3 × ULN) is recommended to be 250 mg once daily (see section 5.2). Crizotinib dose adjustment according to Child-Pugh classification has not been studied in patients with hepatic impairment.

Adjustments for paediatric patients with ALK-positive ALCL or ALK-positive IMT

Adjustments for paediatric patients are based on the clinical study conducted in adult patients (see section 5.2). No starting dose adjustment of crizotinib is recommended for patients with mild hepatic impairment (either AST >ULN and total bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5 × ULN). The recommended starting dose of crizotinib in patients with moderate hepatic impairment (any AST and total bilirubin >1.5 × ULN and ≤3 × ULN) is the first dose reduction based on BSA as shown in Tables 5 and 6. The recommended starting dose of crizotinib in patients with severe hepatic impairment (any AST and total bilirubin >3 × ULN) is the second dose reduction based on BSA as shown in Tables 5 and 6.

Renal impairment

Adjustments for adult patients with ALK-positive or ROS1-positive advanced NSCLC

No starting dose adjustment is recommended for patients with mild (60 ≤creatinine clearance [CLcr] <90 mL/min) or moderate (30 ≤CLcr <60 mL/min) renal impairment, since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients. Crizotinib plasma concentrations may be increased in patients with severe renal impairment (CLcr <30 mL/min). The crizotinib starting 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 sections 4.4 and 5.2).

Adjustments for paediatric patients with ALK-positive ALCL or ALK-positive IMT

Adjustments for paediatric patients are based on information in adult patients (see section 5.2). No starting dose adjustment is needed for patients with mild (60 ≤creatinine clearance [CLcr] <90 mL/min) or moderate (30 ≤CLcr <60 mL/min) renal impairment calculated using the Schwartz equation. The recommended starting dose of crizotinib in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis is the second dose reduction based on BSA as shown in Tables 5 and 6. The dose may be increased to the first dose reduction based on BSA as shown in Tables 5 and 6 and on individual safety and tolerability after at least 4 weeks of treatment.

Elderly

No starting dose adjustment is required (see sections 5.1 and 5.2).

Paediatric population

The safety and efficacy of crizotinib in paediatric patients with ALK-positive or ROS1-positive NSCLC have not been established. No data are available.

The safety and efficacy of crizotinib have been established in paediatric patients with relapsed or refractory systemic ALK-positive ALCL from 3 to <18 years of age or with unresectable, recurrent, or refractory ALK-positive IMT from 2 to <18 years of age (see sections 4.8 and 5.1). No safety or efficacy data are available for crizotinib treatment in ALK-positive ALCL paediatric patients below 3 years of age or ALK-positive IMT paediatric patients below 2 years of age.

Method of administration

For oral use.

XALKORI may be taken either after a meal or while fasted. The Xalkori granules should not be sprinkled on food. Grapefruit or grapefruit juice should be avoided since it may increase crizotinib plasma concentration. St. John's wort should be avoided since it may decrease crizotinib plasma concentration (see section 4.5).

If a dose is missed, then it should be taken as soon as the patient or caregiver remembers unless it is less than 6 hours until the next scheduled 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.

XALKORI 200 mg and 250 mg hard capsules

The XALKORI 200 mg and 250 mg hard capsules should be swallowed whole preferably with water, and should not be crushed, dissolved, or opened.

XALKORI granules in capsules for opening

The granules in capsules for opening should not be chewed, crushed or sprinkled on food. The capsule shell must not be swallowed but carefully be opened as follows:

- The capsule is held so that the printed “Pfizer” is at the top and tapped to ensure all the granules are in the lower half of the capsule.

- The bottom of the capsule is gently squeezed.

- The top and bottom of the capsule are twisted in opposite directions and pulled apart to open the capsule.

- The granules can be administered by 2 options after opening the capsule(s):

1. Emptying the contents directly into the patient's mouth; OR

2. Emptying the contents into a consumer supplied dry oral dosing aid (e.g., spoon, medicine cup). The granules are then administered to the patient's mouth via the dosing aid.

- Whichever option is used, the capsule is tapped to ensure all the granules are administered.

If the entire prescribed dose of granules in capsules for opening cannot be taken at one time, then the granules in capsules for opening are to be administered in portions until the entire prescribed dose is given. Immediately after administration of each portion, a sufficient amount of water should be given to ensure that all medication is swallowed. After the medication has been swallowed, other liquids or foods can be ingested (except as noted in section 4.5, Agents that may increase crizotinib plasma concentrations).

Detailed pictograms on how to administer the granules in capsules for opening are provided in the Package Leaflet.

Paediatric patients with ALK-positive ALCL or ALK-positive IMT

The use of antiemetics prior to and during treatment with crizotinib is recommended to prevent nausea and vomiting for paediatric patients with ALK-positive ALCL or ALK-positive IMT. Standard antiemetic and antidiarrhoeal agents are recommended to manage gastrointestinal toxicities. Supportive care such as intravenous or oral hydration, electrolyte supplementation and nutritional support are recommended as clinically indicated (see section 4.4).

4.3. Contraindications

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

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 (including cases with fatal outcome in adult patients) has been reported in patients treated with crizotinib across clinical studies (see section 4.8). Liver function tests including ALT, AST, and total bilirubin should be monitored once a week 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 who develop transaminase elevations, see section 4.2.

