Crizotinib (Monograph)

Brand name: Xalkori
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Feb 10, 2024. 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).

Guidelines generally support use of crizotinib for the treatment of stage IV NSCLC when other ALK inhibitors are unavailable or were previously used in the first-line setting.

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).

Anaplastic Large Cell Lymphoma (ALCL)

Treatment of pediatric patients ≥1 year of age and young adults with relapsed or refractory ALK-positive systemic anaplastic large cell lymphoma (ALCL) (designated an orphan drug by FDA for this use).

Principal efficacy study did not include adults >21 years of age. Manufacturer states safety and efficacy not established in older adults.

Inflammatory Myofibroblastic Tumor

Treatment of adult and pediatric patients ≥1 year of age with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. Designated an orphan drug by the FDA for use in this condition. Efficacy of crizotinib for treatment of ALK-positive IMT was established in two separate clinical studies; one in patients 1 to ≤21 years of age and another in adults.

While surgical resection is the treatment of choice as patients with completely resected tumors have an excellent prognosis, patients with unresectable or recurrent tumors may respond to crizotinib if the ALK mutation is present and crizotinib administration is followed by complete or incomplete resection.

Crizotinib Dosage and Administration

General

Pretreatment Screening

In patients with metastatic non-small cell lung cancer (NSCLC): Confirm presence of anaplastic lymphoma kinase (ALK)- or c-ros oncogene-1 (ROS-1) rearrangement in tumor specimens prior to initiating therapy with crizotinib.
Verify pregnancy status in females of reproductive potential.
In pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with IMT: Perform ophthalmologic examination prior to initiating therapy.

Patient Monitoring

Monitor complete blood cell counts (CBCs) including differential counts weekly for the first month of therapy and then at least monthly. More frequent testing is recommended in patients with grade 3 or 4 hematologic toxicity, or if fever or infection occurs.
Monitor liver function tests every 2 weeks during the initial 2 months of therapy, monthly thereafter, and as clinically indicated. More frequent testing is recommended if elevated aminotransferase concentrations occur.
Monitor for pulmonary symptoms indicative of interstitial lung disease or pneumonitis.
Monitor ECGs and serum electrolytes in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval.
Monitor heart rate and BP regularly during therapy.
In pediatric and young adult patients with ALCLor pediatric patients with IMT: Ophthalmologic examination including retinal examination is recommended within 1 month of initiating crizotinib therapy, every 3 months thereafter.
Assess visual symptoms monthly during treatment in all patients receiving crizotinib. Patients with new symptoms should be referred to an eye specialist.

Premedication and Prophylaxis

In pediatric and young adult patients with ALCLor pediatric patients with IMT: Administer standard antiemetic and antidiarrheal agents for GI adverse effects; antiemetics are recommended prior to and during treatment with crizotinib.
Consider IV or oral hydration for patients at risk of dehydration; serum electrolytes also should be corrected as clinically indicated.

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), crizotinib is a high-alert mediation that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer capsules or pellets orally twice daily without regard to meals. Swallow capsules whole; do not crush, chew, or split.

Pellets are supplied encapsulated in shells. Do not chew or crush the pellets and do not swallow pellets encapsulated in the shell.

Administer pellets by opening shells containing the pellets and emptying the contents directly into the patient's mouth or by emptying the contents into an oral dosing aid (e.g., spoon, medicine cup) and administering the pellets via the dosing aid directly into the patient's mouth.

Give the patient a sufficient amount of water immediately after administration of the pellets to ensure that all medication is swallowed.

If a dose of crizotinib is missed, take the missed dose as soon as it is remembered unless the next dose is due within 6 hours.

If a dose of crizotinib is vomited after administration, do not take an additional dose to replace the vomited dose. Administer the next dose at the next scheduled time.

Dosage

Pediatric Patients

ALCL

Oral

≥1 year of age: 280 mg/m² twice daily. Recommended dosage is based on body surface area (BSA). See Table 1. Continue therapy until disease progression or unacceptable toxicity occurs.

