Xalkori

Generic Name: Crizotinib
Class: Antineoplastic Agents
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

Introduction

Antineoplastic agent; an inhibitor of several receptor tyrosine kinases including anaplastic lymphoma kinase (ALK).^{1 2 3 4 5 7 15 16}

Uses for Xalkori

Non-small Cell Lung Cancer (NSCLC)

Treatment of locally advanced or metastatic NSCLC in patients with tumors positive for anaplastic lymphoma kinase (ALK) as detected by an FDA-approved companion diagnostic test^{1 15} (designated an orphan drug by FDA for this use).¹² (See Anaplastic Lymphoma Kinase Testing under Cautions.)

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Efficacy based on overall response rate; improvement in patient-reported outcomes and overall survival not demonstrated.^{1 4 7 13}

About 1–7% of patients with NSCLC have ALK-positive disease;^{2 6 9 10 11 13 15} such patients typically are nonsmokers or light smokers and often have adenocarcinoma.^{3 4 6 7 10 13}

Xalkori Dosage and Administration

General

• Obtain crizotinib through a limited network of specialty pharmacies.^{13 17} Contact manufacturer at 877-744-5675 or consult the Xalkori website () for availability and ordering information.¹⁷

• Confirmation of ALK-positive NSCLC by an FDA-approved companion diagnostic test is necessary prior to beginning therapy.¹ (See Anaplastic Lymphoma Kinase Testing under Cautions.)

• Monitor liver function tests and CBC including differential counts monthly and as clinically indicated.¹ More frequent repeat testing recommended in patients with grade 2–4 (as defined by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) hepatotoxicity, patients with grade 3 or 4 (NCI) hematologic toxicity, or if fever or infection occurs.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

Administration

Oral Administration

Administer orally twice daily without regard to meals.¹ Swallow capsules whole; do not crush, dissolve, or open capsules.¹

Dosage

Adults

NSCLC

Oral

250 mg twice daily.¹ Continue therapy for as long as the patient derives clinical benefit.¹

Dosage Modification for Toxicity

Oral

Dosing interruption and/or dosage reduction may be necessary based on individual safety and tolerability.¹ If dosage reduction is necessary, initially reduce dosage to 200 mg twice daily.¹ If further dosage reduction is needed, reduce dosage to 250 mg once daily.¹

Hematologic Toxicity

Oral

If grade 3 (NCI) hematologic toxicity occurs, interrupt therapy.¹ Once hematologic toxicity resolves to grade 2 or less, may resume crizotinib at the same dosage schedule.¹

If grade 4 hematologic toxicity occurs, interrupt therapy.¹ Once hematologic toxicity resolves to grade 2 or less, resume at reduced dosage of 200 mg twice daily.¹ If hematologic toxicity recurs, interrupt therapy until hematologic toxicity resolves to grade 2 or less, then resume drug at a further reduced dosage of 250 mg once daily.¹ If grade 4 hematologic toxicity recurs, permanently discontinue crizotinib.¹

Dosage modification is not necessary for lymphopenia unless associated with clinical events (e.g., opportunistic infections).¹

Hepatic Toxicity

Oral

If grade 3 or 4 (NCI) ALT or AST elevation with grade 1 or less total bilirubin elevation occurs, interrupt therapy.¹ When hepatotoxicity resolves to grade 1 or less or to baseline, may resume crizotinib at reduced dosage of 200 mg twice daily.¹ If hepatotoxicity recurs, interrupt therapy until hepatotoxicity resolves to grade 1 or less, then resume drug at a further reduced dosage of 250 mg once daily.¹ If further grade 3 or 4 hepatotoxicity occurs, permanently discontinue crizotinib.¹

If grade 2–4 ALT or AST elevation with concurrent grade 2–4 total bilirubin elevation occurs (in the absence of cholestasis or hemolysis), permanently discontinue drug.¹ (See Hepatic Toxicity under Cautions.)

Pneumonitis

Oral

If pneumonitis of any grade (NCI) occurs that is not attributable to disease progression, other pulmonary disease, infection, or radiation effect, permanently discontinue crizotinib.¹ (See Pneumonitis under Cautions.)