Interstitial lung disease/pneumonitis

Severe, life-threatening or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with crizotinib. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. Crizotinib treatment should be withheld if ILD/pneumonitis is suspected. Drug-induced ILD/pneumonitis should be considered in the differential diagnosis of patients with ILD-like conditions such as: pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), alveolitis, lung infiltration, pneumonia, pulmonary oedema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, obliterative bronchiolitis and bronchiectasis. Other potential causes of ILD/pneumonitis should be excluded, and crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see sections 4.2 and 4.8).

QT interval prolongation

QTc prolongation has been observed in clinical studies in patients treated with crizotinib (see sections 4.8 and 5.2) which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de Pointes) or sudden death. The benefits and potential risks of crizotinib should be considered before beginning therapy in patients with pre-existing bradycardia, who have a history of or predisposition for QTc prolongation, who are taking antiarrhythmics or other medicinal products that are known to prolong QT interval and in patients with relevant pre-existing cardiac disease and/or electrolyte disturbances. Crizotinib should be administered with caution in these patients and periodic monitoring of electrocardiograms (ECG), electrolytes and renal function is required. When using crizotinib, ECG and electrolytes (e.g., calcium, magnesium, potassium) should be obtained as close as possible prior to the first dose and periodic monitoring with ECGs and electrolytes is recommended, especially at the beginning of treatment in case of vomiting, diarrhoea, dehydration or impaired renal function. Correct electrolytes as necessary. If QTc increases by greater than or equal to 60 msec from baseline but QTc is <500 msec, crizotinib should be withheld and cardiologist advice should be sought. If QTc increases to greater than or equal to 500 msec, cardiologist advice must be immediately sought. For patients who develop QTc prolongation, see sections 4.2, 4.8 and 5.2.

Bradycardia

All-causality bradycardia was reported in clinical studies in 13% of adult patients with ALK-positive or ROS1-positive NSCLC and in 17% of paediatric patients with ALK-positive ALCL or ALK-positive IMT treated with crizotinib. Symptomatic bradycardia (e.g., syncope, dizziness, hypotension) can occur in patients receiving crizotinib. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia. Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. For management of patients who develop symptomatic bradycardia, see Dose Modification and Undesirable Effects sections (see sections 4.2 and 4.8).

Cardiac failure

In clinical studies with crizotinib and during post-marketing surveillance in adult patients, severe, life-threatening or fatal adverse reactions of cardiac failure were reported (see section 4.8).

Patients with or without pre-existing cardiac disorders, receiving crizotinib, should be monitored for signs and symptoms of heart failure (dyspnoea, oedema, rapid weight gain from fluid retention). Dosing interruption, dose reduction or discontinuation should be considered as appropriate if such symptoms are observed.

Neutropenia and leukopenia

In clinical studies with crizotinib in adult patients with either ALK-positive or ROS1-positive NSCLC, Grade 3 or 4 neutropenia has been very commonly reported (12%). In clinical studies with crizotinib in paediatric patients with ALK-positive ALCL or ALK-positive IMT, Grade 3 or 4 neutropenia has been very commonly reported (68%). Grade 3 or 4 leukopenia has been commonly reported (3%) in patients with ALK-positive or ROS1-positive NSCLC and very commonly (24%) in paediatric patients ALK-positive ALCL or ALK-positive IMT (see section 4.8). Less than 0.5% of adult patients with either ALK-positive or ROS1-positive NSCLC experienced febrile neutropenia in clinical studies with crizotinib. In paediatric patients with either ALK-positive ALCL or ALK-positive IMT, febrile neutropenia was commonly reported in one patient (2.4%). 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 (see section 4.2).

Gastrointestinal perforation

In clinical studies with crizotinib, events of gastrointestinal perforations were reported. There were reports of fatal cases of gastrointestinal perforation during post-marketing use of crizotinib (see section 4.8).

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 medicinal products with a recognised risk of gastrointestinal perforation).

Crizotinib should be discontinued in patients who develop gastrointestinal perforation. Patients should be informed of the first signs of gastrointestinal perforations and be advised to consult rapidly in case of occurrence.

Renal effects

Blood creatinine increase and creatinine clearance decreased were observed in patients in clinical studies with crizotinib. Renal failure and acute renal failure were reported in patients treated with crizotinib in clinical studies and during post-marketing. Cases with fatal outcome, cases requiring haemodialysis and cases of Grade 4 hyperkalaemia were also observed in adult patients. Monitoring of patients for renal function at baseline and during therapy with crizotinib is recommended, with particular attention to those who have risk factors or previous history of renal impairment (see section 4.8).

Renal impairment

If patients have severe renal impairment not requiring peritoneal dialysis or haemodialysis, the dose of crizotinib should be adjusted (see sections 4.2 and 5.2).

Visual effects

In clinical studies with crizotinib in adult patients with either ALK-positive or ROS1-positive NSCLC (N=1722), Grade 4 visual field defect with visual loss has been reported in 4 (0.2%) patients. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss.

In clinical studies with crizotinib in paediatric patients with either in ALK-positive ALCL or ALK-positive IMT, visual disorders occurred in 25 of 41 (61%) paediatric patients (see section 4.8).

