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Crizotinib

Class: Antineoplastic Agents
- Anaplastic Lymphoma Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA Class: AN900
Chemical Name: 3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-2-pyridinamine
Molecular Formula: C21H22Cl2FN5O
CAS Number: 877399-52-5
Brands: Xalkori

Medically reviewed by Drugs.com on Jan 25, 2021. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including anaplastic lymphoma kinase (ALK) and c-ros oncogene-1 (ROS-1).

Uses for Crizotinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic NSCLC in patients with tumors positive for anaplastic lymphoma kinase (ALK) or c-ros oncogene-1 (ROS-1) as detected by an FDA-approved diagnostic test (designated an orphan drug by FDA for this use).

About 3–7 or 1–2% of patients with NSCLC have ALK- or ROS-1-positive disease, respectively; such patients typically are nonsmokers or light smokers, female, and younger in age, and often have adenocarcinoma.

Long-term therapeutic potential of crizotinib is limited by eventual development of secondary resistance and development and/or progression of brain metastases (because of poor distribution of crizotinib into CSF). (See Actions.)

Crizotinib Dosage and Administration

General

  • Confirmation of ALK- or ROS-1-positive metastatic NSCLC is necessary prior to beginning therapy.

  • Monitor CBCs including differential counts monthly and as clinically indicated. More frequent testing recommended in patients with grade 3 or 4 hematologic toxicity, or if fever or infection occurs. (See Dosage Modification for Toxicity under Dosage and Administration.)

  • Monitor liver function tests every 2 weeks during the initial 2 months of therapy, monthly thereafter, and as clinically indicated. More frequent testing recommended if elevated aminotransferase concentrations occur. (See Dosage Modification for Toxicity under Dosage and Administration.)

Restricted Distribution

  • Obtain crizotinib through a limited network of specialty pharmacies.

  • Consult the Xalkori website ([Web]) for specific availability and ordering information.

Administration

Oral Administration

Administer orally twice daily without regard to meals. Swallow capsules whole.

Dosage

Adults

NSCLC
Oral

250 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Avoid concomitant use of potent CYP3A inhibitors. If concomitant use cannot be avoided, reduce crizotinib dosage to 250 mg once daily.

Dosage Modification for Toxicity
Oral

Dosing interruption, dosage reduction, and/or discontinuance of therapy may be necessary for adverse reactions.

If dosage reduction is required, reduce dosage as described in Table 1.

Table 1: Recommended Dosage Reduction for Crizotinib Toxicity1

Dose Reduction Level

Dosage Reduction after Recovery from Toxicity (Initial Dosage = 250 mg twice daily)

First

Resume at 200 mg twice daily

Second

Resume at 250 mg once daily

Third

Permanently discontinue drug

Hematologic Toxicity
Oral

If grade 3 hematologic toxicity occurs, interrupt therapy. Once hematologic toxicity resolves to grade 2 or less, may resume crizotinib at the same dosage schedule.

If grade 4 hematologic toxicity occurs, interrupt therapy. Once hematologic toxicity resolves to grade 2 or less, resume at next lower dosage.

Dosage modification is not necessary for lymphopenia unless associated with clinical events (e.g., opportunistic infections).

Hepatic Toxicity
Oral

If ALT or AST concentrations >5 times ULN with total bilirubin concentrations ≤1.5 times ULN occur, interrupt therapy. When liver function test results return to baseline values or ≤3 times ULN, may resume crizotinib at next lower dosage.

If ALT or AST concentrations >3 times ULN with total bilirubin concentrations >1.5 times ULN occur (in the absence of cholestasis or hemolysis), permanently discontinue drug. (See Hepatic Toxicity under Cautions.)

Pulmonary Effects
Oral

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue crizotinib. (See Pulmonary Effects under Cautions.)

Prolongation of QT Interval
Oral

If QTc interval >500 msec on ≥2 separate ECGs occurs, interrupt crizotinib therapy. Once QTc interval returns to baseline values or improves to <481 msec, may resume crizotinib at next lower dosage.

