HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
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`XALKORI® safely and effectively. See full prescribing information for
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`
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`XALKORI.
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`XALKORI® (crizotinib) Capsules, oral
`
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`Initial U.S. Approval: 2011
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`----------------------------INDICATIONS AND USAGE---------------------------
`
`
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`XALKORI is a kinase inhibitor indicated for the treatment of patients with
`
`
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`metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic
`
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`
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`lymphoma kinase (ALK)-positive as detected by an FDA-approved test. (1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
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`Recommended dose: 250 mg orally, twice daily (2.2)
`
`•
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`Renal Impairment: 250 mg orally, once daily in patients with severe
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`•
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`renal impairment (creatinine clearance <30 mL/min) not requiring
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`dialysis. (2.2)
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`Dosing interruption and/or dose reductions may be required based on
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`adverse drug reactions. (2.3)
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`•
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`•
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`•
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`•
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`QT Interval Prolongation: Occurred in 2.7% of patients. Monitor with
`
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`electrocardiograms and electrolytes in patients who have a history of or
`predisposition for QTc prolongation, or who are taking medications that
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`prolong QT. Temporarily suspend, dose reduce, or permanently
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`discontinue XALKORI. (5.3)
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`Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and
`
`blood pressure regularly. Temporarily suspend, dose reduce, or
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`permanently discontinue XALKORI. (5.4)
`
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`Embryofetal Toxicity: XALKORI can cause
`administered to a pregnant woman. (5.5, 8.1)
`
`
`
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`fetal harm when
`
`
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`------------------------------ADVERSE REACTIONS-------------------------------
`
`The most common adverse reactions (≥25%) are vision disorders, nausea,
`
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`
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`diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
`
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`
`(6)
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`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
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`
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`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------DRUG INTERACTIONS-------------------------------
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`CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong
`•
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`CYP3A inhibitors. (7.1)
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`CYP3A Inducers: Avoid concurrent use of XALKORI with strong
`
`CYP3A inducers. (7.2)
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`CYP3A Substrates: Avoid concurrent use of XALKORI with CYP3A
`
`
`substrates with narrow therapeutic indices. (7.3)
`
`
`•
`
`
`•
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`
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`---------------------DOSAGE FORMS AND STRENGTHS----------------------
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`
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`Capsules: 250 mg and 200 mg (3)
`•
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
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`None (4)
`•
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`
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`See 17 for PATIENT COUNSELING INFORMATION and FDA-
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`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`approved patient labeling.
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`Hepatotoxicity: Fatal hepatotoxicity occurred in 0.2% of patients.
`•
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`Monitor with periodic liver testing. Temporarily suspend, dose reduce,
`
`or permanently discontinue XALKORI. (5.1)
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`Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2% of patients.
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`Permanently discontinue in patients with ILD/pneumonitis. (5.2)
`_______________________________________________________________________________________________________________________________________
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`•
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`Revised: 03/2015
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`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
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`2
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`
`8
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`USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`8.6 Hepatic Impairment
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`8.7 Renal Impairment
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`10 OVERDOSAGE
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`
`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`* Sections or subsections omitted from the Full Prescribing Information are
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`not listed.
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`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
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`2.1 Patient Selection
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`2.2 Recommended Dosing
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`2.3 Dose Modification
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`DOSAGE FORMS AND STRENGTHS
`3
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`CONTRAINDICATIONS
`4
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Hepatotoxicity
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`5.2
`Interstitial Lung Disease (Pneumonitis)
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`5.3 QT Interval Prolongation
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`5.4 Bradycardia
`5.5 Embryofetal Toxicity
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`ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`DRUG INTERACTIONS
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`7.1 Drugs That May Increase Crizotinib Plasma Concentrations
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`7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
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`7.3 Drugs Whose Plasma Concentrations May Be Altered By
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`Crizotinib
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`_______________________________________________________________________________________________________________________________________
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`
`6
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`7
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`
`Reference ID: 3719195
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`
`
` 1
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`

