XALKORI (crizotinib) Is Avilble Through Specilty Phrmcies Specilty Phrmcy Ordering Process The Provider s Office Submits XALKORI prescriptions to the specilty phrmcy vi: Phone Fx Internet Submits ny supporting documenttion to the pyer The Specilty Phrmcy Verifies ptient coverge for XALKORI Helps with prior uthoriztion if required Cn refer ptients to Pfizer ptient ssistnce progrm Schedules shipment of product to the ptient s home Bills the pyer for cost of the product Bills the ptient for remining co-py/coinsurnce Not ctul size. Pfizer RxPthwys : Filling Need for Ptient Assistnce Pfizer RxPthwys b is ptient ssistnce progrm tht my help eligible ptients get ccess to the Pfizer medicines they need. This progrm will refer insured ptients to prticipting specilty phrmcies for reimbursement support services nd to obtin their medicines For uninsured ptients, the progrm my be ble to help get certin specilty medicines for free There re no membership fees b Formerly Pfizer Helpful Answers. Visit Pfizer RxPthwys Provider Portl t www.pfizerpap.com or cll 1-866-706-2400 Hve ptients go to www.pfizerrxpth.com or cll 1-866-706-2400 This is not helth insurnce. Terms nd conditions pply. Pfizer Inc, 235 Est 42nd Street, New York, NY 10017. Pfizer Co-Py One c : For Assistnce With Out-of-Pocket Costs Simple enrollment No finncii criteri No enrollment forms No fxing Co-py svings upon ctivtion Reduced out-of-pocket costs no more thn $10 per month c c Limits, terms nd conditions pply. The offer will be ccepted only t prticipting phrmcies. This offer is not helth insurnce. No membership fees pply. Plese see svings crd for complete terms nd conditions. For ny questions, plese cll 1-855-612-1951 or visit www.pfizercopyone.com/phrmcist. Pfizer Inc, 235 Est 42nd Street, New York, NY 10017. Pfizer Co-py One Svings Crd BIN: 610020 GROUP: 99992415 ID#: XXXXXXXXXXX EXPIRATION DATE: 12/31/2014 Limits, terms, nd conditions pply. This crd is not helth insurnce. CO-PAY SAVINGS No more thn $ 10 monthly out-of-pocket cost for the product below for eligible, commercilly insured ptients Plese visit xlkori.com to see full Prescribing Informtion nd Ptient Informtion. There is no membership fee. I gree to the terms nd conditions received with this crd. d d Not ctul size. XALKORI is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) whose tumors re nplstic lymphom kinse (ALK)-positive s detected by n FDA-pproved test. Plese see Importnt Sfety Informtion on pge 6 nd full Prescribing Informtion t the end of this document. For more informtion, plese visit www.xalkorihcp.com. 1
Dose Modifiction Dose-Reduction Guidelines Reduce dose s below if one or more dose reductions re necessry due to dverse rections of Grde 3 or 4 severity, s defined by Ntionl Cncer Institute Common Terminology Criteri for Adverse Events (CTCAE) version 4.0. Recommended Dily Dose One 250-mg cpsule BID XALKORI (crizotinib) my be tken with or without food. Swllow cpsules whole. If dose of XALKORI is missed, mke up tht dose unless the next dose is due within 6 hours. Dose Reduction if Necessry If necessry, reduce dose to Further reduction cn be mde to One 200-mg cpsule BID One 250-mg cpsule QD Permnently discontinue if unble to tolerte XALKORI 250 mg tken once dily. The recommended dose of XALKORI in ptients with severe renl impirment (cretinine clernce <30 ml/min) not requiring dilysis is 250 mg orlly once dily. XALKORI Dose Modifiction Hemtologic Toxicities CTCAE Grde XALKORI Dosing Grde 3 Grde 4 Withhold until recovery to Grde 2, then resume t the sme dose schedule Withhold until recovery to Grde 2, then resume t next lower dose Except lymphopeni (unless ssocited with clinicl events, eg, opportunistic infections). Monitor complete blood counts including differentil white blood cell counts monthly nd s cliniclly indicted, with more frequent repet testing if Grde 3 or 4 bnormlities re observed, or if fever or infection occurs Selected Sfety Informtion Heptotoxicity: Drug-induced heptotoxicity with ftl outcome occurred in 0.2% of ptients treted with XALKORI cross clinicl trils (n=1225). Trnsminse elevtions generlly occurred within the first 2 months of tretment. Monitor with liver function tests including ALT nd totl bilirubin every 2 weeks during the first 2 months of tretment, then once month nd s cliniclly indicted, with more frequent repet testing for incresed liver trnsminses, lkline phosphtse, or totl bilirubin in ptients who develop trnsminse