Crizotinib

Pronunciation: kriz-OH-ti-nib
Class: Tyrosine kinase inhibitor

Trade Names

Xalkori
- Capsules, oral 200 mg
- Capsules, oral 250 mg

Pharmacology

Inhibits receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), c-Met, and recepteur d'origine nantais (RON).

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

T max is 4 to 6 h. Absolute bioavailability is 43% (range, 32% to 66%). A high-fat meal reduced AUC and C max by approximately 14%.

Distribution

Vd is 1,772 L. Plasma protein binding is 91%.

Metabolism

Predominantly metabolized by CYP3A4/5. Primary metabolic pathways are oxidation of the piperidine ring to crizotinib lactam and O-dealkylation with subsequent phase 2 conjugation of O-dealkylated metabolites.

Elimination

Terminal half-life is 42 h. Following a 250 mg dose, 63% (53% as unchanged drug) is recovered in feces and 22% (2.3% as unchanged drug) is recovered in urine. Cl at steady state is 60 L/h.

Special Populations

Renal Function Impairment

Steady-state trough concentrations were similar in patients with mild to moderate renal impairment (CrCl 30 to 90 mL/min) compared with patients with healthy renal function. Limited data are available in severe renal impairment and no data are available in ESRD.

Hepatic Function Impairment

Hepatic impairment is likely to increase crizotinib concentrations, but crizotinib has not been studied in patients with hepatic impairment.

Race

C max and AUC were 1.57- and 1.5-fold higher in Asian patients, respectively.

Indications and Usage

For the treatment of locally advanced or metastatic non–small cell lung cancer that is ALK-positive.

Contraindications

None well documented.

Dosage and Administration

Adults

PO 250 mg twice daily. Continue treatment as long as the patient is deriving clinical benefit from therapy.

Dose Modifications
Adults

PO If dose reduction is necessary, the dosage should be reduced to 200 mg twice daily. If further dose reduction is necessary, reduce the dosage to 250 mg once daily.

Hematologic toxicity

For grade 3 hematologic toxicity, withhold crizotinib until recovery to grade 2 or less, then resume at the same dose schedule. For grade 4 hematologic toxicity, withhold crizotinib until recovery to grade 2 or less, then resume at 200 mg twice daily; in case of recurrence, withhold until recovery to grade 2 or less, then resume at 250 mg once daily. Permanently discontinue in case of grade 4 recurrence.

Hepatic enzymes

For grade 3 or 4 ALT or AST elevations with grade 1 or less total bilirubin, withhold crizotinib until recovery to grade 1 or less or baseline, then resume at 200 mg twice daily; in case of recurrence, withhold until recovery to grade 1 or less, then resume at 250 mg once daily. Permanently discontinue in case of further grade 3 or 4 recurrence. For grade 2, 3, or 4 ALT or AST elevation with concurrent grade 2, 3, or 4 total bilirubin elevation (in the absence of cholestasis or hemolysis), permanently discontinue crizotinib.

Pneumonitis (any grade)

Permanently discontinue crizotinib.

QTc prolongation

For grade 3 QTc prolongation, withhold crizotinib until recovery to grade 1 or less, then resume at 200 mg twice daily; in case of recurrence, withhold until recovery to grade 1 or less, then resume at 250 mg once daily. Permanently discontinue in case of further grade 3 or 4 recurrence. For grade 4 QTc prolongation, permanently discontinue crizotinib.

General Advice

  • Capsules should be swallowed whole. May be taken with or without food.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

CYP3A moderate inhibitors (eg, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil)

Crizotinib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Coadminister moderate CYP3A inhibitors with caution.

CYP3A strong inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort)

Crizotinib plasma concentrations may be reduced, decreasing the efficacy. Avoid coadministration of strong CYP3A inducers.

CYP3A strong inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Crizotinib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration of strong CYP3A inhibitors.

CYP3A substrates (those with a narrow therapeutic index, including alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus)

Because crizotinib is a CYP3A inhibitor, plasma concentrations of CYP3A substrates may be elevated, increasing the pharmacologic effect and risk of adverse reactions. Dose reductions may be needed for coadministration with drugs that are predominantly metabolized by CYP3A. In addition, avoid coadministration of CYP3A substrates with a narrow therapeutic index.

Drugs that elevated gastric pH (eg, antacids, H 2 blockers [eg, cimetidine], proton pump inhibitors [eg, omeprazole])

Drugs that elevate gastric pH may decrease crizotinib solubility and reduce bioavailability. However, no formal studies have been conducted.