`

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`INDICATIONS AND USAGE
`
` FULL PRESCRIBING INFORMATION
`
`
`1
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`
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`
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`XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose
`
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`tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
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`2
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`DOSAGE AND ADMINISTRATION
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`2.1 Patient Selection
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`Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK positivity
`in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved
`
`tests for the detection of ALK rearrangements in NSCLC is available at
`
`http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.
`
` 2.2 Recommended Dosing
`
` The recommended dose of XALKORI is 250 mg orally, twice daily until disease progression or no longer
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` tolerated by the patient. The recommended dose of XALKORI in patients with severe renal impairment
` (creatinine clearance <30 mL/min) not requiring dialysis is 250 mg orally, once daily [see Use in Specific
`
`
`
`
`
`
` Populations (8.7) and Clinical Pharmacology (12.3)].
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`
` XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed,
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` 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.
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`2.3 Dose Modification
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`Reduce dose as below, if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4
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`severity, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:
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`• First dose reduction: XALKORI 200 mg taken orally twice daily
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`• Second dose reduction: XALKORI 250 mg taken orally once daily
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`• Permanently discontinue if unable to tolerate XALKORI 250 mg taken once daily
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`Dose reduction guidelines are provided in Tables 1 and 2.
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` Table 1. XALKORI Dose Modification – Hematologic Toxicitiesa
` XALKORI Dosing
`
` Withhold until recovery to Grade 2 or less, then resume at the same dose schedule
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`
` Withhold until recovery to Grade 2 or less, then resume at next lower dose
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` a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
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` CTCAE Grade
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` Grade 3
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` Grade 4
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`Reference ID: 3719195
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`
`
` 2
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`

`

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` Permanently discontinue
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` Table 2. XALKORI Dose Modification – Non-Hematologic Toxicities
` Criteria
`
` XALKORI Dosing
`
`
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` Alanine aminotransferase (ALT) or aspartate Withhold until recovery to baseline or less than or equal to 3 times
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` aminotransferase (AST) elevation greater
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` ULN, then resume at reduced dose
` than 5 times upper limit of normal (ULN)
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` with total bilirubin less than or equal to
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` 1.5 times ULN
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` ALT or AST elevation greater than 3 times
` ULN with concurrent total bilirubin elevation
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` greater than 1.5 times ULN (in the absence
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` of cholestasis or hemolysis)
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` Any Grade drug-related interstitial lung
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` disease/pneumonitis
` QTc greater than 500 ms on at least
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` 2 separate ECGs
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` Permanently discontinue
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` Withhold until recovery to baseline or to a QTc less than 481 ms,
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` then resume at reduced dose
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` Permanently discontinue
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` QTc greater than 500 ms or greater than or
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` equal to 60 ms change from baseline with
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` Torsade de pointes or polymorphic
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` ventricular tachycardia or signs/symptoms of
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` serious arrhythmia
` Bradycardiaa (symptomatic, may be severe
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` and medically significant, medical
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` intervention indicated)
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` Withhold until recovery to asymptomatic bradycardia or to a heart
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` rate of 60 bpm or above
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` Evaluate concomitant medications known to cause bradycardia, as
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` well as anti-hypertensive medications
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` If contributing concomitant medication is identified and
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` discontinued, or its dose is adjusted, resume at previous dose upon
` recovery to asymptomatic bradycardia or to a heart rate of 60 bpm
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` or above
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` If no contributing concomitant medication is identified, or if
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` contributing concomitant medications are not discontinued or dose
` modified, resume at reduced dose upon recovery to asymptomatic
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` bradycardia or to a heart rate of 60 bpm or above
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` Bradycardiaa,b (life-threatening
` consequences, urgent intervention indicated)
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` Permanently discontinue if no contributing concomitant medication
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` is identified
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`If contributing concomitant medication is identified and
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` discontinued, or its dose is adjusted, resume at 250 mg once daily
` upon recovery to asymptomatic bradycardia or to a heart rate of
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` 60 bpm or above, with frequent monitoring
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` a Heart rate less than 60 beats per minute (bpm).
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`b Permanently discontinue for recurrence.
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` Monitor complete blood counts including differential white blood cell counts monthly and as clinically
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`indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection
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`occurs.
`
`
`Reference ID: 3719195
`
`
`
` 3
`
`