For paediatric patients with ALCL or IMT, baseline ophthalmologic examination should be obtained prior to starting crizotinib. Follow-up ophthalmologic examination including retinal examination is recommended within 1 month of starting crizotinib, every 3 months thereafter, and upon any new visual symptoms. Healthcare professionals should inform patients and caregivers of the symptoms of ocular toxicity and potential risk of visual loss. For Grade 2 vision disorders, symptoms should be monitored and reported to an eye specialist with consideration of a dose reduction. Crizotinib should be withheld pending evaluation for any Grade 3 or 4 ocular disorder, and crizotinib should be permanently discontinued for Grade 3 or 4 severe visual loss unless another cause is identified (see section 4.2 Table 8).

In any patient 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 (see section 4.2). 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 visual loss and for other visual symptoms as clinically warranted, should be performed (see sections 4.2 and 4.8). There is insufficient information to characterise the risks of resumption of crizotinib in patients who develop visual symptoms or visual loss. A decision to resume crizotinib should consider the potential benefit versus risks to the patient.

Ophthalmological evaluation is recommended if vision disorder persists or worsens in severity (see section 4.8).

Photosensitivity

Photosensitivity has been reported in patients treated with XALKORI (see section 4.8). Patients should be advised to avoid prolonged sun exposure while taking XALKORI and, when outdoors, to take protective measures (e.g., use of protective clothing and/or sunscreen).

Drug-drug interactions

The concomitant use of crizotinib with strong CYP3A4 inhibitors or with strong and moderate CYP3A4 inducers should be avoided (see section 4.5).

The concomitant use of crizotinib with CYP3A4 substrates with narrow therapeutic indices should be avoided (see section 4.5). Avoid using crizotinib in combination with other bradycardic agents, medicinal products that are known to prolong QT interval and/or antiarrhythmics (see section 4.4 QT interval prolongation, Bradycardia, and section 4.5).

Drug-food interaction

Grapefruit or grapefruit juice should be avoided during treatment with crizotinib (see sections 4.2 and 4.5).

Non-adenocarcinoma histology (NSCLC)

Limited information is available in patients with ALK-positive and ROS1-positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma (SCC) (see section 5.1).

XALKORI 200 mg and 250 mg hard capsules

Dietary sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg or 250 mg capsule, that is to say essentially 'sodium-free'.

XALKORI granules in capsules for opening

Dietary sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

Paediatric population

Gastrointestinal toxicity

Crizotinib can cause severe gastrointestinal toxicities in paediatric patients with ALK-positive ALCL or ALK-positive IMT. In paediatric patients with either ALK-positive ALCL or ALK-positive IMT, vomiting and diarrhoea occurred in 95% and 85%, respectively.

The use of antiemetics prior to and during treatment with crizotinib is recommended to prevent nausea and vomiting. Standard antiemetic and antidiarrhoeal agents are recommended to manage gastrointestinal toxicities. If paediatric patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhoea or vomiting despite maximum medical therapy, it is recommended to withhold crizotinib until resolved, and then resuming crizotinib at the next lower dose level. Supportive care such as hydration, electrolyte supplementation and nutritional support are recommended as clinically indicated (see section 4.2).

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies with other medicinal products have been performed in adults.

Pharmacokinetic interactions

Agents that may increase crizotinib plasma concentrations

Coadministration of crizotinib with strong CYP3A inhibitors is expected to 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 versus 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, those seen when crizotinib was administered alone.

Coadministration of repeated doses of crizotinib (250 mg once daily) with repeated doses of itraconazole (200 mg once daily), a strong CYP3A inhibitor, resulted in increases in crizotinib steady-state AUCtau and Cmax, that were approximately 1.6-fold and 1.3-fold, respectively, those seen when crizotinib was administered alone.

Therefore, the concomitant use of strong CYP3A inhibitors (including but not limited to atazanavir, ritonavir, cobicistat, itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin and erythromycin) should be avoided. Unless the potential benefit to the patient outweighs the risk, in which case patients should be closely monitored for crizotinib adverse events (see section 4.4).

Physiologically-based pharmacokinetic (PBPK) simulations predicted a 17% increase in crizotinib steady-state AUC after treatment with the moderate CYP3A inhibitors, diltiazem or verapamil. Caution is therefore recommended in case of coadministration of crizotinib with moderate CYP3A inhibitors.

Grapefruit or grapefruit juice may also increase plasma concentrations of crizotinib and should be avoided (see sections 4.2 and 4.4).

Agents that may decrease crizotinib plasma concentrations

Coadministration of repeated doses of crizotinib (250 mg twice daily) with repeated doses of 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. The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifampicin and St. John's wort, should be avoided (see section 4.4).

The effect of a moderate inducer including but not limited to efavirenz or rifabutin is not clearly established; therefore, their combination with crizotinib should be also avoided (see section 4.4).

Coadministration with medicinal products that increase gastric pH

The aqueous solubility of crizotinib is pH dependent, with low (acidic) pH resulting in higher solubility.

XALKORI 200 mg and 250 mg hard capsules

Administration of a single 250 mg crizotinib dose of capsules 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 considered clinically meaningful.

XALKORI granules in capsules for opening

Administration of a single 250 mg crizotinib dose of oral granules in capsules for opening following treatment with esomeprazole 40 mg once daily for 5 days resulted in an approximately 19% decrease in crizotinib AUCinf and 23% decrease in Cmax. The extent of the change in total exposure was not considered clinically meaningful.

A 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).