Cardiovascular Toxicity

Oral

If grade 3 (NCI) QT_c-interval prolongation occurs, interrupt crizotinib therapy.¹ Once QT_c-interval prolongation improves to grade 1 or less, may resume crizotinib at reduced dosage of 200 mg twice daily.¹ If grade 3 QT_c-interval prolongation recurs at a dosage of 200 mg twice daily, interrupt therapy again until the QT_c-interval prolongation resolves to grade 1 or less, then resume crizotinib at a further reduced dosage of 250 mg once daily.¹ If grade 3 or 4 QT_c-interval prolongation recurs at a dosage of 250 mg once daily, permanently discontinue crizotinib.¹

If grade 4 QT_c-interval prolongation occurs, permanently discontinue drug.¹

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time for patients with preexisting hepatic impairment.¹ Because increased plasma crizotinib concentrations are likely, use with caution.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–90 mL/minute): No adjustment of initial dosage needed.¹

Severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease: Need for adjustment of initial dosage not determined.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.¹

Cautions for Xalkori

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Hepatic Toxicity

Fatal drug-induced hepatotoxicity has occurred; such cases reported in <1% of crizotinib-treated patients in clinical trials.¹ ALT elevations >5 times ULN reported in 4–7% of patients in 2 main clinical trials; elevations were generally asymptomatic and reversible upon dosage interruption.¹ Transaminase elevations usually develop within the first 2 months of treatment.¹ (See Advice to Patients.)

Monitor liver function tests, including ALT and total bilirubin, once every month and as clinically indicated.¹ More frequent repeat testing for increased transaminases, alkaline phosphatase, or total bilirubin necessary in patients who develop grade 2–4 transaminase elevations.¹ (See Hepatic Toxicity under Dosage and Administration.)

Pneumonitis

Severe, life-threatening, or fatal pneumonitis reported in 1.6% of patients in 2 main clinical studies; all cases occurred within 2 months of therapy initiation.^{1 4}

Monitor patients for pulmonary symptoms indicative of pneumonitis (see Advice to Patients).¹ Exclude other causes of pneumonitis (e.g., disease progression, other pulmonary disease, infection, radiation therapy).¹ If treatment-related pneumonitis occurs, permanently discontinue crizotinib.¹

Prolongation of QT Interval

QT_c-interval prolongation reported.¹

Avoid use in patients with congenital long QT syndrome.¹

Consider periodic monitoring of ECGs and serum electrolytes in patients with CHF, bradyarrhythmias, or electrolyte abnormalities or during concomitant use of drugs known to prolong the QT interval.¹ (See Cardiovascular Toxicity under Dosage and Administration and see Specific Drugs and Foods under Interactions.)

Anaplastic Lymphoma Kinase Testing

Detection of ALK-positive NSCLC using an FDA-approved companion diagnostic test (Vysis ALK Break Apart FISH Probe Kit) indicated for this use is necessary for selecting patients for crizotinib therapy.¹

Only laboratories with demonstrated proficiency in the specific technology being used should perform ALK testing; improper assay performance may cause unreliable results.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals.¹

Avoid pregnancy during therapy.¹ Women of childbearing potential and men who are partners of such women should use adequate methods of contraception while receiving the drug and for ≥90 days after the drug is discontinued.¹ If used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise of potential fetal hazard.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether crizotinib is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Decreased bone formation in growing long bones observed in juvenile animals; other toxicities of potential concern not evaluated in juvenile animal studies.¹

Geriatric Use

No overall differences in safety or efficacy in patients ≥65 years of age compared with younger adults.¹

Hepatic Impairment

Not studied in patients with hepatic impairment.¹ Because extensively metabolized in the liver, increased plasma crizotinib concentrations likely.¹ Use with caution.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Mild or moderate renal impairment did not substantially affect plasma crizotinib concentrations in one clinical study.¹

Limited data in patients with severe renal impairment and no data in patients with end-stage renal disease; use with caution in such patients.¹ (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Visual disturbances (e.g., diplopia, photopsia, photophobia, blurred vision, visual field defect, visual impairment, vitreous floaters, visual brightness, reduced visual acuity),^{1 2 4 7 13} nausea,^{1 2 4 7 13} diarrhea,^{1 2 4 7 13} vomiting,^{1 2 4 7 13} constipation,^{1 2 13} esophageal disorder,¹ abdominal pain,¹ stomatitis,¹ edema (e.g., localized edema, peripheral edema),^{1 2 13} fatigue,^{1 2 13} chest pain/discomfort,¹ fever,¹ upper respiratory infection,¹ increased ALT^{1 2 4 13} or AST concentrations,^{1 2} decreased appetite,^{1 2 13} arthralgia,¹ back pain,¹ dizziness,^{1 2 13} neuropathy,^{1 13} headache,¹ dysgeusia,^{1 13} insomnia,¹ dyspnea,^{1 4} cough,¹ rash.¹