If QTc interval >500 msec or a decrease from baseline of ≥60 msec occurs with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, permanently discontinue drug. (See Prolongation of QT Interval under Cautions.)

Bradycardia
Oral

If symptomatic, but non-life-threatening, bradycardia (heart rate <60 beats/minute) requiring medical intervention occurs, interrupt crizotinib therapy until symptoms resolve or heart rate improves to ≥60 beats/minute. If concomitant therapy includes drugs known to cause bradycardia and is modified (dosage adjusted or drug discontinued), may resume crizotinib therapy at the same dosage; if such modification is not possible or if no concomitant contributory drugs are identified, may resume crizotinib at next lower dosage. (See Interactions.)

If life-threatening bradycardia requiring urgent intervention occurs in patients receiving concomitant contributory drugs known to cause bradycardia, interrupt crizotinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute. If concomitant therapy is modified (dosage adjusted or drug discontinued), may resume crizotinib at a reduced dosage of 250 mg once daily with frequent monitoring; permanently discontinue crizotinib in case of recurrence.

If life-threatening bradycardia requiring urgent intervention occurs in patients not receiving concomitant contributory drugs, permanently discontinue drug. (See Bradycardia under Cautions.)

Visual Disturbances
Oral

If grade 4 vision loss occurs, discontinue crizotinib therapy. (See Visual Disturbances under Cautions.)

Special Populations

Hepatic Impairment

Mild preexisting hepatic impairment (AST concentration exceeding the ULN with total bilirubin concentration no more than the ULN, or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration): No dosage adjustment required.

Moderate preexisting hepatic impairment (total bilirubin concentrations >1.5 times the ULN, but ≤3 times the ULN, with any AST): Reduce dosage to 200 mg twice daily.

Severe preexisting hepatic impairment (total bilirubin >3 times the ULN with any AST concentration): Reduce dosage to 250 mg once daily. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Clcr <30 mL/minute) not requiring dialysis: Reduce dosage to 250 mg once daily. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.

Cautions for Crizotinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Hepatic Toxicity

Fatal drug-induced hepatotoxicity has occurred; such cases reported in 0.1% of crizotinib-treated patients in clinical trials. ALT or AST elevations >5 times ULN reported in 11 or 6% of patients, respectively, in clinical trials. Serum aminotransferase elevations usually develop within the first 2 months of treatment. (See Advice to Patients.)

Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of therapy, monthly thereafter, and as clinically indicated. More frequent testing necessary in patients who develop aminotransferase elevations. If hepatic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of crizotinib may be necessary. (See Hepatic Toxicity under Dosage and Administration.)

Pulmonary Effects

Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis reported in 2.9% of patients in clinical studies; grade 3 or 4 ILD occurred in 1% of patients, and fatal ILD occurred in 0.5% of patients. Cases generally occurred within 3 months of therapy initiation.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (see Advice to Patients). Exclude other causes of ILD/pneumonitis. If treatment-related ILD/pneumonitis occurs, permanently discontinue crizotinib.

Prolongation of QT Interval

QTc-interval prolongation reported.

Avoid use in patients with congenital long QT syndrome.

Monitor ECGs and serum electrolytes in patients with CHF, bradyarrhythmias, or electrolyte abnormalities or during concomitant use of drugs known to prolong the QT interval. ( See Specific Drugs and Foods under Interactions.)

If QTc-interval prolongation occurs, temporary interruption, dosage reduction, or permanent discontinuance of crizotinib may be necessary. (See Prolongation of QT Interval under Dosage and Administration.)

Bradycardia

Symptomatic bradycardia reported.

Avoid concomitant use with other drugs known to cause bradycardia when possible. (See Interactions.)

Monitor heart rate and BP regularly during crizotinib therapy. If symptomatic or life-threatening bradycardia occurs, interrupt therapy; dosage reduction or discontinuance of crizotinib therapy may be necessary depending on concomitant use of other drugs known to cause bradycardia. (See Bradycardia under Dosage and Administration.)