Agents whose plasma concentrations may be altered by crizotinib

Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUCinf was 3.7-fold of those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A. Therefore, coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cisapride, cyclosporine, ergot derivatives, fentanyl, pimozide, quinidine, sirolimus and tacrolimus should be avoided (see section 4.4). If the combination is needed, then close clinical monitoring should be exercised.

In vitro studies indicated that crizotinib is an inhibitor of CYP2B6. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicinal products that are metabolised by CYP2B6 (e.g., bupropion, efavirenz).

In vitro studies in human hepatocytes indicated that crizotinib may induce pregnane X receptor (PXR)- and constitutive androstane receptor (CAR)-regulated enzymes (e.g., CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1). However, there was no observed induction in vivo when crizotinib was coadministered with the CYP3A probe substrate midazolam. Caution should be exercised in administering crizotinib in combination with medicinal products that are predominantly metabolised by these enzymes. Of note, the effectiveness of concomitant administration of oral contraceptives may be reduced.

In vitro studies indicated that crizotinib is a weak inhibitor of uridine diphosphate glucuronosyltransferase (UGT)1A1 and UGT2B7. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicinal products that are metabolised predominantly by UGT1A1 (e.g., raltegravir, irinotecan) or UGT2B7 (e.g., morphine, naloxone).

Based on an in vitro study, crizotinib is predicted to inhibit intestinal P-gp. Therefore, administration of crizotinib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when crizotinib is administered with these medicinal products.

Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicinal products that are substrates of OCT1 or OCT2 (e.g., metformin, procainamide).

Pharmacodynamic interactions

In clinical studies, prolonged QT interval was observed with crizotinib. Therefore, the concomitant use of crizotinib with medicinal products known to prolong QT interval or medicinal products able to induce Torsades de pointes (e.g., class IA [quinidine, disopyramide] or class III [e.g., amiodarone, sotalol, dofetilide, ibutilide], methadone, cisapride, moxifloxacine, antipsychotics, etc.) should be carefully considered. A monitoring of the QT interval should be made in case of combinations of such medicinal products (see sections 4.2 and 4.4).

Bradycardia has been reported during clinical studies; therefore, use crizotinib with caution due to the risk of excessive bradycardia when used in combination with other bradycardic agents (e.g., non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, beta-blockers, clonidine, guanfacine, digoxin, mefloquine, anticholinesterases, pilocarpine) (see sections 4.2 and 4.4).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI.

Contraception in males and females

Adequate contraceptive methods should be used during therapy, and for at least 90 days after completing therapy (see section 4.5).

Pregnancy

XALKORI may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3).

There are no data in pregnant women using crizotinib. This medicinal product should not be used during pregnancy unless the clinical condition of the mother requires treatment. Pregnant women, or patients becoming pregnant while receiving crizotinib, or treated male patients as partners of pregnant women, should be apprised of the potential hazard to the foetus.

Breast-feeding

It is not known whether crizotinib and its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should be advised to avoid breast-feeding while receiving XALKORI (see section 5.3).

Fertility

Based on non-clinical safety findings, male and female fertility may be compromised by treatment with XALKORI (see section 5.3). Both men and women should seek advice on fertility preservation before treatment.

4.7. Effects on ability to drive and use machines

XALKORI has minor influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension), vision disorder or fatigue while taking XALKORI (see sections 4.2, 4.4 and 4.8).

4.8. Undesirable effects

Summary of the safety profile in adult patients with ALK-positive or ROS1-positive advanced NSCLC

The data described below reflect exposure to XALKORI in 1669 patients with ALK-positive advanced NSCLC who participated in 2 randomised Phase 3 studies (Studies 1007 and 1014) and in 2 single-arm studies (Studies 1001 and 1005), and in 53 patients with ROS1-positive advanced NSCLC who participated in single-arm Study 1001, for a total of 1722 patients (see section 5.1). 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 study 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.

The most serious adverse reactions in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC were hepatotoxicity, ILD/pneumonitis, neutropenia and QT interval prolongation (see section 4.4). 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.

The most frequent adverse reactions (≥3%, all-causality frequency) associated with dosing interruptions were neutropenia (11%), elevated transaminases (7%), vomiting (5%) and nausea (4%). The most frequent adverse reactions (≥3%, all-causality frequency) associated with dose reductions were elevated transaminases (4%) and neutropenia (3%). All-causality adverse events associated with permanent treatment discontinuation occurred in 302 (18%) patients of which the most frequent (≥1%) were ILD (1%) and elevated transaminases (1%).

Tabulated list of adverse reactions

Table 9 presents adverse reactions reported in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC who received crizotinib across 2 randomised Phase 3 studies (1007 and 1014) and 2 single-arm clinical studies (1001 and 1005) (see section 5.1).

