HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
`XALKORI® safely and effectively. See full prescribing information for
`
`
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`
`XALKORI® .
`
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`XALKORI® (crizotinib) Capsules, oral
`
`
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`Initial U.S. Approval: August 2011
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`Dosage and Administration, Dose Modification (2.2)
`10/2013
`
`
`
`Dosage and Administration, Renal Impairment (2.3)
`10/2013
`
`
`
`Warnings and Precautions, Bradycardia (5.4)
`10/2013
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`XALKORI is a kinase inhibitor indicated for the treatment of patients with
`
`locally advanced or metastatic non-small cell lung cancer (NSCLC) that is
`
`anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved
`
`
`
`
`
`test. (1) This indication is based on response rate. There are no data available
`
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`
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`demonstrating improvement in patient reported outcomes or survival with
`
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`XALKORI.
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`•
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`
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`----------------------DOSAGE AND ADMINISTRATION----------------------­
`250 mg taken orally twice daily with or without food. (2.1)
`
`
`
`
`•
`Dosing interruption and/or dose reduction to 200 mg taken orally twice
`
`
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`•
`daily may be required based on individual safety and tolerability, then to
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`250 mg taken orally once daily if further reduction is necessary. (2.2)
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`Renal Impairment: Administer XALKORI at a starting dose of 250 mg
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`
`
`
`taken orally once daily in patients with severe renal impairment
`
`(creatinine clearance <30 mL/min) not requiring dialysis. (2.3)
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`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Capsules: 250 mg and 200 mg (3)
`
`
`
`•
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None (4)
`
`
`•
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has
`
`
`
`
`•
`occurred. Monitor monthly and as clinically indicated with more
`
`
`frequent testing in patients with Grade 2-4 elevations. Temporarily
`
`
`suspend, dose reduce, or permanently discontinue XALKORI as
`
`indicated. (5.1)
`
`
`Pneumonitis: Severe, including fatal, treatment-related pneumonitis has
`
`been observed. Monitor patients for pulmonary symptoms indicative of
`
`
`pneumonitis. Permanently discontinue in patients diagnosed with
`
`
`treatment-related pneumonitis. (5.2)
`
`
`QT Interval Prolongation: In patients who have a history of or
`
`
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`
`
`
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`predisposition for QTc prolongation, or who are taking medications that
`
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`
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`
`
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`are known to prolong the QT interval, consider periodic monitoring with
`
`electrocardiograms and electrolytes. (5.3)
`
`
`Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and
`
`
`blood pressure regularly. Temporarily suspend, dose reduce, or
`
`
`
`permanently discontinue XALKORI as indicated. (5.4)
`
`ALK Testing: Detection of ALK-positive NSCLC using an FDA­
`
`
`approved test, indicated for this use, is necessary for selection of patients
`
`
`
`for treatment with XALKORI. (5.5)
`
`Pregnancy: XALKORI can cause fetal harm when administered to a
`
`
`pregnant woman. (5.6, 8.1)
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`•
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`•
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`•
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`•
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`•
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`•
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`•
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`The most common adverse reactions (≥25%) are vision disorder, nausea,
`
`
`
`
`
`
`
`
`
`
`diarrhea, vomiting, edema, and constipation. (6)
`
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`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1­
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`
`
`800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong
`
`
`
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`
`•
`
`CYP3A inhibitors. (7.1)
`CYP3A Inducers: Avoid concurrent use of XALKORI with strong
`
`
`
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`CYP3A inducers. (7.2)
`CYP3A Substrates: Dose reduction may be needed for coadministered
`
`
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`drugs that are predominantly metabolized by CYP3A. Avoid concurrent
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`use of XALKORI with CYP3A substrates with narrow therapeutic
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`indices. (7.3)
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`Revised: 10/2013
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`
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`See 17 for PATIENT COUNSELING INFORMATION and FDA­
`approved patient labeling.
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`_______________________________________________________________________________________________________________________________________
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`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`2
`
`
`8
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`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
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`8.3 Nursing Mothers
`
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`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
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`8.6 Hepatic Impairment
`
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`8.7 Renal Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
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`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`
`
`2.2 Dose Modification
`
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`2.3 Renal Impairment
`
`
`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
`
`
`5.2 Pneumonitis
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`5.3 QT Interval Prolongation
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`5.4 Bradycardia
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`5.5 ALK Testing
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`5.6 Pregnancy
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`ADVERSE REACTIONS
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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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`* Sections or subsections omitted from the Full Prescribing Information are
`
`Crizotinib
`
`not listed.
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`_______________________________________________________________________________________________________________________________________
`
`
`6
`
`7
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`
`Reference ID: 3385676
`
`
`
` 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`1. INDICATIONS AND USAGE
`
`
`
`XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung
`
`
`cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
`
`
`This indication is based on response rate. There are no data available demonstrating improvement in patient
`
`reported outcomes or survival with XALKORI.
`
`
`2. DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`The recommended dose and schedule of XALKORI is 250 mg taken orally twice daily. Continue treatment as
`long as the patient is deriving clinical benefit from therapy. 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
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`6 hours.
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`2.2 Dose Modification
`
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`Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose
`
`
`reduction is necessary, then reduce the dose of XALKORI to 200 mg taken orally twice daily. If further dose
`
`
`reduction is necessary, then reduce the dosage to 250 mg taken orally once daily. Dose reduction guidelines for
`
`
`hematologic and non-hematologic toxicities are provided in Tables 1 and 2.
`Table 1: XALKORI Dose Modification – Hematologic Toxicitiesa
`
`
` CTCAEb Grade
`
`
`
` XALKORI Dosing
` Withhold until recovery to Grade ≤2, then resume at the same dose schedule
`
` Grade 3
`
` Withhold until recovery to Grade ≤2, then resume at 200 mg twice dailyc
`
` a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
`
`
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` b NCI Common Terminology Criteria for Adverse Events.
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`c In case of recurrence, withhold until recovery to Grade ≤2, then resume at 250 mg once daily. Permanently
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`discontinue in case of further Grade 4 recurrence.
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` Grade 4
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`
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`Reference ID: 3385676
`
`
`
` 2
`
`

