`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`XALKORI® safely and effectively. See full prescribing information for
`
`
`
`XALKORI.
`
`
`
`
`
`
`XALKORI® (crizotinib) capsules, for oral use
`
`Initial U.S. Approval: 2011
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES ---------------------------
`
`
`
`Indications and Usage (1.2)
`1/2021
`
`
`
`
`
`Dosage and Administration (2.3, 2.4, 2.5, 2.6, 2.7, 2.8)
`1/2021
`
`
`Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)
`1/2021
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE---------------------------­
`
`XALKORI is a kinase inhibitor indicated for the treatment of
`
`
`patients with metastatic non-small cell lung cancer (NSCLC) whose
`•
`
`
`tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as
`
`
`detected by an FDA-approved test. (1.1, 2.1)
`
`
`
`pediatric patients 1 year of age and older and young adults with relapsed
`
`
`
`or refractory, systemic anaplastic large cell lymphoma (ALCL) that is
`
`
`ALK-positive. (1.2, 2.3)
`
`Limitations of Use: The safety and efficacy of XALKORI have
`o
`
`not been established in older adults with relapsed or refractory,
`
`systemic ALK-positive ALCL.
`
`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
`
`
`
`
`
`• Metastatic NSCLC: The recommended dosage is 250 mg orally twice
`
`
`
`
`
`daily. (2.2)
`
`Systemic ALCL: The recommended dosage is 280 mg/m2 orally twice
`
`
`daily based on body surface area. (2.3)
`
`
`
`See full prescribing information for dosage adjustments by indication for
`
`
`patients with moderate or severe hepatic impairment or severe renal
`
`
`
`
`
`impairment. (2.6, 2.7)
`
`
`
`--------------------DOSAGE FORMS AND STRENGTHS----------------------­
`
`Capsules: 250 mg, 200 mg. (3)
`
`
`
`
`------------------------------ CONTRAINDICATIONS ------------------------------
`
`
`
`
`None. (4)
`
`
`----------------------- WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`
`Hepatotoxicity: Fatal hepatotoxicity has occurred. Monitor with periodic
`
`
`
`•
`liver testing. Temporarily suspend, dose reduce, or permanently
`
`
`discontinue XALKORI. (2.5, 5.1)
`
`
`
`Interstitial Lung Disease (ILD)/Pneumonitis: Permanently discontinue in
`
`patients with ILD/pneumonitis. (2.5, 5.2)
`
`
`
`
`QT Interval Prolongation: Monitor electrocardiograms and electrolytes
`
`Revised: 1/2021
`
`in patients who have a history of or predisposition for QTc prolongation,
`
`_______________________________________________________________________________________________________________________________________
`
`
`or who are taking medications that prolong QT. Temporarily suspend,
`
`dose reduce, or permanently discontinue XALKORI. (2.5, 5.3)
`
`
`Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and
`
`blood pressure regularly. Temporarily suspend, dose reduce, or
`
`permanently discontinue XALKORI. (2.5, 5.4)
`
`Severe Visual Loss: XALKORI can cause visual changes including
`
`
`severe visual loss. Discontinue XALKORI in patients with severe visual
`
`
`loss. Monitor and evaluate for ocular toxicity throughout treatment. (2.5,
`
`
`
`5.5)
`
`
`Gastrointestinal Toxicity in Patients with ALCL: XALKORI can cause
`
`
`
`
`
`severe nausea, vomiting, diarrhea, and stomatitis. Provide standard
`
`
`
`antiemetic and antidiarrheal agents. Temporarily suspend, dose reduce,
`
`
`
`
`
`or permanently discontinue XALKORI. (2.4, 2.5, 5.6)
`
`
`
`Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
`
`
`reproductive potential of the potential risk to a fetus and use of effective
`
`contraception. (5.7, 8.1, 8.3)
`
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`The most common adverse reactions (≥25%) in patients with NSCLC are
`
`
`
`vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated
`
`
`transaminases, fatigue, decreased appetite, upper respiratory infection,
`
`
`dizziness, and neuropathy. (6.1)
`
`
`
`
`
`
`
`
`The most common adverse reactions (≥35%) in patients with ALCL,
`
`
`
`excluding laboratory abnormalities, are diarrhea, vomiting, nausea, vision
`
`
`
`
`disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased
`
`
`
`
`
`
`appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3-4 laboratory
`
`
`
`
`abnormalities (≥15%) are neutropenia, lymphopenia, and thrombocytopenia.