`

`
`3
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`
`
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`DOSAGE FORMS AND STRENGTHS
`
`
`250 mg capsules
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`Hard gelatin capsule, size 0, pink opaque cap and body, with “Pfizer” on the cap and “CRZ 250” on the body.
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`200 mg capsules
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`Hard gelatin capsule, size 1, white opaque body and pink opaque cap, with “Pfizer” on the cap and “CRZ 200”
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`on the body.
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`CONTRAINDICATIONS
`
`
`4
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`None
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`
`
`5 WARNINGS AND PRECAUTIONS
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`
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`5.1 Hepatotoxicity
`
`
`Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.2%) of the 1225 patients treated with
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`XALKORI across three main clinical trials. Concurrent elevations in alanine aminotransferase (ALT) greater
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`than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal,
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`
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`with normal alkaline phosphatase, occurred in 7 patients (0.6%). Additionally, elevations in ALT greater than
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`five times the upper limit of normal occurred in 109 patients (9.2%). Eight patients (0.7%) required permanent
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`discontinuation due to elevated transaminases. These laboratory findings were generally reversible upon dosing
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`interruption. Transaminase elevations generally occurred within the first 2 months of treatment.
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`Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of
`
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`treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver
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`transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations.
`Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage
`
`
`
`
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`and Administration (2.3) and Adverse Reactions (6)].
`
`
`
`
`5.2 Interstitial Lung Disease (Pneumonitis)
`
`
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`Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with
`
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`
`
`XALKORI. Across clinical trials (n=1225), 31 XALKORI-treated patients (2.5%) had any grade ILD,
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`11 patients (0.9%) had Grade 3 or 4, and 6 patients (0.5%) had fatal cases. These cases generally occurred
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`within 2 months after the initiation of treatment.
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`Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of
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`ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related
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`ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6)].
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`5.3 QT Interval Prolongation
`
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`QTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc
`
`
`
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`prolongation (all grades) was observed in 34 (2.7%) patients and QTc greater than 500 ms on at least 2 separate
`
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`ECGs occurred in 17 (1.4%) patients.
`
`
`Reference ID: 3719195
`
`
`
` 4
`
`

`

`
`
`
`
` Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with
`
`
` electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias,
` electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval.
`
`
`
`
`
`
` Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal
` to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or
`
`
`
`
`
`
`
`
` signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms
` on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a
`
`
`
`
`
`
`
`
` reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)].
`
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`
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`5.4 Bradycardia
`
`
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`Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a
`
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`
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`heart rate less than 50 beats per minute occurred in 11% of 1174 patients treated with XALKORI. In Study 1,
`
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`Grade 3 syncope occurred in 2.9% of XALKORI-treated patients and in none of the chemotherapy-treated
`
`patients.
`
`Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers,
`
`non-dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. Monitor heart rate
`
`
`
`
`and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI
`
`
`until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of
`
`
`concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening
`
`
`bradycardia due to XALKORI; however, if associated with concomitant medications known to cause
`
`
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`bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of
`
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`
`
`
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`60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg
`
`
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`once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)].
`
`
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`
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`5.5 Embryofetal Toxicity
`
`
`
`XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. In
`nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in
`
`
`humans at the recommended clinical dose of 250 mg twice daily. There are no adequate and well-controlled
`
`
`studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient becomes
`pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific
`
`Populations (8.1)].
`
`
`6
`
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`
`
`• Hepatotoxicity [see Warnings and Precautions (5.1)]
`
`
`
`
`Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
`
`
`
`
`
`•
`• QT Interval Prolongation [see Warnings and Precautions (5.3)]
`
`
`
`
`• Bradycardia [see Warnings and Precautions (5.4)]
`
`
`
`
`
`ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`
`
`
`reflect the rates observed in clinical practice.
`
`
`
`Safety evaluation of XALKORI is based on more than 1200 patients with ALK-positive metastatic NSCLC who
`
`
`
`
`
`received XALKORI as monotherapy at a starting oral dose of 250 mg twice daily continuously.
`
`
`
`
` 5
`
`Reference ID: 3719195
`
`