Visual Disturbances

Visual disturbances, sometimes resulting in partial or complete loss of vision in one or both eyes, reported; generally occurs within 1 week of initiating therapy. Optic atrophy and optic nerve disorder may cause vision loss.

If new-onset severe visual loss (best corrected vision <20/200 in one or both eyes) occurs, discontinue crizotinib. Perform comprehensive ophthalmologic evaluation (i.e., best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography).

Insufficient data to determine risks of resuming crizotinib in patients with severe vision loss; potential benefit of the drug must be carefully weighed against potential risks of continued therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of crizotinib in women of reproductive potential. Women of reproductive potential should use effective contraceptive methods while receiving the drug and for ≥45 days after the drug is discontinued. Men who are partners of such women should use effective contraceptive methods during therapy and for ≥90 days after the drug is discontinued. If used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise of potential fetal hazard.

Impairment of Fertility

Results of animal studies suggest that crizotinib may impair female and male fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether crizotinib is distributed into milk. Women should not breast-feed during therapy and for 45 days after drug discontinuance.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Decreased bone formation in growing long bones observed in juvenile animals; other toxicities of potential concern not evaluated in juvenile animal studies.

Geriatric Use

In clinical studies evaluating crizotinib in patients with ALK-positive metastatic NSCLC, 16% of patients were ≥65 years of age and 3.8% were ≥75 years of age. No overall differences in safety or efficacy in patients ≥65 years of age compared with younger adults.

Insufficient experience in patients ≥65 years of age with ROS-1-positive metastatic NSCLC to determine whether efficacy and safety are similar to those in younger adults.

Hepatic Impairment

Mild hepatic impairment did not substantially affect systemic exposure; no dosage adjustment necessary. (See Special Populations under Pharmacokinetics.)

Increased systemic exposure in individuals with preexisting moderate or severe hepatic impairment; dosage reduction necessary. (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Mild or moderate renal impairment did not substantially affect systemic exposure.

Increased peak plasma concentrations and AUC in patients with severe renal impairment who do not require dialysis; dosage reduction necessary. (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Previously untreated ALK-positive metastatic NSCLC: visual disturbances (including diplopia, photopsia, photophobia, blurred vision, visual field defect, visual impairment, vitreous floaters, and reduced visual acuity), diarrhea, vomiting, edema (including localized edema and peripheral edema), constipation, abdominal pain, upper respiratory infection, headache, dysgeusia, pyrexia, extremity pain, dyspepsia, dizziness, dysphagia, lymphopenia, elevated ALT and/or AST concentrations, hypophosphatemia.

Previously treated ALK-positive metastatic NSCLC: visual disturbances (including diplopia, photopsia, photophobia, blurred vision, visual impairment, vitreous floaters, and reduced visual acuity), diarrhea, nausea, vomiting, constipation, edema (including localized edema and peripheral edema), upper respiratory infection, decreased weight, dysgeusia, dizziness, neutropenia, elevated ALT and/or AST concentrations, hypokalemia.

ROS-1-positive metastatic NSCLC: Adverse effects similar to those in patients with ALK-positive NSCLC.

Interactions for Crizotinib

Predominantly metabolized by CYP3A.

In vitro, inhibits CYP2B6, but does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, or 2D6, or UGT 1A1, 1A4, 1A6, 1A9, or 2B7. Does not induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A.

In vitro, inhibitor and substrate of P-gp. Inhibits organic cation transporter (OCT) 1 and OCT2; does not inhibit organic anion transport protein (OATP) B1, OATP1B3, renal organic anion transporter (OAT) 1, OAT3, or bile salt export pump (BSEP).

