Table of Contents
1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

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1. Name of the medicinal product
 XALKORI 200 mg hard capsules

XALKORI 250 mg hard capsules

2. Qualitative and quantitative composition
 Each hard capsule contains 200 mg of crizotinib.

Each hard capsule contains 250 mg of crizotinib.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form
 Hard capsule.

White opaque and pink opaque hard capsule, with “Pfizer” imprinted on the cap and “CRZ 200” on the body.

Pink opaque hard capsule, with “Pfizer” imprinted on the cap and “CRZ 250” on the body.

4. Clinical particulars
  
4.1 Therapeutic indications
 XALKORI is indicated for the treatment of adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).

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 testing

An accurate and validated ALK assay is necessary for the selection of patients for treatment with XALKORI (see section 5.1 for information on assays used in the trials).

ALK-positive NSCLC status should be established prior to initiation of XALKORI therapy.

Assessment should be performed by laboratories with demonstrated proficiency in the specific technology being utilised (see section 4.4).

Posology

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

If a dose 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.

Dose adjustments

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. In randomised Phase 3 Study 1, the most frequent adverse reactions that led to dosing interruptions were neutropenia, elevated transaminases, nausea and vomiting. The most frequent adverse reactions that led to dose reductions were elevated transaminases, electrocardiogram QT prolonged, and neutropenia. If dose reduction is necessary, then the dose of XALKORI should be reduced to 200 mg taken twice daily. If further dose reduction is necessary, then the dose should be modified to 250 mg taken once daily based on individual safety and tolerability. Dose reduction guidelines for hematologic and non-hematologic toxicities are provided in Tables 1 and 2.

Table 1. XALKORI dose modification – Hematologic toxicitiesa,b

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.

Table 2. XALKORI dose modification – Non-hematologic toxicities
 
 

a. 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. See sections 4.4 and 4.8.

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

e. Permanently discontinue for recurrence.

Hepatic impairment

XALKORI has not been studied in patients with hepatic impairment. Clinical studies that were conducted excluded patients with AST or ALT >2.5×upper limit of normal (ULN), or if due to underlying malignancy, >5.0×ULN or with total bilirubin >1.5×ULN. Treatment with XALKORI should be used with caution in patients with mild and moderate hepatic impairment. XALKORI should not be used in patients with severe hepatic impairment (see sections 4.3, 4.4 and 4.8).

Renal impairment

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 dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis. 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).

Elderly

Of the 172 crizotinib-treated patients in randomised Phase 3 Study 1, 27 (16%) were 65 years or older. Of the 149 patients in Study A, 20 (13%) were 65 years or older. Of the 934 patients in Study B, 152 (16%) were 65 years or older (see section 5.2). No overall differences in safety or efficacy were observed in comparison with younger patients.

Paediatric population

The safety and efficacy of XALKORI in paediatric patients has not been established. No data are available.

Method of administration

The capsules should be swallowed whole preferably with water, and should not be crushed, dissolved, or opened. They may be taken with or without 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).

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

Severe hepatic impairment (see sections 4.2, 4.4 and 4.8).
4.4 Special warnings and precautions for use
 Assessment of ALK status

When assessing the ALK 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 has occurred. These cases have occurred during XALKORI treatment in less than 1% of patients in clinical trials. Concurrent elevations in ALT greater than 3×ULN and total bilirubin greater than 2×ULN without elevated alkaline phosphatase have been observed in less than 1% patients in clinical trials. Increases to Grade 3 or 4 ALT elevations were observed in 17% of patients receiving crizotinib versus 4% of patients receiving chemotherapy in randomised Phase 3 Study 1. Increases to Grade 3 or 4 ALT elevations were observed in 7% of patients in Study A and 8% of patients in Study B. Grade 3 and 4 elevations were generally reversible upon dosing interruption. Two patients from randomised Phase 3 Study 1 (1%), 1 patient from Study A (< 1%) and 6 patients from Study B (< 1%) required permanent discontinuation from treatment. Transaminase elevations generally occurred within the first 2 months of treatment. XALKORI should not be used in patients with severe hepatic impairment (including patients with total bilirubin > 3 × ULN regardless of ALT/AST) (see sections 4.2, 4.3 and 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, and/or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across randomized Phase 3 Study 1 and Studies A and B (n=1255), 33 (2.6%) patients treated with crizotinib had any grade ILD, including 13 (1%) patients with Grade 3 or 4, and 6 (0.5%) patients with fatal cases. These cases generally occurred within 2 months after the initiation of treatment. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. XALKORI 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 edema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, obliterative bronchiolitis, and bronchiectasis. Other potential causes of ILD/pneumonitis should be excluded, and XALKORI 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 XALKORI (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. XALKORI should be administered with caution in these patients and periodic monitoring of electrocardiograms (ECG), electrolytes and renal function is required. When using XALKORI, 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

Treatment-emergent all-causality bradycardia was reported in clinical studies in 5 to 10% of patients treated with crizotinib. Symptomatic bradycardia (e.g., syncope, dizziness, hypotension) can occur in patients receiving XALKORI. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after start of treatment. Avoid using crizotini