`
`
` 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
`
`
`
`
`XALKORI® (crizotinib) oral pellets
`
`
`
`
`Initial U.S. Approval: 2011
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES ---------------------------
`
`
`Dosage and Administration (2)
`9/2023
`
`--------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`
`XALKORI is a kinase inhibitor indicated for the treatment of
`
`
`•
` adult 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, 2.2)
` Limitations of Use: The safety and efficacy of XALKORI have not
`
`
`o
`
`
` been established in older adults with relapsed or refractory,
` systemic ALK-positive ALCL.
`
`
`
`
`
` adult and pediatric patients 1 year of age and older with unresectable,
` recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that
`
`
`
` is ALK-positive. (1.3, 2.2)
`
`
`
`•
`
`
`•
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`-----------------------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. (2.2)
`
`Unresectable IMT:
`
`○ Adult: The recommended dosage is 250 mg orally twice daily.
`
`
`
`
`
` (2.2)
`
`
`○
` Pediatric: The recommended dosage is 280 mg/m2 orally twice
`
`
` daily based on body surface area. (2.2)
` See full prescribing information for dosage adjustments by indication for
`
` patients with moderate or severe hepatic impairment or severe renal
`
`
` impairment. (2.5, 2.6)
`
`
`
`
`
` --------------------- DOSAGE FORMS AND STRENGTHS----------------------
` Capsules: 200 mg, 250 mg (3)
`
`
`
`
` Oral pellets: 20 mg, 50 mg, 150 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. (2.4, 5.1)
`
`Interstitial Lung Disease (ILD)/Pneumonitis: Permanently discontinue in
`
`patients with ILD/pneumonitis. (2.4, 5.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`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. (2.4, 5.3)
`
`Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and
`
`blood pressure regularly. Temporarily suspend, dose reduce, or
`
`permanently discontinue XALKORI. (2.4, 5.4)
`
`
`
`Severe Visual Loss: XALKORI can cause visual changes including
`
`severe visual loss. Monitor and evaluate for ocular toxicity throughout
`
`
`treatment. Discontinue XALKORI in patients with severe visual loss.
`
`(2.4, 5.5)
`
`
`
`Gastrointestinal Toxicity in Pediatric and Young Adult Patients with
`
`
`ALCL or Pediatric Patients with IMT: 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, 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 adult 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 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)
`
`
`
`
`
`
`
`
`The most common adverse reactions (≥35%) in adult patients with IMT are
`
`
`vision disorders, nausea, and edema. (6.1)
`
`
`
`
`
`
`
`
`The most common adverse reactions (≥35%) in pediatric patients with IMT
`
`
`
`are vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper
`respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue,
`
`
`edema, constipation, and headache. (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. (2.9, 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: 9/2023
`
`
` _______________________________________________________________________________________________________________________________________
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`
`
`2
`
`
`INDICATIONS AND USAGE
`
`1.1 ALK- or ROS1-Positive Metastatic NSCLC
`
`
`
`1.2 Relapsed or Refractory, Systemic ALK-Positive ALCL
`
`
`1.3 Unresectable, Recurrent, or Refractory ALK-Positive IMT
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Patient Selection
`
`
`2.2 Recommended Testing During Treatment with XALKORI
`
`
`
`2.3 Recommended Dosage
`
`
`2.4 Administration
`
`
`2.5 Concomitant Treatments for Pediatric and Young Adult Patients
`
`
`with ALCL or Pediatric Patients with IMT
`
`2.6 Dosage Modifications for Adverse Reactions
`
`
`2.7 Dosage Modifications for Moderate and Severe Hepatic
`
`
`Impairment
`
`
`2.8 Dosage Modification for Severe Renal Impairment
`
`
`2.9 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
`
`
`5.4 Bradycardia
`
`5.5 Severe Visual Loss
`
`
`5.6 Gastrointestinal Toxicity in Pediatric and Young Adult Patients
`
`
`with ALCL or Pediatric Patients with IMT
`
`
`5.7 Embryo-Fetal Toxicity
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6
`
`
`Reference ID: 5239813
`
`
`
` 1
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
` 7
`
`8
`
`
`
`INDICATIONS AND USAGE
`
`
`
`ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer
`
`Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma
`
`
`12 CLINICAL PHARMACOLOGY
`
`
` 6.2 Postmarketing Experience
`
`DRUG INTERACTIONS
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`7.1 Effect of Other Drugs on XALKORI
`
`
`
`
`12.3 Pharmacokinetics
`
`
`7.2 Effect of XALKORI on Other Drugs
`
`
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`7.3 Drugs That Prolong the QT Interval
`
`
`
`7.4 Drugs That Cause Bradycardia
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`USE IN SPECIFIC POPULATIONS
`14 CLINICAL STUDIES
`
`
`8.1 Pregnancy
`
`
`14.1 ALK- or ROS1-Positive Metastatic NSCLC
`
`
`
`8.2 Lactation
`
`
`14.2 Relapsed or Refractory, Systemic ALK-Positive ALCL
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`14.3 Unresectable, Recurrent, or Refractory ALK-Positive IMT
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`8.4 Pediatric Use
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`
`8.7 Renal Impairment
`
`
`* Sections or subsections omitted from the full prescribing information are not
`11 DESCRIPTION
`
`
`listed.
