Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
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).
Treatment with XALKORI should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
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 trials).
Either ALK-positive or ROS1-positive NSCLC 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).
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 1722 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.
Dose reduction guidelines for haematological and non-haematological toxicities are provided in Tables 1 and 2. For patients treated with a lower dose of crizotinib than 250 mg twice daily, then follow the dose reduction guidelines provided in Tables 1 and 2 accordingly.
Table 1. 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 2. 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 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.
Crizotinib is extensively metabolized in the liver. Treatment with crizotinib should be used with caution in patients with hepatic impairment (see Table 2 and sections 4.4, 4.8 and 5.2).
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.
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).
No starting dose adjustment is required (see sections 5.1 and 5.2).
The safety and efficacy of crizotinib in paediatric patients has not been established. No data are available.
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).
Treatment of overdose with the medicinal product consists of general supportive measures. There is no antidote for XALKORI.
Shelf life: 4 years.
This medicinal product does not require any special storage conditions.
XALKORI 200 mg hard capsules:
HDPE bottles with a polypropylene closure containing 60 hard capsules.
PVC-foil blisters containing 10 hard capsules.
Each carton contains 60 hard capsules.
XALKORI 250 mg hard capsules:
HDPE bottles with a polypropylene closure containing 60 hard capsules.
PVC-foil blisters containing 10 hard capsules.
Each carton contains 60 hard capsules.
Not all pack sizes may be marketed.
Any unused product or waste material should be disposed of in accordance with local requirements.
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