`(6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------ DRUG INTERACTIONS------------------------------­
`
`
`
`Strong CYP3A Inhibitors: Avoid concomitant use. (2.8, 7.1)
`
`
`
`•
`Strong CYP3A Inducers: Avoid concomitant use. (7.1)
`
`
`•
`CYP3A Substrates: Avoid concomitant use with CYP3A substrates,
`
`
`•
`where minimal concentration changes may lead to serious adverse
`
`
`reactions. (7.2)
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`
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`
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`Lactation: Advise not to breastfeed. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
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`•
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`•
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`•
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`•
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`•
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 ALK- or ROS1-Positive Metastatic NSCLC
`
`
`
`1.2 Relapsed or Refractory, Systemic ALK-Positive ALCL
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Patient Selection
`
`
`2.2 Recommended Dosage for ALK- or ROS1-Positive Metastatic
`
`
`NSCLC
`
`2.3 Recommended Dosage for Relapsed or Refractory, Systemic
`
`
`
`ALK-Positive ALCL
`
`
`2.4 Concomitant Treatments for Patients with ALCL
`
`
`
`2.5 Dosage Modifications for Adverse Reactions
`
`
`2.6 Dosage Modifications for Moderate and Severe Hepatic
`
`
`Impairment
`
`
`2.7 Dosage Modification for Severe Renal Impairment
`
`
`2.8 Dosage Modification for Concomitant Use of Strong CYP3A
`
`
`Inhibitors
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Hepatotoxicity
`
`
`5.2
`Interstitial Lung Disease/Pneumonitis
`
`
`5.3 QT Interval Prolongation
`
`
`
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`5.4 Bradycardia
`
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`5.5 Severe Visual Loss
`
`
`
`
`5.6 Gastrointestinal Toxicity in Patients with ALCL
`
`5.7 Embryo-Fetal Toxicity
`
`
`ADVERSE REACTIONS
`
`2
`
`
`
`6
`
`Reference ID: 4730020
`
`
`•
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`
`•
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`
`•
`
`
`•
`
`7
`
`
`8
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`7.1 Effect of Other Drugs on XALKORI
`
`
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`7.2 Effect of XALKORI on Other Drugs
`
`
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`7.3 Drugs That Prolong the QT Interval
`
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`7.4 Drugs That Cause Bradycardia
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
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`8.3 Females and Males of Reproductive Potential
`
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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
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
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`
`
`14.1 ALK- or ROS1-Positive Metastatic NSCLC
`
`
`
`14.2 Relapsed or Refractory, Systemic ALK-Positive ALCL
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`

`

`
` * Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
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`
`
`
`
`
`
`Reference ID: 4730020
`
`
`

`

`
`
`
`INDICATIONS AND USAGE
`
`
`
`ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer
`
`
`
`Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`1
`
`
`1.1
`
`
`
`XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose
`
`
`tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test [see
`
`Dosage and Administration (2.1)].
`
`
`
`
`1.2
`
`
`
`
`
`
`
`XALKORI is indicated for the treatment of pediatric patients 1 year of age and older and young adults with
` relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive.
`
`
`
`
`
`
`
`
`
`
`
`Limitations of Use: The safety and efficacy of XALKORI have not been established in older adults with
` relapsed or refractory, systemic ALK-positive ALCL.
`
`
`
`
`2
`
`
`
`2.1 Patient Selection
`
`
`
`
`
`Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK or ROS1
`
`
`positivity in tumor specimens [see Clinical Studies (14.1, 14.2)].
`
`
`
`Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available
`
`
`at http://www.fda.gov/companiondiagnostics.
`
`
`
`
`
`
`
`2.2 Recommended Dosage for ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer
`
`
`
`
`
`
`The recommended dosage of XALKORI for patients with NSCLC is 250 mg orally twice daily, with or without
`
`
`food, until disease progression or no longer tolerated by the patient.
`
`
`
`
`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.
`
`
`
`
`
`
`2.3 Recommended Dosage for Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell
`
`Lymphoma
`
`The recommended dosage of XALKORI for patients with ALCL is 280 mg/m2 orally twice daily until disease
`
`
`
`
`
` progression or unacceptable toxicity. The recommended dosage of XALKORI is based on body surface area
`
`
`
`
`
`
`(BSA) is provided in Table 1. If needed, attain the desired dose by combining different strengths of XALKORI
`
`capsules.