`_______________________________________________________________________________________________________________________________________
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1
`
`1.1
`
`
`
`
`XALKORI is indicated for the treatment of adult 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.
`
`1.3
`
`
`
`
`
`XALKORI is indicated for the treatment of adult and pediatric patients 1 year of age and older with
`
`
`
`unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.
`
`2
`
`2.1
`
`
`
`
`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, 14.3)].
`
`
`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
`
`
`
`Unresectable, Recurrent, or Refractory ALK-Positive Inflammatory Myofibroblastic Tumor
`
`
`DOSAGE AND ADMINISTRATION
`
`
`Patient Selection
`
`
`Recommended Testing During Treatment with XALKORI
`
`
`
`
`• Monitor liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase
`(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
`
`Reference ID: 5239813
`
`2
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`2.3
`
`
`
`
` phosphatase, or total bilirubin in patients who develop increased transaminases [see Warnings and
`
` Precautions (5.1)].
`
`
`
` • 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
`
` [see Adverse Reactions (6.1)].
`
`
`
`
`
` • For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and
`
`
`
`
`
` follow-up ophthalmologic examinations including retinal examination within 1 month of starting
` XALKORI and every 3 months thereafter [see Warnings and Precautions (5.5)].
`
`
`
`
`
`
`
`
`
`Recommended Dosage
`
`
`
`Unresectable, Recurrent, or
`
`Refractory ALK-Positive IMT
`
`
`
`
`
`
`
`The recommended dosage of XALKORI is provided in Table 1.
`
`Table 1. Recommended Dosage of XALKORI
` Recommended Dosage of XALKORI
`
` Indication
`
`
` Adults:
` ALK- or ROS1-Positive
`
`250 mg orally twice daily
`
` Metastatic NSCLC
` Relapsed or Refractory,
`
`
` Pediatric Patients and Young Adults:
` 280 mg/m2 orally twice dailya
`
`Systemic ALK-Positive ALCL
`
`
`
`
` Adults:
` 250 mg orally twice daily
`
` Pediatric Patients:
` 280 mg/m2 orally twice dailyb
`
`
`
`
`
`
`
`
`
`
`
` a See Table 2 for Recommended Dosage based on body surface area for pediatric
`
`
`
` patients and young adults with ALCL for the capsules and oral pellets.
`
`
`
`
`
`
`
`
`
`b See Table 3 for Recommended Dosage based on body surface area for pediatric
`
`
`
`
`
`
`
`
`
`
` patients with IMT for the capsules and oral pellets.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommended Dosage for Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC
`
`
`
`
`
`
` • The recommended dosage for adult patients with ALK- or ROS1-positive metastatic NSCLC is
`
`
`
`
`
` XALKORI capsules 250 mg orally, twice daily, with or without food until disease progression or
` unacceptable toxicity occurs.
