Usual Adult Dose for Non-Small Cell Lung Cancer

Initial dose: 90 mg orally once a day for the first 7 days
Maintenance dose: 180 mg orally once a day

Comments:

• Patients should be selected for the treatment of metastatic NSCLC based on the presence of ALK positivity in tumor specimens.
• FDA-approved test for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostic
• Treatment should be continued until disease progression or unacceptable toxicity.

Use: For treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test

Renal Dose Adjustments

Mild to moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment recommended.
Severe renal dysfunction (CrCl 15 to 29 mL/min): Reduce once daily dose by approximately 50% (i.e., from 180 mg to 90 mg OR 90 mg to 60 mg).

Liver Dose Adjustments

Mild to moderate liver dysfunction (Child-Pugh A to B) : No adjustment recommended.
Severe liver dysfunction (Child-Pugh C): Reduce once daily dose by approximately 40% (i.e., from 180 mg to 120 mg, OR 120 mg to 90 mg, OR 90 mg to 60 mg).

Dose Adjustments

DOSE REDUCTION FOR ADVERSE REACTIONS:
STARTING DOSE 90 MG ONCE A DAY:

• First reduction: 60 mg once a day
• Second reduction: Permanently discontinue therapy.
• Third reduction: N/A

STARTING DOSE 180 MG ONCE A DAY:

• First reduction: 120 mg once a day
• Second reduction: 90 mg once a day
• Third reduction: 60 mg once a day

Comments:

• Once the dose is reduced, do not subsequently increase the dose.
• Permanently discontinue this drug if patients are unable to tolerate 60 mg once a day.
• Dosing interruption of 14 days or longer (for reasons other than adverse reactions): Resume at 90 mg once a day for 7 days before increasing to the previously tolerated dose.

STRONG OR MODERATE CYP450 3A INHIBITORS:

• Avoid concomitant use.
• If concomitant use of a strong CYP450 3A inhibitor cannot be avoided, reduce the once a day dose of this drug by approximately 50% (i.e., from 180 mg to 90 mg OR from 90 mg to 60 mg).
• If coadministration of a moderate CYP450 3A inhibitor cannot be avoided, reduce the once daily dose of this drug by approximately 40% (i.e., from 180 mg to 120 mg, OR 120 mg to 90 mg, OR from 90 mg to 60 mg).
• After discontinuation of a strong or moderate CYP450 3A inhibitor, resume the dose of this drug that was tolerated prior to initiating the CYP450 3A inhibitor.

MODERATE CYP450 3A INDUCERS:

• Avoid concomitant use.
• If coadministration of a moderate CYP450 3A inducer cannot be avoided, increase the once daily dose of this drug in 30 mg increments after 7 days of therapy with the current dose as tolerated, up to a maximum of twice the dose that was tolerated prior to initiating the moderate CYP450 3A inducer.
• After discontinuation of a moderate CYP450 3A inducer, resume the dose of this drug that was tolerated prior to initiating the moderate CYP450 3A inducer.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:
*GRADE 1:

• If new pulmonary symptoms occur during the first 7 days of therapy, withhold this drug until recovery to baseline, then resume at the same dose and do not escalate to 180 mg if ILD/pneumonitis is suspected.
• If new pulmonary symptoms occur after the first 7 days of therapy, withhold this drug until recovery to baseline, then resume at same dose.
• If ILD/pneumonitis recurs, permanently discontinue this drug.

*GRADE 2:

• If new pulmonary symptoms occur during the first 7 days of therapy, withhold this drug until recovery to baseline; resume at next lower dose and do not dose escalate if ILD/pneumonitis is suspected.
• If new pulmonary symptoms occur after the first 7 days of therapy, withhold this drug until recovery to baseline.
• If ILD/pneumonitis is suspected, resume at next lower dose; otherwise, resume at same dose.
• If ILD/pneumonitis recurs, permanently discontinue this drug.

*Grade 3 or 4: Permanently discontinue this drug.
HYPERTENSION:
*GRADE 3 (SBP 160 mmHg or greater or DBP 100 mmHg or greater, medical intervention indicated, more than 1 antihypertensive drug, or more intensive therapy than previously used indicated):

• Withhold dosing until recovery to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg) then resume at the next lower dose.
• Recurrence: Withhold the drug until recovery to Grade 1 or less and resume at next lower dose or permanently discontinue this drug.