`

` Table 2: XALKORI Dose Modification – Non-Hematologic Toxicities
`
`
`
`
` CTCAE Grade
` XALKORI Dosing
` Grade 3 or 4 alanine aminotransferase (ALT)
` Withhold until recovery to Grade ≤1 or baseline, then resume at
`
`
`200 mg twice dailya
` or aspartate aminotransferase (AST)
`
`
` elevation with Grade ≤1 total bilirubin
`
` Grade 2, 3 or 4 ALT or AST elevation with
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`concurrent Grade 2, 3 or 4 total bilirubin
`
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`elevation (in the absence of cholestasis or
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` hemolysis)
` Any Grade pneumonitisb
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` Permanently discontinue
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` Grade 3 QTc prolongation
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` Grade 4 QTc prolongation
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` Grade 2 bradycardia (symptomatic, medical
`
`
` intervention indicated)
`
` Permanently discontinue
`
` Withhold until recovery to Grade ≤1, then resume at 200 mg twice
`
`dailya
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` Permanently discontinue
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` Withhold until recovery to Grade ≤1, evaluate concomitant
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` medications, then resume at 200 mg twice daily
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` Grade 3 bradycardia (severe, medically
` significant, medical intervention indicated)
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` Grade 4 bradycardia due to XALKORI (life­
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`
`
`
`
` threatening consequences, urgent
` intervention indicated)
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` Grade 4 bradycardia associated with
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` concomitant medications known to cause
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` bradycardia or hypotension (life-threatening
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` consequences, urgent intervention indicated)
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` Permanently discontinue.
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` Withhold until recovery to Grade ≤1, and if concomitant
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`
`
` medications can be discontinued, resume at 250 mg once daily with
`
` frequent monitoring.
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` a In case of recurrence, withhold until recovery to Grade ≤1, then resume at 250 mg once daily. Permanently
`
` discontinue in case of further Grade 3 or 4 recurrence.
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`b Not attributable to NSCLC progression, other pulmonary disease, infection, or radiation effect.
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`
`
` 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.
`
`
`
` 2.3 Renal Impairment
`
`
`
`
`Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal
`
`impairment (creatinine clearance <30 mL/min) not requiring dialysis [see Use in Specific Populations (8.7) and
`Clinical Pharmacology (12.3)].
`
`
`
`3. 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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`
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`4. CONTRAINDICATIONS
`
`None
`
`Reference ID: 3385676
`
`
`
` 3
`
`

