Prescription Drug Information: Xalkori

XALKORI- crizotinib capsule
Pfizer Laboratories Div Pfizer Inc

1 INDICATIONS AND USAGE

1.1 ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer

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 Relapsed or Refractory, Systemic ALK-Positive Anaplastic Large Cell Lymphoma

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 Unresectable, Recurrent, or Refractory ALK-Positive Inflammatory Myofibroblastic Tumor

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 DOSAGE AND ADMINISTRATION

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

Table 1: Recommended Dosage of XALKORI
Indication Recommended Dosage of XALKORI Duration of Treatment
*
Assess pediatric patients for their ability to swallow intact capsules before prescribing XALKORI. If needed, attain the desired dose by combining different strengths of XALKORI capsules. Administer XALKORI to pediatric patients under adult supervision.
See Table 2 for Recommended Dosage based on body surface area for pediatric patients and young adults with ALCL.
See Table 2 for Recommended Dosage based on body surface area for pediatric patients with IMT.

ALK- or ROS1-Positive Metastatic NSCLC

Adults:250 mg orally twice daily

Until disease progression or unacceptable toxicity

Relapsed or Refractory, Systemic ALK-Positive ALCL

Pediatric Patients and Young Adults: 280 mg/m2 orally twice daily *,

Unresectable, Recurrent, or Refractory ALK-Positive IMT

Adults:250 mg orally twice daily

Pediatric Patients: 280 mg/m2 orally twice daily *,

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.

Table 2. Recommended XALKORI Dosage for Pediatric and Young Adult Patients with ALCL and for Pediatric Patients with IMT
Body Surface Area * Recommended XALKORI Dosage
*
The recommended dosage for patients less than 1 year of age or with a BSA less than 0.60 m 2 has not been established.

0.60 to 0.80 m2

200 mg orally twice daily

0.81 to 1.16 m2

250 mg orally twice daily

1.17 to1.51 m2

400 mg orally twice daily

1.52 to 1.69 m2

450 mg orally twice daily

1.70 m2 or greater

500 mg orally twice daily

2.3 Concomitant Treatments for Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

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) ] .

2.4 Dosage Modifications for Adverse Reactions

Recommended Dosage Reductions

Adult Patients with ALK- or ROS1-positive Metastatic NSCLC or Adult Patients with ALK-positive IMT

The recommended dose reductions for adverse reactions 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.

Pediatric and Young Adult Patients with ALK-positive ALCL or Pediatric Patients with ALK-positive IMT

The recommended dose reductions for adverse reactions are provided in Table 3.

Table 3. Recommended Dose Reductions for XALKORI in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT
Body Surface Area First Dose Reduction Second Dose Reduction
Dose Dose
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

0.60 to 0.80 m2

250 mgOnce daily

Permanently discontinue

0.81 to 1.16 m2

200 mgTwice daily

250 mgOnce daily *

1.17 to 1.69 m2

250 mgTwice daily

200 mgTwice daily *

1.70 m2 or greater

400 mgTwice daily

250 mgTwice daily *

Recommended Dosage Modifications for Adult Patients with NSCLC or IMT

Recommended dosage modifications for hematologic and non-hematologic adverse reactions for adult patients with NSCLC or IMT are provided in Tables 4 and 5.

Table 4. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Hematologic Toxicities *
Severity of Adverse Reaction XALKORI Dosage Modification
*
Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

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.

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 5. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Non-Hematologic Toxicities
Severity of Adverse Reaction * XALKORI Dosage Modification
*
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Heart rate less than 60 beats per minute (bpm).
Permanently discontinue for recurrence.

Hepatotoxicity [see Warnings and Precautions (5.1)]

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN

Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage.

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)

Permanently discontinue.

Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2)]

Any grade drug-related interstitial lung disease/pneumonitis

Permanently discontinue.

QT Interval Prolongation [see Warnings and Precautions (5.3)]

QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs)

Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage.

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

Permanently discontinue.

Bradycardia [see Warnings and Precautions (5.4)]

Bradycardia (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.

Bradycardia , (life-threatening consequences, urgent intervention indicated)

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.

Recommended Dosage Modifications for Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

Recommended dosage modifications for hematologic and non-hematologic adverse reactions are provided in Tables 6 and 7.

Table 6. Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI Dosage Modification for Hematologic Adverse Reactions
Severity of Adverse Reaction XALKORI Dosage Modification
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise indicated in Table 3.

Absolute Neutrophil Count (ANC)

Less than 0.5 × 109 /L

First occurrence: Withhold until recovery to ANC greater than 1.0 × 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 × 109 /L, then resume at the next lower dosage.*

Platelet Count

25 to 50 × 109 /L with concurrent bleeding

Withhold until recovery to platelet count greater than 50 × 109 /L and bleeding resolves, then resume at the same dosage.

Less than 25 × 109 /L

Withhold until recovery to platelet count greater than 50 × 109 /L, then resume at the next lower dosage. Permanently discontinue for recurrence.

Anemia

Hemoglobin less than 8 g/dL

Withhold until recovery to hemoglobin 8 g/dL or more, then resume at the same dosage.

Life-threatening anemia; urgent intervention indicated.

Withhold until recovery to hemoglobin 8 g/dL or more, 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.

Table 7. Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions
Severity of Adverse Reaction * XALKORI Dosage Modification
*
Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
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.
Permanently discontinue for recurrence.
§
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise indicated in Table 3.

Hepatotoxicity [see Warnings and Precautions (5.1) ]

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN

Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at next lower dosage.

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)

Permanently discontinue.

Interstitial Lung Disease (Pneumonitis) [see Warnings and Precautions (5.2) ]

Any grade drug-related interstitial lung disease/pneumonitis

Permanently discontinue.

QT Interval Prolongation [see Warnings and Precautions (5.3) ]

QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms (ECGs)

Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage.

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

Permanently discontinue.

Bradycardia [see Warnings and Precautions (5.4) ]

Bradycardia (symptomatic, may be severe and medically significant, medical intervention indicated)

Withhold until recovery to a resting heart rate according to the patient’s age (based on the 2.5th percentile per age-specific norms) as follows:

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

Bradycardia , (life-threatening consequences, urgent intervention indicated)

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 3 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 Grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living)

Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disorders.

Visual Loss (Grade 3 or 4 Ocular Disorder, marked decrease in vision)

Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss if no other cause found on evaluation.

Gastrointestinal Toxicity [see Warnings and Precautions (5.6) ]

Nausea (Grade 3: inadequate oral intake for more than 3 days, medical intervention required)

Grade 3 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.§

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)

Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.§

Diarrhea (Grade 3: increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated; Grade 4: life-threatening consequences, urgent intervention indicated)

Grade 3 or 4 (despite maximum medical therapy): Withhold until resolved, and then resume at the next lower dose level.§

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