`

`
`
`
`The most common adverse reactions (≥25%) of XALKORI are vision disorder, nausea, diarrhea, vomiting,
`
`constipation, edema, elevated transaminases, and fatigue.
`
`
`
`
`ALK-positive metastatic NSCLC-Study 1
`
`
`
`The data in Table 3 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a
`
`randomized, multicenter, active-controlled, open-label trial (Study 1). Patients in the XALKORI arm (n=172)
`
`
`received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or
`
`
`
`
`
`the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients
`in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous
`
`
`
`
`
`
`
`infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator
`
`
`
`
`
`
`
`determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm
`
`received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.
`
`
`
`
`
`
`The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months
`
`
`
`
`for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343
`
`
`
`
`received at least one dose of study treatment), the median age was 50 years; 84% of patients in the XALKORI
`
`
`
`
`
`
`arm and 87% of patients in the chemotherapy arm were younger than 65 years. A total of 57% of patients on
`
`
`
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`XALKORI and 55% of chemotherapy patients were female. Forty-six percent (46%) of XALKORI-treated and
`
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`45% of chemotherapy-treated patients were from Asia.
`
`
`
`
`
`
`Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%)
`
`
`
`in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with
`
`
`
`
`
`XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and interstitial lung disease
`
`
`
`
`(ILD; 2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 1 occurred in 9 (5%) patients,
`
`
`consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary
`
`
`
`
`embolism, ILD, respiratory failure, and sepsis.
`
`
`
`Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most
`
`
`frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were alanine
`
`
`
`
`
`aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase
`
`
`
`(AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%).
`
`
`
`
`
`Discontinuation of therapy in XALKORI-treated patients for adverse reactions was 17.0%. The most frequent
`
`
`
`
`adverse reactions that led to discontinuation in XALKORI-treated patients were ILD (1.7%), ALT and AST
`
`
`
`
`elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 3 and 4 summarize common
`
`Adverse Reactions and Laboratory Abnormalities in XALKORI-treated patients.
`
`
`Reference ID: 3719195
`
`
`
` 6
`
`