Table 1. Recommended Crizotinib Dosage Based on BSA in Pediatric Patients ≥1 Year of Age and Young Adults with ALK-positive ALCL or Pediatric Patients ≥1 Year of Age with ALK-positive IMT1
Body Surface Area (m²)	Recommended Dosage (280 mg/m² twice daily)
0.38–0.46	120 mg twice daily
0.47–0.51	140 mg twice daily
0.52–0.61	150 mg twice daily
0.62–0.80	200 mg twice daily
0.81-0.97	250 mg twice daily
0.98-1.16	300 mg twice daily
1.17-1.33	350 mg twice daily
1.34-1.51	400 mg twice daily
1.52-1.69	450 mg twice daily
≥1.7	500 mg twice daily

Inflammatory Myofibroblastic Tumor

Oral

≥1 year of age : 280 mg/m² orally twice daily until disease progression or unacceptable toxicity occurs. Recommended dosage is based on BSA. (See Table 1.)

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 2 for pediatric patients with ALCL or IMT; the recommended dosage modification for pediatric patients with ALCL or IMT are based on BSA.

Permanently discontinue in patients who are unable to tolerate crizotinib therapy after 2 dose reductions.

Table 2. Recommended Dosage Reduction for Crizotinib Toxicity in Pediatric Patients with ALCL or IMT and Young Adults with ALCL.1
Body Surface Area (m²)	First Dose Reduction	Second Dose Reduction
0.38-0.46	90 mg twice daily	70 mg twice daily
0.47-0.51	100 mg twice daily	80 mg twice daily
0.52-0.61	120 mg twice daily	90 mg twice daily
0.62-0.80	150 mg twice daily	120 mg twice daily
0.81-0.97	200 mg twice daily	150 mg twice daily
0.98-1.16	220 mg twice daily	170 mg twice daily
1.17-1.33	250 mg twice daily	200 mg twice daily
1.34-1.69	250 mg twice daily	200 mg twice daily
≥1.7	400 mg twice daily	250 mg twice daily

Hematologic Toxicity

Oral

If ANC <500/mm³ occurs, interrupt therapy until ANC recovers to >1000/mm³, then resume crizotinib at next lower dosage. If ANC <500/mm³ recurs, permanently discontinue drug if recurrence is complicated by febrile neutropenia or infection. If uncomplicated grade 4 neutropenia occurs, withhold therapy until ANC recovers to >1000/mm³ and then resume at next lower dosage or permanently discontinue drug. Permanently discontinue crizotinib in patients who are unable to tolerate crizotinib after 2 dosage reductions, unless indicated otherwise.

If platelet count of 25,000–50,000/mm³ occurs with concurrent bleeding, interrupt therapy until platelet count recovers to >50,000/mm³ and bleeding resolves, then resume at same dosage. If platelet count <25,000/mm³ occurs, withhold crizotinib until platelet count recovers to >50,000/mm³, then resume at next lower dosage, permanently discontinue for recurrence.

If hemoglobin concentration <8 g/dL occurs, interrupt therapy until hemoglobin concentration recovers to ≥8 g/dL, then resume at same dosage. If life-threatening anemia occurs and urgent intervention is needed, withhold crizotinib until hemoglobin recovers to ≥8 g/dL, then resume at next lower dosage. If life-threatening anemia recurs, permanently discontinue drug.

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.

Pulmonary Effects

Oral

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue crizotinib.

Prolongation of QT Interval

Oral

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

If QT_c 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.

Bradycardia

Oral

If symptomatic but non-life-threatening, bradycardia (resting heart rate <2.5^th percentile for age in pediatric patients) requiring medical intervention occurs, withhold therapy with crizotinib until recovery according to age-specific norms occurs. See Table 3.

