Usual Adult Dose for Non-Small Cell Lung Cancer

250 mg orally twice a day
Duration of therapy: Until disease progression or unacceptable toxicity

Comments:

• Selection of patients for the treatment of metastatic non-small cell lung cancer (NSCLC) should be based on the presence of anaplastic lymphoma kinase (ALK) or ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) positivity in tumor specimens.
• For information on US FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC: www.fda.gov/companiondiagnostics

Usual Adult Dose for Anaplastic Large Cell Lymphoma - ALK-Positive

Young adults: 280 mg/m2 orally twice a day
Duration of therapy: Until disease progression or unacceptable toxicity

Recommended dosage based on body surface area (BSA):

• BSA 0.6 to 0.8 m2: 200 mg orally twice a day
• BSA 0.81 to 1.16 m2: 250 mg orally twice a day
• BSA 1.17 to 1.51 m2: 400 mg orally twice a day
• BSA 1.52 to 1.69 m2: 450 mg orally twice a day
• BSA at least 1.7 m2: 500 mg orally twice a day

• The clinical trial for ALK-positive anaplastic large cell lymphoma (ALCL) included young adults up to 21 years of age.
• Limitations of Use: Safety and efficacy have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.
• If needed, the desired dose can be attained by combining different capsule strengths.
• Standard antiemetic and antidiarrheal agents should be provided for gastrointestinal (GI) toxicities; antiemetics are recommended before and during therapy to prevent nausea and vomiting.
• IV or oral hydration should be considered for patients at risk of dehydration; electrolytes should be replaced as clinically indicated.

Usual Adult Dose for Inflammatory Myofibroblastic Tumor

250 mg orally twice a day
Duration of therapy: Until disease progression or unacceptable toxicity

Use: For the treatment of patients with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive

Usual Pediatric Dose for Inflammatory Myofibroblastic Tumor

1 year and older: 280 mg/m2 orally twice a day
Duration of therapy: Until disease progression or unacceptable toxicity

Recommended dosage based on BSA:

• BSA 0.6 to 0.8 m2: 200 mg orally twice a day
• BSA 0.81 to 1.16 m2: 250 mg orally twice a day
• BSA 1.17 to 1.51 m2: 400 mg orally twice a day
• BSA 1.52 to 1.69 m2: 450 mg orally twice a day
• BSA at least 1.7 m2: 500 mg orally twice a day

• Pediatric patients should be assessed for ability to swallow intact capsules before this drug is prescribed.
• If needed, the desired dose can be attained by combining different capsule strengths.
• This drug should be administered under adult supervision.
• Standard antiemetic and antidiarrheal agents should be provided for GI toxicities; antiemetics are recommended before and during therapy to prevent nausea and vomiting.
• IV or oral hydration should be considered for patients at risk of dehydration; electrolytes should be replaced as clinically indicated.

• For the treatment of patients with relapsed or refractory, systemic ALCL that is ALK-positive
• For the treatment of patients with unresectable, recurrent, or refractory IMT that is ALK-positive

Usual Pediatric Dose for Anaplastic Large Cell Lymphoma - ALK-Positive

1 year and older: 280 mg/m2 orally twice a day
Duration of therapy: Until disease progression or unacceptable toxicity

Recommended dosage based on BSA:

• BSA 0.6 to 0.8 m2: 200 mg orally twice a day
• BSA 0.81 to 1.16 m2: 250 mg orally twice a day
• BSA 1.17 to 1.51 m2: 400 mg orally twice a day
• BSA 1.52 to 1.69 m2: 450 mg orally twice a day
• BSA at least 1.7 m2: 500 mg orally twice a day

• Pediatric patients should be assessed for ability to swallow intact capsules before this drug is prescribed.
• If needed, the desired dose can be attained by combining different capsule strengths.
• This drug should be administered under adult supervision.
• Standard antiemetic and antidiarrheal agents should be provided for GI toxicities; antiemetics are recommended before and during therapy to prevent nausea and vomiting.
• IV or oral hydration should be considered for patients at risk of dehydration; electrolytes should be replaced as clinically indicated.