`
`
`
`Assess pediatric patients for their ability to swallow intact capsules before prescribing XALKORI. Administer
`
`
`
`XALKORI to pediatric patients under adult supervision.
`
`
`
`DOSAGE AND ADMINISTRATION
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
`
` Table 1. Recommended XALKORI Dosage for Patients with ALCL
`
` Recommended XALKORI Dosage
`
` Body Surface Area *
`
` 0.60 – 0.80 m2
`
`
` 200 mg orally twice daily
`
`
` 0.81 – 1.16 m2
`
` 250 mg orally twice daily
`
`
`
` 1.17 – 1.51 m2
`
` 400 mg orally twice daily
`
`
`
` 1.52 – 1.69 m2
`
` 450 mg orally twice daily
`
`
`
` 1.70 m2 or greater
`
` 500 mg orally twice daily
`
`
` * The recommended dosage for patients with a BSA less than 0.60 m2 has not been established.
`
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` Take XALKORI 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.
`
`
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`
`
`
`
`
`2.4 Concomitant Treatments for Patients with ALCL
`
`
`
`Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities. Antiemetics are
`
`
`
`
`
`recommended prior to and during treatment with XALKORI to prevent nausea and vomiting.
`
`
`
`
`
`
`
`Consider intravenous or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically
`
`
`indicated [see Warnings and Precautions (5.6)].
`
`
`
`
`2.5 Dosage Modifications for Adverse Reactions
`
`
`Recommended Dosage Reductions
`
`
`
`ALK- or ROS1-positive metastatic NSCLC
`
`
`
`
`The recommended dose reductions for adverse reactions in patients with metastatic NSCLC are:
`
`
`•
`
`•
`
`•
`
`
`Systemic ALK-positive ALCL
`
`
`
`
`
`
`The recommended dose reductions for adverse reactions in patients with ALCL are provided in Table 2.
`
`
`
`
`
`First dose reduction: XALKORI 200 mg taken orally twice daily
`
`
`
`
`Second dose reduction: XALKORI 250 mg taken orally once daily
`
`
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`Permanently discontinue if unable to tolerate XALKORI 250 mg taken orally once daily.
`
`
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`
`
`Table 2. Recommended Dose Reductions for XALKORI in Patients with ALCL
` First Dose Reduction
` Second Dose Reduction
`
`
` Body Surface Area
`
`
`
` Dose
` Dose
` 250 mg
`
` Permanently discontinue
` Once daily
`
`
` 200 mg
` 250 mg
`
` Once daily*
` Twice daily
`
`
` 250 mg
` 200 mg
`
` Twice daily*
` Twice daily
`
`
` 400 mg
` 250 mg
`
` 1.70 m2 or greater
`
` Twice daily*
`
` Twice daily
`
`
`
` * Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.
`
`
`
`
`
` 0.60 – 0.80 m2
`
`
`
`0.81 – 1.16 m2
`
`
`
`
`
` 1.17 – 1.69 m2
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`Reference ID: 4730020
`
`
`
`
`

`

`
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`
`
`
` Recommended Dosage Modifications for Patients with NSCLC
`
`
`
`
`
`
`Recommended dosage modifications for hematologic and non-hematologic adverse reactions for patients with
`
`
`
`
`NSCLC are provided in Tables 3 and 4.
`
`
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`
`
`
`Table 3. Patients with NSCLC: XALKORI Dosage Modification – Hematologic Toxicitiesa
` Severity of Adverse Reactionb
`
`
` XALKORI Dosage Modification
`
` Withhold until recovery to Grade 2 or less, then resume at the same dosage.
`
` Grade 3
` Withhold until recovery to Grade 2 or less, then resume at next lower dosage.
`
` Grade 4
`
`
`
`
`
` a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
`
`
`
`
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`
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`b Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`
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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.
`
`
`
`
`
`
` Table 4. Patients with NSCLC: XALKORI Dosage Modification – Non-Hematologic Toxicities
`
` Severity of Adverse Reactiona
`
`
` XALKORI Dosage Modification
` Hepatotoxicity [see Warnings and Precautions (5.1)]
`
`
`
`Alanine aminotransferase (ALT) or aspartate
` Withhold until recovery to baseline or less than or equal to
`
`
`
`
` aminotransferase (AST) greater than 5 times upper
` 3 times ULN, then resume at next lower dosage.