The adverse reactions listed in Table 9 are presented by system organ class and frequency categories, defined using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 9. Adverse reactions reported in crizotinib clinical studies of NSCLC (N=1722)

System organ class

Very common

Common

Uncommon

Blood and lymphatic system disorders

Neutropaeniaa (22%)

Anaemiab (15%)

Leukopeniac (15%)

Metabolism and nutrition disorders

Decreased appetite (30%)

Hypophosphataemia (6%)

Nervous system disorders

Neuropathyd (25%)

Dysgeusia (21%)

Eye disorders

Vision disordere (63%)

Cardiac disorders

Dizzinessf (26%)

Bradycardiag (13%)

Cardiac failureh (1%)

Electrocardiogram QT prolonged (4%)

Syncope (3%)

Respiratory, thoracic and mediastinal disorders

Interstitial lung diseasei (3%)

Gastrointestinal disorders

Vomiting (51%)

Diarrhoea (54%)

Nausea (57%)

Constipation (43%)

Abdominal painj (21%)

Oesophagitisk (2%)

Dyspepsia (8%)

Gastrointestinal perforationl (<1%)

Hepatobiliary disorders

Elevated transaminasesm (32%)

Blood alkaline phosphatase increased (7%)

Hepatic failure (<1%)

Skin and subcutaneous tissue disorders

Rash (13%)

Photosensitivity (<1%)

Renal and urinary disorders

Renal cystn (3%)

Blood creatinine increasedo (8%)

Acute renal failure (<1%)

Renal failure (<1%)

General disorders and administration site conditions

Oedemap (47%)

Fatigue (30%)

Investigations

Blood testosterone decreasedq (2%)

Blood creatine phosphokinase increased (<1%)*

Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse drug reaction in Table 9. Terms actually reported in the study up to the data cutoff date and contributing to the relevant adverse drug reaction are indicated in parentheses, as listed below.

* Creatine phosphokinase was not a standard laboratory test in the crizotinib clinical trials.

a. Neutropaenia (Febrile neutropaenia, Neutropaenia, Neutrophil count decreased).

b. Anaemia (Anaemia, Haemoglobin decreased, Hypochromic anaemia).

c. Leukopenia (Leukopenia, White blood cell count decreased).

d. Neuropathy (Burning sensation, Dysaesthesia, Formication, Gait disturbance, Hyperaesthesia, Hypoaesthesia, Hypotonia, Motor dysfunction, Muscle atrophy, Muscular weakness, Neuralgia, Neuritis, Neuropathy peripheral, Neurotoxicity, Paraesthesia, Peripheral motor neuropathy, Peripheral sensorimotor neuropathy, Peripheral sensory neuropathy, Peroneal nerve palsy, Polyneuropathy, Sensory disturbance, Skin burning sensation).

e. Vision disorder (Diplopia, Halo vision, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual brightness, Visual impairment, Visual perseveration, Vitreous floaters).

f. Dizziness (Balance disorder, Dizziness, Dizziness postural, Presyncope).

g. Bradycardia (Bradycardia, Heart rate decreased, Sinus bradycardia).

h. Cardiac failure (Cardiac failure, Cardiac failure congestive, Ejection fraction decreased, Left ventricular failure, Pulmonary oedema). Across clinical studies (n=1722), 19 (1.1%) patients treated with crizotinib had any grade cardiac failure, 8 (0.5%) patients had Grade 3 or 4, and 3 (0.2%) patients had fatal outcome.

i. Interstitial lung disease (Acute respiratory distress syndrome, Alveolitis, Interstitial lung disease, Pneumonitis).

j. Abdominal pain (Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness).

k. Oesophagitis (Oesophagitis, Oesophageal ulcer).

l. Gastrointestinal perforation (Gastrointestinal perforation, Intestinal perforation, Large intestine perforation).

m. Elevated transaminases (Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Liver function test abnormal, Transaminases increased).

n. Renal cyst (Renal abscess, Renal cyst, Renal cyst haemorrhage, Renal cyst infection).

o. Blood creatinine increased (blood creatinine increased, creatinine renal clearance decreased).

p. Oedema (Face oedema, Generalised oedema, Local swelling, Localised oedema, Oedema, Oedema peripheral, Periorbital oedema).

q. Blood testosterone decreased (Blood testosterone decreased, Hypogonadism, Secondary hypogonadism).

Summary of the safety profile in paediatric patients

The safety analysis population for 110 paediatric patients with all tumour types (ages 1 to <18 years), which included 41 patients with relapsed or refractory systemic ALK-positive ALCL or with unresectable, recurrent, or refractory ALK-positive IMT is based on patients who received crizotinib from 2 single-arm studies, Study 0912 (n=36) and Study 1013 (n=5). In Study 0912, patients received crizotinib at a starting dose of 100 mg/m2, 130 mg/m2, 165 mg/m2, 215 mg/m2, 280 mg/m2, or 365 mg/m2 twice daily. In Study 1013, crizotinib was administered at a starting dose of 250 mg twice daily. There was a total population of 25 paediatric patients with ALK-positive ALCL from 3 to <18 years of age and 16 paediatric patients with ALK-positive IMT from 2 to <18 years of age. Experience on the use of crizotinib in paediatric patients in the different subgroups (age, gender and race) is limited and does not allow for definitive conclusions to be made. The safety profiles were consistent across the subgroups of age, gender and race, although there were slight differences in adverse reactions frequencies within each subgroup. The most frequent adverse reactions (≥80%) reported in all subgroups (age, gender and race) were elevated transaminases, vomiting, neutropenia, nausea, diarrhoea and leukopenia. The most frequent serious adverse reaction (90%) was neutropenia.

The median duration of treatment for paediatric patients with all tumour types was 2.8 months. Permanent discontinuation from treatment due to an adverse event occurred in 11 (10%) patients. Dosing interruptions and dose reductions occurred in 47 (43%) and 15 (14%), respectively. The most frequent adverse reactions (>60%) were elevated transaminases, vomiting, neutropenia, nausea, diarrhoea and leukopenia. The most frequent Grade 3 or 4 adverse reactions (≥40%) was neutropenia.