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inhibitors: Possible increased systemic exposure to, and increased toxicity of, crizotinib. Avoid concomitant use of potent CYP3A inhibitors. If concomitant use cannot be avoided, reduce crizotinib dosage to 250 mg once daily. When concomitant use of potent CYP3A inhibitor is discontinued, return crizotinib dosage to dosage used prior to initiation of the CYP3A inhibitor. Use caution with concomitant use of moderate CYP3A inhibitors.

Potent CYP3A inducers: Possible decreased plasma concentrations and decreased therapeutic efficacy of crizotinib. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible increased plasma concentrations and increased toxicity of CYP3A substrate. May need to reduce dosage of concurrently used drugs that are predominantly metabolized by CYP3A. Avoid concomitant use of crizotinib and CYP3A substrates with narrow therapeutic indices. If concomitant use of CYP3A substrates with narrow therapeutic indices cannot be avoided, reduce dosage of substrate drug.

Drugs that Prolong QT Interval

Potential pharmacologic interactions (additive effect on QT-interval prolongation). Avoid concomitant use, if possible. If concomitant use cannot be avoided, monitor ECGs and electrolytes during concomitant use. (See Prolongation of QT Interval under Cautions.)

Drugs Associated with Bradycardia

Possible increased risk of bradycardia. Avoid concomitant use, if possible. (See Bradycardia under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Possible increased crizotinib concentrations

Ketoconazole increased peak concentrations and AUC of crizotinib (single 150-mg dose) by 44- and 216%, respectively

Itraconazole increased peak concentrations and AUC of crizotinib (250 mg once daily) by 33 and 57%, respectively

Potent CYP3A inhibitors (e.g., itraconazole, ketoconazole): Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of crizotinib to 250 mg once daily

If potent CYP3A inhibitor is discontinued, resume crizotinib at dosage used prior to initiation of the antifungal

Moderate CYP3A inhibitors: Caution advised.

β-Adrenergic blocking agents

Possible increased risk of bradycardia

Avoid concomitant use, if possible

Calcium-channel blocking agents, nondihydropyridine

Possible increased risk of bradycardia

Avoid concomitant use, if possible

Clonidine

Possible increased risk of bradycardia

Avoid concomitant use, if possible

Digoxin

Possible increased risk of bradycardia

Avoid concomitant use, if possible

Esomeprazole

No clinically important changes in pharmacokinetics of crizotinib

Grapefruit or grapefruit juice

Possible increased crizotinib concentrations

Avoid concomitant use

Midazolam

Crizotinib (250 mg twice daily) increased AUC of oral midazolam by 3.7-fold

Consider midazolam dosage reduction

Rifampin

Decreased peak concentrations and AUC of crizotinib (250 mg twice daily) by 84 and 79%, respectively

Avoid concomitant use

Crizotinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in a median of 4–6 hours.

Steady-state concentrations are achieved within 15 days; median accumulation ratio is 4.8.

Absolute bioavailability is approximately 43%.

Systemic exposure increases in greater than dose-proportional manner following repeated administration of crizotinib 200–300 mg twice daily.

Food

High-fat meal reduced crizotinib AUC and peak plasma concentrations by approximately 14%.

Special Populations

Mild hepatic impairment (AST concentration exceeding the ULN with total bilirubin concentration no more than the ULN, or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration) decreases mean AUC and peak plasma concentrations by 9%.

In patients with moderate hepatic impairment (total bilirubin concentration >1.5 times the ULN, but ≤3 times the ULN, with any AST concentration) receiving crizotinib 200 mg twice daily, mean AUC and peak plasma concentrations at steady state increase by 14 or 9%, respectively, compared with those with normal hepatic function receiving crizotinib 250 mg twice daily.

In patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration) receiving crizotinib 250 mg once daily, mean AUC and peak plasma concentrations decrease by 35 and 27%, respectively, compared with patients with normal hepatic function receiving crizotinib 250 mg twice daily.

Mild or moderate renal impairment (Clcr 30–89 mL/minute) does not affect systemic exposure.