` limit of normal (ULN) with total bilirubin less
`
`
`
`
`
` than or equal to 1.5 times ULN
`
` ALT or AST greater than 3 times ULN with
` concurrent total bilirubin greater than 1.5 times
`
` ULN (in the absence of cholestasis or hemolysis)
`
`Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)]
`
`
`
`
` Permanently discontinue.
` Any grade drug-related interstitial lung
`
`
`
`
` disease/pneumonitis
`
`
` QT Interval Prolongation [see Warnings and Precautions (5.3)]
`
`
` QT corrected for heart rate (QTc) greater than
` Withhold until recovery to baseline or to a QTc less than 481 ms,
`
`
` 500 ms on at least 2 separate electrocardiograms
`
`
`
`
` then resume at next lower dosage.
` (ECGs)
`
` 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
`
`Bradycardia [see Warnings and Precautions (5.4)]
`
`
` Bradycardiab (symptomatic, may be severe and
`
`
` medically significant, medical intervention
`
`
` indicated)
`
`
`
`
`
` Permanently discontinue.
`
`
`
`
`
`
`
`
`
` Permanently discontinue.
`
`
`
`
`
`
`Withhold until recovery to asymptomatic bradycardia or to a
`
`
` heart rate of 60 bpm or above.
`
` 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.
`
`
`
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
` Severity of Adverse Reactiona
`
`
`
`
` Bradycardiab,c (life-threatening consequences,
`
` urgent intervention indicated)
`
`
`
`
`
`
`
`
`
`
`
` XALKORI Dosage Modification
`
`
` 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.
`
`
` 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 asymptomatic bradycardia or to a heart rate of
`
` 60 bpm or above, with frequent monitoring.
`
`
`
` Severe Visual Loss [see Warnings and Precautions (5.5)]
`
` Visual Loss (Grade 4 Ocular Disorder)
`
`
` Discontinue during evaluation of severe visual loss.
`
`
`
` a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`
`
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`
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`
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`b Heart rate less than 60 beats per minute (bpm).
`
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`c Permanently discontinue for recurrence.
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`
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`
`
`
`
`
`
` Recommended Dosage Modifications for Patients with ALCL
`
`
`
`
`
`Recommended dosage modifications for hematologic and non-hematologic adverse reactions for patients with
`
`
`
`ALCL are provided in Tables 5 and 6.
`
`
`
`
`
`
`
`Table 5. Patients with ALCL: XALKORI Dosage Modification for Hematologic Adverse Reactions
`
` Severity of Adverse Reaction
` XALKORI Dosage Modification
`
`
` Absolute Neutrophil Count (ANC)
`
`
`
`
` Less than 0.5 x 109/L
`
`
`
`
`
`
`
`
` First occurrence: Withhold until recovery to ANC greater than 1.0 x
` 109/L, then resume at the next lower dosage.
`
`
`
`
` Second occurrence:
`
`
`
` • Permanently discontinue for recurrence complicated by febrile
` neutropenia or infection.
`
` • For uncomplicated Grade 4 neutropenia, either permanently
`
`
`
`
`
`
` discontinue, or withhold until recovery to ANC greater than 1.0 x
` 109/L, then resume at the next lower dosage.a
`
`
`
` Platelet Count
`
`
`25 to 50 x 109/L with concurrent
`
` bleeding
` Less than 25 x 109/L
`
`
` Anemia
` Withhold until recovery to hemoglobin 8 g/dL or more, then resume at
` Hemoglobin less than 8 g/dL
`
`
`
` the same dosage.
`
` Withhold until recovery to hemoglobin 8 g/dL or more, then resume at
` Life-threatening anemia; urgent
` intervention indicated.
`
`
`
` the next lower dosage. Permanently discontinue for recurrence.
`
` a Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise
`
`
`
`
`
`
`
`
`
`
` indicated in Table 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Withhold until recovery to platelet count greater than 50 x 109/L and
`
` bleeding resolves, then resume at the same dosage.
` Withhold until recovery to platelet count greater than 50 x 109/L, then
`
`
`
` resume at the next lower dosage. Permanently discontinue for recurrence.
