`
`
`
`
`
`
`
`
`
`QT Interval Prolongation: Monitor electrocardiograms and electrolytes
`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 -----------------------
`Lactation: Advise not to breastfeed. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`Revised: 9/2021
`
`6
`
`7
`
`8
`
`5.4 Bradycardia
`5.5 Severe Visual Loss
`5.6 Gastrointestinal Toxicity in Patients with ALCL
`5.7 Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Effect of Other Drugs on XALKORI
`7.2 Effect of XALKORI on Other Drugs
`7.3 Drugs That Prolong the QT Interval
`7.4 Drugs That Cause Bradycardia
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`
`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)
`o
`Limitations of Use: The safety and efficacy of XALKORI have 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)
`
`
`
`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
`
`2
`
`Reference ID: 4860921
`
`1
`
`
`
`
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 ALK- or ROS1-Positive Metastatic NSCLC
`14.2 Relapsed or Refractory, Systemic ALK-Positive ALCL
`_______________________________________________________________________________________________________________________________________
`
`
` Sections or subsections omitted from the full prescribing information are not
`listed.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
` *
`
`Reference ID: 4860921
`
`2
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`
`
`INDICATIONS AND USAGE
`
`ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer
`
`Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma
`
`
`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.
`
`DOSAGE AND ADMINISTRATION
`
` 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.
`
`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.
`
`Reference ID: 4860921
`
`3
`
`
`
`
`
`
`Table 1. Recommended XALKORI Dosage for Patients with ALCL
`Body Surface Area *
`Recommended XALKORI Dosage
`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.
`
`
`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:
`
`
`
`First dose reduction: XALKORI 200 mg taken orally twice daily
`Second dose reduction: XALKORI 250 mg taken orally once daily
`Permanently discontinue if unable to tolerate XALKORI 250 mg taken orally once daily.
`
`
`
`
`
`Systemic ALK-positive ALCL
`The recommended dose reductions for adverse reactions in patients with ALCL are provided in Table 2.
`
`
`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
`
`
`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.
`
`
`Reference ID: 4860921
`
`4
`
`
`
`
`
`Table 3. Patients with NSCLC: XALKORI Dosage Modification – Hematologic Toxicitiesa
`Severity of Adverse Reactionb XALKORI Dosage Modification
`Grade 3
`Withhold until recovery to Grade 2 or less, then resume at the same dosage.
`Grade 4
`Withhold until recovery to Grade 2 or less, then resume at next lower dosage.
`a Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
`b Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`
`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.
`
`
`Permanently discontinue.
`
`Permanently discontinue.
`
`
`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)]
`Withhold until recovery to baseline or less than or equal to
`Alanine aminotransferase (ALT) or aspartate
`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)]
`Any grade drug-related interstitial lung
`Permanently discontinue.
`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)
`
`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.
`
`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
`5
`
`Bradycardiab,c (life-threatening consequences,
`urgent intervention indicated)
`
`Reference ID: 4860921
`
`
`
`
`
`Severity of Adverse Reactiona
`
`XALKORI Dosage Modification
`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.
`b Heart rate less than 60 beats per minute (bpm).
`c Permanently discontinue for recurrence.
`
`
`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)
`
`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
`
`Less than 0.5 x 109/L
`
`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
`the next lower dosage. Permanently discontinue for recurrence.
`intervention indicated.
`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: 4860921
`
`6
`
`
`
`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)]
`Any grade drug-related interstitial lung
`Permanently discontinue.
`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.
`Consider dose reduction for Grade 2 visual disorders.
`Grade 2 (moderate symptoms affecting ability
`to perform age-appropriate activities of daily
`living)
`Visual Loss (Grade 3 or 4 Ocular Disorder,
`marked decrease in vision)
`
`Bradycardiab,c (life-threatening consequences,
`urgent intervention indicated)
`
`
`
`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: 4860921
`
`7
`
`
`
`
`
`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)].
`
`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)].
`8
`
`Reference ID: 4860921
`
`
`
`
`
`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.
`
`DOSAGE FORMS AND STRENGTHS
`
` 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
`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
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`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)].
`
`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%.
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`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 the 56 patients who experienced visual disorders, one patient experienced Grade 3
`optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment.
`
`For patients with ALCL, obtain baseline ophthalmologic examination prior to starting XALKORI. Follow-up
`ophthalmologic examination including retinal examination is recommended within 1 month of starting
`XALKORI, every 3 months thereafter, and upon any new visual symptoms. Assessment of visual symptoms is
`recommended monthly during treatment. Report any visual symptoms to an eye specialist. Withhold XALKORI
`pending evaluation for any Grade 3 or 4 ocular disorders, and permanently discontinue XALKORI for Grade 3
`or 4 ocular disorders unless another cause is identified [see Dosage and Administration (2.5)].
`
`Discontinue XALKORI in any patient with new onset of severe visual loss (best corrected vision less than
`20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity,
`retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate for
`new onset of visual loss and for other visual symptoms as clinically warranted [see Dosage and Administration
`(2.5), Adverse Reactions (6.1)].
`
`There is insufficient information to characterize the risks of resumption of XALKORI in patients who develop
`visual symptoms or visual loss. A decision to resume XALKORI should consider the potential benefits versus
`risks to the patient.
`
`5.6 Gastrointestinal Toxicity in Patients with ALCL
`
`XALKORI can cause severe gastrointestinal toxicities in patients with ALCL [see Adverse Reactions (6.1)]. In
`patients with ALCL (n=26), gastrointestinal toxicity occurred in 100% of patients; Grade 3 gastrointestinal
`toxicity occurred in 27% of patients and included diarrhea, nausea, vomiting, and stomatitis.
`
`Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in patients with ALCL.
`Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. If
`patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhea or vomiting despite maximum medical
`therapy, withhold XALKORI until resolved, and then resume at the next lower dose level. Consider supportive
`care such as hydration, electrolyte supplementation, and nutritional support as clinically indicated [see Dosage
`and Administration (2.5)].
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`5.7 Embryo-Fetal Toxicity
`
`Based on its mechanism of action, XALKORI can cause fetal harm when ad