Drugs that prolong the QT interval (eg, antiarrhythmic agents [eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, quinidine, sotalol], arsenic trioxide, chlorpromazine, cisapride, dolasetron, droperidol, gatifloxacin, halofantrine, levomethadyl, mefloquine, mesoridazine, moxifloxacin, pentamidine, pimozide, probucol, sparfloxacin, thioridazine, ziprasidone)

The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Caution is advised when 2 drugs that are suspected to prolong the QT interval are given concurrently. If coadministration is not contraindicated in the respective product information, monitor patients for QT prolongation, especially when a new drug is added to a stable regimen of another QT-prolonging agent.

Adverse Reactions

Cardiovascular

Bradycardia (5%).

CNS

Fatigue (31%); dizziness (24%); neuropathy (23%); dysgeusia, headache (13%); insomnia (12%).

Dermatologic

Rash (16%).

EENT

Vision disorder, including diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual brightness, and reduced visual acuity (64%).

GI

Nausea (57%); diarrhea (49%); vomiting (45%); constipation (38%); esophageal disorder (20%); abdominal pain (16%); stomatitis (11%).

Genitourinary

Complex renal cysts (1%).

Hematologic

Grade 3 or 4 lymphopenia (11%); grade 3 or 4 neutropenia (5%).

Hepatic

ALT increased (15%); AST increased (11%).

Metabolic-Nutritional

Decreased appetite (27%).

Musculoskeletal

Arthralgia, back pain (11%).

Respiratory

Dyspnea (22%); cough (21%); upper respiratory tract infection (20%); pneumonitis (2%).

Miscellaneous

Edema (38%); chest pain/discomfort, fever (12%).

Precautions

Monitor

Monitor for pulmonary symptoms indicative of pneumonitis. LFTs, including ALT and total bilirubin, should be monitored once a month and as clinically indicated, with more frequent testing for patients who develop grade 2, 3, or 4 transaminase elevations. CBC, including differential WBC, should be monitored monthly and as clinically indicated, with more frequent testing if grade 3 or 4 abnormalities are observed or if fever or infection occur. Consider periodically monitoring the ECG and electrolytes in patients with CHF, bradyarrhythmias, or electrolyte abnormalities, or those who are taking medications known to prolong the QT interval. Consider ophthalmological evaluation if vision disorders occur, particularly in patients who experience photopsia or new or increased vitreous floaters.


Pregnancy

Category D . Women of childbearing potential or partners of women of childbearing potential receiving this drug should use adequate contraceptive measures during therapy and for at least 90 days after completing therapy.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Use with caution in patients with severe renal impairment or ESRD.

Hepatic Function

Use with caution.

ALK testing

Detection of ALK-positive non–small cell lung cancer using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with crizotinib.

Hepatic effects

Grade 3 or 4 elevation of ALT has been observed. These elevations were generally asymptomatic and reversible upon dosing interruption. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times ULN without elevated alkaline phosphatase have also been detected.

Pneumonitis

Has been associated with severe, life-threatening, or fatal treatment-related pneumonitis. All cases in clinical trials occurred within 2 mo after initiation of treatment.

QT prolongation

Has occurred. Avoid crizotinib in patients with congenital long QT syndrome.

Overdosage

Symptoms

No data available.

Patient Information

  • Inform patients that nausea, diarrhea, vomiting, and constipation were the most commonly reported GI adverse reactions; supportive care for these reactions requiring treatment may include standard antiemetic and/or antidiarrheal or laxative medications.
  • Inform patients that visual changes (eg, perceived flashes of light, blurry vision, light sensitivity, floaters) were commonly reported and usually began during the first 2 wk of therapy. Advise patients to report flashes or floaters to their health care provider.
  • Advise patients that caution should be exercised while driving or operating machinery if they experience vision disorder, dizziness, or fatigue.
  • Advise patients to inform their health care provider of all concomitant medications, including prescription medications, OTC drugs, vitamins, and herbal products.
  • Advise patients to take medication exactly as prescribed, and not to change their dose or stop therapy unless told to do so by their health care provider. Inform patients that medication may be taken with or without food and that capsules should be swallowed whole and not crushed, dissolved, or opened.
  • Advise patients to avoid grapefruit and grapefruit juice while taking crizotinib.
  • Advise patients that if they miss a dose, they should take it as soon as they remember unless it is less than 6 h until the next dose, in which case they should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.
  • Instruct patients of childbearing potential to use adequate contraceptive methods during therapy and for at least 90 days after completing therapy. Advise patients to inform their health care provider if they or their partners are pregnant or think they may be pregnant.
  • Advise patients not to breast-feed while taking crizotinib.

Copyright © 2009 Wolters Kluwer Health.

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