crizotinib

kriz-OH-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

REMS

Metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK) or ROS1.
Relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is positive for ALK.
Unresectable, recurrent, or refractory inflammatory myofibroblastic tumor that is positive for ALK.

Inhibits receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1, and Recepteur d'Origine Nantais (RON).

Therapeutic effects:

Decreased spread of lung cancer and improved survival.
Decreased spread of systemic ALCL or inflammatory myofibroblastic tumor.

Absorption: 43% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver (CYP3A4/5 isoenzymes); also acts as an inhibitor of CYP3A. 53% excreted in feces unchanged, 2.3% eliminated unchanged in urine.

Half-Life: 42 hr.

(blood levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4–6 hr	unknown

Contraindicated in:

Concurrent use of strong CYP3A inhibitors or inducers;
Congenital long QT syndrome;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Heart failure, bradyarrhythmias, electrolyte abnormalities, concurrent medications that prolong QT interval (↑ risk of arrhythmias);
Asian patients (↑ blood levels);
Moderate or severe hepatic impairment (↓ dose);
Severe renal impairment;
Rep: Women of reproductive potential and men with female sexual partners of reproductive potential;
Pedi: Safety and effectiveness not established in children 18 yr (NSCLC) or 1 yr (ALCL or inflammatory myofibroblastic tumor).

CV: bradycardia, edema, QT interval prolongation, chest pain

Derm: rash

EENT: visual disturbances

Endo: ↓testosterone

GI: ↑liver enzymes, constipation, diarrhea, nausea, stomatitis, vomiting, ↓appetite, abdominal pain, esophagitis, HEPATOTOXICITY

GU: ↓fertility, renal impairment

Neuro: dysgeusia, fatigue, headache, insomnia, neuropathy

Resp: INTERSTITIAL LUNG DISEASE/PNEUMONITIS

Misc: fever

Drug-drug:

Strong CYP3A inhibitors including atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, and voriconazole may ↑ levels; concurrent use should be avoided; if concurrent use unavoidable, ↓ crizotinib dose.
Strong CYP3A inducers including carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin may ↓ levels and effectiveness; concurrent use should be avoided.
May ↑ levels of cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus; avoid concurrent use.
Beta-blockers, verapamil, diltiazem, digoxin, and clonidine may ↑ risk of bradycardia; avoid concurrent use, if possible.

Drug-Natural Products:

Concurrent use of St. John's wort may ↓ levels and effectiveness and should be avoided.

Grapefruit or grapefruit juice may ↑ levels and should be avoided.

Non-Small Cell Lung Cancer

PO (Adults ): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Adults ): CCr <30 mL/min (not on dialysis): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Adults ): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 200 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Systemic Anaplastic Large Cell Lymphoma

PO (Children ≥1 yr and body surface area [BSA] ≥1.70 m²): 500 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg twice daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 1.52–1.69 m²): 450 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 1.17–1.51 m²): 400 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg once daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 0.81–1.16 m²): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg once daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 0.60–0.80 m²): 200 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: Permanently discontinue crizotinib.

Renal Impairment

PO (Children ≥1 yr and BSA ≥1.70 m²): CCr <30 mL/min (not on dialysis): 250 mg twice daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA ≥1.17–1.69 m²): CCr <30 mL/min (not on dialysis): 200 mg twice daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA ≥0.81–1.16 m²): CCr <30 mL/min (not on dialysis): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA 0.60–0.80 m²): CCr <30 mL/min (not on dialysis): Permanently discontinue therapy.

Hepatic Impairment

PO (Children ≥1 yr and BSA ≥1.70 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 400 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 250 mg twice daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Children ≥1 yr and BSA ≥1.17–1.69 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 200 mg twice daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Children ≥1 yr and BSA ≥0.81–1.16 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 200 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Children ≥1 yr and BSA 0.60–0.80 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 250 mg once daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): Permanently discontinue therapy.

Inflammatory Myofibroblastic Tumor

PO (Adults ): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg once daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and body surface area [BSA] ≥1.70 m²): 500 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg twice daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 1.52–1.69 m²): 450 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg twice daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 1.17–1.51 m²): 400 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 200 mg once daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 0.81–1.16 m²): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 250 mg once daily. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and BSA 0.60–0.80 m²): 200 mg twice daily. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: Permanently discontinue crizotinib.

Renal Impairment

PO (Adults ): CCr <30 mL/min (not on dialysis): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA ≥1.70 m²): CCr <30 mL/min (not on dialysis): 250 mg twice daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA ≥1.17–1.69 m²): CCr <30 mL/min (not on dialysis): 200 mg twice daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA ≥0.81–1.16 m²): CCr <30 mL/min (not on dialysis): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment

PO (Children ≥1 yr and BSA 0.60–0.80 m²): CCr <30 mL/min (not on dialysis): Permanently discontinue therapy.

Hepatic Impairment

PO (Children ≥1 yr and BSA ≥1.70 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 400 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 250 mg twice daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Children ≥1 yr and BSA ≥1.17–1.69 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 250 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 200 mg twice daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Children ≥1 yr and BSA ≥0.81–1.16 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 200 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Children ≥1 yr and BSA 0.60–0.80 m²): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 250 mg once daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): Permanently discontinue therapy.

