crizotinib (Rx)

Non-Small Cell Lung Cancer

Indicated for metastatic non-small cell lung cancer (NSCLC) in adults whose tumors are anaplastic lymphoma kinase (ALK)- or ROS1-positive

250 mg PO BID

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dosage reductions

• First dose reduction: 200 mg PO BID
• Second dose reduction: 250 mg PO qDay
• Unable to tolerate 250 mg PO qDay: Permanently discontinue

Hematologic toxicities

• For all hematologic toxicities except lymphopenia (unless associated with clinical events, eg, opportunistic infections)
• Grade 3: Withhold until recovery to Grade ≤2, then resume at same dose
• Grade 4: Withhold until recovery to Grade ≤2, then resume at next dose reduction

Hepatotoxicity

• ALT or AST >5x ULN with total bilirubin [TB] ≤1.5x ULN: Withhold until recovery to baseline or ≤3x ULN, then resume at next dose reduction
• ALT or AST >3x with concurrent TB >1.5x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue

Interstitial lung disease

• Any grade pneumonitis: Permanently discontinue

QT prolongation

• Correct QT (QTc) >500 ms on at least 2 separate electrocardiograms (ECGs): Withhold until recovery to baseline or at QTc <481 ms, then resume at next dose reduction
• QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia: Permanently discontinue

Bradycardia

Symptomatic, may be severe and medically intervention indicated

• Withhold until recovery to asymptomatic bradycardia or HR ≥60 bpm
• Evaluate concomitant medications known to cause bradycardia (eg, antihypertensives)
• Discontinue or adjust dose of any contributing medication; resume at previous dose upon recovery to asymptomatic bradycardia or HR ≥60 bpm
• Contributing medication not identified, or if contributing medications not discontinue or dose modified: Resume at next dose reduction upon recovery to asymptomatic bradycardia or to a HR ≥60 bpm

Life-threatening consequences, urgent intervention indicated

• No contributing medications identified: Permanently discontinue
• If contributing medication identified AND discontinued, or its dose adjusted: Resume at 250 mg qDay upon recovery to asymptomatic bradycardia or to a HR ≥60 bpm, closely monitor
• Permanently discontinue for recurrence

Visual loss

• Grade 4 ocular disorder: Discontinue during evaluation of severe visual loss

Strong CYP3A4 inhibitors

• Avoid coadministration
• If use is unavoidable, reduce crizotinib dose to 250 mg PO qDay
• After discontinuation of strong CYP3A inhibitor, resume crizotinib dose used before initiating strong CYP3A inhibitor

Renal impairment

• Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
• Severe (CrCl <30 mL/min) and not requiring dialysis: 250 mg PO qDay

Hepatic impairment

• Mild (AST >ULN and TB ≤1x ULN or any AST and TB >1x to ≤1.5x ULN): Steady-state mean AUC and Cmax decreased by 9%
• Moderate (any AST and TB >1.5x ULN and ≤3x ULN): 200 mg PO BID
• Severe (any AST and TB>3x ULN): 250 mg PO qDay

Dosing Considerations

Verify pregnancy status in females of reproductive potential before initiation

Monitoring parameters

• CBC including differential WBC counts: Monthly and as clinically indicated, more frequently test if Grade 3 or 4 abnormalities are observed or if fever or infection occurs
• Liver function tests: Every 2 weeks during the first 2 months of treatment, then monthly, and as clinically needed

Limitation of use

• Safety and efficacy not established in adults with relapsed or refractory, systemic ALK-positive ALCL

Patient selection

• Select patients based presence of ALK- or ROS1- positive tumor specimens
• Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics

Anaplastic Large Cell Lymphoma

Indicated for relapsed or refractory, systemic ALK-positive anaplastic large cell lymphoma (ALCL) in children and young adults aged ≥1 year

Assess the ability to swallow intact capsules before prescribing

280 mg/m² PO BID

Continue until disease progression or unacceptable toxicity

Recommended dosage based on BSA

<0.6 m²: Dose not established

0.6-0.8 m²: 200 mg PO BID

0.81-1.16 m²: 250 mg PO BID

1.17-1.51 m²: 400 mg PO BID

1.52-1.69 m²: 450 mg PO BID

≥1.70 m²: 500 mg PO BID

Dosage Modifications

Dose reductions based on BSA

• First dose reduction

  • 0.6-0.8 m²: 250 mg PO qDay
  • 0.81-1.16 m²: 200 mg PO BID
  • 1.17-1.69 m²: 250 mg PO BID
  • ≥1.70 m²: 400 mg PO BID

• Second dose reduction

  • 0.6-0.8 m²: Permanently discontinue
  • 0.81-1.16 m²: 250 mg PO qDay
  • 1.17-1.69 m²: 200 mg PO BID
  • ≥1.70 m²: 250 mg PO BID

• Unable to tolerate after 2 dose reductions

  • Permanently discontinue

Absolute neutrophil count (ANC)