`

`
`
` 5. WARNINGS AND PRECAUTIONS
`
`5.1 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 times the
`
`upper limit of normal and total bilirubin greater than 2 times the upper limit of normal, with normal alkaline
`
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`phosphatase, occurred in less than 1% of patients in clinical trials. Elevation in ALT greater than 5 times the
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`upper limit of normal occurred in 7% of patients in Study A and in 4% of patients in Study B. These laboratory
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`findings were generally asymptomatic and reversible upon dosing interruption. Patients usually resumed
`
`
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`treatment at a lower dose without recurrence; however, 3 patients from Study A (2%) and 1 patient from Study
`
`B (less than 1%) required permanent discontinuation from treatment. Transaminase elevations generally
`
`
`occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total
`
`bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver
`transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations [see
`
`Dosage and Administration (2.2) and Adverse Reactions (6)].
`
`
`
`5.2 Pneumonitis
`
`XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical
`
`trials with a frequency of 4 in 255 (1.6%) patients across Studies A and B. All of these cases occurred within
`
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`2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis.
`
`Exclude other causes of pneumonitis, and permanently discontinue XALKORI in patients diagnosed with
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`treatment-related pneumonitis [see Dosage and Administration (2.2)].
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`
`
`5.3 QT Interval Prolongation
`
`
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`QTc prolongation has been observed. 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 Grade 4 QTc prolongation.
`Withhold XALKORI in patients who develop Grade 3 QTc prolongation until recovery to less than or equal to
`
`Grade 1, then resume XALKORI at 200 mg twice daily. In case of recurrence of Grade 3 QTc prolongation,
`
`
`withhold XALKORI until recovery to less than or equal to Grade 1, then resume XALKORI at 250 mg once
`daily. Permanently discontinue XALKORI if Grade 3 QTc prolongation recurs [see Dosage and
`
`
`
`Administration(2.2) and Clinical Pharmacology (12.2)].
`
`
`5.4 Bradycardia
`Symptomatic bradycardia can occur in patients receiving XALKORI. Bradycardia with a heart rate <50 beats
`
`
`
`
`per minute occurred in 10% of 890 patients and 14% of 114 patients treated with XALKORI in Studies A and
`
`B, respectively. 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.
`
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`Monitor heart rate and blood pressure regularly. In cases of Grade 2 and 3 symptomatic bradycardia hold
`
`
`XALKORI, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently
`
`
`discontinue for Grade 4 bradycardia due to XALKORI. In cases of Grade 4 bradycardia associated with
`
`
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`concomitant medications known to cause bradycardia or hypotension, hold XALKORI until Grade 1 or less,
`and if concomitant medications can be discontinued, restart XALKORI at 250 mg once daily with frequent
`
`
`
`monitoring [see Dosage and Administration (2.2) and Adverse Reactions (6)].
`
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`
`
`
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`5.5 ALK Testing
`
`Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for
`
`
`
`selection of patients for treatment with XALKORI [see Clinical Studies (14)].
`
`
`
`Reference ID: 3385676
`
`
`
` 4
`
`