GRADE 4 (life-threatening consequences, urgent intervention indicated):

• Withhold this drug until recovery to Grade 1 or less and resume at the next lower dose OR permanently discontinue this drug.

*GRADE 4 RECURRENCE: Permanently discontinue this drug.
BRADYCARDIA (HR less than 60 bpm):
*SYMPTOMATIC BRADYCARDIA:

• Withhold this drug until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.
• If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume this drug at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.
• If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume this drug at next lower dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.

*LIFE-THREATENING BRADYCARDIA (urgent intervention indicated):

• Permanently discontinue this drug if no contributing concomitant medication is identified.
• If contributing concomitant medication is identified and discontinued or dose-adjusted, resume this drug at next lower dose upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.
• Recurrence: Permanently discontinue this drug.

VISUAL DISTURBANCE:
*GRADE 2 OR 3: Withhold this drug until recovery to Grade 1 or baseline, then resume at the next lower dose.
*GRADE 4: Permanently discontinue this drug.
CREATINE PHOSPHOKINASE (CPK) ELEVATION:
*GRADE 3 OR 4 CPK ELEVATION (greater than 5 times upper level of normal [ULN] with Grade 2 or higher muscle pain or weakness):

• Withhold this drug until recovery to Grade 1 or less ((less than or equal to 2.5 x ULN) or to baseline, then resume at the same dose.
• Recurrence: Withhold until recovery to Grade 1 or less (less than or equal to 2.5 x ULN) or to baseline, then resume at next lower dose

LIPASE/AMYLASE ELEVATION:
*GRADE 3 (greater than 2 x ULN): Withhold this drug until recovery to Grade 1 or less (1.5 x ULN or less) or to baseline, then resume at the same dose.
*RECURRENCE: Withhold until recovery to Grade 1 or less (less than or equal to 1.5 x ULN) or to baseline, then resume at next lower dose.
*GRADE 4 (greater than 5 x ULN): Withhold dosing until recovery to Grade 1 or less (1.5 x ULN or less) or to baseline, then resume at the next lower dose.
HYPERGLYCEMIA:
*GRADE 3 (greater than 250 mg/dL OR 13.9 mmol/L) OR GRADE 4:

• Withhold this drug until adequate hyperglycemic control is achieved and resume at next lower dose OR permanently discontinue therapy.

OTHER ADVERSE REACTIONS:
*GRADE 3:

• Withhold this drug until recovery to baseline, then resume at the same dose.
• Recurrence: Withhold this drug until recovery to baseline, then resume at the next lower dose OR discontinue therapy.

*GRADE 4:

• Withhold dosing until recovery to baseline, then resume at the next lower dose.
• Recurrence: Permanently discontinue therapy.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Swallow tablets whole; do not crush or chew.
• Administer with or without food.
• In the event of a missed or vomited dose, skip that dose and administer the next dose at the regularly scheduled time.

Storage requirements:

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

Monitoring:

• Cardiovascular: Blood pressure (at 2 weeks, then at least monthly), heart rate (during treatment)
• Endocrine: Fasting serum glucose (prior to treatment initiation, then periodically thereafter)
• Gastrointestinal: Amylase and lipase (during treatment)
• Musculoskeletal: Creatine phosphokinase levels (during treatment)
• Respiratory: New or worsening respiratory symptoms (during treatment, particularly during the first week)

Patient advice:

• This drug may cause side effects such as double vision; avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.
• Advise diabetic patients that hyperglycemic medications may need to be adjusted during treatment.
• Advise patients to inform their healthcare provider of any new or worsening vision symptoms.
• Advise patients to report any new or worsening respiratory symptoms immediately.
• Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness.
• Advise patients to report any bradycardia symptoms and inform their healthcare provider about the use of heart and blood pressure medications.
• Advise patients of risks of hypertension and to promptly report signs or symptoms of hypertension.
• Advise patients to limit sun exposure during treatment and for at least 5 days after the last dose.
• To help protect against sunburn, advise patients to wear protective clothing and use a broad-spectrum sunscreen and lip balm (SPF 30 or greater).
• Inform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment.
• Avoid grapefruit and grapefruit juice while taking this drug.