Hepatic Impairment

PO (Adults ): Moderate hepatic impairment (AST and total bilirubin >1.5× and ≤3× ULN): 200 mg twice daily. Continue until disease progression or unacceptable toxicity. Severe hepatic impairment (AST and total bilirubin >3× ULN): 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Capsules: 200 mg; 250 mg

Assess respiratory function (lung sounds, dyspnea, oxygen saturation) periodically during therapy.
Monitor for signs and symptoms of interstitial lung disease ILD)/pneumonitis (difficulty breathing, shortness of breath, cough with or without mucus, fever) periodically during therapy. If any Grade of ILD/pneumonitis occurs, permanently discontinue.
Assess for signs and symptoms of neuropathy (burning, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy sensory and motor) periodically during therapy. Usually Grade 1.
Monitor ECG periodically during therapy in patients with HF, bradyarrhythmias, electrolyte imbalances, or taking medications that may prolong QT interval. If QTc >500 msec on at least 2 separate ECGs, hold until recovery to baseline or to a QTc <481 msec, then resume at next lower dose. If QTc >500 msec or ≥60 msec change from baseline with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently discontinue. If symptomatic bradycardia occurs, hold dose until heart rate returns to ≥60 bpm for adults, for 1 to < 2 yrs: ≥91 bpm, for 2–3 yrs: ≥82 bpm, for 4–5 yrs: ≥72 bpm, 6–8 yrs: ≥64 bpm. Evaluate concomitant medications; if contributing medication is identified and dose reduced or discontinued, return to previous dose of crizotinib once heart rate is ≥60 bpm and/or bradycardia is asymptomatic. If no contributing medication is identified or dose modifications are not made, resume crizotinib at a reduced dose once heart rate ≥60 bpm and/or bradycardia is asymptomatic. If bradycardia is life-threatening and no contributing medication identified, discontinue crizotinib. If contributing medication is identified and dose is reduced or discontinued, for adults, reduce crizotinib dose to 250 mg once daily with frequent monitoring once heart rate ≥60 bpm and/or bradycardia is asymptomatic; for pediatrics and young adults, resume at 2nd reduction level.
Monitor vision during therapy. If 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. If visual loss (Grade 3 or 4 Ocular Disorder, marked decrease in vision) occurs, hold crizotinib pending evaluation of severe visual loss. For Grade 3 or 4 ocular disorders, with no other cause found on evaluation permanently discontinue crizotinib. Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate for new onset of severe visual loss.
Monitor for signs and symptoms of GI toxicity (diarrhea, nausea, vomiting, stomatitis) during therapy. If Grade 3 nausea (inadequate oral intake for >3 days, intervention required) occurs, hold crizotinib until resolved, then resume at next lower dose. If Grade 3 vomiting (>6 episodes in 24 hrs for >3 days, intervention required [tube feeding or hospitalization]) or Grade 4 vomiting (life-threatening consequences, urgent intervention indicated) occurs, hold crizotinib until resolved, then resume at next lower dose level. If Grade 3 diarrhea (increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated) or Grade 4 (life-threatening consequences, urgent intervention indicated) occurs, hold crizotinib until resolved, then resume at next lower dose level.
Monitor hydration status. Consider IV or oral hydration for patients at risk of dehydration, and replace electrolytes as clinically indicated.

Lab Test Considerations:

