Posology : מינונים

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.

Patient Selection
Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens

Recommended Dosing
The recommended dose of XALKORI is 250 mg orally, twice daily until disease progression or no longer tolerated by the patient.

The recommended dose of XALKORI in patients with severe renal impairment [creatinine clearance (CLcr) <30 mL/min] not requiring dialysis is 250 mg orally, once daily

XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of XALKORI, take the next dose at the regular time.

Dose Modification

Reduce dose as below, if 1 or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0:
• 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 are provided in Tables 1 and 2.

Table 1. XALKORI Dose Modification – Hematologic Toxicitiesa
Grade                      XALKORI Dosing
Grade 3                    Withhold until recovery to Grade 2 or less, then resume at the same dose schedule
Grade 4                    Withhold until recovery to Grade 2 or less, then resume at next lower dose a
Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Table 2. XALKORI Dose Modification – Non-Hematologic Toxicities
Criteria                                  XALKORI Dosing
Alanine aminotransferase (ALT)            Withhold until recovery to baseline or less than or or aspartate aminotransferase             equal to 3 times ULN, then resume at reduced dose.
(AST) elevation greater than
5 times upper limit of normal
(ULN) with total bilirubin less than or equal to 1.5 times ULN
ALT or AST elevation greater              Permanently discontinue.
than 3 times ULN with concurrent total bilirubin elevation greater than 1.5 times ULN (in the absence of cholestasis or hemolysis)
Any grade drug-related interstitial       Permanently discontinue.
lung disease/pneumonitis
QT corrected for heart rate (QTc)         Withhold until recovery to baseline or to a QTc less greater than 500 ms on at least           than 481 ms, then resume at reduced dose.
2 separate electrocardiograms
(ECGs)
        QTc greater than 500 ms or                Permanently discontinue.
greater than or equal to 60 ms change from baseline with
Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia
Bradycardiaa (symptomatic, may            Withhold until recovery to asymptomatic be severe and medically                   bradycardia or to a heart rate of 60 bpm or above.
significant, medical intervention indicated)                                Evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications.

If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above.

If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified,
resume at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of
60 bpm or above.
Bradycardiaa,b (life-threatening          Permanently discontinue if no contributing consequences, urgent intervention         concomitant medication is identified.
indicated)
If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at
250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above,
with frequent monitoring.
Visual Loss (Grade 4 Ocular               Discontinue during evaluation of severe vision loss.
Disorder) a Heart rate less than 60 beats per minute (bpm).
b
Permanently discontinue for recurrence.


Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.

Hepatic impairment

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:
Hepatic impairment grade                       XALKORI Dosing mild hepatic impairment (either AST >          no starting dose adjustment of crizotinib is Upper Limit of Normal (ULN) and total          recommended bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5 × ULN)

moderate hepatic impairment (any AST and         The starting crizotinib dose is recommended total bilirubin >1.5 × ULN and ≤3 × ULN)         to be 200 mg twice daily severe hepatic impairment (any AST and           The starting crizotinib dose is recommended total bilirubin >3 × ULN)                        to be 250 mg once daily 
Crizotinib dose adjustment according to Child-Pugh classification has not been studied in patients with hepatic impairment.

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