`
`
`
`
`
`
`
`
`
`
`
`Monitor complete blood counts including differential weekly for the first month of therapy and then at least
` monthly, with more frequent monitoring if Grade 3 or 4 abnormalities, fever, or infection occur.
`
`
`
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` Bradycardiab,c (life-threatening consequences,
`
` urgent intervention indicated)
`
`
`
` Permanently discontinue.
`
`
`
` Permanently discontinue.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 6. Patients with ALCL: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions
`
`
`
` Severity of Adverse Reactiona
`
`
` XALKORI Dosage Modification
` Hepatotoxicity [see Warnings and Precautions (5.1)]
`
`
`
`Alanine aminotransferase (ALT) or aspartate
` Withhold until recovery to baseline or less than or equal to
`
`
`
`
` 3 times ULN, then resume at next lower dosage.
`
` aminotransferase (AST) greater than 5 times
`upper limit of normal (ULN) with total
`
`
`
` bilirubin less than or equal to 1.5 times ULN
` ALT or AST greater than 3 times ULN with
`
`
`
` concurrent total bilirubin greater than 1.5 times
`
` ULN (in the absence of cholestasis or
`
` hemolysis)
`Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)]
`
`
`
`
` Permanently discontinue.
` Any grade drug-related interstitial lung
`
`
`
`
` disease/pneumonitis
`
` QT Interval Prolongation [see Warnings and Precautions (5.3)]
`
`
` QT corrected for heart rate (QTc) greater than
` Withhold until recovery to baseline or to a QTc less than 481 ms,
`
`
`
` 500 ms on at least 2 separate
`
`
`
` then resume at next lower dosage.
` electrocardiograms (ECGs)
`
` 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
`Bradycardia [see Warnings and Precautions (5.4)]
`
`
` Bradycardiab (symptomatic, may be severe and
`
` Withhold until recovery to a resting heart rate according to the
`
`
`
` patient’s age (based on the 2.5th percentile per age-specific
` medically significant, medical intervention
`
`
`
` indicated)
`
`
` norms) as follows:
`
`
` • 1 to <2 years: 91 bpm or above
`
`
` • 2 to 3 years: 82 bpm or above
`
`
`
`
` • 4 to 5 years: 72 bpm or above
`
`
`
`
` • 6 to 8 years: 64 bpm or above
`
`
`
`
` • >8 years: 60 bpm or above
`
`
` Permanently discontinue if no contributing concomitant
`
` medication is identified.
`
`
`If contributing concomitant medication is identified and
`
` discontinued, or its dose is adjusted, resume at the second dose
`
` reduction level in Table 2c upon recovery to asymptomatic
`bradycardia or to the heart rate criteria listed for management of
`
`
`
`symptomatic or severe, medically significant bradycardia, with
`
`
`
`
` frequent monitoring.
`
`
`
` Ocular Toxicity, including Visual Loss [see Warnings and Precautions (5.5)]
`
`
` Visual Symptoms, Grade 1 (mild symptoms) or
` Monitor symptoms and report any symptoms to an eye specialist.
`
`
`
` Grade 2 (moderate symptoms affecting ability
`
`
`Consider dose reduction for Grade 2 visual disorders.
` to perform age-appropriate activities of daily
`
`
` living)
`
`
` Visual Loss (Grade 3 or 4 Ocular Disorder,
` marked decrease in vision)
`
`
` Withhold pending evaluation of severe visual loss.
`
`
`
` Permanently discontinue XALKORI for Grade 3 or 4 ocular
`
` disorders, if no other cause found on evaluation.
`
`
`
`
`
`
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
` XALKORI Dosage Modification
`
`
`
`
` Grade 3 or 4 (despite maximum medical therapy): Withhold until
` resolved, and then resume at the next lower dose level.d
`
`
`
`
`
`
`
`
` Grade 3 or 4 (despite maximum medical therapy): Withhold until
` resolved, and then resume at the next lower dose level.d
`
`
`
`
`
`
`
` Severity of Adverse Reactiona
`
`Gastrointestinal Toxicity [see Warnings and Precautions (5.6)]
`
`
`
`
` Nausea (Grade 3: inadequate oral intake for
` Grade 3 (despite maximum medical therapy): Withhold until
`
`
`
` resolved, and then resume at the next lower dose level.d
`
`more than 3 days, medical intervention
`
`
` required)
`
` Vomiting (Grade 3: more than 6 episodes in
` 24 hours for more than 3 days, medical
`
`
`
`
`
` intervention required, i.e. tube feeding or
`
`
`hospitalization; Grade 4: life-threatening
`
`
` consequences, urgent intervention indicated)
`Diarrhea (Grade 3: increase of 7 or more stools
`
` per day over baseline; incontinence;
` hospitalization indicated; Grade 4:
`
` life-threatening consequences, urgent
`
` intervention indicated)
`
`
`
` a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` b Adult patients: Heart rate less than 60 beats per minute (bpm); Pediatric patients: Resting heart rate less than the 2.5th
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`percentile per age-specific norms.