elevtions. Permnently discontinue for ALT or AST elevtion >3 times ULN with concurrent totl bilirubin elevtion >1.5 times ULN (in the bsence of cholestsis or hemolysis); otherwise, temporrily suspend nd dose-reduce XALKORI s indicted. Interstitil Lung Disese (Pneumonitis): Severe, life-thretening, or ftl interstitil lung disese (ILD)/pneumonitis cn occur in ptients treted with XALKORI. Across clinicl trils (n=1225), 2.5% of XALKORI-treted ptients hd ny grde ILD, 0.9% hd Grde 3/4, nd 0.5% hd ftl cses. These cses generlly occurred within 2 months fter initition of tretment. Monitor for pulmonry symptoms indictive of ILD/pneumonitis. Exclude other potentil cuses nd permnently discontinue XALKORI in ptients with drug-relted ILD/pneumonitis. Plese see Importnt Sfety Informtion on pge 6 nd full Prescribing Informtion t the end of this document. 2
XALKORI (crizotinib) Dose Modifiction Non-Hemtologic Toxicities Heptotoxicity CTCAE Grde Criteri XALKORI Dosing Grde 3/4 sprtte minotrnsferse (AST) or lnine minotrnsferse (ALT) elevtion With Grde 1 bilirubin elevtion AST or ALT elevtion >5 times upper limit of norml (ULN) With totl bilirubin 1.5 times ULN Withhold until recovery to bseline or 3 times ULN, then resume t reduced dose Grde 2, 3, or 4 AST or ALT elevtion With Grde 2, 3, or 4 bilirubin elevtion AST or ALT elevtion >3 times ULN With concurrent totl bilirubin elevtion >1.5 times ULN (in the bsence of cholestsis or hemolysis) Permnently discontinue ILD/Pneumonitis CTCAE Grde Criteri XALKORI Dosing Any grde Drug-relted Permnently discontinue QTc Prolongtion CTCAE Grde Criteri XALKORI Dosing Grde 3 QTc >500 ms on t lest 2 seprte electrocrdiogrms Withhold until recovery to bseline or to QTc <481 ms, then resume t reduced dose Grde 4 QTc >500 ms or 60 ms chnge from bseline with Torsde de pointes or polymorphic ventriculr tchycrdi or signs/symptoms of serious rrhythmi Permnently discontinue XALKORI is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) whose tumors re nplstic lymphom kinse (ALK)-positive s detected by n FDA-pproved test. Plese see Importnt Sfety Informtion on pge 6 nd full Prescribing Informtion t the end of this document. 3
XALKORI (crizotinib) Dose Modifiction Non-Hemtologic Toxicities (continued) Brdycrdi CTCAE Grde Criteri Concomitnt Mediction b XALKORI Dosing Grde 2/3 Symptomtic, my be severe nd mediclly significnt, medicl intervention indicted No contributing concomitnt mediction is identified, or contributing concomitnt medictions re not discontinued or dose modified Contributing concomitnt mediction is identified nd discontinued, or its dose is djusted Withhold until recovery to symptomtic brdycrdi or to hert rte of 60 bpm Resume t reduced dose upon recovery to symptomtic brdycrdi or to hert rte of 60 bpm Withhold until recovery to symptomtic brdycrdi or to hert rte of 60 bpm Resume t previous dose upon recovery to symptomtic brdycrdi or to hert rte of 60 bpm Grde 4 Life-thretening consequences, urgent intervention indicted No contributing concomitnt mediction is identified, or contributing concomitnt medictions re not discontinued or dose modified Contributing concomitnt mediction is identified nd discontinued, or its dose is djusted Permnently discontinue Resume t 250 mg once dily upon recovery to symptomtic brdycrdi or to hert rte of 60 bpm, with frequent monitoring Permnently discontinue for recurrence Hert rte <60 bets per minute (bpm); b Evlute concomitnt medictions known to cuse brdycrdi, s well s ntihypertensive medictions. Selected Sfety Informtion QT Intervl Prolongtion: QTc prolongtion cn occur in ptients treted with XALKORI. Across clinicl trils (n=1225), QTc prolongtion (ll grdes) ws observed in 2.7% of ptients nd QTc >500 ms on t lest 2 seprte electrocrdiogrms (ECGs) occurred in 1.4% of ptients. Avoid use of XALKORI in ptients with congenitl long QT syndrome. Consider periodic monitoring with ECGs nd electrolytes in ptients with congestive hert filure, brdyrrhythmis, electrolyte bnormlities, or who re tking medictions tht prolong the QT intervl. Permnently discontinue XALKORI in ptients who develop QTc >500 ms or 60 ms chnge from bseline with Torsde de pointes, polymorphic ventriculr tchycrdi, or signs/symptoms of serious rrhythmi. Withhold XALKORI in ptients who develop QTc >500 ms on t lest 2 seprte ECGs until recovery to QTc 480 ms, then resume t reduced dose. Plese see Importnt Sfety Informtion on pge 6 nd full Prescribing Informtion t the end of this document. For more informtion, plese visit www.xalkorihcp.com. 4