`

`
`
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`
`
`
`
`
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`
`
`
`
` All Grades
`
` (%)
`
`
` 22
`
` 26
`
` 3
`
`
` 60
`
`
` 5
`
` 5
`
`
` 10
`
`
` 47
`
` 55
`
` 60
`
` 42
`
` 8
`
`
` 26
`
`
`
` 6
`
`
` 31
`
`
`
` Grade 3/4
`
` (%)
`
`
` 1
`
` 0
`
` 3
`
`
` 0
`
`
` 3
`
` 0
`
`
` 1
`
`
` 1
`
` 1
`
` 0
`
` 2
`
` 0
`
`
` 0
`
`
`
` 5
`
`
` 0
`
`
`
`
`
`
`
`
`
` Table 3. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher
` for Grades 3/4) with XALKORI than Chemotherapy in Study 1
`
`
`
`
`
`
`
` XALKORI
` Chemotherapy
`
`
` (Pemetrexed or Docetaxel)
` (N=172)
`
` (N=171)
` Grade 3/4
`
` All Grades
`
` (%)
`
` (%)
`
`
`
` 0
`
` 8
`
` 0
`
` 9
`
` 0
`
` 0
`
`
`
` 0
`
` 9
`
`
`
` 0
`
` 0
`
` 0
`
` 0
`
`
`
` 0
`
` 4
`
`
`
` 0
`
` 18
`
` 1
`
` 37
`
` 1
`
` 19
`
` 0
`
` 23
`
` 0
`
` 3
`
`
`
` 1
`
` 13
`
`
`
`
`
` 2
`
` 2
`
`
`
`
` 0
` 16
`
` Nervous System Disorder
`
` Dizzinessa
`
`
` Dysgeusia
`
`
`
` Syncope
` Eye Disorders
`
`
` Vision disorderb
`
`
`
` Cardiac Disorders
` Electrocardiogram QT prolonged
`
`
` Bradycardiac
`
` Investigations
`
`
`
` Weight decreased
` Gastrointestinal Disorders
`
`
` Vomiting
`
`
` Nausea
`
`
` Diarrhea
` Constipation
`
`
`
` Dyspepsia
` Infections and Infestations
`
`
` Upper respiratory infectiond
`
` Respiratory, Thoracic and
`
`
` Mediastinal Disorders
`
`
`Pulmonary embolisme
`
` General Disorders and
`
` Administration Site Conditions
`
`
`Edemaf
`
` Includes cases reported within the clustered terms:
`
`
`
`a Dizziness (Balance disorder, Dizziness, Dizziness postural)
`
`
`
`
`b Vision Disorder (Diplopia, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous floaters)
`
`
`
`
`c Bradycardia (Bradycardia, Sinus bradycardia)
`
`
`
`d Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection)
`
`
`
`
`e Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism)
`
`
`
`f Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Edema peripheral, Periorbital edema)
`
`
`
`
`
` Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with
`
`
`
`
`
`
`
`
`
`
`
` XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance,
` hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy,
`
`
`
`
`
`
` polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD,
`
`
`
` pneumonitis), renal cyst (4%), and hepatic failure (1%).
`
`
`
`
` Adverse Reaction
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3719195
`
`
`
` 7
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` Table 4. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of
`
`
`
`
` ≥4% in XALKORI-Treated Patients
` Crizotinib
`
`
`
` Any Grade
`
` Grade 3/4
`
`
`
` 49%
`
` 12%
`
` 51%
` 9%
`
`
`
`
` 76%
`
` 17%
`
` 61%
` 9%
`
`
` 18%
`
` 4%
`
` 28%
`
` 5%
`
` Chemotherapy
`
`
`
` Any Grade
`
` Grade 3/4
`
`
`
` 28%
`
` 12%
`
` 60%
`
` 25%
`
`
`
` 38%
`
` 4%
`
` 33%
`
` 0%
`
` 10%
`
` 1%
`
` 25%
`
` 6%
`
` Laboratory Abnormality
`
` Hematology
`
` Neutropenia
`
` Lymphopenia
`
`
` Chemistry
`
` ALT elevation
`
` AST elevation
`
` Hypokalemia
` Hypophosphatemia
`
`
`
`
` ALK-positive metastatic NSCLC- Study 2
`
`
`
`
`
`The safety analysis population in Study 2 included 934 patients with ALK-positive metastatic NSCLC who
`
`
`
`
`received XALKORI in a clinical trial. The median duration of treatment was 23 weeks. Dosing interruptions
`
`and reductions due to treatment-related adverse events occurred in 23% and 12% of patients, respectively. The
`
`rate of treatment-related adverse events resulting in permanent discontinuation was 5%. The most common
`
`
`
`
`
`adverse reactions (≥25%) included vision disorder (55%), nausea (51%), vomiting (46%), diarrhea (46%),
`
`
`
`
`edema (39%), constipation (38%), and fatigue (26%).
`
`
`
`Description of selected adverse drug reactions
`
`Vision disorders
`
`Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in
`
`
`
`
`
`691 (56%) patients across clinical trials (n=1225). The majority (99%) of these patients had Grade 1 or 2 visual
`
`
`adverse reactions. Across clinical studies, one patient had a treatment-related grade 3 vision abnormality.
`
`
`
`Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in
`
`Study 1 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 drug administration. The majority of patients
`
`
`
`
`
`on the XALKORI arm in Study 1 (> 50%) reported visual disturbances; these visual disturbances occurred at a
`
`
`
`
`
`
`
`
`frequency of 4-7 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 in a patient questionnaire.
`
`
`Neuropathy
`
`
`
`
`
`Neuropathy, most commonly sensory in nature, occurred in 235 (19%) of 1225 patients. Most events (95%)
`
`
`
`
`were Grade 1 or Grade 2 in severity.
`
`
`
`Renal Cysts
`
`
`
`
`
`Renal cysts occurred in 7 (4%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy
`
`
`
`
`
`in Study 1. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion
`
`
`
`
`beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation.
`
`
`
`However, across clinical trials no renal abscesses were confirmed by microbiology tests.
`
`
`7
`
`
`
`
`7.1 Drugs That May Increase Crizotinib Plasma Concentrations
`
`Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see
`
`Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to
`
`
` 8
`
`
`
`
`
`
`
`
`
`
`DRUG INTERACTIONS
`
`Reference ID: 3719195
`
`