The median duration of treatment for paediatric patients with ALK-positive ALCL was 5.1 months. Permanent discontinuation from treatment due to an adverse event occurred in 1 patient (4%). Eleven of 25 (44%) patients with ALK-positive ALCL permanently discontinued crizotinib treatment due to subsequently having a haematopoietic stem cell transplant (HSCT). Dosing interruptions and dose reductions occurred in 17 (68%) and 4 (16%) patients, respectively. The most frequent adverse reactions (≥80%) were diarrhoea, vomiting, elevated transaminases, neutropenia, leukopenia and nausea. The most frequent Grade 3 or 4 adverse reactions (≥40%) were neutropenia, leukopenia and lymphopenia.

The median duration of treatment for paediatric patients with ALK-positive IMT was 21.8 months. Permanent discontinuation from treatment due to an adverse event occurred in 4 (25%) patients. Dosing interruptions and dose reductions occurred in 12 (75%) and 4 (25%) patients, respectively. The most frequent adverse reactions (≥80%) were neutropenia, nausea and vomiting. The most frequent Grade 3 or 4 adverse reaction (≥40%) was neutropenia.

The safety profile of crizotinib in paediatric patients with ALK-positive ALCL or with ALK-positive IMT was generally consistent with that previously established in adults with ALK-positive or ROS1-positive advanced NSCLC, with some variations in frequencies. Grade 3 or 4 adverse reactions of neutropenia, leukopenia and diarrhoea were reported with higher frequency (difference of ≥10%) in paediatric patients with either ALK-positive ALCL or ALK-positive IMT than in adult patients with ALK-positive or ROS1-positive NSCLC. The age, comorbidities and underlying conditions are different in these 2 populations, which could explain the differences in the frequencies.

The adverse reactions for paediatric patients of all tumour types listed in Table 10 are presented by system organ class and frequency categories, defined using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 10. Adverse reactions reported in paediatric patients (N=110)

All Tumour Types

(N=110)

System organ class

Very common

Common

Blood and lymphatic system disorders

Neutropeniaa (71%)

Leukopeniab (63%)

Anaemiac (52%)

Thrombocytopeniad (21%)

Metabolism and nutrition disorders

Hypophosphataemia (30%)

Decreased appetite (39%)

Nervous system disorders

Neuropathye (26%)

Dysgeusia (10%)

Eye disorders

Vision disorderf (44%)

Cardiac disorders

Bradycardiag (14%)

Dizziness (16%)

Electrocardiogram QT prolonged (4%)

Gastrointestinal disorders

Vomiting (77%)

Diarrhoea (69%)

Nausea (71%)

Constipation (31%)

Dyspepsia (10%)

Abdominal painh (43%)

Oesophagitis (4%)

Hepatobiliary disorders

Elevated transaminasesi (87%)

Blood alkaline phosphatase increased (19%)

Skin and subcutaneous tissue disorders

Rash (3%)

Renal and urinary disorders

Blood creatinine increased (45%)

General disorders and administration site conditions

Oedemaj (20%)

Fatigue (46%)

Date of Data Cutoff: 03 Sep 2019.

Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse drug reaction in Table 10. Terms actually reported in the study up to the data cutoff date and contributing to the relevant adverse drug reaction are indicated in parentheses, as listed below.

a. Neutropenia (Febrile neutropenia, Neutropenia, Neutrophil count decreased)

b. Leukopenia (Leukopenia, White blood cell count decreased)

c. Anaemia (Anaemia, Anaemia macrocytic, Anaemia megaloblastic, Haemoglobin, Haemoglobin decreased, Hyperchromic anaemia, Hypochromic anaemia, Hypoplastic anaemia, Microcytic anaemia, Normochromic normocytic anaemia)

d. Thrombocytopenia (Platelet count decreased, Thrombocytopenia)

e. Neuropathy (Burning sensation, Gait disturbance, Muscular weakness, Paraesthesia, Peripheral motor neuropathy, Peripheral sensory neuropathy)

f. Vision disorder (Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous floaters)

g. Bradycardia (Bradycardia, Sinus bradycardia)

h. Abdominal pain (Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness)

i. Elevated transaminases (Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased)

j. Oedema (Face oedema, Localised oedema, Oedema peripheral, Periorbital oedema)

Although not all adverse reactions identified in the adult population have been observed in clinical trials of paediatric patients, the same adverse reactions for adult patients should be considered for paediatric patients. The same warnings and precautions for adult patients should also be considered for paediatric patients.

Description of selected adverse reactions

Hepatotoxicity

Patients should be monitored for hepatotoxicity and managed as recommended in sections 4.2 and 4.4.

Adult patients with NSCLC

Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of 1722 adult patients with NSCLC treated with crizotinib across clinical studies. Concurrent elevations in ALT and/or AST ≥3 × ULN and total bilirubin ≥2 × ULN without significant elevations of alkaline phosphatase (≤2 × ULN) have been observed in less than 1% of patients treated with crizotinib.

Increases to Grade 3 or 4 ALT or AST elevations were observed in 187 (11%) and 95 (6%) of adult patients, respectively. 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 4 (see section 4.2). In randomised Phase 3 Study 1014, increases to Grade 3 or 4 ALT or AST elevations were observed in 15% and 8% of patients receiving crizotinib versus 2% and 1% of patients receiving chemotherapy. In randomised Phase 3 Study 1007, increases to Grade 3 or 4 ALT or AST elevations were observed in 18% and 9% of patients receiving crizotinib and 5% and <1% of patients receiving chemotherapy.