Recommended Dosing The recommended dose of XALKORI (crizotinib) is 250 mg tken orlly twice dily, with or without food Tretment should be continued until disese progression or no longer tolerted by the ptient Cpsules should be swllowed whole If dose is missed then it should be tken s soon s the ptient remembers, unless it is less thn 6 hours to the next dose, in which cse the ptient should not tke the missed dose Ptients should not tke 2 doses t the sme time to mke up for missed dose If vomiting occurs fter tking dose of XALKORI, tke the next dose t the regulr time RECOMMENDED DOSE is one 250-mg cpsule tken twice dily. Dosing interruption nd/or dose reduction my be required bsed on dverse drug rections. XALKORI is metbolized predominntly by the CYP3A pthwy nd inhibits CYP3A both in vivo nd in vitro Concomitnt use of strong CYP3A inducers or inhibitors cn decrese or increse blood plsm levels of XALKORI, respectively Avoid concomitnt use of strong CYP3A inducers, inhibitors, nd other CYP3A substrtes with nrrow therpeutic rnge Exercise cution with concomitnt use of moderte CYP3A inhibitors Avoid grpefruit or grpefruit juice, which my increse plsm concentrtions of XALKORI Not ctul size. XALKORI is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) whose tumors re nplstic lymphom kinse (ALK)-positive s detected by n FDA-pproved test. Plese see Importnt Sfety Informtion on pge 6 nd full Prescribing Informtion t the end of this document. For more informtion, plese visit www.xalkorihcp.com. 5
XALKORI (crizotinib) is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) whose tumors re nplstic lymphom kinse (ALK)-positive s detected by n FDA-pproved test. IMPORTANT SAFETY INFORMATION Heptotoxicity: Drug-induced heptotoxicity with ftl outcome occurred in 0.2% of ptients treted with XALKORI cross clinicl trils (n=1225). Trnsminse elevtions generlly occurred within the first 2 months of tretment. Monitor with liver function tests including ALT nd totl bilirubin every 2 weeks during the first 2 months of tretment, then once month nd s cliniclly indicted, with more frequent repet testing for incresed liver trnsminses, lkline phosphtse, or totl bilirubin in ptients who develop trnsminse elevtions. Permnently discontinue for ALT or AST elevtion >3 times ULN with concurrent totl bilirubin elevtion >1.5 times ULN (in the bsence of cholestsis or hemolysis); otherwise, temporrily suspend nd dose-reduce XALKORI s indicted. Interstitil Lung Disese (Pneumonitis): Severe, life-thretening, or ftl interstitil lung disese (ILD)/pneumonitis cn occur in ptients treted with XALKORI. Across clinicl trils (n=1225), 2.5% of XALKORI-treted ptients hd ny grde ILD, 0.9% hd Grde 3/4, nd 0.5% hd ftl cses. These cses generlly occurred within 2 months fter initition of tretment. Monitor for pulmonry symptoms indictive of ILD/pneumonitis. Exclude other potentil cuses nd permnently discontinue XALKORI in ptients with drug-relted ILD/pneumonitis. QT Intervl Prolongtion: QTc prolongtion cn occur in ptients treted with XALKORI. Across clinicl trils (n=1225), QTc prolongtion (ll grdes) ws observed in 2.7% of ptients nd QTc >500 ms on t lest 2 seprte electrocrdiogrms (ECGs) occurred in 1.4% of ptients. Avoid use of XALKORI in ptients with congenitl long QT syndrome. Consider periodic monitoring with ECGs nd electrolytes in ptients with congestive hert filure, brdyrrhythmis, electrolyte bnormlities, or who re tking medictions tht prolong the QT intervl. Permnently discontinue XALKORI in ptients who develop QTc >500 ms or 60 ms chnge from bseline with Torsde de pointes, polymorphic ventriculr tchycrdi, or signs/symptoms of serious rrhythmi. Withhold XALKORI in ptients who develop QTc >500 ms on t lest 2 seprte ECGs until recovery to QTc 480 ms, then resume t reduced dose. Brdycrdi: Symptomtic brdycrdi cn occur in ptients receiving XALKORI. Across clinicl trils, brdycrdi with hert rte <50 bets per minute (bpm) occurred in 11% of ptients treted with XALKORI (n=1174). Avoid using XALKORI in combintion with other gents known to cuse brdycrdi to the extent possible. Monitor hert rte nd blood pressure regulrly. In cses of symptomtic brdycrdi tht is not life-thretening, hold XALKORI until recovery to symptomtic brdycrdi or to hert rte of 60 bpm, re-evlute the use of concomitnt medictions, nd djust the dose of XALKORI. Permnently discontinue