• For the treatment of patients with relapsed or refractory, systemic ALCL that is ALK-positive
• For the treatment of patients with unresectable, recurrent, or refractory IMT that is ALK-positive

Renal Dose Adjustments

Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC or Adult Patients with ALK-Positive IMT:

• Mild to moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment recommended
• Severe renal dysfunction (CrCl less than 30 mL/min) not requiring dialysis: 250 mg orally once a day

• Mild to moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment recommended
• Severe renal dysfunction (CrCl less than 30 mL/min) not requiring dialysis:
• BSA 0.6 to 0.8 m2: This drug should be permanently discontinued.
• BSA 0.81 to 1.16 m2: 250 mg orally once a day
• BSA 1.17 to 1.69 m2: 200 mg orally twice a day
• BSA at least 1.7 m2: 250 mg orally twice a day

• CrCl calculated using the modified Cockcroft-Gault equation for adult patients and the Schwartz equation for pediatric patients

Liver Dose Adjustments

Adult Patients with ALK- or ROS1-Positive Metastatic NSCLC or Adult Patients with ALK-Positive IMT:

• Mild liver dysfunction (AST greater than the upper limit of normal [ULN] and total bilirubin up to 1 times ULN [1 x ULN] or any AST and total bilirubin greater than 1 to 1.5 x ULN): No adjustment recommended
• Moderate liver dysfunction (any AST and total bilirubin greater than 1.5 to 3 x ULN): 200 mg orally twice a day
• Severe liver dysfunction (any AST and total bilirubin greater than 3 x ULN): 250 mg orally once a day

• Mild liver dysfunction (AST greater than ULN and total bilirubin up to 1 x ULN or any AST and total bilirubin greater than 1 to 1.5 x ULN): No adjustment recommended
• Moderate liver dysfunction (any AST and total bilirubin greater than 1.5 to 3 x ULN):
• BSA 0.6 to 0.8 m2: 250 mg orally once a day
• BSA 0.81 to 1.16 m2: 200 mg orally twice a day
• BSA 1.17 to 1.69 m2: 250 mg orally twice a day
• BSA at least 1.7 m2: 400 mg orally twice a day
• Severe liver dysfunction (any AST and total bilirubin greater than 3 x ULN):
• BSA 0.6 to 0.8 m2: This drug should be permanently discontinued.
• BSA 0.81 to 1.16 m2: 250 mg orally once a day
• BSA 1.17 to 1.69 m2: 200 mg orally twice a day
• BSA at least 1.7 m2: 250 mg orally twice a day

• ALT or AST greater than 5 x ULN with total bilirubin up to 1.5 x ULN: This drug should be withheld until recovery to baseline or up to 3 x ULN, then should resume at the next lower dosage
• ALT or AST greater than 3 x ULN with concurrent total bilirubin greater than 1.5 x ULN (without cholestasis or hemolysis): This drug should be permanently discontinued.

Dose Adjustments

ADULT PATIENTS WITH ALK- OR ROS1-POSITIVE METASTATIC NSCLC OR ADULT PATIENTS WITH ALK-POSITIVE IMT:
Dosage Reductions for Adverse Reactions:

• First dose reduction: 200 mg orally twice a day
• Second dose reduction: 250 mg orally once a day
• If unable to tolerate 250 mg orally once a day: This drug should be permanently discontinued.

• Grade 3: This drug should be withheld until recovery to grade 2 or less, then should resume at the same dosage
• Grade 4: This drug should be withheld until recovery to grade 2 or less, then should resume at the next lower dosage

• Bradycardia (symptomatic, may be severe and medically significant, medical intervention indicated): This drug should be withheld until recovery to asymptomatic bradycardia or to a heart rate of at least 60 bpm; concomitant agents known to cause bradycardia should be evaluated, as well as antihypertensive drugs.
• If contributing concomitant agent is identified and discontinued, or its dose is adjusted: Should resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of at least 60 bpm
• If no contributing concomitant agent is identified, or if contributing concomitant agents are not discontinued or dose modified: Should resume at reduced dosage upon recovery to asymptomatic bradycardia or to a heart rate of at least 60 bpm
• Bradycardia (life-threatening consequences, urgent intervention indicated):
• If no contributing concomitant agent is identified: This drug should be permanently discontinued.
• If contributing concomitant agent is identified and discontinued, or its dose is adjusted: Should resume at 250 mg orally once a day upon recovery to asymptomatic bradycardia or to a heart rate of at least 60 bpm, with frequent monitoring
• For recurrence: This drug should be permanently discontinued.

• Any grade drug-related interstitial lung disease/pneumonitis: This drug should be permanently discontinued.

• QT corrected for heart rate (QTc) greater than 500 ms on at least 2 separate ECGs: This drug should be withheld until recovery to baseline or to a QTc less than 481 ms, then should resume at the next lower dosage
• QTc greater than 500 ms or at least 60 ms change from baseline with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia: This drug should be permanently discontinued.