Table 3. Resting Heart Rate Based on the 2.5th Percentile Per Age-specific Norms.1
Age (years)	Resting Heart Rate
1 to <2	≥91 beats/minute
2–3	≥82 beats/minute
4–5	≥72 beats/minute
6–8	≥64 beats/minute
>8	≥60 beats/minute

If concomitant drugs known to cause bradycardia are identified and discontinued or their dosage is adjusted, resume crizotinib therapy at the same dosage upon recovery to asymptomatic bradycardia or to the age specific heart rate. If no concomitant drugs known to cause bradycardia are identified or if discontinuance or dosage adjustment of such concomitant drugs is not possible, resume crizotinib at the next lower dosage upon recovery to asymptomatic bradycardia or to the age-specific heart rate.

If life-threatening bradycardiarequiring urgent intervention occurs in patients not receiving concomitant contributory drugs, permanently discontinue drug. If a concomitant contributory drug is identified and discontinued or the dosage of the contributory drug is adjusted, resume crizotinib at the second dosage reduction level (see Table 2) upon recovery to asymptomatic bradycardia or to the heart rate criteria listed for management of symptomatic, but non-life-threatening bradycardia, with frequent monitoring. Permanently discontinue crizotinib therapy for recurrence.

Visual Disturbances

Oral

If visual symptoms (grade 1 or 2 ocular toxicity) occur, monitor symptoms and consult an eye specialist; consider dosage reduction for grade 2 visual disorders.

If visual loss (grade 3 or 4 ocular disorder, marked decrease in vision) occurs, withhold crizotinib pending evaluation of severe visual loss.

If grade 3 or 4 ocular toxicity or severe vision loss occurs with no other identified etiology, permanently discontinue drug.

GI Toxicity

Oral

If grade 3 nausea occurs, interrupt therapy until symptoms resolve and then resume at next lower dosage level.

If grade 3 or 4 vomiting occurs, interrupt therapy until symptoms resolve and then resume at next lower dosage level.

If grade 3 or 4 diarrhea occurs, interrupt therapy until symptoms resolve and then resume at next lower dosage level.

In patients experiencing GI toxicity who are unable to tolerate crizotinib after 2 dosage reductions, permanently discontinue drug unless otherwise indicated.

Adults

NSCLC

Oral

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

ALCL

Oral

Young adults: 280 mg/m² twice daily. Recommended dosage is based on body surface area (BSA). See Table 1. Continue therapy until disease progression or unacceptable toxicity occurs.

Inflammatory Myofibroblastic Tumor

Oral

250 mg orally twice daily. Continue until disease progression or unaceptable toxicity occurs.

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 4 in adult patients with NSCLC or IMT or Table 2 in young adult patients with ALCL.

Table 4. Recommended Dosage Reduction for Crizotinib Toxicity in Adults with NSCLC or IMT.1
Dose Reduction Level	Dosage Reduction after Recovery from Toxicity (Initial Adult 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

In patients receiving crizotinib for the treatment of NSCLC or IMT:

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

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

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

In young adult patients receiving crizotinib for the treatment of ALCL:

Hepatic Toxicity

Oral

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.

Pulmonary Effects

Oral

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue crizotinib.

Prolongation of QT Interval

Oral

If QT_c interval >500 msec or a change from baseline of ≥60 msec occurs with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, permanently discontinue drug.

Bradycardia

Oral

If symptomatic, but non-life-threatening, bradycardia (heart rate <60 beats/minute) requiring medical intervention occurs, withhold therapy until recovery to a resting heart rate (≥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.

If life-threatening bradycardia requiring urgent intervention occurs in patients not receiving concomitant contributory drugs, permanently discontinue drug. If concomitant drugs known to cause bradycardia are identified and discontinued or their dosage is adjusted, crizotinib therapy may be resumed at the second dose reduction level in Table 4 upon recovery to asymptomatic bradycardia, with frequent monitoring. Permanently discontinue therapy for recurrence.

Visual Disturbances

Oral

If visual loss (grade 3 or 4 ocular disorder, marked decrease in vision) occurs, discontinue crizotinib therapy and perform an ophthalmologic evaluation. Permanently discontinue crizotinib for grade 3 or 4 ocular disorders or severe visual loss if no other etiology is discovered during the ophthalmologic evaluation.