for life-thretening brdycrdi due to XALKORI; however, if ssocited with concomitnt medictions known to cuse brdycrdi or hypotension, hold XALKORI until recovery to symptomtic brdycrdi or to hert rte of 60 bpm. If concomitnt medictions cn be djusted or discontinued, restrt XALKORI t 250 mg once dily with frequent monitoring. Otherwise, temporrily suspend nd resume or dose-reduce XALKORI s indicted. Embryofetl Toxicity: XALKORI cn cuse fetl hrm when dministered to pregnnt womn. Women of childbering potentil should be dvised to void pregnncy while receiving XALKORI. If the ptient or ptient s prtner becomes pregnnt while tking this drug, pprise the ptient of potentil hzrd to the fetus. Adverse Rections: Sfety ws evluted in phse 3 study in ptients with ALK-positive metsttic NSCLC rndomized to XALKORI (n=172) or chemotherpy (n=171). Serious dverse rections were reported in 37.2% ptients treted with XALKORI nd 23.4% in the chemotherpy rm. The most frequent serious dverse rections reported in ptients treted with XALKORI were pneumoni (4.1%), pulmonry embolism (3.5%), dyspne (2.3%), nd ILD (2.9%). Ftl dverse rections in XALKORI-treted ptients occurred in 9 (5%) ptients, consisting of cute respirtory distress syndrome, rrhythmi, dyspne, ILD, pneumoni, pneumonitis, pulmonry embolism, respirtory filure, nd sepsis. Common dverse rections (ll grdes) occurring in 25% nd more commonly ( 5%) in ptients treted with XALKORI vs chemotherpy were vision disorder (60% vs 9%), dirrhe (60% vs 19%), nuse (55% vs 37%), vomiting (47% vs 18%), constiption (42% vs 23%), edem (31% vs 16%), upper respirtory infection (26% vs 13%), nd dysgeusi (26% vs 9%). Grde 3/4 events occurring t higher incidence with XALKORI vs chemotherpy nd t >2% incidence were syncope (3% vs 0%), QT prolongtion (3% vs 0%), nd pulmonry embolism (5% vs 2%). In ptients treted with XALKORI vs chemotherpy, the following occurred: elevtion of ALT (ny grde [76% vs 38%] or Grde 3/4 [17% vs 4%]); elevtion of AST (ny grde [61% vs 33%] or Grde 3/4 [9% vs 0%]); neutropeni (ny grde [49% vs 28%] or Grde 3/4 [12% vs 12%]); lymphopeni (ny grde [51% vs 60%] or Grde 3/4 [9% vs 25%]). In ptients treted with XALKORI vs chemotherpy, renl cysts occurred (4% vs 1%). Decresed ppetite (27%), ftigue (27%), nd neuropthy (19%) lso occurred in ptients tking XALKORI. Drug Interctions: Exercise cution with concomitnt use of moderte CYP3A inhibitors. Avoid grpefruit or grpefruit juice which my increse plsm concentrtions of crizotinib. Avoid concomitnt use of strong CYP3A inducers nd inhibitors. Avoid concomitnt use of CYP3A substrtes with nrrow therpeutic rnge in ptients tking XALKORI. If concomitnt use of CYP3A substrtes with nrrow therpeutic rnge is required in ptients tking XALKORI, dose reductions of the CYP3A substrtes my be required due to dverse rections. Nursing Mothers: Given the potentil for serious dverse rections in nursing infnts, consider whether to discontinue nursing or discontinue XALKORI. Heptic Impirment: XALKORI hs not been studied in ptients with heptic impirment. As crizotinib is extensively metbolized in the liver, heptic impirment is likely to increse plsm crizotinib concentrtions. Use cution in ptients with heptic impirment. Renl Impirment: Administer XALKORI t strting dose of 250 mg tken orlly once dily in ptients with severe renl impirment (CLcr<30 ml/min) not requiring dilysis. No strting dose djustment is needed for ptients with mild nd moderte renl impirment. Plese see full Prescribing Informtion t the end of this document. For more informtion, plese visit www.xalkorihcp.com. CRI669305 2014 Pfizer Inc. All rights reserved. Printed in USA/July 2014 6
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use XALKORI sfely nd effectively. See full prescribing informtion for XALKORI. XALKORI (crizotinib) Cpsules, orl Initil U.S. Approvl: 2011 ----------------------------------------RECENT MAJOR CHANGES-------------------------------------------- Indictions nd Usge (1) 11/2013 Dosge nd Administrtion, Ptient Selection (2.1) 11/2013 Dosge nd Administrtion, Recommended Dosing (2.2) 11/2013 Dosge nd Administrtion, Dose Modifiction (2.3) 11/2013 Wrnings nd Precutions (5.1, 5.2, 5.3, 5.4) 11/2013 -------------------------------------------INDICATIONS AND USAGE------------------------------------------ XALKORI is kinse inhibitor indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) whose tumors re nplstic lymphom kinse (ALK)-positive s