`

`Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in
`
`the specific technology being utilized. Improper assay performance can lead to unreliable test results.
`
`
`
`
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`Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for
`
`
`
`treatment with XALKORI.
`
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`5.6 Pregnancy
`
`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 and above 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. ADVERSE REACTIONS
`
`
`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 practice.
`
`
`In Studies A and B, patients with locally advanced or metastatic ALK-positive NSCLC received crizotinib
`250 mg orally twice daily continuously. Among the 255 patients for whom data on Grade 1-4 adverse reactions
`
`
`
`
`are available, median exposure to study drug was 5.1 months in Study A and 7.8 months in Study B. Dosing
`
`
`
`interruptions occurred in 36% and 45% of patients in Studies A and B, and lasted greater than 2 weeks in 13%
`
`and 19% of patients in Studies A and B, respectively. Dose reductions occurred in 44% and 29% of patients in
`
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`Studies A and B, respectively. The rates of treatment-related adverse events resulting in permanent
`
`discontinuation were 6% in Study A and 3% in Study B. The most common adverse reactions (≥25%) across
`
`
`
`
`
`both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse
`
`reactions in at least 4% of patients in both studies included ALT increased and neutropenia.
`
`
`
`
`Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths
`
`
`within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of
`
`their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9),
`and other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1), dyspnea (1),
`
`pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other causes of deaths included septic shock,
`DIC, cardiovascular event, and death due to unknown cause (1 each). Serious adverse events in greater than or
`
`
`
`
`equal to 2% of patients included pneumonia, dyspnea, and pulmonary embolism.
`
`
`
`Table 3 lists the common adverse reactions on Studies A and B in patients receiving XALKORI.
`
`
`
`
`Reference ID: 3385676
`
`
`
` 5
`
`