Test patient for ALK or ROS1 positivity in tumor specimens through an FDA approved test http://www.fda.gov/companiondiagnostics prior to starting therapy.
- Verify negative pregnancy test prior to starting therapy.
- Monitor CBC with differential monthly and as clinically indicated; more frequently if Grade 3 or 4 toxicities occur. Adults:If ANC <0.5 × 10⁹/L and 1st occurrence, hold dose until ANC recovery to 1.0 × 10⁹ /L, then resume at the next lower dose. If 2nd occurrence, permanently discontinue crizotinib if patient develops febrile neutropenia or infection. For uncomplicated Grade 4 neutropenia, permanently discontinue or hold dose until ANC recovery to 1.0 × 10⁹ /L, then resume at next lower dose. If platelet count 25–50 × 10⁹/L, hold crizotinib until recovery to platelet count >50 × 10⁹ /L and bleeding resolves, then resume at same dose. If platelet count <25 × 10⁹/L, hold until recovery to platelet count >50 × 10⁹/L, then resume at next lower dose. Permanently discontinue for recurrence. If hemoglobin <8 g/dL, hold crizotinib until recovery to hemoglobin ≥8 g/dL, then resume at same dose. If anemia is life-threatening and urgent intervention needed, hold until recovery to hemoglobin ≥8 g/dL, then resume at next lower dose. Permanently discontinue for recurrence.Pediatric and Young Adults: If ANC < 0.5 x 10⁹ /L,1st occurrence: hold until ANC > 1.0 x 10⁹ /L, then resume at the next lower dose. 2nd occurrence: Permanently discontinue for recurrence complicated by febrile neutropenia or infection. For uncomplicated Grade 4 neutropenia, either permanently discontinue, or hold until recovery to ANC > 1.0 x 10⁹ /L, then resume at the next lower dose. If platelet count 25 to 50 x 10⁹ /L with concurrent bleeding,hold until platelet count > 50 x 10⁹ /L and bleeding resolves, then resume at the same dose. If platelet count < 25 x 10⁹ /L, hold until platelet count > 50 x 109 /L, then resume at the next lower dose. Permanently discontinue for recurrence. If hemoglobin < 8 g/dL,hold until ≥ hemoglobin 8 g/dL, then resume at the same dose. If life-threatening anemia occurs, hold until hemoglobin ≥ 8 g/dL, then resume at next lower dose. Permanently discontinue for recurrence.
- Monitor liver function tests every 2 wk during first 2 mo, then monthly and as clinically indicated; more frequently if Grade 2, 3, 4 abnormalities occur. Adults:If ALT or AST ↑ >5 × upper limit of normal (ULN) with total bilirubin ≤ 1.5 times ULN, hold crizotinib until recovery to baseline or ≤ 3 × ULN, then resume at next lower dose. If ALT or AST ↑ >3 × ULN with concurrent total bilirubin ↑ >1.5 × ULN (in the absence of cholestasis or hemolysis), permanently discontinue crizotinib. If Grade 3 or 4 AST or ALT ↑ with Grade ≤1 total bilirubin occurs, hold until recovery to Grade ≤1 or baseline, then resume at 200 mg twice daily. Pediatric and Young Adults:If ALT or AST > 5 times upper limit of normal (ULN) with total bilirubin ≤ 1.5 times ULN,hold until recovery to baseline or ≤ 3 times ULN, then resume at next lower dose. If ALT or AST > 3 times ULN with total bilirubin > 1.5 times ULN (in the absence of cholestasis or hemolysis), permanently discontinue crizotinib.

Recommended dose reductions:Adults1st dose reduction, 200 mg twice daily. 2nd dose reduction, 250 mg once daily. If unable to tolerate 250 mg of crizotinib once daily, permanently discontinue crizotinib. Pediatric and Young AdultsBody Surface Area (BSA) 0.60 to 0.80 m², 1st dose reduction: 250 mg once daily. 2nd dose reduction: permanently discontinue therapy. BSA 0.81 to 1.16 m², 1st dose reduction: 200 mg twice daily. 2nd dose reduction: 250 mg once daily. BSA 1.17 to 1.69 m², 1st dose reduction: 250 mg twice daily. 2nd dose reduction: 200 mg twice daily. BSA ≥ 1.70 m², 1st dose reduction: 400 mg twice daily. 2nd dose reduction: 250 twice daily. Discontinue permanently in any patient unable to tolerate two dose reductions.
Antiemetics are recommended before and during therapy. May require antidiarrheal therapy.
PO: Administer twice daily without regard to food. DNC: Swallow capsules whole, do not crush, dissolve, or open.

Instruct patient to take crizotinib as directed; do not change dose or stop taking without consulting health care professional. If vomiting occurs, do not take extra dose, just take next dose at regular scheduled time. Take missed doses as soon as remembered unless <6 hr until next dose. If <6 hr to next dose, skip dose and return to regular schedule; do not double doses. Advise patient to read the Patient Information before starting and with each Rx refill in case of changes.
Advise patient to avoid eating grapefruit or drinking grapefruit juice during therapy.
Caution patient that dizziness and visual disorders may occur. Advise patient to avoid driving or other activities requiring alertness until response to medication is known. Visual disturbances generally start within 2 wk of therapy. Instruct patient to notify health care professional if flashes of light, blurry vision, light sensitivity, or new or worse vitreous floaters occur; ophthalmological evaluation should be considered.
Advise patient to notify health care professional immediately if signs and symptoms of liver problems (weakness, fatigue, anorexia, nausea, vomiting, abdominal pain [especially RUQ abdominal pain], jaundice, dark urine, generalized pruritus, bleeding); lung problems (trouble breathing or shortness of breath, cough with or without mucus, fever); or heart problems (dizziness or fainting, abnormal heartbeats) occur.
Inform patient that nausea, diarrhea, vomiting, and constipation are common side effects and usually occur during first few days of therapy. Standard anti-emetic, antidiarrheal, and laxative medications are usually effective.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception and to avoid breast feeding during and for 45 days following last dose of therapy. Because of potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment and for 90 days after final dose. May cause reduced fertility in females and males of reproductive potential; may be irreversible.

Decreased spread of non-small cell lung cancer.
Decreased spread of systemic ALCL or inflammatory myofibroblastic tumor.

Xalkori

NDC Code

0069- Pfizer Laboratories Div Pfizer Inc
- 0069-8140- Xalkori
  - 0069-8140-20- 60 CAPSULE in 1 BOTTLE (0069-8140-20)

0069- Pfizer Laboratories Div Pfizer Inc
- 0069-8141- Xalkori
  - 0069-8141-20- 60 CAPSULE in 1 BOTTLE (0069-8141-20)

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