Interactions for Xalkori

Predominantly metabolized by CYP3A4/5.¹ Moderate inhibitor of CYP3A.¹ Inhibitor and substrate of P-glycoprotein (P-gp) in vitro.¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of crizotinib).¹ Avoid concomitant use of potent CYP3A inhibitors; use caution with concomitant use of moderate CYP3A inhibitors.¹

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of crizotinib).¹ Avoid concomitant use.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate).¹ May need to reduce dosage of concurrently used drugs that are predominantly metabolized by CYP3A.¹ Avoid concomitant use of crizotinib and CYP3A substrates with narrow therapeutic indices.¹

Substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6: Clinically important pharmacokinetic interactions not expected.¹

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased solubility and reduced oral bioavailability of crizotinib) with drugs that increase gastric pH.¹

Substrates of P-glycoprotein Transport Systems

Substrates of P-gp: Possible pharmacokinetic interaction (increased plasma concentrations of the P-gp substrate).¹

Substrates of Organic Anion-transporting Polypeptide 1B1 and 1B3

Substrates of hepatic uptake transport proteins OATP1B1 or OATP1B3: Clinically important pharmacokinetic interactions unlikely.¹

Drugs that Prolong QT Interval

Potential pharmacologic interactions (additive effect on QT-interval prolongation).¹ Consider periodic monitoring of ECGs and electrolytes during concomitant use.¹ (See Prolongation of QT Interval under Cautions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antacids	Possible decreased crizotinib bioavailability secondary to decreased solubility at higher pH1
Antiarrhythmic agents, class IA (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol)	Possible additive effect on QT-interval prolongation1 18 19 (see also Quinidine)	Consider periodic monitoring of ECG and electrolytes1
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased crizotinib concentrations1	Avoid concomitant use1
Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)	Possible increased crizotinib concentrations1 Ketoconazole (200 mg twice daily) increased peak concentrations and AUC of crizotinib (single 150-mg dose) by 1.4- and 3.2-fold, respectively1	Avoid concomitant use1
Antimycobacterials, rifamycins (e.g., rifabutin, rifampin)	Possible decreased crizotinib concentrations1 Rifampin (600 mg daily) decreased peak concentrations and AUC of crizotinib (single 250-mg dose) by 69 and 82%, respectively1	Avoid concomitant use1
Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, mesoridazine, pimozide, thioridazine)	Possible additive effect on QT-interval prolongation1 18 19	Consider periodic monitoring of ECG and electrolytes1
Citalopram	Possible additive effect on QT-interval prolongation1 18	Consider periodic monitoring of ECG and electrolytes1
Ergot derivatives (e.g., dihydroergotamine, ergotamine)	Possible increased concentrations of ergot derivative1	Avoid concomitant use1
Grapefruit or grapefruit juice	Possible increased crizotinib concentrations1	Avoid concomitant use1
Histamine H2-receptor antagonists	Possible decreased crizotinib bioavailability secondary to decreased solubility at higher pH1
HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased crizotinib concentrations1	Avoid concomitant use1
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Possible increased concentrations of the immunosuppressive agent1	Avoid concomitant use1
Macrolides (e.g., clarithromycin, telithromycin)	Possible increased crizotinib concentrations1 Possible additive effect on QT-interval prolongation1 19	Avoid concomitant use1
Midazolam	Crizotinib (250 mg twice daily) increased AUC of oral midazolam by 3.7-fold1	Consider midazolam dosage reduction1
Nefazodone	Possible increased crizotinib concentrations1	Avoid concomitant use1
Opiate agonists (alfentanil, fentanyl)	Possible increased concentrations of opiate agonist1	Avoid concomitant use1
Pimozide	Possible increased pimozide concentrations1 Possible additive effect on QT-interval prolongation1 18 19	Avoid concomitant use1
Proton-pump inhibitors	Possible decreased crizotinib bioavailability secondary to decreased solubility at higher pH1
Quinidine	Possible increased quinidine concentrations1 Possible additive effect on QT-interval prolongation1 18 19	Avoid concomitant use1
St. John's wort (Hypericum perforatum)	Possible decreased crizotinib concentrations1	Avoid concomitant use1

