XALKORI (crizotinib) Dosage And Administration | Pfizer Medical Information

Recommended Dose and Dosage Adjustment

The recommended dose schedule of XALKORI (crizotinib) is 250 mg taken orally twice daily with or without food. Treatment should be continued as long as the patient is deriving clinical benefit from therapy. Capsules should be swallowed whole.

For patients with moderate hepatic impairment (any AST and total bilirubin >1.5×ULN and ≤3×ULN), the starting XALKORI dose is recommended to be 200 mg twice daily. For patients with severe hepatic impairment (any AST and total bilirubin >3×ULN), the starting XALKORI dose is recommended to be 250 mg once daily.

The starting dose of XALKORI should be 250 mg once daily in patients with severe renal impairment (CLcr < 30 mL/min) not requiring peritoneal dialysis or hemodialysis.

The concurrent use of strong CYP3A inhibitors such as ketoconazole should be avoided (see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY sections).

The concurrent use of strong CYP3A inducers such as rifampin should be avoided (see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY sections).

Missed Dose

If a dose of XALKORI is missed, then it should be taken as soon as possible. If it is less than 6 hours until the next dose, then 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 Modification

Dose reduction and/or treatment interruption may be required based on individual safety and tolerability.

The recommended dose reductions for patients treated with XALKORI 250 mg orally twice daily are:

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 modification guidelines for hematologic and non-hematologic toxicities are provided in Tables 6 and 7. For dose modifications in patients treated with a XALKORI dose lower than 250 mg twice daily follow the recommendations in Table 6 and Table 7 accordingly.

Table 6. XALKORI Dose Modification – Hematologic Toxicities^a
a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections) b NCI Common Terminology Criteria for Adverse Events c In case of recurrence, withhold until recovery to Grade ≤2 or baseline, then resume at 250 mg taken orally once daily. Permanently discontinue in case of further Grade 4 recurrence. d For patients treated with 250 mg once daily or whose dose was reduced to 250 mg once daily, discontinue during evaluation.
CTCAE^b Grade	XALKORI Dosing
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 the next lower dose ^c,d

Table 7. XALKORI Dose Modification – Non-Hematologic Toxicities
a NCI Common Terminology Criteria for Adverse Events b In case of recurrence, withhold until recovery to Grade ≤ 1or baseline, then resume at 250 mg taken orally once daily. Permanently discontinue in case of further Grade 3 or 4 recurrence. c For patients treated with 250 mg once daily or whose dose was reduced to 250 mg once daily, discontinue during evaluation. d In the absence of NSCLC progression, other pulmonary disease, infection, or radiation effect e Heart rate less than 60 beats per minute (bpm). f Permanently discontinue for recurrence.
CTCAE^a Grade	XALKORI Dosing
Grade 3 or 4 ALT or AST elevation with Grade <1 total bilirubin	Withhold until recovery to Grade ≤ 1 or baseline, then resume at the next lower dose ^b,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 hemolysis)	Permanently discontinue
Any grade interstitial lung disease/pneumonitis^d	Permanently discontinue
Grade 3 QTc prolongation (≥500 msec)	Withhold until recovery to Grade <1 (≤ 470 msec), then resume at the next lower dose^b,c
Grade 4 QTc prolongation (≥500 msec [or >60 msec change from baseline] and Torsade de Pointes or polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmias)	Permanently discontinue
Grade 2, 3 Bradycardia^e(symptomatic, may be severe and medically significant, medical intervention indicated)	Withhold until recovery to Grade ≤ 1 or to heart rate of 60 bpm or above Evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to Grade ≤ 1 or to 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 Grade ≤ 1 or to heart rate of 60 bpm or above
Grade 4 Bradycardia^e,f (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 250 mg once daily upon recovery to Grade ≤ 1 or to heart rate of 60 bpm or above, with frequent monitoring
Grade 4 Visual Loss	Discontinue during evaluation of severe vision loss

QT Interval Prolongation

In the event of a QTc of ≥500 msec (Grade 3), dosing with XALKORI should be withheld until recovery to Grade ≤1 (≤470 msec), then resumed at a reduced dose of 200 mg twice daily. Permanent discontinuation of XALKORI is recommended in the event of a Grade 4 QTc prolongation (≥500 msec [or >60 msec change from baseline] and Torsade de Pointes or polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmias). Machine-read QTc measurements may not be accurate. Consultation with a cardiologist should be considered when assessing the QTcF to ensure appropriate treatment decisions. Baseline ECG QTcF should be measured prior to initiating treatment with XALKORI and ECGs should be repeated periodically during treatment with XALKORI. Hypokalemia, hypomagnesemia, and hypocalcemia must be corrected prior to XALKORI administration. Serum levels of calcium, potassium, and magnesium should be monitored periodically during treatment, particularly in patients at risk for these electrolyte abnormalities (see WARNINGS AND PRECAUTIONS).

Special Populations

Hepatic Impairment
Crizotinib is extensively metabolized in the liver. Treatment with XALKORI should be used with caution in patients with hepatic impairment. Based on the results from a clinical study in patients with advanced cancer and varying degrees of hepatic impairment (based on National Cancer Institute (NCI) classification), no starting dose adjustment of XALKORI 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). For patients with moderate hepatic impairment (any AST and total bilirubin >1.5×ULN and ≤3×ULN), the starting XALKORI dose is recommended to be 200 mg twice daily. For patients with severe hepatic impairment (any AST and total bilirubin >3×ULN), the starting XALKORI dose is recommended to be 250 mg once daily. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Impairment.)

Renal Impairment
The starting dose of XALKORI should be reduced by 50% (250 mg once daily) in patients with severe renal impairment (CLcr < 30 mL/min) not requiring peritoneal dialysis or hemodialysis. No starting dose adjustment is recommended in patients with mild or moderate renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

No data are available for patients with severe renal impairment requiring peritoneal dialysis or hemodialysis (CLcr < 30 mL/min) (see Serious Warnings and Precautions, and ACTION AND CLINICAL PHARMACOLOGY).