`
`
`
`
`
`
`
`c Permanently discontinue for recurrence.
`d Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise indicated
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` in Table 2.
`
`
`
`
` 2.6 Dosage Modifications for Moderate and Severe Hepatic Impairment
`
` ALK- or ROS1-positive metastatic NSCLC
`
`
`
` The recommended dose of XALKORI in patients with moderate hepatic impairment [any aspartate
` aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than
`
`
`
` or equal to 3 times ULN] is 200 mg orally twice daily.
`
`
`
`
` The recommended dose of XALKORI in patients with severe hepatic impairment (any AST and total bilirubin
`
`
`
`
`
`
` greater than 3 times ULN) is 250 mg orally once daily [see Use in Specific Populations (8.6), Clinical
`
`
` Pharmacology (12.3)].
`
`
` Systemic ALK-positive ALCL
`
`
`
`
`The recommended dose of XALKORI in patients with moderate hepatic impairment [any aspartate
`
`
`
`aminotransferase (AST) and total bilirubin greater than 1.5 times the upper limit of normal (ULN) and less than
`
`
`
`
`or equal to 3 times ULN] is the first dose reduction based on BSA as shown in Table 2 [see Dosage and
`
`
`Administration (2.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`
`
`The recommended dose of XALKORI in patients with severe hepatic impairment (any AST and total bilirubin
`
`
`
`
`greater than 3 times ULN) is the second dose reduction based on BSA as shown in Table 2 [see Dosage and
`
`Administration (2.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
` 2.7 Dosage Modification for Severe Renal Impairment
`
`
`
`ALK- or ROS1-positive metastatic NSCLC
`
`
`The recommended dosage of XALKORI in patients with severe renal impairment [creatinine clearance (CLcr)
`
`
`
`
`
`
`less than 30 mL/min, calculated using the modified Cockcroft-Gault equation] not requiring dialysis is 250 mg
`
`orally once daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`
`Systemic ALK-positive ALCL
`
`
`
`
`
` The recommended dosage of XALKORI in patients with severe renal impairment (CLcr) less than 30 mL/min,
`calculated using the modified Cockcroft-Gault equation for adult patients and the Schwartz equation for pediatric
`
`patients not requiring dialysis is the second dose reduction based on BSA as shown in Table 2 [see Dosage and
`
`
`
`Administration (2.5), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`
`2.8 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors
`
`
`
`
`
`ALK- or ROS1-positive metastatic NSCLC
`
`
`Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is
`
`
`
`unavoidable, reduce the dose of XALKORI to 250 mg orally once daily [see Drug Interactions (7.1)]. After
`
`
`discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong
`
`
`CYP3A inhibitor.
`
`
`Systemic ALK-positive ALCL
`
`
`
`
`
`Avoid concomitant use of strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors is
` unavoidable, reduce the dose of XALKORI to the second dose reduction based on BSA as shown in Table 2
`
`
` [see Dosage and Administration (2.5), Drug Interactions (7.1)]. After discontinuation of a strong CYP3A
`
`
`
` inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.
`
`
`
`
` 3
`
`
` Capsules:
` • 250 mg: hard gelatin capsule, size 0, pink opaque cap and body, with “Pfizer” on the cap and “CRZ 250” on
`
`
` the body.
`
` • 200 mg: hard gelatin capsule, size 1, white opaque body and pink opaque cap, with “Pfizer” on the cap and
`
` “CRZ 200” on the body.
`
`
`CONTRAINDICATIONS
`
`
`
`
`
`4
`
`
`
`None.