`

`
`
`
`
`
`
`
`
` All Grades
`
` n (%)
`
` 159 (62%)
`
`
` 136 (53%)
`
` 109 (43%)
`
` 101 (40%)
` 69 (27%)
`
`
` 29 (11%)
` 20 (8%)
`
`
` 15 (6%)
`
`
` 72 (28%)
`
` 51 (20%)
`
` 3 (1%)
` 2 (<1%)
`
`
`
` 4 (2%)
`
` 34 (13%)
`
`
` 24 (9%)
`
` 49 (19%)
`
` 4 (2%)
`
` 2 (<1%)
`
`
`
` 42 (16%)
`
` 34 (13%)
` 10 (4%)
`
` 30 (12%)
`
`
`
` 8 (3%)
`
`
` 5 (2%)
`
` 9 (4%)
`
` 25 (10%)
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3: Adverse Reactions in ≥10% of Patients with Locally Advanced or
`
`
` Metastatic ALK-Positive NSCLC on Studies A and B1
` Treatment Related
`
` Treatment Emergent
`
`
` N=255
` N=255
`
` Grade 3/4
`
` Grade 3/4
`
` All Grades
`
` n (%)
`
`
` n (%)
` n (%)
`
`
`
` Eye Disorders
`
`
` Vision Disorder2
`
` 0
`
` 0
` 163 (64%)
`
`
`
`
` Gastrointestinal Disorders
`
`
` 0
`
` 2 (<1%)
`
` 145 (57%)
`
`
` Nausea
`
` 0
`
` 1 (<1%)
`
` 124 (49%)
`
`
` Diarrhea
`
` 0
`
` 116 (45%)
`
`
` Vomiting
`
` 3 (1%)
`
` 1 (<1%)
` 98 (38%)
`
`
`
` Constipation
`
` 2 (<1%)
`
` Esophageal Disorder3
`
` 0
`
` 51 (20%)
`
` 3 (1%)
`
`Abdominal Pain4
`
` 40 (16%)
`
` 0
`
` 1 (<1%)
`
`
`
` Stomatitis5
`
` 1 (<1%)
`
` 1 (<1%)
`
` 27 (11%)
`
`
`
`
` General Disorders
`
`
` Edema6
` 0
`
` 2 (<1%)
`
` 97 (38%)
`
`
`
` 80 (31%)
` 6 (2%)
`
` 4 (2%)
`
` Fatigue
`
`
` Chest Pain/Discomfort7
`
` 1 (<1%)
`
` 30 (12%)
`
` 0
`
` 1 (<1%)
`
` 30 (12%)
`
` 0
`
` Fever
`
`
`
`
` Infections and Infestations
`
`
` Upper Respiratory Infection8
`
` 1 (<1%)
` 50 (20%)
`
` 0
`
`
`
` Investigations
`
`
` 17 (7%)
`
` 38 (15%)
`
` 14 (5%)
`
`
` Alanine Aminotransferase Increased
`
` 7 (3%)
`
` 29 (11%)
`
` 5 (2%)
`
` Aspartate Aminotransferase Increased
`
`
`
` Metabolism and Nutrition
`
`
` 3 (1%)
` 69 (27%)
`
` 0
` Decreased Appetite
`
`
`
`
`
`
` Musculoskeletal
`
` 3 (1%)
`
` 29 (11%)
`
` 0
`
`
` Arthralgia
` Back Pain
`
`
` 0
`
` 28 (11%)
`
` 0
`
`
`
`
` Nervous System Disorders
`
` Dizziness9
`
` 0
`
` 60 (24%)
` 0
`
`
`
` Neuropathy10
`
` 58 (23%)
`
` 1 (<1%)
`
` 1 (<1%)
`
` 34 (13%)
`
` 1 (<1%)
`
` 0
`
`
`Headache
`
` 33 (13%)
`
` 0
`
` 0
`
` Dysgeusia
`
`
`
`
` Psychiatric Disorders
`
` Insomnia
` 30 (12%)
`
` 0
`
` 0
`
`
`
`
` Respiratory Disorders
`
` 57 (22%)
`
` 16 (6%)
`
` 3 (1%)
`
`
` Dyspnea
`
` 54 (21%)
`
` 3 (1%)
`
` 0
`
` Cough
`
`
`
`
`
` Skin Disorders
` 41 (16%)
` 0
` 0
`
`
`
` Rash
`
` 1Study A used CTCAE v4.0, and Study B used CTCAE v3.0.
`
`
`
`
` 2Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual
`
`
`
`brightness, and visual acuity reduced.
`
` 3Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis, esophageal obstruction/pain/spasm/ulcer,
`
`gastroesophageal reflux, odynophagia, and reflux esophagitis.
`
`
`4Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal tenderness.
`
`
`
`5Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation, oropharyngeal pain/discomfort, oral pain,
`
`
`
`
`
`
`and stomatitis.
`
`
`6Includes edema, edema localized, and peripheral edema.
`
`
`7Includes chest pain, chest discomfort, and musculoskeletal chest pain.
`
`
`
`8Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection.
`
`
` 9Includes balance disorder, dizziness, and presyncope.
`
`
`
`
`
`
` Adverse Event
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
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`
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`Reference ID: 3385676
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`
`6
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`