If visual symptoms (grade 1 or 2 ocular toxicity) occur, monitor symptoms and consult an eye specialist; dosage reduction of crizotinib should be considered for grade 2 visual disorders.

GI Toxicity

Oral

In young adult patients receiving crizotinib for the treatment of ALCL:

If grade 3 nausea occurs, interrupt therapy until symptoms resolve and then resume at next lower dosage level.

If grade 3 or 4 vomiting occurs, interrupt therapy until symptoms resolve and then resume at next lower dosage level.

If grade 3 or 4 diarrhea occurs, interrupt therapy until symptoms resolve and then resume at next lower dosage level.

In patients experiencing GI toxicity who are unable to tolerate crizotinib after 2 dosage reductions, permanently discontinue drug unless otherwise indicated.

Concomitant Use of Drugs or Foods Affecting Hepatic Microsomal Enzymes

Avoid concomitant use of crizotinib with potent CYP3A inhibitors. If concomitant use of a potent CYP3A inhibitor cannot be avoided, reduce the crizotinib dose to the second dose reduction (see Table 4 for adults with NSCLC or IMT and Table 2 for pediatric patients with ALCL or IMT and young adults with ALCL). When concomitant use of a potent CYP3A inhibitor is discontinued, resume the crizotinib dosage used prior to initiation of the potent CYP3A inhibitor.

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 in adult patients with NSCLC or IMTand reduce dosage according to the first dosage reduction level in pediatric and young adult patients with ALCLor pediatric patients with IMT (see Table 2)

Severe preexisting hepatic impairment (total bilirubin >3 times the ULN with any AST concentration): Reduce dosage to 250 mg once daily in adult patients with NSCLC or IMT and reduce dosage according to the second dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT (see Table 2).

Renal Impairment

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

Severe renal impairment (Cl_cr <30 mL/minute) not requiring dialysis: Reduce dosage to 250 mg once daily in adult patients with NSCLC or IMT.

Severe renal impairment (Cl_cr <30 mL/minute) calculated using modified Cockcroft-Gault equation for adult patients and Schwartz equation for pediatric patients not requiring dialysis: Reduce dosage according to second dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT(see Table 2).

Geriatric Patients

No specific dosage recommendations.

Cautions for Crizotinib

Contraindications

None.

Warnings/Precautions

Hepatic Toxicity

Fatal drug-induced hepatotoxicity has occurred. ALT or AST elevations also reported. Serum aminotransferase elevations usually develop within the first 2 months of treatment.

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.

Pulmonary Effects

Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with crizotinib. Cases generally occurred within 3 months of therapy initiation.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other causes of ILD/pneumonitis. If treatment-related ILD/pneumonitis occurs, permanently discontinue crizotinib.

Prolongation of QT Interval

QT_c-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.

If QT_c-interval prolongation occurs, temporary interruption, dosage reduction, or permanent discontinuance of crizotinib may be necessary.

Bradycardia

Symptomatic bradycardia reported.

Avoid concomitant use with other drugs known to cause bradycardia when possible.

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.

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.

In pediatric and young adult patients with ALCL or pediatric patients with IMT, perform ophthalmologic examination prior to starting crizotinib. Follow-up ophthalmologic examination including retinal examination is recommended within 1 month of treatment initiation, every 3 months thereafter. Assess visual symptoms monthly for all patients during treatment. If visual disturbances occur, consult an eye specialist. Permanently discontinue crizotinib for grade 3 or 4 ocular disorders or severe vision loss (best corrected vision less than 20/200 in one or both eyes) unless other etiology is identified.

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

GI Toxicity

Severe GI toxicities reported in patients receiving crizotinib. Provide standard antiemetic and antidiarrheal agents for GI toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT.

Antiemetics are recommended prior to and during treatment with crizotinib to prevent nausea and vomiting. In patients who develop grade 3 nausea lasting 3 days or grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold crizotinib until symptoms resolve, and then resume at the next lower dosage level. When clinically indicated, consider supportive care such as hydration, electrolyte supplementation, and nutritional support.