detected by n FDA-pproved test. (1) ----------------------------------------DOSAGE AND ADMINISTRATION-------------------------------------- Recommended dose: 250 mg orlly, twice dily (2.2) Renl Impirment: 250 mg orlly, once dily in ptients with severe renl impirment (cretinine clernce <30 ml/min) not requiring dilysis. (2.2) Dosing interruption nd/or dose reductions my be required bsed on dverse drug rections (2.3) -------------------------------------DOSAGE FORMS AND STRENGTHS------------------------------------- Cpsules: 250 mg nd 200 mg (3) ---------------------------------------------CONTRAINDICATIONS--------------------------------------------- None (4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Ptient Selection 2.2 Recommended Dosing 2.3 Dose Modifiction 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Heptotoxicity 5.2 Interstitil Lung Disese (Pneumonitis) 5.3 QT Intervl Prolongtion 5.4 Brdycrdi 5.5 Embryofetl Toxicity 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 7 DRUG INTERACTIONS 7.1 Drugs Tht My Increse Crizotinib Plsm Concentrtions 7.2 Drugs Tht My Decrese Crizotinib Plsm Concentrtions 7.3 Drugs Whose Plsm Concentrtions My Be Altered By Crizotinib FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE XALKORI is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) whose tumors re nplstic lymphom kinse (ALK)-positive s detected by n FDA-pproved test. 2 DOSAGE AND ADMINISTRATION 2.1 Ptient Selection Select ptients for the tretment of metsttic NSCLC with XALKORI bsed on the presence of ALK positivity in tumor specimens [see Indictions nd Usge (1) nd Clinicl Studies (14)]. Informtion on FDA-pproved tests for the detection of ALK rerrngements in NSCLC is vilble t http://www.fd.gov/medicldevices/productsndmediclprocedures/invitrodignostics/ucm301431.htm. 2.2 Recommended Dosing The recommended dose of XALKORI is 250 mg orlly, twice dily until disese progression or no longer tolerted by the ptient. The recommended dose of XALKORI in ptients with severe renl impirment (cretinine clernce <30 ml/min) not requiring dilysis is 250 mg orlly, once dily [see Use in Specific Popultions (8.7) nd Clinicl Phrmcology (12.3)]. XALKORI my be tken with or without food. Swllow cpsules whole. If dose of XALKORI is missed, mke up tht dose unless the next dose is due within 6 hours. If vomiting occurs fter tking dose of XALKORI, tke the next dose t the regulr time. 2.3 Dose Modifiction Reduce dose s below, if one or more dose reductions re necessry due to dverse rections of Grde 3 or 4 severity, s defined by NCI Common Terminology Criteri for Adverse Events (CTCAE) version 4.0: First dose reduction: XALKORI 200 mg tken orlly twice dily Second dose reduction: XALKORI 250 mg tken orlly once dily Permnently discontinue if unble to tolerte XALKORI 250 mg tken once dily Dose reduction guidelines re provided in Tbles 1 nd 2. Tble 1. XALKORI Dose Modifiction Hemtologic Toxicities CTCAE Grde XALKORI Dosing Grde 3 Withhold until recovery to Grde 2 or less, then resume t the sme dose schedule Grde 4 Withhold until recovery to Grde 2 or less, then resume t next lower dose Except lymphopeni (unless ssocited with clinicl events, e.g., opportunistic infections). ---------------------------------------WARNINGS AND PRECAUTIONS--------------------------------------- Heptotoxicity: Ftl heptotoxicity occurred in 0.2% of ptients. Monitor with periodic liver testing. Temporrily suspend, dose reduce, or permnently discontinue XALKORI. (5.1) Interstitil Lung Disese (ILD)/Pneumonitis: Occurred in 2% of ptients. Permnently discontinue in ptients with ILD/pneumonitis. (5.2) QT Intervl Prolongtion: Occurred in 2.7% of ptients. Monitor with electrocrdiogrms nd electrolytes in ptients who hve history of or predisposition for QTc prolongtion, or who re tking medictions tht prolong QT. Temporrily suspend, dose reduce, or permnently discontinue XALKORI (5.3) Brdycrdi: XALKORI cn cuse brdycrdi. Monitor hert rte nd blood pressure regulrly. Temporrily suspend, dose reduce, or permnently discontinue XALKORI. (5.4) Embryofetl Toxicity: XALKORI cn cuse fetl hrm when dministered to pregnnt womn. (5.5, 8.1) ---------------------------------------------ADVERSE REACTIONS--------------------------------------------- The most common dverse rections ( 25%) re vision disorders, nuse, dirrhe, vomiting, constiption, edem, elevted trnsminses, nd ftigue. (6) To report SUSPECTED ADVERSE REACTIONS, contct Pfizer Inc. t 