`
` • For adults who cannot swallow capsules, the recommended dosage of XALKORI pellets is 250 mg
`
`
`
`
`
` (2 x 50 mg + 1 x 150 mg) orally, twice daily, with or without food until disease progression or
`
` unacceptable toxicity occurs.
`
`Recommended Dosage for Pediatric and Young Adult Patients with ALK-Positive ALCL
`
`
`
`
`
`
`
`
`
`• The recommended dosage for pediatric patients 1 year of age and older and young adults with relapsed
`
`
`
`
`or refractory, systemic ALK-positive ALCL is based on body surface area (BSA) and is provided in
`
`
`Table 2.
`
`• Administer XALKORI capsules or pellets orally, twice daily, with or without food until disease
`
`
`
`progression or unacceptable toxicity occurs.
`
`
`
`
`Reference ID: 5239813
`
`
`
`3
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`Table 2 provides the dosage based on body surface area (BSA) for XALKORI capsules or pellets.
`
`
`
`
`
`
`Table 2. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older and Young
`
`
`
`Adults With ALK-Positive ALCL Using Either XALKORI Capsules or Pellets
`Dose Strength
`
` Body Surface
`
` Recommended XALKORI
`Dose Strength
`
` Area (BSA)
`Dosage to Achieve
`Combinations of
`Combinations of
`
` 280 mg/m2
`XALKORI Pellets to
` XALKORI Capsules to
` Twice Daily
`
` Administera
`
`
` Administer
`
` 0.38 to 0.46 m2
`
`
` 120 mg twice daily
`
`
` 1 x 20 mg + 2 x 50 mg
`
`---
`
` 0.47 to 0.51 m2
`
`
` 140 mg twice daily
`
`
` 2 x 20 mg + 2 x 50 mg
`
`---
`
` 0.52 to 0.61 m2
`
` 150 mg twice daily
`
` 1 x 150 mg
`
`
`---
`
` 0.62 to 0.80 m2
`
` 200 mg twice daily
`
`
` 1 x 50 mg + 1 x 150 mg
`
`
`---
`
` 0.81 to 0.97 m2
`
` 250 mg twice daily
`
`
`
` 2 x 50 mg + 1 x 150 mg
`
`---
`
` 0.98 to 1.16 m2
`
` 300 mg twice daily
`
` 2 x 150 mg
`
`
`---
`
` 1.17 to 1.33 m2
`
` 350 mg twice daily
`
`
` 1 x 50 mg + 2 x 150 mg
`
`
`---
`
` 1.34 to 1.51 m2
` 400 mg twice daily
`
`
`
` 2 x 50 mg + 2 x 150 mg
` 2 x 200 mg
`
`
` 1.52 to 1.69 m2
`
` 450 mg twice daily
` 3 x 150 mg
`
`
` 1 x 200 mg + 1 x 250 mg
` 1.7 m2 or greater
`
`
` 500 mg twice daily
`
`
` 1 x 50 mg + 3 x 150 mg
`
` 2 x 250 mg
`
`
` a No more than 4 oral pellet shells are to be used for a single dose.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommended Dosage for Pediatric and Adult Patients with ALK-Positive IMT
`
`
` • The recommended dosage for adult patients with unresectable, recurrent, or refractory ALK-positive IMT
`
` is provided in Table 1.
`
`
` • The recommended dosage for pediatric patients 1 year of age and older with unresectable, recurrent, or
`
` refractory ALK-positive IMT is based on BSA and is provided in Table 3.
`
` • Administer XALKORI capsules or pellets orally twice daily, with or without food, until disease
`
`
`
` progression or unacceptable toxicity occurs.