Severe renal impairment (not requiring dialysis) increases mean peak plasma concentrations and AUC by 34 and 79%, respectively; similar effects on AUC and peak plasma concentrations of active metabolite.

Age, sex, ethnicity, and body weight do not affect pharmacokinetics of crizotinib.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

91%; independent of drug concentration.

Elimination

Metabolism

Predominantly metabolized by CYP3A.

Elimination Route

Eliminated in feces (63%) and in urine (22%). Eliminated mainly as unchanged drug in feces (53%).

Half-life

Mean terminal half-life: 42 hours.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

  • Inhibits multiple receptor tyrosine kinases, including ALK, hepatocyte growth factor receptor (HGFR, c-Met), ROS-1, and recepteur d’origine nantais (RON).

  • Activating mutations or translocations of the ALK gene identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4], ALK). Formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

  • ALK or ROS-1 rearrangements identified in approximately 3–7 or 1–2% of patients, respectively, with NSCLC.

  • Clinical resistance to crizotinib attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways. CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF.

  • Crizotinib inhibits ALK, ROS-1, and c-Met phosphorylation in vitro.

  • Exhibits antitumor activity in mice bearing tumor xenografts that express EML4-ALK or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

Advice to Patients

  • Importance of reading the manufacturer's patient information.

  • Importance of ALK or ROS-1 testing for therapy with crizotinib.

  • Importance of taking crizotinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by clinician. Importance of swallowing crizotinib capsules whole.

  • If a dose is missed, importance of taking the missed dose as soon as it is remembered, unless it is less than 6 hours before the next dose, in which case the missed dose should be omitted. Do not take a double dose to make up for a missed dose. If a dose is vomited after administration, an additional dose should not be administered to replace the vomited dose. The next dose should be administered at the next scheduled time.

  • Importance of not eating or drinking grapefruit products while taking crizotinib.

  • Risk of fetal harm. Necessity of advising women of reproductive potential that they should use effective contraceptive methods while receiving the drug and for ≥45 days after the drug is discontinued. Importance of advising men who are partners with women of reproductive potential to use effective methods of contraception while receiving the drug and for ≥90 days after the drug is discontinued. Importance of patients informing their clinicians if they or their partners are pregnant or think they may be pregnant. If pregnancy occurs, advise of potential risk to fetus.

  • Importance of advising women to avoid breast-feeding while receiving crizotinib therapy and for 45 days after discontinuance of therapy.

  • Risk of impaired female and male fertility.

  • Risk of hepatotoxicity; importance of regular liver function test monitoring. Importance of immediately reporting possible symptoms of hepatotoxicity (e.g., weakness, fatigue, anorexia, nausea, vomiting, abdominal pain [especially right upper quadrant pain], jaundice, dark urine, generalized pruritus, bleeding diathesis), particularly in combination with fever and rash.

  • Potential for nausea, diarrhea, vomiting, and constipation.

  • Risk of ILD/pneumonitis. Importance of immediately reporting any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough with or without mucus, fever); ILD/pneumonitis symptoms may be similar to those from lung cancer.

  • Risk of QT-interval prolongation or bradycardia. Importance of informing clinicians immediately if changes in heartbeat or feelings of dizziness or faintness occur.

  • Risk of visual disturbances, sometimes severe, that may result in vision loss; such changes occur commonly, usually during the first week of therapy. Importance of immediately reporting loss of vision or other visual disturbances (i.e., double vision, blurred vision, flashes of light, photosensitivity, floaters) to clinicians.

  • Importance of exercising caution when driving or operating machinery in the event that visual changes, dizziness, or fatigue occurs.

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (e.g., cardiac or antihypertensive agents) and OTC drugs and herbal supplements (e.g., grapefruit-containing products), as well as any concomitant illnesses (e.g., hepatic or renal impairment, cardiovascular disease [including congenital long QT syndrome]).

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Crizotinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg

Xalkori

Pfizer

250 mg

Xalkori

Pfizer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions January 25, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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