Fetal/Neonatal Morbidity and Mortality

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

Females receiving crizotinib and partners of male patients receiving the drug should avoid pregnancy during therapy. Perform pregnancy test prior to initiation of crizotinib in females of reproductive potential. If used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

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

Females and Males of Reproductive Potential

Perform pregnancy test prior to initiation of crizotinib in females of reproductive potential. Females of reproductive potential should use effective contraceptive methods while receiving the drug and for ≥45 days after the drug is discontinued. Males who are partners of such females should use condoms during therapy and for ≥90 days after the drug is discontinued.

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

Pediatric Use

Safety and efficacy established in pediatric patients ≥12 months of age with relapsed or refractory systemic anaplastic lymphoma kinase (ALK)-positive ALCL or unresectable, recurrent, or refractory (ALK)-positive IMT. Safety and efficacy not established in pediatric patients <12 months of age with ALCL or IMT or in any pediatric patients with NSCLC.

The safety and efficacy of crizotinib in combination with chemotherapy not established in patients with newly diagnosed ALCL.

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.

Increased systemic exposure in individuals with preexisting moderate or severe hepatic impairment; dosage reduction necessary.

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 not on dialysis; dosage reduction necessary.

Common Adverse Effects

ALK-positive metastatic NSCLC (≥25%): Vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated aminotransferase concentrations, fatigue, decreased appetite, upper respiratory infection, dizziness, neuropathy.

Pediatric patients with IMT (≥35%): vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, headache. Adult patients with IMT (≥20%): vision disorders, nausea, edema.

ALCL (≥35%): Diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, pruritus.

Grade 3 or 4 laboratory abnormalities in patients with ALCL (≥15%): Neutropenia, lymphopenia, thrombocytopenia.

Drug Interactions

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 dailyin adult patients with NSCLC or IMT and reduce the dosage according to the second dosage reduction level in pediatric and young adult patients with ALCL or pediatric patients with IMT (See Table 2). 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.

Drugs Associated with Bradycardia

Possible increased risk of bradycardia. Avoid concomitant use, if possible.

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 in adult patients with NSCLC or IMT and reduce dosage according to the second dosage reduction level in pediatric patients with ALCL or IMT and young adults with ALCL (see Table 2) 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 following oral administration of capsules is approximately 43%.

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

Oral pellets have a comparable crizotinib bioavailability compared to capsules.

Food

High-fat meal reduced crizotinib capsule AUC and peak plasma concentrations by approximately 14%; AUC and peak plasma concentrations reduced by 15% and 23%, respectively, for the pellet formulation.

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 in patients 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 (Cl_cr 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, and ethnicity (Asian and non-Asian) do not affect pharmacokinetics of crizotinib. In patients ≤18 years of age, crizotinib exposure is lower in patients with higher body weight.

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 (excursions permitted between 15–30°C).

Pellets

20–25°C (excursions permitted between 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.
In vitro, induced apoptosis and inhibited proliferation and ALK-mediated signaling in anaplastic large cell lymphoma-derived cell lines at clinically achievable exposures.

Advice to Patients

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. Administer crizotinib pellets by opening the shells containing the pellets and emptying the contents directly into the patient's mouth or via use of a dosing aid (e.g., spoon, medicine cup).
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 avoiding grapefruit and grapefruit juice while taking crizotinib.
Risk of fetal harm. Necessity of advising females 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 males who are partners with females of reproductive potential to use a condom 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 females 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.
Risk of GI toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) and in pediatric patients with inflammatory myofibroblastic tumor (IMT). Inform patients of the risk of severe nausea, vomiting, diarrhea, and stomatitis, and to immediately inform their clinician if problems with swallowing, vomiting, or diarrhea occur.
Risk of photosensitivity. Advise patients to avoid prolonged sun exposure and to use sunscreen or protective clothing.
Risk of interstitial lung disease/pneumonitis. Importance of immediately reporting any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough with or without mucus, fever); interstitial lung disease/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 (e.g., 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.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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 is available only from designated specialty pharmacies. Consult the manufacturer's website for additional information.