• Visual loss (grade 4 ocular disorder): This drug should be discontinued during evaluation of severe visual loss.

• Concomitant use of strong CYP450 3A inhibitors should be avoided.
• If concomitant use of strong CYP450 3A inhibitors is unavoidable, the dosage should be reduced to 250 mg orally once a day.
• After discontinuation of a strong CYP450 3A inhibitor: Should resume the dosage used before starting the strong CYP450 3A inhibitor

• BSA 0.6 to 0.8 m2:
• First dose reduction: 250 mg orally once a day
• Second dose reduction: This drug should be permanently discontinued.
• BSA 0.81 to 1.16 m2:
• First dose reduction: 200 mg orally twice a day
• Second dose reduction: 250 mg orally once a day
• If unable to tolerate this drug after 2 dose reductions: This drug should be permanently discontinued.
• BSA 1.17 to 1.69 m2:
• First dose reduction: 250 mg orally twice a day
• Second dose reduction: 200 mg orally twice a day
• If unable to tolerate this drug after 2 dose reductions: This drug should be permanently discontinued.
• BSA at least 1.7 m2:
• First dose reduction: 400 mg orally twice a day
• Second dose reduction: 250 mg orally twice a day
• If unable to tolerate this drug after 2 dose reductions: This drug should be permanently discontinued.

• Less than 0.5 x 10(9)/L (first occurrence): This drug should be withheld until recovery to ANC greater than 1 x 10(9)/L, then should resume at the next lower dosage
• Less than 0.5 x 10(9)/L (second occurrence):
• For recurrence complicated by febrile neutropenia or infection: This drug should be permanently discontinued.
• For uncomplicated grade 4 neutropenia: This drug should be either permanently discontinued, or withheld until recovery to ANC greater than 1 x 10(9)/L, then should resume at the next lower dosage
• If unable to tolerate this drug after 1 dose reduction (BSA 0.6 to 0.8 m2) or after 2 dose reductions (BSA at least 0.81 m2): This drug should be permanently discontinued.

• Hemoglobin less than 8 g/dL: This drug should be withheld until recovery to hemoglobin at least 8 g/dL, then should resume at the same dosage
• Life-threatening anemia (urgent intervention indicated): This drug should be withheld until recovery to hemoglobin at least 8 g/dL, then should resume at the next lower dosage
• For recurrence: This drug should be permanently discontinued.

• Platelet count 25 to 50 x 10(9)/L with concurrent bleeding: This drug should be withheld until recovery to platelet count greater than 50 x 10(9)/L and bleeding resolves, then should resume at the same dosage
• Platelet count less than 25 x 10(9)/L: This drug should be withheld until recovery to platelet count greater than 50 x 10(9)/L, then should resume at the next lower dosage
• For recurrence: This drug should be permanently discontinued.

• Bradycardia (symptomatic, may be severe and medically significant, medical intervention indicated): This drug should be withheld 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:
• Age 1 to less than 2 years: At least 91 bpm
• Age 2 to 3 years: At least 82 bpm
• Age 4 to 5 years: At least 72 bpm
• Age 6 to 8 years: At least 64 bpm
• Age older than 8 years: At least 60 bpm
• Bradycardia (life-threatening consequences, urgent intervention indicated):
• If no contributing concomitant agent is identified: This drug should be permanently discontinued.
• If contributing concomitant agent is identified and discontinued, or its dose is adjusted: Should resume at the second dose reduction level upon recovery to asymptomatic bradycardia or to the heart rate criteria listed for management of symptomatic or severe, medically significant bradycardia, with frequent monitoring
• For recurrence: This drug should be permanently discontinued.

• Diarrhea:
• Grade 3 diarrhea (increase of at least 7 stools per day over baseline; incontinence; hospitalization indicated) or grade 4 diarrhea (life-threatening consequences, urgent intervention indicated) despite maximum medical therapy: This drug should be withheld until resolved, then should resume at the next lower dose level
• Nausea:
• Grade 3 nausea (inadequate oral intake for more than 3 days, medical intervention required) despite maximum medical therapy: This drug should be withheld until resolved, then should resume at the next lower dose level
• Vomiting:
• Grade 3 vomiting (more than 6 episodes in 24 hours for more than 3 days, medical intervention required [i.e., tube feeding or hospitalization]) or grade 4 vomiting (life-threatening consequences, urgent intervention indicated) despite maximum medical therapy: This drug should be withheld until resolved, then should resume at the next lower dose level
• If unable to tolerate this drug after 1 dose reduction (BSA 0.6 to 0.8 m2) or after 2 dose reductions (BSA at least 0.81 m2): This drug should be permanently discontinued.