• ANC <0.5 x 10⁹/L

• First occurrence

  • Withhold until recovery to ANC >1 x 10⁹/L, then resume at next dose reduction

• Second occurrence

  • Recurrence complicated by febrile neutropenia: Permanently discontinue
  • Uncomplicated Grade 4: Either permanently discontinue or withhold until recovery to ANC >1 x 10⁹/L, then resume at next dose reduction
  • Unable to tolerate 2 dose reductions: Permanently discontinue

Platelet count

• 25-50 x 10⁹/L with concurrent bleeding: Withhold until recovery to platelet count >50 x 10⁹/L and bleeding resolves, then resume at same dose
• <25 x 10⁹/L: Withhold until recovery to platelet count >50 x 10⁹/L and bleeding resolves, then resume at next dose reduction
• Permanently discontinue for recurrence

Anemia

• Hemoglobin (Hgb) <8 g/dL: Withhold until recovery to Hgb >8 g/dL, then resume at same dose
• Life-threatening anemia (urgent intervention indicated): Withhold until recovery to Hgb >8 g/dL, then resume at next dose reduction
• Permanently discontinue for recurrence

Hepatotoxicity

• ALT or AST >5x ULN with total bilirubin [TB] ≤1.5x ULN: Withhold until recovery to baseline or ≤3x ULN, then resume at next dose reduction
• ALT or AST >3x AND TB >1.5x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue

Interstitial lung disease/pneumonitis

• Any grade (drug-related): Permanently discontinue

QT prolongation

• Correct QT (QTc) >500 ms on at least 2 separate ECG: Withhold until recovery to baseline or at QTc <481 ms, then resume at next dose reduction
• QTc >500 ms or ≥60 ms change from baseline with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia: Permanently discontinue

Bradycardia

• Resting HR <2.5th percentile per age-specific norms

  • 1 to <2 years: ≥91 bpm
  • 2-3 years: ≥82 bpm
  • 4-5 years: ≥72 bpm
  • 6-8 years: ≥64 bpm
  • >8 years: ≥60 bpm

• Symptomatic, may be severe and medically intervention indicated

  • Withhold until recovery to resting HR according to age (based on 2.5^th percentile per age-specific norms)

• Life-threatening consequences (urgent intervention indicated)

• No contributing medications identified: Permanently discontinue
• If contributing medication is identified, and discontinued, or its dose adjusted: Resume at second dose reduction upon recovery to asymptomatic bradycardia or manage HR based on criteria of symptomatic or severe, medically significant bradycardia, with frequent monitoring
• Permanently discontinue for recurrence

Ocular toxicity

• Grade 1 or 2 (mild or moderate visual symptoms affecting ability to perform age-appropriate activities of daily living)

  • Monitor and report any symptoms to an eye specialist
  • Grade 2 visual disorders: Consider dose reduction

• Grade 3 or 4 ocular disorder (marked decrease in vision)

  • Withhold pending evaluation of severe visual loss
  • Permanently discontinue, if no other cause found on evaluation

Gastrointestinal toxicity

• Occurs despite maximum medical therapy
• Grade 3 nausea (inadequate oral intake for >3 days, medical intervention required)
• Grade 3 vomiting (> 6 episodes in 24 hr for >3 days, medical intervention required [eg, tube feeding or hospitalization)
• Grade 3 diarrhea (increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated)
• Grade 4 vomiting or diarrhea (life-threatening consequences, urgent intervention indicated)
• Withhold until resolved for any of of above descriptions, then resume at next dose reduction
• Permanently discontinue if unable to tolerate after 2 dose reductions, unless otherwise indicated

Strong CYP3A4 inhibitors

• Avoid coadministration
• If use is unavoidable, reduce criztotinib dose to second dose reduction
• After discontinuation of strong CYP3A inhibitor, resume crizotinib dose used before initiating strong CYP3A inhibitor

Renal impairment

• Calculate CrCl with Schwartz equation
• Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
• Severe (CrCl <30 mL/min) and not requiring dialysis: Second dose reduction

Hepatic impairment

• Moderate (any AST and TB >1.5x ULN and ≤3x ULN): First dose reduction
• Severe (any AST and TB >3x ULN): Second dose reduction

Dosing Considerations

Verify pregnancy status in females of reproductive potential before initiation

Monitoring parameters

• CBC including differential WBC counts: Monthly and as clinically indicated, more frequently if Grade 3 or 4 abnormalities are observed or if fever or infection occurs
• Ophthalmologic examination: Obtain at baseline before initiation; consider follow-up including retinal examination within 1 month of initiation, every 3 months thereafter, and upon any new visual symptoms; assess symptoms regularly during treatment
• Liver function tests: Every 2 weeks during the first 2 months of treatment, then monthly, and as clinically needed

Supportive care

• Provide standard antiemetic and antidiarrheal agents before and during treatment
• Consider IV or oral hydration and replace electrolytes as clinically indicated

Limitation of use

• Safety and efficacy not established in older adults with relapsed or refractory, systemic ALK-positive ALCL

No overall differences in safety or efficacy were observed in comparison with younger patients