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
| Indication | Recommended Dosage of XALKORI | Duration of Treatment |
|---|---|---|
| ||
| 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.
| Body Surface Area * | Recommended XALKORI Dosage |
|---|---|
| |
| 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.
| Body Surface Area | First Dose Reduction | Second Dose Reduction |
|---|---|---|
| Dose | Dose | |
| ||
| 0.60 to 0.80 m2 | 250 mg Once daily | Permanently discontinue |
| 0.81 to 1.16 m2 | 200 mg Twice daily | 250 mg Once daily* |
| 1.17 to 1.69 m2 | 250 mg Twice daily | 200 mg Twice daily* |
| 1.70 m2 or greater | 400 mg Twice daily | 250 mg Twice 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.
| Severity of Adverse Reaction† | 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. |
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.
| Severity of Adverse Reaction* | XALKORI Dosage Modification |
|---|---|
| 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.
| Severity of Adverse Reaction | XALKORI Dosage Modification |
|---|---|
| |
| 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:
|
| 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.
| Severity of Adverse Reaction* | XALKORI Dosage Modification |
|---|---|
| |
| 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:
|
| 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.§ |
2.5 Dosage Modifications for Moderate and Severe Hepatic Impairment
Adult Patients with ALK- or ROS1-positive Metastatic NSCLC or with ALK-positive IMT
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)].
Pediatric and Young Adult Patients with ALK-positive ALCL or Pediatric Patients with ALK-positive IMT
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 3 [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 3 [see Dosage and Administration (2.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
2.6 Dosage Modification for Severe Renal Impairment
Adult Patients with ALK- or ROS1-positive Metastatic NSCLC or with ALK-positive IMT
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)].
Pediatric and Young Adult Patients with ALK-positive ALCL or Pediatric Patients with ALK-positive IMT
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 3 [see Dosage and Administration (2.6), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
2.7 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors
Adult Patients with ALK- or ROS1-positive metastatic NSCLC or with ALK-positive IMT
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.
Pediatric and Young Adult Patients with ALK-positive ALCL or Pediatric Patients with ALK-positive IMT
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 3 [see Dosage and Administration (2.4), Drug Interactions (7.1)]. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.