• Any grade drug-related interstitial lung disease/pneumonitis: This drug should be permanently discontinued.

• Visual symptoms, grade 1 (mild symptoms) or grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living): Symptoms should be monitored, and any symptoms should be reported to an eye specialist; dose reduction should be considered for grade 2 visual disorders.
• Visual loss (grade 3 or 4 ocular disorder, marked decrease in vision): This drug should be permanently discontinued for grade 3 or 4 ocular disorders or severe visual loss if no other cause is found on evaluation.

• QTc greater than 500 ms on at least 2 separate ECGs: This drug should be withheld until recovery to baseline or to a QTc less than 481 ms, then should resume at the next lower dosage
• QTc greater than 500 ms or at least 60 ms change from baseline with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia: This drug should be permanently discontinued.

• Concomitant use of strong CYP450 3A inhibitors should be avoided.
• If concomitant use of strong CYP450 3A inhibitors is unavoidable, the dosage should be reduced to:
• BSA 0.6 to 0.8 m2: This drug should be permanently discontinued.
• BSA 0.81 to 1.16 m2: 250 mg orally once a day
• BSA 1.17 to 1.69 m2: 200 mg orally twice a day
• BSA at least 1.7 m2: 250 mg orally twice a day
• After discontinuation of a strong CYP450 3A inhibitor: Should resume the dosage used before starting the strong CYP450 3A inhibitor

Precautions

CONTRAINDICATIONS: None

Safety and efficacy have not been established in patients with ALCL or IMT with a BSA less than 0.6 m2 or younger than 1 year. Safety and efficacy have not been established in patients younger than 18 years with NSCLC.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Administer with or without food.
• Swallow capsules whole.
• If vomiting occurs after dosing, do not administer an extra dose; administer the next dose at the regular time.

• Store at 20C to 25C (68C to 77F); excursions permitted to 15C to 30C (59F to 86F).

• Cardiovascular: ECGs in patients with CHF, bradyarrhythmias, electrolyte abnormalities, taking agents that prolong the QT interval; heart rate and blood pressure (regularly)
• Hematologic:
• Adult patients with NSCLC or IMT: CBC including differential WBC counts (monthly and as clinically indicated; more frequently if grade 3 or 4 abnormalities observed or if fever/infection occurs)
• Pediatric and young adult patients with ALK-positive ALCL or pediatric patients with ALK-positive IMT: CBC including differential (weekly for first month of therapy and then at least monthly; more frequently if grade 3 or 4 abnormalities, fever, or infection occur)
• Hepatic: Liver function tests including ALT, AST, and total bilirubin (every 2 weeks during the first 2 months of therapy, then once a month, and as clinically indicated)
• Metabolism: Electrolytes in patients with CHF, bradyarrhythmias, electrolyte abnormalities, taking agents that prolong the QT interval
• Ocular: Visual symptoms for all patients (monthly during therapy)
• Respiratory: For pulmonary symptoms indicative of interstitial lung disease/pneumonitis

• Read the US FDA-approved patient labeling (Medication Guide).
• Immediately report symptoms of hepatotoxicity or any new/worsening pulmonary symptoms.
• Report any symptoms of bradycardia; inform health care provider about use of any heart or blood pressure medications.
• Contact health care provider immediately if severe visual loss develops. Visual changes (e.g., perceived flashes of light, blurry vision, light sensitivity, floaters) may occur while driving or operating machinery.
• Patients with ALCL or pediatric patients with IMT: Immediately inform health care provider of problems with swallowing, vomiting, or diarrhea.
• Avoid grapefruit or grapefruit juice while taking this drug.
• Avoid prolonged sun exposure and use sunscreen or protective clothing during therapy.
• If a dose is missed, take it as soon as remembered as long as there are at least 6 hours until the next dose; if the next dose is due within 6 hours, do not take the missed dose.
• Patients of childbearing potential: Inform health care provider of a known/suspected pregnancy; use effective contraception during therapy and for at least 45 days after the last dose.
• Male patients with female partners of childbearing potential: Use condoms during therapy and for at least 90 days after the last dose.
• Do not breastfeed during therapy and for 45 days after the last dose.

Frequently asked questions

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