Transaminase elevations generally occurred within the first 2 months of treatment. Across studies with crizotinib in adult 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.

Grade 3 and 4 transaminase elevations were generally reversible upon dosing interruption. Across studies with crizotinib in adult 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.

Paediatric patients

In clinical studies of 110 paediatric patients with various tumour types treated with crizotinib, 70% and 75% of patients had increases of AST and ALT, respectively, with Grade 3 and 4 increases in 7% and 6% of patients, respectively.

Gastrointestinal effects

Supportive care should include the use of antiemetic medicinal products. For additional supportive care for paediatric patients, see section 4.4.

Adult patients with NSCLC

Nausea (57%), diarrhoea (54%), vomiting (51%) and constipation (43%) were the most commonly reported all-causality gastrointestinal events in adult patients with either ALK-positive or ROS1-positive NSCLC. Most events were mild to moderate in severity. Median times to onset for nausea and vomiting were 3 days, and these events declined in frequency after 3 weeks of treatment. 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 medicinal products, respectively.

In clinical studies of adult patients with NSCLC treated with crizotinib, events of gastrointestinal perforations were reported. There were reports of fatal cases of gastrointestinal perforation during post-marketing use of crizotinib (see section 4.4).

Paediatric patients

In clinical trials, vomiting (77%), diarrhoea (69%), nausea (71%), abdominal pain (43%) and constipation (31%) were the most frequently reported all-causality gastrointestinal events in 110 paediatric patients with a variety of tumour types treated with crizotinib. For those patients with either ALK-positive ALCL or ALK-positive IMT treated with crizotinib, vomiting (95%), diarrhoea (85%), nausea (83%), abdominal pain (54%) and constipation (34%) were the most frequently reported all-causality gastrointestinal events (see section 4.4). Crizotinib can cause severe gastrointestinal toxicities in paediatric patients with ALCL or IMT (see section 4.4).

QT interval prolongation

QT prolongation can result in arrhythmias and is a risk factor for sudden death. QT prolongation may clinically manifest as bradycardia, dizziness and syncope. Electrolyte disturbances, dehydration and bradycardia may further increase the risk of QTc prolongation and thus, periodic monitoring of ECG and electrolyte levels is recommended in patients with GI toxicity (see section 4.4).

Adult patients with NSCLC

Across studies in adult patients with either ALK-positive or ROS1-positive advanced NSCLC, QTcF (corrected QT by the Fridericia method) ≥500 msec was recorded in 34 (2.1%) of 1619 patients with at least 1 postbaseline ECG assessment and a maximum increase from baseline in QTcF ≥60 msec was observed in 79 (5.0%) of 1585 patients with a baseline and at least 1 postbaseline ECG assessment. All-causality Grade 3 or 4 Electrocardiogram QT prolonged was reported in 27 (1.6%) out of 1722 patients (see sections 4.2, 4.4, 4.5 and 5.2).

In a single-arm ECG substudy in adult patients (see section 5.2) using blinded manual ECG measurements 11 (21%) patients had an increase from Baseline in QTcF value ≥30 to <60 msec and 1 (2%) patient had an increase from Baseline in QTcF value of ≥60 msec. No patients had a maximum QTcF ≥480 msec. The central tendency analysis indicated that the largest mean change from baseline in QTcF was 12.3 msec (95% CI 5.1-19.5 msec, least squares mean [LS] from Analysis of Variance [ANOVA]) and occurred at 6 hours post-dose on Cycle 2 Day 1. All upper limits of the 90% CI for the LS mean change from Baseline in QTcF at all Cycle 2 Day 1 time points were <20 msec.

Paediatric patients

In clinical studies with crizotinib in 110 paediatric patients with a variety of tumour types, electrocardiogram QT prolonged was reported in 4% of patients.

Bradycardia

The use of concomitant medicinal products associated with bradycardia should be carefully evaluated. Patients who develop symptomatic bradycardia should be managed as recommended in the Dose Modification and Warnings and Precautions sections (see sections 4.2, 4.4 and 4.5).

Adult patients with NSCLC

In studies with crizotinib in adult 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 postbaseline vital sign assessment had a pulse rate <50 bpm.

Paediatric patients

In clinical studies with crizotinib in 110 paediatric patients with a variety of tumour types, all-causality bradycardia was reported in 14% of patients, including Grade 3 bradycardia in 1% of patients.

Interstitial lung disease/pneumonitis

Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. Other potential causes of ILD/pneumonitis should be excluded (see sections 4.2 and 4.4).

Adult patients with NSCLC

Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with crizotinib. Across studies in adult patients with either ALK-positive or ROS1-positive NSCLC (N=1722), 50 (3%) patients treated with crizotinib had any grade all-causality ILD, including 18 (1%) patients with Grade 3 or 4, and 8 (<1%) patients with fatal cases. According to an independent review committee (IRC) assessment of patients with ALK-positive NSCLC (N=1669), 20 (1.2%) patients had ILD/pneumonitis, including 10 (<1%) patients with fatal cases. These cases generally occurred within 3 months after the initiation of treatment.