1-800-438-1985 or FDA t 1-800-FDA-1088 or www.fd.gov/medwtch. ---------------------------------------------DRUG INTERACTIONS--------------------------------------------- CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong CYP3A inhibitors. (7.1) CYP3A Inducers: Avoid concurrent use of XALKORI with strong CYP3A inducers. (7.2) CYP3A Substrtes: Avoid concurrent use of XALKORI with CYP3A substrtes with nrrow therpeutic indices. (7.3) See 17 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient lbeling. Revised: 05/2014 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Heptic Impirment 8.7 Renl Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the Full Prescribing Informtion re not listed. Tble 2. XALKORI Dose Modifiction Non-Hemtologic Toxicities Criteri XALKORI Dosing Alnine minotrnsferse (ALT) or sprtte Withhold until recovery to bseline or minotrnsferse (AST) elevtion greter thn less thn or equl to 3 times ULN, 5 times upper limit of norml (ULN) with totl then resume t reduced dose bilirubin less thn or equl to 1.5 times ULN ALT or AST elevtion greter thn 3 times ULN with Permnently discontinue concurrent totl bilirubin elevtion greter thn 1.5 times ULN (in the bsence of cholestsis or hemolysis) Any Grde drug-relted interstitil lung Permnently discontinue disese/pneumonitis QTc greter thn 500 ms on t lest 2 seprte ECGs Withhold until recovery to bseline or to QTc less thn 481 ms, then resume t reduced dose QTc greter thn 500 ms or greter thn or equl to Permnently discontinue 60 ms chnge from bseline with Torsde de pointes or polymorphic ventriculr tchycrdi or signs/symptoms of serious rrhythmi Brdycrdi (symptomtic, my be severe nd Withhold until recovery to symptomtic mediclly significnt, medicl intervention indicted) brdycrdi or to hert rte of 60 bpm or bove Evlute concomitnt medictions known to cuse brdycrdi, s well s nti-hypertensive medictions If contributing concomitnt mediction is identified nd discontinued, or its dose is djusted, resume t previous dose upon recovery to symptomtic brdycrdi or to hert rte of 60 bpm or bove If no contributing concomitnt mediction is identified, or if contributing concomitnt medictions re not discontinued or dose modified, resume t reduced dose upon recovery to symptomtic brdycrdi or to hert rte of 60 bpm or bove
Tble 2. XALKORI Dose Modifiction Non-Hemtologic Toxicities (cont d) Criteri Brdycrdi,b (life-thretening consequences, urgent intervention indicted) XALKORI Dosing Permnently discontinue if no contributing concomitnt mediction is identified If contributing concomitnt mediction is identified nd discontinued, or its dose is djusted, resume t 250 mg once dily upon recovery to symptomtic brdycrdi or to hert rte of 60 bpm or bove, with frequent monitoring Hert rte less thn 60 bets per minute (bpm). b Permnently discontinue for recurrence. Monitor complete blood counts including differentil white blood cell counts monthly nd s cliniclly indicted, with more frequent repet testing if Grde 3 or 4 bnormlities re observed, or if fever or infection occurs. 3 DOSAGE FORMS AND STRENGTHS 250 mg cpsules Hrd geltin cpsule, size 0, pink opque cp nd body, with Pfizer on the cp nd CRZ 250 on the body. 200 mg cpsules Hrd geltin cpsule, size 1, white opque body nd pink opque cp, with Pfizer on the cp nd CRZ 200 on the body. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Heptotoxicity Drug-induced heptotoxicity with ftl outcome occurred in 2 (0.2%) of the 1225 ptients treted with XALKORI cross three min clinicl trils. Concurrent elevtions in lnine minotrnsferse (ALT) greter thn three times the upper limit of norml nd totl bilirubin greter thn two times the upper limit of norml, with norml lkline phosphtse, occurred in 7 ptients (0.6%). Additionlly, elevtions in ALT greter thn five times the upper limit of norml occurred in 109 ptients (9.2%). Eight ptients (0.7%) required permnent discontinution due to elevted trnsminses. These lbortory findings were generlly reversible upon dosing interruption. Trnsminse elevtions generlly occurred within the first 2 months of tretment. Monitor with liver function tests including ALT nd totl bilirubin every 2 weeks during the first 2 months of tretment, then once month nd s cliniclly indicted, with more frequent repet testing for incresed liver trnsminses, lkline phosphtse, or totl bilirubin in ptients who develop trnsminse elevtions. Temporrily suspend, dose reduce, or permnently discontinue XALKORI s described in Tble 2 [see Dosge nd Administrtion (2.3) nd Adverse Rections (6)]. 