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XALKORI®Dosage and Administration (crizotinib)

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 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.

Table 1. Recommended XALKORI Dosage for Patients with ALCL
Body Surface Area *Recommended XALKORI Dosage
*
The recommended dosage for patients with a BSA less than 0.60 m2 has not been established.
0.60 – 0.80 m2200 mg orally twice daily
0.81 – 1.16 m2250 mg orally twice daily
1.17 – 1.51 m2400 mg orally twice daily
1.52 – 1.69 m2450 mg orally twice daily
1.70 m2 or greater500 mg orally twice daily

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
Body Surface AreaFirst Dose ReductionSecond Dose Reduction
DoseDose
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.
0.60 – 0.80 m2250 mg
Once daily
Permanently discontinue
0.81 – 1.16 m2200 mg
Twice daily
250 mg
Once daily*
1.17 – 1.69 m2250 mg
Twice daily
200 mg
Twice daily*
1.70 m2 or greater400 mg
Twice daily
250 mg
Twice daily*

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.

Table 3. Patients with NSCLC: XALKORI Dosage Modification – Hematologic Toxicities*
Severity of Adverse ReactionXALKORI 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 3Withhold 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 4. Patients with NSCLC: 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 ULNWithhold 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/pneumonitisPermanently 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 arrhythmiaPermanently 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 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 ReactionXALKORI Dosage Modification
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions, unless otherwise indicated in Table 2.
Absolute Neutrophil Count (ANC)
  Less than 0.5 × 109/LFirst 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 bleedingWithhold until recovery to platelet count greater than 50 × 109/L and bleeding resolves, then resume at the same dosage.
  Less than 25 × 109/LWithhold 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/dLWithhold 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 6. Patients with ALCL: 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 2.
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 ULNWithhold 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/pneumonitisPermanently 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 arrhythmiaPermanently 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 <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
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 2 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)Withhold pending evaluation of severe visual loss.
Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders, 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.§

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)].

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.

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