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Hepatotoxicity
`
`
`
`
`Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of the 1719 patients treated with XALKORI
`
`
`for NSCLC across clinical trials [see Adverse Reactions (6.1)]. Concurrent elevations in ALT or AST ≥3 times
`
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
` the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in <1% of patients
` treated with XALKORI. Increased ALT or AST >5 times the ULN occurred in 11% and 6% of patients,
`
`
`
`
` respectively. One percent (1.0%) of patients required permanent discontinuation due to elevated transaminases.
`
`
` Increased transaminases generally occurred within the first 2 months of treatment.
`
`
`
`In Study ADVL0912, of 121 patients ages 1 to ≤21 years treated with XALKORI for relapsed or refractory
`tumors including ALCL, 71% and 79% had increases of AST and ALT, respectively, with increased ALT or
`
`AST >5 times the ULN in 6% each. Of the 26 patients with ALCL treated with XALKORI, 65% and 81% had
`
`
`
`
`
`
`increases of AST and ALT, respectively, with increases >5 times the ULN in 4% each.
`
`
`
`
`
`Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of
`
`
`
`
`treatment, then 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 increased transaminases.
`Withhold, reduce dose, or permanently discontinue XALKORI for hepatotoxicity as recommended [see Dosage
`
`and Administration (2.5)].
`
`
`5.2 Interstitial Lung Disease/Pneumonitis
`
`
`
`
`Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with
`
`
`
`XALKORI. Across clinical trials in patients with NSCLC (n=1719), 2.9% of XALKORI-treated patients had
`
`
`
`
`
`
`ILD of any grade, 1% had Grade 3 or 4 ILD, and 0.5% had fatal ILD [see Adverse Reactions (6.1)]. Interstitial
`
`
`
`
`
`
`lung disease generally occurred within 3 months after the initiation of XALKORI.
`
`
`
`
`In Study ADVL0912, among 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including
`
`
`
`ALCL, ILD occurred in 0.8% of patients.
`
`
`
`
`Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of
`
`ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related
`
`
`ILD/pneumonitis [see Dosage and Administration (2.5)].
`
`
`
`5.3 QT Interval Prolongation
`
`
`
`QTc prolongation can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC,
`
`2.1% of 1616 patients had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to
`
`
`
`
`
`500 ms and 5% of 1582 patients had an increase from baseline QTcF greater than or equal to 60 ms by
`
`
`
`automated machine-read evaluation of ECGs.
`
`
`In Study ADVL0912, QTc prolongation was reported as an adverse reaction in 4.1% of patients, including 8%
`
`
`
`
`of patients with ALCL.
`
`
`
`Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor 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. Withhold, reduce dose, or permanently discontinue
`
`
`
`XALKORI for QT/QTc interval prolongation as recommended [see Dosage and Administration (2.5), Clinical
`
`Pharmacology (12.2)].
`
`
`
`Reference ID: 4730020
`
`
`
`
`

`

`
`
`
`
`
` 5.4 Bradycardia
`
`
`
`Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials in patients with
`
`
`
`
`
`NSCLC, bradycardia occurred in 13% of 1719 patients treated with XALKORI. Grade 3 syncope occurred in
`
`
`
`2.4% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients [see Adverse Reactions
`
`(6.1)].
`
`
`
`
`
`
`
`In Study ADVL0912, among 121 patients ages 1 to ≤21 years treated with XALKORI, bradycardia was
`reported in 14%, including Grade 3 bradycardia in 0.8% of patients. Of the 26 patients with ALCL treated with
`
`
`
`
`XALKORI, bradycardia (all Grade 1) was reported in 19%.
`
`
`
`
` Avoid using XALKORI in combination with other medications 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. If bradycardia occurs, re-evaluate for the use of concomitant medications known
`
`
`
`
` to cause bradycardia. Withhold, reduce dose, or permanently discontinue XALKORI for bradycardia as
`
`
` recommended [see Dosage and Administration (2.5)].
`
`
`
`5.5 Severe Visual Loss
`
`
`
`
`Across all clinical trials in patients with NSCLC, the incidence of Grade 4 visual field defect with visual loss
`
`
`
`was 0.2% of 1719 patients [see Adverse Reactions (6.1)]. Optic atrophy and optic nerve disorder have been
`
`
`
`reported as potential causes of visual loss.
`
`In Study ADVL0912, visual disorders occurred in 46% of 121 patients with XALKORI, including 65% of
`26 patients with ALCL. Of th