crizotinib

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.

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.

Drug-Food:

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

Capsules: 200 mg; 250 mg

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.

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.

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

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

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.

NDC Code

0069- Pfizer Laboratories Div Pfizer Inc
- 0069-0251- Xalkori
  - 0069-0251-60- 60 CAPSULE, COATED PELLETS in 1 BOTTLE (0069-0251-60)

0069- Pfizer Laboratories Div Pfizer Inc
- 0069-0507- Xalkori
  - 0069-0507-60- 60 CAPSULE, COATED PELLETS in 1 BOTTLE (0069-0507-60)

0069- Pfizer Laboratories Div Pfizer Inc
- 0069-1500- Xalkori
  - 0069-1500-60- 60 CAPSULE, COATED PELLETS in 1 BOTTLE (0069-1500-60)

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)

53869- Pfizer Manufacturing Deutschland GmbH (Betriebssttte Freiburg)
- 53869-2230-
  - 53869-2230-1- 60 CAPSULE in 1 BOTTLE (53869-2230-1)

53869- Pfizer Manufacturing Deutschland GmbH (Betriebssttte Freiburg)
- 53869-2231-
  - 53869-2231-1- 60 CAPSULE in 1 BOTTLE (53869-2231-1)

54893- MSN Laboratories Private Limited
- 54893-0501-
  - 54893-0501-1- 30 kg in 1 DRUM (54893-0501-1)

60715- Pfizer Ireland Pharmaceuticals Unlimited Company
- 60715-1551-
  60715-1551-1- 1 BAG in 1 DRUM (60715-1551-1) / 16 kg in 1 BAG

68554- HETERO LABS LIMITED
- 68554-0170-
  68554-0170-1- 1 kg in 1 DRUM (68554-0170-1)

68724- Pfizer Asia Manufacturing Pte Ltd
- 68724-1020-
  68724-1020-0- 1 BAG in 1 DRUM (68724-1020-0) / 25 kg in 1 BAG

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