Paediatric patients

ILD/pneumonitis was reported in clinical studies with crizotinib in paediatric patients with a variety of tumour types in 1 patient (1%), which was Grade 1 pneumonitis.

Visual effects

Ophthalmological evaluation is recommended if vision disorder persists or worsens in severity. Baseline and follow-up ophthalmologic examinations should be obtained for paediatric patients (see sections 4.2 and 4.4).

Adult patients with NSCLC

In clinical studies with crizotinib in adult patients with either ALK-positive or ROS1-positive advanced 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 (see section 4.4).

All-causality, all grade, vision disorder, most commonly visual impairment, photopsia, vision blurred and vitreous floaters, was experienced by 1084 (63%) of 1722 adult patients treated with crizotinib. Of the 1084 patients who experienced vision disorder, 95% had events that were mild 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), adult 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 disorders generally started within the first week of medicinal product administration. The majority of patients on the crizotinib arm in randomised Phase 3 Studies 1007 and 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.

An ophthalmology substudy using specific ophthalmic assessments at specified time points was conducted in 54 adult patients with NSCLC who received crizotinib 250 mg twice daily. Thirty-eight (70.4%) of the 54 patients experienced an Eye Disorders System Organ Class treatment-emergent all-causality adverse event of which 30 patients had ophthalmic examinations. Of the 30 patients, an ophthalmic abnormality of any type was reported in 14 (36.8%) patients and no ophthalmic finding was seen in 16 (42.1%) patients. The most common findings concerned slit lamp biomicroscopy (21.1%), fundoscopy (15.8%) and visual acuity (13.2%). Pre-existing ophthalmic abnormalities and concomitant medical conditions which could be contributory to ocular findings were noted in many patients, and no conclusive causal relationship to crizotinib could be determined. There were no findings related to aqueous cell count and anterior chamber aqueous flare assessment. No visual disturbances associated with crizotinib appeared to be related to changes in best corrected visual acuity, the vitreous, the retina or the optic nerve.

In adult patients with new onset of Grade 4 visual loss, crizotinib treatment should be discontinued and ophthalmological evaluation should be performed.

Paediatric patients

In clinical studies with crizotinib in 110 paediatric patients with a variety of tumour types, vision disorder has been reported in 48 (44%) patients. The most common visual symptoms were blurred vision (20%) and visual impairment (11%).

In clinical studies with crizotinib, 41 patients with ALK-positive ALCL or ALK-positive IMT, vision disorder has been reported in 25 (61%) patients. Of these paediatric patients who experienced visual disorders, one patient with IMT experienced Grade 3 myopic optic nerve disorder, which was present as Grade 1 at baseline. The most common visual symptoms were blurred vision (24%), visual impairment (20%), photopsia (17%) and vitreous floaters (15%). All were Grade 1 or 2.

Nervous system effects

Adult patients with NSCLC

All-causality neuropathy, as defined in Table 9, was experienced by 435 (25%) out of 1722 adult patients with either ALK-positive or ROS1-positive advanced NSCLC treated with crizotinib. Dysgeusia was also very commonly reported in these studies and was primarily Grade 1 in severity.

Paediatric patients

In clinical studies with crizotinib in 110 paediatric patients with a variety of tumour types, neuropathy and dysgeusia were reported in 26% and 9% of patients, respectively.

Renal cyst

Periodic monitoring with imaging and urinalysis should be considered in patients who develop renal cysts.

Adult patients with NSCLC

All-causality complex renal cysts were experienced by 52 (3%) of 1722 adult patients with either ALK-positive or ROS1-positive advanced NSCLC treated with crizotinib. Local cystic invasion beyond the kidney was observed in some patients.

Paediatric patients

In clinical studies with crizotinib in 110 paediatric patients with a variety of tumour types, renal cyst was not reported.

Neutropenia and leukopenia

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. For patients who develop haematologic laboratory abnormalities, see section 4.2.

Adult patients with NSCLC

Across studies in adult patients with either ALK-positive or ROS1-positive advanced NSCLC (N=1722), Grade 3 or 4 neutropenia was observed in 212 (12%) patients treated with crizotinib. Median time to onset of any grade neutropenia was 89 days. Neutropenia was associated with dose reduction or permanent treatment discontinuation for 3% and <1% of patients, respectively. Less than 0.5% of patients experienced febrile neutropenia in clinical studies with crizotinib.

Across studies in adult patients with either ALK-positive or ROS1-positive advanced NSCLC (N=1722), Grade 3 or 4 leukopenia was observed in 48 (3%) patients treated with crizotinib. Median time to onset of any grade leukopenia was 85 days. Leukopenia was associated with a dose reduction for <0.5% of patients, and no patients permanently discontinued crizotinib treatment associated with leukopenia.

In clinical studies of crizotinib in adult patients with either ALK-positive or ROS1-positive advanced NSCLC, shifts to Grade 3 or 4 decreases in leukocytes and neutrophils were observed at frequencies of 4% and 13%, respectively.

Paediatric patients

In clinical studies with crizotinib in 110 paediatric patients with a variety of tumour types, neutropenia was reported in 71% of patients, including Grade 3 or 4 neutropenia observed in 58 patients (53%). Febrile neutropenia was experienced by 4 patients (3.6%). Leukopenia was reported in 63% of patients, including Grade 3 or 4 leukopenia observed in 18 patients (16%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Treatment of overdose with the medicinal product consists of general supportive measures. There is no antidote for XALKORI.