`

`atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
`telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase
`
`
`plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors.
`
`
`7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
`
`
`
`Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see
`
`Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inducers, including but not limited to
`
`
`carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort.
`
`
`7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
`
`
`
`Crizotinib inhibits CYP3A both in vitro and in vivo [see Clinical Pharmacology (12.3)]. Avoid concomitant use
`
`
`
`
`of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine,
`
`dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking
`
`
`XALKORI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients
`
`
`
`
`
`taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.
`
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8
`
`
` 8.1 Pregnancy
`
` Pregnancy Category D [see Warnings and Precautions (5.5)]
`
` XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
`
`
`
` There are no adequate and well-controlled studies of XALKORI in pregnant women. In nonclinical studies in
` rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the
`
`
`
`
`
` recommended clinical dose of 250 mg twice daily. Crizotinib was administered to pregnant rats and rabbits
`during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at
`
`
` doses ≥ 50 mg/kg/day (approximately 0.6 times the AUC at the recommended human dose) in rats. No
` teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day
`
`
`
`
`
` (approximately 2.7 times the AUC at the recommended human dose) or in rabbits at doses of up to
`
`
` 60 mg/kg/day (approximately 1.6 times the AUC at the recommended human dose), though fetal body weights
`
`
`
` were reduced at these doses.
`
`
` Advise women of childbearing potential to avoid becoming pregnant while receiving XALKORI. Women of
`
`
` childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this
`
` drug, should use adequate contraceptive methods during therapy and for at least 90 days after completing
`
`
`
` therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking
`
`this drug, apprise the patient of the potential hazard to a fetus.
`
` 8.3 Nursing Mothers
`
`It is not known whether XALKORI is excreted in human milk. Because many drugs are excreted in human milk
`
`
`and because of the potential for serious adverse reactions in nursing infants from XALKORI, consider whether
`
`
`
`to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
`
`
`
`8.4 Pediatric Use
`
`
`The safety and efficacy of XALKORI in pediatric patients has not been established. Decreased bone formation
`
`
`in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days
`
`
`
`
` 9
`
`
`
`
`
`
`
`Reference ID: 3719195
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
` (approximately 5.4 times the AUC in adult patients at the recommended human dose). Other toxicities of
`
`
`
`potential concern to pediatric patients have not been evaluated in juvenile animals.
`
`
`8.5 Geriatric Use
`
`
`
`
`Of XALKORI treated patients in Study 1, 27 (16%) were 65 years or older, in Study 2, 152 (16%) were
`
`
`
`
`
`
`65 years or older, and in Study 3, 16 (13%) were 65 years or older. No overall differences in safety or
`
`
`effectiveness were observed between these patients and younger patients.
`
`
`
`8.6 Hepatic Impairment
`
`
`
`XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in
`
`the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded
`
`patients with AST or ALT greater than 2.5 x ULN, or greater than 5 x ULN, if due to liver metastases. Patients
`
`
`with total bilirubin greater than 1.5 x ULN were also excluded. Therefore, use caution in patients with hepatic
`
`impairment [see Clinical Pharmacology (12.3)].
`
`
`
`
`8.7 Renal Impairment
`
`
`
`
`No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60-89 mL/min) or
`
`
`
`
`
`moderate (CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.
`
`
`
`
`Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not
`
`
`requiring dialysis. Administer XALKORI at a dose of 250 mg taken orally once daily in patients with severe
`
`
`renal impairment not requiring dialysis [see Dosage and Administration (2.2) and Clinical
`
`
`Pharmacology (12.3)].
`
`
`10 OVERDOSAGE
`
`
`
`
`There have been no known cases of XALKORI overdose. There is no antidote for XALKORI.
`
`
`
`11 DESCRIPTION
`
`XALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor. The molecular formula for crizotinib is
`
`
`C21 H22 Cl2FN5O. The molecular weight is 450.34 Daltons. Crizotinib is described chemically as (R)-3-[1-(2,6-
`Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.
`
`
`
`
`
`
`
`Reference ID: 3719195
`
`
`
` 10
`
`

`

`
`The chemical structure of crizotinib is shown below:
`
`
`NH
`
`NN
`
`Cl
`
`CH3
`
`(R)
`
`O
`
`Cl
`
`N
`
`NH2
`
`F
`
`
`
`
`
`Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).
`
`The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than
`
`
`10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
`
`
`
`
`XALKORI capsules are supplied as printed hard-shell capsules containing 250 mg or 200 mg of crizotinib
`
`together with colloidal silicon dioxide, microcrystalline cellulose, a