`
`
` Table 3 provides the dosage based on BSA for XALKORI capsules or pellets.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3. Recommended XALKORI Dosage for Pediatric Patients 1 Year of Age and Older with ALK-
`
`
`
`
`
` positive IMT Using Either XALKORI Capsules or Pellets
` Recommended XALKORI
`Dose Strength
`
`Dosage to Achieve
`Combinations of
`
` 280 mg/m2
`
` XALKORI Pellets to
` Twice Daily
`
` Administera
`
`
` 0.38 to 0.46 m2
`
`
` 120 mg twice daily
`
`
` 1 x 20 mg + 2 x 50 mg
`
` 0.47 to 0.51 m2
`
`
` 140 mg twice daily
`
`
` 2 x 20 mg + 2 x 50 mg
`
` 0.52 to 0.61 m2
`
` 150 mg twice daily
`
` 1 x 150 mg
`
`
` 0.62 to 0.80 m2
`
` 200 mg twice daily
`
`
` 1 x 50 mg + 1 x 150 mg
`
`
` 0.81 to 0.97 m2
`
` 250 mg twice daily
`
`
`
` 2 x 50 mg + 1 x 150 mg
`
` 0.98 to 1.16 m2
`
` 300 mg twice daily
`
` 2 x 150 mg
`
`
` 1.17 to 1.33 m2
`
` 350 mg twice daily
`
`
` 1 x 50 mg + 2 x 150 mg
`
`
`
` 1.34 to 1.51 m2
` 400 mg twice daily
`
`
`
` 2 x 50 mg + 2 x 150 mg
`
` 1.52 to 1.69 m2
`
` 450 mg twice daily
` 3 x 150 mg
`
` 1.7 m2 or greater
`
`
` 500 mg twice daily
`
`
` 1 x 50 mg + 3 x 150 mg
`
`
` a No more than 4 oral pellet shells are to be used for a single dose.
`
`
`
`
`
`
`
`
`
`
` Body Surface
`
` Area (BSA)
`
`
`
`
`
`
`
`
`
`Reference ID: 5239813
`
`4
`
`
`Dose Strength
`Combinations of
`
` XALKORI Capsules to
` Administer
`
`
`---
`
`---
`
`---
`
`---
`
`---
`
`---
`
`---
` 2 x 200 mg
`
`
` 1 x 200 mg + 1 x 250 mg
` 2 x 250 mg
`
`
`
`
`
`
`
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`2.4
`
`
`Administration
`
`
`
`
`• Administer XALKORI capsules or pellets orally, twice daily, with or without food.
`
`
`
`
`If a dose of XALKORI capsules or pellets is missed, make up that dose unless the next dose is due
`•
`
`within 6 hours.
`
`
`If vomiting occurs after taking a dose of XALKORI capsules or pellets, do not take an additional dose.
`
`
`Take the next dose at the regular scheduled time.
`
`
`•
`
`
`
`XALKORI Capsules
`
`
`
`
`• Swallow XALKORI capsules whole, with or without food twice daily.
`
`
`
`
`
`• Do not chew, crush or split XALKORI capsules.
`
`
`
`XALKORI Pellets
`
`
`
`
`
`• XALKORI pellets are supplied encapsulated in shells.
`
`
`
`
`• Do not chew or crush XALKORI pellets.
`
`
`
`
`• Do not swallow XALKORI pellets encapsulated in the shell.
`
`
`
`• XALKORI pellets can be administered by 2 options:
`
`
`
`
`
`
`
`1. Open shell(s) containing XALKORI pellets and empty the contents directly into the patient’s mouth.
`
`
`
`2. Open shell(s) containing XALKORI pellets and empty the contents into a consumer -supplied oral
`
`
`dosing aid (e.g., spoon, medicine cup). Administer XALKORI pellets via the dosing aid directly
`
`
`into the patient’s mouth.
`
`
`
`
`
`Immediately after administration, give a sufficient amount of water to ensure that all medication is
`
`swallowed.
`
`
`•
`
`
`2.5
`
`
`
`
`Concomitant Treatments for Pediatric and Young Adult Patients with ALCL or Pediatric Patients
`
`with IMT
`
`
`
`
`
`Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting.
`
`
`
`Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities.
`
`
`
`
`
`
`
`Consider intravenous or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically
`
`indicated [see Warnings and Precautions (5.6)].
`
`2.6
`
`
`
`The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are
`
`
`provided in Table 4.