5.2 Interstitil Lung Disese (Pneumonitis) Severe, life-thretening, or ftl interstitil lung disese (ILD)/pneumonitis cn occur in ptients treted with XALKORI. Across clinicl trils (n=1225), 31 XALKORI-treted ptients (2.5%) hd ny grde ILD, 11 ptients (0.9%) hd Grde 3 or 4, nd 6 ptients (0.5%) hd ftl cses. These cses generlly occurred within 2 months fter the initition of tretment. Monitor ptients for pulmonry symptoms indictive of ILD/pneumonitis. Exclude other potentil cuses of ILD/pneumonitis, nd permnently discontinue XALKORI in ptients dignosed with drugrelted ILD/pneumonitis [see Dosge nd Administrtion (2.3) nd Adverse Rections (6)]. 5.3 QT Intervl Prolongtion QTc prolongtion cn occur in ptients treted with XALKORI. Across clinicl trils (n=1225), QTc prolongtion (ll grdes) ws observed in 34 (2.7%) ptients nd QTc greter thn 500 ms on t lest 2 seprte ECGs occurred in 17 (1.4%) ptients. Avoid use of XALKORI in ptients with congenitl long QT syndrome. Consider periodic monitoring with electrocrdiogrms (ECGs) nd electrolytes in ptients with congestive hert filure, brdyrrhythmis, electrolyte bnormlities, or who re tking medictions tht re known to prolong the QT intervl. Permnently discontinue XALKORI in ptients who develop QTc greter thn 500 ms or greter thn or equl to 60 ms chnge from bseline with Torsde de pointes or polymorphic ventriculr tchycrdi or signs/symptoms of serious rrhythmi. Withhold XALKORI in ptients who develop QTc greter thn 500 ms on t lest 2 seprte ECGs until recovery to QTc less thn or equl to 480 ms, then resume XALKORI t reduced dose s described in Tble 2 [see Dosge nd Administrtion (2.3) nd Clinicl Phrmcology (12.2)]. 5.4 Brdycrdi Symptomtic brdycrdi cn occur in ptients receiving XALKORI. Across clinicl trils, brdy crdi with hert rte less thn 50 bets per minute occurred in 11% of 1174 ptients treted with XALKORI. In Study 1, Grde 3 syncope occurred in 2.9% of XALKORI-treted ptients nd in none of the chemotherpy-treted ptients. Avoid using XALKORI in combintion with other gents known to cuse brdycrdi (e.g., bet-blockers, non-dihydropyridine clcium chnnel blockers, clonidine nd digoxin) to the extent possible. Monitor hert rte nd blood pressure regulrly. In cses of symptomtic brdycrdi tht is not life-thretening, hold XALKORI until recovery to symptomtic brdycrdi or to hert rte of 60 bpm or bove, re-evlute the use of concomitnt medictions, nd djust the dose of XALKORI. Permnently discontinue for life-thretening brdycrdi due to XALKORI; however, if ssocited with concomitnt medictions known to cuse brdycrdi or hypotension, hold XALKORI until recovery to symptomtic brdycrdi or to hert rte of 60 bpm or bove, nd if concomitnt medictions cn be djusted or discontinued, restrt XALKORI t 250 mg once dily with frequent monitoring [see Dosge nd Administrtion (2.3) nd Adverse Rections (6)]. 5.5 Embryofetl Toxicity XALKORI cn cuse fetl hrm when dministered to pregnnt womn bsed on its mechnism of ction. In nonclinicl studies in rts, crizotinib ws embryotoxic nd fetotoxic t exposures similr to those observed in humns t the recommended clinicl dose of 250 mg twice dily. There re no dequte nd well-controlled studies in pregnnt women using XALKORI. If this drug is used during pregnncy, or if the ptient becomes pregnnt while tking this drug, pprise the ptient of the potentil hzrd to fetus [see Use in Specific Popultions (8.1)]. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lbeling: Heptotoxicity [see Wrnings nd Precutions (5.1)] Interstitil Lung Disese/Pneumonitis [see Wrnings nd Precutions (5.2)] QT Intervl Prolongtion [see Wrnings nd Precutions (5.3)] Brdycrdi [see Wrnings nd Precutions (5.4)] 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in clinicl prctice. Sfety evlution of XALKORI is bsed on more thn 1200 ptients with ALK-positive metsttic NSCLC who received XALKORI s monotherpy t strting orl dose of 250 mg twice dily continuously. The most common dverse rections ( 25%) of XALKORI re vision disorder, nuse, dirrhe, vomiting, constiption, edem, elevted trnsminses, nd ftigue. ALK-positive metsttic NSCLC-Study 1 The dt in Tble 3 re derived from 343 ptients with ALK-positive metsttic NSCLC enrolled in rndomized, multicenter, ctive-controlled, open-lbel tril (Study 1). Ptients in the XALKORI rm (n=172) received XALKORI 250 mg orlly twice dily until documented disese