weakness [30:<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 Crizotinib 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 pH 1 Antiarrhythmic agents, class IA (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol) Possible additive effect on QT-interval prolongation 1 18 19 (see also Quinidine) Consider periodic monitoring of ECG and electrolytes 1 Anticonvulsants (carbamazepine, phenobarbital, phenytoin) Possible decreased crizotinib concentrations 1 Avoid concomitant use 1 Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole) Possible increased crizotinib concentrations 1 Ketoconazole (200 mg twice daily) increased peak concentrations and AUC of crizotinib (single 150-mg dose) by 1.4- and 3.2-fold, respectively 1 Avoid concomitant use 1 Antimycobacterials, rifamycins (e.g., rifabutin, rifampin) Possible decreased crizotinib concentrations 1 Rifampin (600 mg daily) decreased peak concentrations and AUC of crizotinib (single 250-mg dose) by 69 and 82%, respectively 1 Avoid concomitant use 1 Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, mesoridazine, pimozide, thioridazine) Possible additive effect on QT-interval prolongation 1 18 19 Consider periodic monitoring of ECG and electrolytes 1 Citalopram Possible additive effect on QT-interval prolongation 1 18 Consider periodic monitoring of ECG and electrolytes 1 Ergot derivatives (e.g., dihydroergotamine, ergotamine) Possible increased concentrations of ergot derivative 1 Avoid concomitant use 1 Grapefruit or grapefruit juice Possible increased crizotinib concentrations 1 Avoid concomitant use 1 Histamine H 2 -receptor antagonists Possible decreased crizotinib bioavailability secondary to decreased solubility at higher pH 1 HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir) Possible increased crizotinib concentrations 1 Avoid concomitant use 1 Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus) Possible increased concentrations of the immunosuppressive agent 1 Avoid concomitant use 1 Macrolides (e.g., clarithromycin, telithromycin) Possible increased crizotinib concentrations 1 Possible additive effect on QT-interval prolongation 1 19 Avoid concomitant use 1 Midazolam Crizotinib (250 mg twice daily) increased AUC of oral midazolam by 3.7-fold 1 Consider midazolam dosage reduction 1 Nefazodone Possible increased crizotinib concentrations 1 Avoid concomitant use 1 Opiate agonists (alfentanil, fentanyl) Possible increased concentrations of opiate agonist 1 Avoid concomitant use 1 Pimozide Possible increased pimozide concentrations 1 Possible additive effect on QT-interval prolongation 1 18 19 Avoid concomitant use 1 Proton-pump inhibitors Possible decreased crizotinib bioavailability secondary to decreased solubility at higher pH 1 Quinidine Possible increased quinidine concentrations 1 Possible additive effect on QT-interval prolongation 1 18 19 Avoid concomitant use 1 St. John's wort ( Hypericum perforatum ) Possible decreased crizotinib concentrations 1 Avoid concomitant use 1 Crizotinib 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 malignancies 2 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. 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 2017, Selected Revisions October 31, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. PfizerLabs. Xalkori (crizotinib) capsules prescribing information. New York, NY; 2012 Feb. 2. Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med . 2010; 363:1693-703. [PubMed 20979469] 3. Pearson R, Kolesar JM. Targeted therapy for NSCLC: ALK inhibition. J Oncol Pharm Pract . 2011; :[Epub ahead of print]. 4. Crinò L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol . 2011; 29 (American Society of Clinical Oncology Annual Meeting Abstracts):Abstr. No. 7514. 5. Li C, Alvey C, Bello A, et al. Pharmacokinetics (PK) of crizotinib (PF-02341066) in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors. J Clin Oncol . 2011; 29 (Suppl.):Abstr. No. e13065. 6. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res . 2011; 17:7213-8. [PubMed 22010214] 7. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK -positive non-small cell lung cancer (NSCLC). J Clin Oncol . 2011; 29 (Suppl.):Abstr. No. 2501. 8. Christensen JG, Zou HY, Arango ME et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther . 2007; 6:3314-22. [PubMed 18089725] 9. Tiseo M, Gelsomino F, Bartolotti M et al. Anaplastic lymphoma kinase as a new target for the treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther . 2011; 11:1677-87. [PubMed 22050016] 10. Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol . 2011; 3:113-25. [PubMed 21904575] 11. Garber K. ALK, lung cancer, and personalized therapy: portent of the future?. J Natl Cancer Inst . 2010; 102:672-5. [PubMed 20460631] 12. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and approvals. Rockville, MD. From FDA web site. 13. Pfizer Inc. New York, NY: Personal communication. 14. Pfizer Oncology. Crizotinib clinical trials - currently open and enrolling fact sheet. 2011 Sept. From Pfizer website. 15. Food and Drug Administration. FDA news release: FDA approves Xalkori with companion diagnostic test for a type of late-stage lung cancer. Rockville, MD; 2011 Aug 26. From FDA web site. 16. Husain H, Rudin CM. ALK-targeted therapy for lung cancer: ready for prime time. J Oncology . 2011; 25:1-6. 17. Pfizer Oncology. Xalkori (crizotinib) is available through specialty pharmacies. 2012 Mar. From Pfizer for Professionals website. 18. Forest Pharmaceuticals, Inc. Celexa (citalopram hydrobromide) tablets and oral solution prescribing information. St. Louis, MO; 2012 Mar. 19. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol . 2010; 70:16-23. [PubMed 20642543] Next Interactions Print this page Add to My Med List More about crizotinib Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 4 Reviews Add your own review/rating Drug class: multikinase inhibitors Consumer resources Crizotinib Crizotinib (Advanced Reading) Professional resources Crizotinib (Wolters Kluwer) Other brands: Xalkori Related treatment guides Non-Small Cell Lung Cancer ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only D Pregnancy Category Positive evidence of risk N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Multikinase inhibitors Related Drugs Non-Small Cell Lung Cancer Avastin , methotrexate , Taxol , Opdivo , cisplatin , Taxotere , Tarceva , Keytruda , paclitaxel , nivolumab , gemcitabine , Gemzar , Abraxane , docetaxel , Alimta , bevacizumab , pembrolizumab , pemetrexed , erlotinib , Trexall , Tecentriq , Tagrisso , Cyramza , atezolizumab , More... 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