`
`
`
`
`Dosage Modifications for Adverse Reactions
`
`
`
`Table 4. Recommended Dosage Reductions for Adverse Reactions for Adult Patients with NSCLC or
`
`IMT Using XALKORI Capsules or Pellets
`
`
`
` Dose Reduction
`
` Dose and Schedule
`
` First Dose Reduction
`
`
` 200 mg twice daily
` Second Dose Reduction
`
`
` 250 mg once daily
` Permanently discontinue XALKORI capsules or pellets if unable to tolerate 250 mg taken
`
`
`
`
` once daily.
`
`5
`
`
`Reference ID: 5239813
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`The recommended dosage modifications for adverse reactions for pediatric patients with ALCL or IMT and
`
`
`
`
`young adults with ALCL are based on body surface area and are provided in Table 5.
`
`
`
`
`
`
` 90 mg
`
`
` twice daily
`
`
` 100 mg
` twice daily
`
`
` 120 mg
` twice daily
`
`
` 150 mg
` twice daily
`
`
`
` Pellets:1 x 20 mg +
`
`
`2 x 50 mg
` Pellets: 1 x 150 mg
`
`
`
`
`
`
`
`
`
` 200 mg
`
`
` twice daily
`
`
` 220 mg
` twice daily
`
`
`
`
`Body Surface
`
`Area
`
`(BSA)
` 0.38 to 0.46 m2
`
`
`
`
`
` 0.47 to 0.51 m2
`
`
`
` 0.52 to 0.61 m2
`
`
`
` 0.62 to 0.80 m2
`
`
`
` 0.81 to 0.97 m2
`
`
`
` 0.98 to 1.16 m2
`
`
`
` 1.17 to 1.33 m2
`
`
`
`
`
` 1.34 to 1.69 m2
`
`
` 1.7 m2 or
` greater
`
`
`
`
`
`
`
`
`
`
` Pellets:4 x 20 mg
`
` 70 mg
`
` twice daily
`
` 80 mg
` twice daily
`90 mg
`Pellets:2 x 20 mg +
`
`
`
`twice daily
`1 x 50 mg
`
`
`
` 120 mg
` Pellets:1 x 20 mg +
`
` twice daily
`
`2 x 50 mg
`
`
`
` 150 mg
` twice daily Pellets: 1 x 150 mg
`
`
`
`
` 170 mg
` Pellets:1 x 20 mg +
` twice daily
`1 x 150 mg
`
`
`
`
`
`
`
`
`
`
`
`Table 5. Recommended Dosage Reductions for Adverse Reactions for Pediatric Patients with ALCL or
`
`
`
`IMT and Young Adults with ALCL Using XALKORI Capsules or Pellets
`
` First Dose Reduction
` Second Dose Reduction*
`
`
` Dosage Form and Strength
`
`
` Dosage Form and Strength
`
`
`
`
`Dosage
` Dosage
`
`
`
` to Achieve Recommended
`
` to Achieve Recommended
`
`
`
`
` Dose Reduction
` Dose Reduction
`
`
` Pellets:2 x 20 mg +
`
`
` Pellets:1 x 20 mg +
`1 x 50 mg
`
`1 x 50 mg
`
`
`
` Pellets: 2 x 50 mg
`
`
`
` Pellets:1 x 50 mg +
`1 x 150 mg
`
`
`
` Pellets:1 x 20 mg +
` 1 x 50 mg +
`
`
`
`
` 1 x 150 mg
` Pellets:1 x 50 mg +
`
` Pellets:2 x 50 mg +
`
`
`1 x 150 mg
`
`1 x 150 mg
` Pellets:1 x 50 mg +
`
` Pellets:2 x 50 mg +
`
`
`1 x 150 mg
`
`1 x 150 mg
`
` Or
`
` Or
` Capsule: 1 x 200 mg
`
` Capsule: 1 x 250 mg
`
`
`
` Pellets:2 x 50 mg +
`
`
` Pellets:2 x 50 mg +
`1 x 150 mg
`
`2 x 150 mg
`
`
` Or
`
` Or
` Capsule: 1 x 250 mg
` Capsule: 2 x 200 mg
`
`
`
`
`
`
`
`
` *Permanently discontinue in patients who are unable to tolerate XALKORI capsules or pellets after 2 dose reductions.
