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, 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 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 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)].

2.3 Recommended Dosage

The recommended dosage of XALKORI is provided in Table 1.

Table 1. Recommended Dosage of XALKORI
*
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.
†
See Table 3 for Recommended Dosage based on body surface area for pediatric patients with IMT for the capsules and oral pellets.

Indication

Recommended Dosage of XALKORI

ALK- or ROS1-Positive Metastatic NSCLC

Adults:
250 mg orally twice daily

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†

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.

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
*
No more than 4 oral pellet shells are to be used for a single dose.

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer*

Dose Strength Combinations of XALKORI Capsules to 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

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
*
No more than 4 oral pellet shells are to be used for a single dose.

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer*

Dose Strength Combinations of XALKORI Capsules to 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

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 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4.

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.

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.

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
*
Permanently discontinue in patients who are unable to tolerate XALKORI capsules or pellets after 2 dose reductions.

Body Surface Area

(BSA)

First Dose Reduction

Second Dose Reduction*

Dosage

Dosage Form and Strength to Achieve Recommended Dose Reduction

Dosage

Dosage Form and Strength to Achieve Recommended Dose Reduction

0.38 to 0.46 m2

90 mg

twice daily

Pellets: 2 x 20 mg +

             1 x 50 mg

70 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 50 mg

0.47 to 0.51 m2

100 mg

twice daily

Pellets: 2 x 50 mg

80 mg

twice daily

Pellets: 4 x 20 mg

0.52 to 0.61 m2

120 mg

twice daily

Pellets: 1 x 20 mg +

             2 x 50 mg

90 mg

twice daily

Pellets: 2 x 20 mg +

             1 x 50 mg

0.62 to 0.80 m2

150 mg

twice daily

Pellets: 1 x 150 mg

120 mg

twice daily

Pellets: 1 x 20 mg +

             2 x 50 mg

0.81 to 0.97 m2

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

150 mg

twice daily

Pellets: 1 x 150 mg

0.98 to 1.16 m2

220 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 50 mg +

             1 x 150 mg

170 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 150 mg

1.17 to 1.33 m2

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

1.34 to 1.69 m2

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 250 mg

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 200 mg

1.7 m2 or greater

400 mg

twice daily

Pellets: 2 x 50 mg +

             2 x 150 mg

                   Or

Capsule: 2 x 200 mg

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 250 mg

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.

Table 6. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Hematologic Toxicities*
*
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.

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 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
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

Severity of Adverse Reaction

XALKORI Dosage Modification

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.*

Platelet Count

25 to 50 x 109/L with concurrent bleeding

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

Less than 25 x 109/L

Withhold until recovery to platelet count greater than 50 x 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.

Recommended Dosage Modifications for Non-Hematologic Adverse Reactions

The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8.

Table 8. All Patients: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions
*
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.
‡
Dosage modifications for gastrointestinal toxicity for pediatric patients with ALCL or IMT and young adults with ALCL only.
§
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

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:

•
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

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.

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 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)]

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)

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 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.§

2.7 Dosage Modifications for Moderate and Severe Hepatic Impairment

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 Dosage Modification for Severe Renal Impairment

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 Schwartz equation for pediatric patients] not requiring dialysis 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 Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.9 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors [see Drug Interactions (7.1)]. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to 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. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.

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Dosage and Administration

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, 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 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 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)].

2.3 Recommended Dosage

The recommended dosage of XALKORI is provided in Table 1.

Table 1. Recommended Dosage of XALKORI
*
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.
†
See Table 3 for Recommended Dosage based on body surface area for pediatric patients with IMT for the capsules and oral pellets.

Indication

Recommended Dosage of XALKORI

ALK- or ROS1-Positive Metastatic NSCLC

Adults:
250 mg orally twice daily

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†

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.

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
*
No more than 4 oral pellet shells are to be used for a single dose.

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer*

Dose Strength Combinations of XALKORI Capsules to 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

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
*
No more than 4 oral pellet shells are to be used for a single dose.

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer*

Dose Strength Combinations of XALKORI Capsules to 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

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 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4.

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.

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.

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
*
Permanently discontinue in patients who are unable to tolerate XALKORI capsules or pellets after 2 dose reductions.

Body Surface Area

(BSA)

First Dose Reduction

Second Dose Reduction*

Dosage

Dosage Form and Strength to Achieve Recommended Dose Reduction

Dosage

Dosage Form and Strength to Achieve Recommended Dose Reduction

0.38 to 0.46 m2

90 mg

twice daily

Pellets: 2 x 20 mg +

             1 x 50 mg

70 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 50 mg

0.47 to 0.51 m2

100 mg

twice daily

Pellets: 2 x 50 mg

80 mg

twice daily

Pellets: 4 x 20 mg

0.52 to 0.61 m2

120 mg

twice daily

Pellets: 1 x 20 mg +

             2 x 50 mg

90 mg

twice daily

Pellets: 2 x 20 mg +

             1 x 50 mg

0.62 to 0.80 m2

150 mg

twice daily

Pellets: 1 x 150 mg

120 mg

twice daily

Pellets: 1 x 20 mg +

             2 x 50 mg

0.81 to 0.97 m2

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

150 mg

twice daily

Pellets: 1 x 150 mg

0.98 to 1.16 m2

220 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 50 mg +

             1 x 150 mg

170 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 150 mg

1.17 to 1.33 m2

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

1.34 to 1.69 m2

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 250 mg

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 200 mg

1.7 m2 or greater

400 mg

twice daily

Pellets: 2 x 50 mg +

             2 x 150 mg

                   Or

Capsule: 2 x 200 mg

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 250 mg

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.