`
`
` 10Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy,
`
`
`
` peripheral motor neuropathy, and peripheral sensory neuropathy.
`
`
`
`
`Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and
`
`
` diplopia were reported in 159 (62%) patients in clinical trials. These events generally started within two weeks
` of drug administration. Consider ophthalmological evaluation, particularly if patients experience photopsia or
`
`
`
` experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also
`
` be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or
`
`
`
` operating machinery due to the risk of developing a vision disorder [see Patient Counseling Information (17)].
`
`
`
`
`
`
`
`
` Neuropathy as defined in Table 3 and attributed to study drug by the investigator was reported in 34 (13%)
`
`
`
`
` patients. While most events were Grade 1, Grade 2 motor neuropathy and Grade 3 peripheral neuropathy were
` reported in 1 patient each. Dizziness and dysgeusia were also very commonly reported in these studies, but were
`
`
`
` all Grade 1 or 2 in severity.
`
`
`
`
`
` Complex renal cysts occurred in 2 (1%) patients treated with XALKORI. There were no reports of abnormal
`
` urinalyses or renal impairment in these cases.
`
`
`
` Laboratory Abnormalities
`
` Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 5.2%, 0.4%, and 11.4% of patients,
`
` respectively.
`
`
`
`
`
` 7. DRUG INTERACTIONS
`
` 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
` 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 concurrent 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)]. Dose reduction may be
`
`
` needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid coadministration of
`
`
`
`
` crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil,
` cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
`
`
`
`
`
`
` 8. USE IN SPECIFIC POPULATIONS
`
`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 and above 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 1.2 times the AUC at the recommended human dose) in rats. No
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`Reference ID: 3385676
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`teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day
`
`
`
`
`
`(approximately 5 times the AUC at the recommended human dose) or in rabbits at doses of up to 60 mg/kg/day
`
`
`(approximately 3 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
`
`
`
`(approximately 10 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
`
`Clinical studies of XALKORI did not include sufficient numbers of patients aged 65 and older to determine
`
`
`whether they respond differently from younger patients. Of the 136 patients in Study A, 19 (14%) were 65 years
`
`
`
`
`or older. Of the 119 patients in Study B, 16 (13%) were 65 years or older.
`
`
`
`
`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 to 89 mL/min) and
`
`
`moderate (CLcr 30 to 59 mL/min) renal impairment, as steady-state trough concentrations in these two groups
`
`
`
`
`were similar to those in patients with normal renal function (CLcr ≥90 mL/min) in Study B. Increased exposure
`
`
`
`
`to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis.
`
`
`
`
`Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal
`
`
`
`impairment not requiring dialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
`
`10. OVERDOSAGE
`
`There have been no known cases of XALKORI overdose. Treatment of overdose with XALKORI should
`consist of general supportive measures. There is no antidote for XALKORI.
`
`
`
`
`11. DESCRIPTION
`
`XALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor. The molecular formula for crizotinib is
`
`
`C21H22Cl2FN5O. 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.
`
`
`
`The chemical structure of crizotinib is shown below:
`
`
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` 8
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`Reference ID: 3385676
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`

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`NH
`
`N N
`
`Cl
`
`CH3
`
`
`(R)
`
`O
`
`
`Cl
`
`N
`
`NH2
`
`
` 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.
`
`
`
`F
`
`
`
` XALKORI capsules are supplied as printed hard-shell capsules containing 250 mg or 200 mg of crizotinib
`
`
` together with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium
`
`
`
`
`
` starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients.
`
` The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron oxide. The white
`
`
`opaque capsule shell components contain gelatin, and titanium dioxide. The printing ink contains shellac,
`
`
`
` propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide.
`
`
`
`
`
` 12. CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
` Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor
`
` (HGFR, c-Met), and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene resulting in
`
`
`
`
`the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and
`
` dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and
` survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of
`
`
` ALK and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity
` in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
`
`
`
`
`
`
`
`
`
`
`
`
` 12.2 Pharmacodynamics
`
` Cardiac Electrophysiology
`
`
` The QT interval prolongation potential of crizotinib was assessed in patients who received XALKORI 250 mg
`
` twice daily. Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the
`
`
`
` effect of crizotinib on QT intervals. Four of 308 patients (1.3%) were found to have QTcF (corrected QT by the
`
` Fridericia method) greater than or equal to 500 msec, and 10 of 289 patients (3.5%) had an increase from
`
`
`
`
` baseline QTcF greater than or equal to 60 msec by automated machine-read evaluation of ECG. A
`
`
`
` pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent increase in QTcF [see
`
`
` Warnings and Precautions (5.3)].
`
` 12.3 Pharmacokinetics
`
` Absorption
`
`Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak
`
`
` concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days
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`
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`Reference ID: 3385676
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` 9
`
`

`

`and remained stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (Cmin and AUC)
`
`
` appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily.
`
`
`
`
`
` The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following the administration of a
`
`single 250 mg oral dose.
`
`
`
` A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. XALKORI can be administered
`
`
`
`
`with or without food [see Dosage and Administration (2.1)].
`
`
`
`
`
`
`Distribution
`
`The geometric mean volume of