`
` 250 mg
`
`
` twice daily
`
`
`
` 250 mg
`
`
` twice daily
`
`
`
`
` 400 mg
`
` twice daily
`
`
`
`
`
`
`
` 200 mg
`
` twice daily
`
`
` 200 mg
`
` twice daily
`
`
`250 mg
` twice daily
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommended Dosage Modifications for Hematologic Adverse Reactions for Adult Patients with NSCLC or
`
` IMT
`
`The recommended dosage modifications for hematologic adverse reactions for adult patients with NSCLC or
`
`
`
`
`IMT are provided in Table 6.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5239813
`
`6
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
` Table 6. Adult Patients with NSCLC or IMT: 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).
`
`
`
`
`
`
`
`b Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`Recommended Dosage Modifications for Hematologic Adverse Reactions in Pediatric and Young Adult
`
`
`Patients with ALCL or Pediatric Patients with IMT
`
`
`
`
`The recommended dosage modifications for hematologic adverse reactions in pediatric and young adult patients
`
`
`
`
`with ALCL or pediatric patients with IMT are provided in Table 7.
`
`
`
`
`
`Table 7. Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI
`
`Dosage Modification for Hematologic Adverse Reactions
` XALKORI Dosage Modification
`
` Severity of Adverse Reaction
` 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
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Recommended Dosage Modifications for Non-Hematologic Adverse Reactions
`
`
`
`The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8.
`
`
`
`
`Reference ID: 5239813
`
`7
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Permanently discontinue.
`
`
`
`
`
`
`
` Permanently discontinue.
`
`
`
`
`
`
`
`
`Table 8. All Patients: 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
`
`
`aminotransferase (AST) greater than 5 times
`
` 3 times ULN, then resume at next lower dosage.
`
`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
`
`
`
` norms) as follows:
`indicated)
` • 1 to less than 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
`
`
` • Older than 8 years: 60 bpm or above
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Bradycardiab (life-threatening consequences,
`
`
` urgent intervention indicated)
`
`
`
`Reference ID: 5239813
`
`
` 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 the age-specific
`
`
`
`
` heart rate provided above.
`
` If no contributing concomitant medication is identified, or if
`
` contributing concomitant medications are not discontinued or
`dose adjusted, resume at reduced dose upon recovery to
`asymptomatic bradycardia or to the age-specific heart rate
`
`
` provided 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
`8
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
` Severity of Adverse Reactiona
`
`
`
`
`
`
`
` XALKORI Dosage Modification
`
`
`
`
` reduction level in Table 4 or 5 upon recovery to asymptomatic
` bradycardia or to the heart rate criteria listed for management of
`
`
` symptomatic or severe, medically significant bradycardia, with
`
` frequent monitoring.
` Permanently discontinue for recurrence.
` Ocular Toxicity, including Visual Loss [see Warnings and Precautions (5.5)]
`
`
` Monitor symptoms and report any symptoms to an eye specialist.
`
` Visual Symptoms, Grade 1 (mild symptoms) or
`
`
`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)
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Discontinue during evaluation of severe visual loss.
`
`
` Permanently discontinue XALKORI for Grade 3 or 4 ocular
` disorders or severe visual loss if no other cause found on
`
`
`
` evaluation.
` Gastrointestinal Toxicityc [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 Dosage modifications for gastrointestinal toxicity for pediatric patients with ALCL or IMT and young adults with ALCL only.
`
`
`
`
`
`
`
`
`
`
`
` d Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.7
`
` 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 shown in Table 4 for adult patients with NSCLC or IMT and
`
`
`
`
`
`
`Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Use in Specific Populations
`
`
`
`
`
`
`
`(8.7), 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 shown in Table 4 for adult patients with NSCLC or IMT
`
`
`
`
`
`and Table 5 for pediatric patients with ALCL or IMT and young adults with ALCL [see Dosage and
`
`
`
`
`
`Administration (2.6), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`2.8
`
`
`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 for adult patients and the
`
`
`
`
`
`
`
`
`
`
` Dosage Modifications for Moderate and Severe Hepatic Impairment
`
`
`
`Dosage Modification for Severe Renal Impairment
`
`
`Reference ID: 5239813
`
`9
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fd