Table 6. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Hematologic Toxicities*
*
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.

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 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
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

Severity of Adverse Reaction

XALKORI Dosage Modification

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.*

Platelet Count

25 to 50 x 109/L with concurrent bleeding

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

Less than 25 x 109/L

Withhold until recovery to platelet count greater than 50 x 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.

Recommended Dosage Modifications for Non-Hematologic Adverse Reactions

The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8.

Table 8. All Patients: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions
*
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.
‡
Dosage modifications for gastrointestinal toxicity for pediatric patients with ALCL or IMT and young adults with ALCL only.
§
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

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:

•
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

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.

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 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)]

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)

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 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.§

2.7 Dosage Modifications for Moderate and Severe Hepatic Impairment

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 Dosage Modification for Severe Renal Impairment

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 Schwartz equation for pediatric patients] not requiring dialysis 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 Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.9 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors [see Drug Interactions (7.1)]. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to 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. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.
Prescribing Information
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Health Professional Information

Dosage and Administration

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, 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 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 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)].

2.3 Recommended Dosage

The recommended dosage of XALKORI is provided in Table 1.

Table 1. Recommended Dosage of XALKORI
*
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.
†
See Table 3 for Recommended Dosage based on body surface area for pediatric patients with IMT for the capsules and oral pellets.

Indication

Recommended Dosage of XALKORI

ALK- or ROS1-Positive Metastatic NSCLC

Adults:
250 mg orally twice daily

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†

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.

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
*
No more than 4 oral pellet shells are to be used for a single dose.

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer*

Dose Strength Combinations of XALKORI Capsules to 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

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
*
No more than 4 oral pellet shells are to be used for a single dose.

Body Surface Area (BSA)

Recommended XALKORI Dosage to Achieve 280 mg/m2

Twice Daily

Dose Strength Combinations of XALKORI Pellets to Administer*

Dose Strength Combinations of XALKORI Capsules to 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

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 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for adverse reactions for adult patients with NSCLC or IMT are provided in Table 4.

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.

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.

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
*
Permanently discontinue in patients who are unable to tolerate XALKORI capsules or pellets after 2 dose reductions.

Body Surface Area

(BSA)

First Dose Reduction

Second Dose Reduction*

Dosage

Dosage Form and Strength to Achieve Recommended Dose Reduction

Dosage

Dosage Form and Strength to Achieve Recommended Dose Reduction

0.38 to 0.46 m2

90 mg

twice daily

Pellets: 2 x 20 mg +

             1 x 50 mg

70 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 50 mg

0.47 to 0.51 m2

100 mg

twice daily

Pellets: 2 x 50 mg

80 mg

twice daily

Pellets: 4 x 20 mg

0.52 to 0.61 m2

120 mg

twice daily

Pellets: 1 x 20 mg +

             2 x 50 mg

90 mg

twice daily

Pellets: 2 x 20 mg +

             1 x 50 mg

0.62 to 0.80 m2

150 mg

twice daily

Pellets: 1 x 150 mg

120 mg

twice daily

Pellets: 1 x 20 mg +

             2 x 50 mg

0.81 to 0.97 m2

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

150 mg

twice daily

Pellets: 1 x 150 mg

0.98 to 1.16 m2

220 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 50 mg +

             1 x 150 mg

170 mg

twice daily

Pellets: 1 x 20 mg +

             1 x 150 mg

1.17 to 1.33 m2

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

1.34 to 1.69 m2

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 250 mg

200 mg

twice daily

Pellets: 1 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 200 mg

1.7 m2 or greater

400 mg

twice daily

Pellets: 2 x 50 mg +

             2 x 150 mg

                   Or

Capsule: 2 x 200 mg

250 mg

twice daily

Pellets: 2 x 50 mg +

             1 x 150 mg

                   Or

Capsule: 1 x 250 mg

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.

Table 6. Adult Patients with NSCLC or IMT: XALKORI Dosage Modification – Hematologic Toxicities*
*
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.

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 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
*
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

Severity of Adverse Reaction

XALKORI Dosage Modification

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.*

Platelet Count

25 to 50 x 109/L with concurrent bleeding

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

Less than 25 x 109/L

Withhold until recovery to platelet count greater than 50 x 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.

Recommended Dosage Modifications for Non-Hematologic Adverse Reactions

The recommended dosage modifications for non-hematologic adverse reactions are provided in Table 8.

Table 8. All Patients: XALKORI Dosage Modification for Non-Hematologic Adverse Reactions
*
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.
‡
Dosage modifications for gastrointestinal toxicity for pediatric patients with ALCL or IMT and young adults with ALCL only.
§
Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose reductions.

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:

•
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

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.

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 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)]

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)

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 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.§

2.7 Dosage Modifications for Moderate and Severe Hepatic Impairment

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 Dosage Modification for Severe Renal Impairment

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 Schwartz equation for pediatric patients] not requiring dialysis 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 Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.9 Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors [see Drug Interactions (7.1)]. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the dose of XALKORI to 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. After discontinuation of a strong CYP3A inhibitor, resume the XALKORI dose used prior to initiating the strong CYP3A inhibitor.

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