Xalkori Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 4–6 hours.^{1 5}

Steady-state concentrations are achieved within 15 days.^{1 5}

Absolute bioavailability is 43% (range: 32–66%).¹

Food

High-fat meal reduced crizotinib AUC and peak plasma concentrations by approximately 14%.¹

Special Populations

Higher systemic exposure reported in Asian patients compared with non-Asian patients; body size might have been a factor.^{1 5}

Steady-state trough concentrations in patients with mild or moderate renal impairment were similar to those in patients with normal renal function in a clinical study.¹ (See Renal Impairment under Cautions.)

Distribution

Extent

Extensively distributed into tissues.¹

Not known whether distributed into human milk.¹

Plasma Protein Binding

91%; independent of drug concentration.¹

Elimination

Metabolism

Predominantly metabolized by CYP3A4/5.¹

Elimination Route

Eliminated in feces (63%) and in urine (22%).¹ Eliminated mainly as unchanged drug in feces (53%).¹

Half-life

Mean terminal half-life: 42 hours.^{1 5}

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).¹

Actions

• Inhibits several receptor tyrosine kinases, including ALK, hepatocyte growth factor receptor (HGFR, c-Met), and recepteur d’origine nantais (RON).^{1 2 4 5 7 15 16}

• Activating mutations or translocations of the ALK gene identified in several malignancies² and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4], ALK).^{1 3 6 15 16} 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.^{1 2 6 16}

• The EML4-ALK oncogene is identified in approximately 1–7% of patients with NSCLC.^{2 6 9 10 11 13 15}

• Crizotinib inhibits ALK and c-Met phosphorylation in vitro.^{1 8}

• Exhibits antitumor activity in mice bearing tumor xenografts that express EML4-ALK or nucleophosmin (NPM)-ALK fusion proteins or c-Met.¹

Advice to Patients

• Importance of reading the manufacturer's patient information before starting crizotinib therapy and each time the prescription is refilled.¹

• Importance of ALK testing for therapy with crizotinib.¹

• Importance of taking crizotinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by clinician.¹ Importance of swallowing crizotinib capsules whole and not crushing, dissolving, or opening the capsules.¹

• 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.¹ Do not take a double dose to make up for a missed dose.¹

• Importance of not eating or drinking grapefruit products while taking crizotinib.¹

• Risk of fetal harm.¹ Necessity of advising women of childbearing potential and men who are partners of such women that they should use adequate methods of contraception while receiving the drug and for ≥90 days after the drug is discontinued.¹ Importance of patients informing their clinicians if they or their partners are pregnant or think they may be pregnant.¹ If pregnancy occurs, advise of potential risk to fetus.¹

• Importance of advising women to avoid breast-feeding while receiving crizotinib therapy.¹

• Risk of hepatotoxicity; importance of regular liver function test monitoring.¹ 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.¹

• Potential for nausea, diarrhea, vomiting, and constipation;^{1 2} these effects occur commonly and may require treatment with antiemetic and/or antidiarrheal agents or laxatives.¹

• Risk of pneumonitis.¹ Importance of immediately reporting any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough with or without mucus, fever); pneumonitis symptoms may be similar to those from lung cancer.¹

• Risk of QT-interval prolongation.¹ Importance of informing clinicians immediately if an abnormal heartbeat or feelings of dizziness or faintness occur.¹

• Potential for visual changes (e.g., perceived flashes of light, blurred vision, photosensitivity, floaters); such changes occur commonly, usually during the first 2 weeks of therapy.¹ Importance of reporting flashes or floaters to clinicians.¹

• Importance of exercising caution when driving or operating machinery in the event that visual changes, dizziness, or fatigue occurs.¹

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., hepatic or renal impairment, cardiovascular disease [including congenital long QT syndrome]).¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Crizotinib

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	200 mg	Xalkori	Pfizer
		250 mg	Xalkori	Pfizer