progression, intolernce to therpy, or the investigtor determined tht the ptient ws no longer experiencing clinicl benefit. A totl of 171 ptients in the chemotherpy rm received pemetrexed 500 mg/m 2 (n=99) or docetxel 75 mg/m 2 (n=72) by intrvenous infusion every three weeks until documented disese progression, intolernce to therpy, or the investigtor determined tht the ptient ws no longer experiencing clinicl benefit. Ptients in the chemotherpy rm received pemetrexed unless they hd received pemetrexed s prt of first-line or mintennce tretment. The medin durtion of study tretment ws 7.1 months for ptients who received XALKORI nd 2.8 months for ptients who received chemotherpy. Across the 347 ptients who were rndomized to study tretment (343 received t lest one dose of study tretment), the medin ge ws 50 yers; 84% of ptients in the XALKORI rm nd 87% of ptients in the chemotherpy rm were younger thn 65 yers. A totl of 57% of ptients on XALKORI nd 55% of chemotherpy ptients were femle. Forty-six percent (46%) of XALKORI-treted nd 45% of chemotherpy-treted ptients were from Asi. Serious dverse rections were reported in 64 ptients (37.2%) treted with XALKORI nd 40 ptients (23.4%) in the chemotherpy rm. The most frequent serious dverse rections reported in ptients treted with XALKORI were pneumoni (4.1%), pulmonry embolism (3.5%), dyspne (2.3%), nd interstitil lung disese (ILD; 2.9%). Ftl dverse rections in XALKORI-treted ptients in Study 1 occurred in 9 (5%) ptients, consisting of: cute respirtory distress syndrome, rrhythmi, dyspne, pneumoni, pneumonitis, pulmonry embolism, ILD, respirtory filure, nd sepsis. Dose reductions due to dverse rections were required in 16% of XALKORI-treted ptients. The most frequent dverse rections tht led to dose reduction in the ptients treted with XALKORI were lnine minotrnsferse (ALT) elevtion (7.6%) including some ptients with concurrent sprtte minotrnsferse (AST) elevtion, QTc prolongtion (2.9%), nd neutropeni (2.3%). Discontinution of therpy in XALKORI-treted ptients for dverse rections ws 17.0%. The most frequent dverse rections tht led to discontinution in XALKORI-treted ptients were ILD (1.7%), ALT nd AST elevtion (1.2%), dyspne (1.2%), nd pulmonry embolism (1.2%). Tbles 3 nd 4 summrize common Adverse Rections nd Lbortory Abnormlities in XALKORI-treted ptients. Tble 3. Adverse Rections Reported t Higher Incidence ( 5% Higher for All Grdes or 2% Higher for Grdes 3/4) with XALKORI thn Chemotherpy in Study 1 XALKORI Chemotherpy Adverse Rection (N=172) (Pemetrexed or Docetxel) (N=171) All Grdes Grde 3/4 All Grdes Grde 3/4 (%) (%) (%) (%) Nervous System Disorder Dizziness 22 1 8 0 Dysgeusi 26 0 9 0 Syncope 3 3 0 0 Eye Disorders Vision disorder b 60 0 9 0 Crdic Disorders Electrocrdiogrm QT prolonged 5 3 0 0 Brdycrdi c 5 0 0 0 Investigtions Weight decresed 10 1 4 0 Gstrointestinl Disorders Vomiting 47 1 18 0 Nuse 55 1 37 1 Dirrhe 60 0 19 1 Constiption 42 2 23 0 Dyspepsi 8 0 3 0 Infections nd Infesttions Upper respirtory infection d 26 0 13 1 Respirtory, Thorcic nd Medistinl Disorders Pulmonry embolism e 6 5 2 2 Generl Disorders nd Administrtion Site Conditions Edem f 31 0 16 0 Includes cses reported within the clustered terms: Dizziness (Blnce disorder, Dizziness, Dizziness posturl) b Vision Disorder (Diplopi, Photophobi, Photopsi, Vision blurred, Visul cuity reduced, Visul impirment, Vitreous floters) c Brdycrdi (Brdycrdi, Sinus brdycrdi) d Upper respirtory infection (Lryngitis, Nsophryngitis, Phryngitis, Rhinitis, Upper respirtory trct infection) e Pulmonry embolism (Pulmonry rtery thrombosis, Pulmonry embolism) f Edem (Fce edem, Generlized edem, Locl swelling, Loclized edem, Edem, Edem peripherl, Periorbitl edem)
Additionl dverse rections occurring t n overll incidence between 1% nd 30% in ptients treted with XALKORI included decresed ppetite (27%), ftigue (27%), neuropthy (19%; dysesthesi, git disturbnce, hypoesthesi, musculr wekness, neurlgi, peripherl neuropthy, prsthesi, peripherl sensory neuropthy, polyneuropthy, burning senstion in skin), rsh (9%), ILD (4%; cute respirtory distress syndrome, ILD, pneumonitis), renl cyst (4%), nd heptic filure (1%). Tble 4. Summry of Tretment-Emergent Lbortory Abnormlities with Grde 3 or 4 Incidence of 4% in XALKORI-Treted Ptients Lbortory Abnormlity Crizotinib Chemotherpy Any Grde Grde 3/4 Any Grde Grde 3/4 Hemtology Neutropeni 49% 12% 28% 12% Lymphopeni 51% 9% 60% 25% Chemistry ALT elevtion 76% 17% 38% 4% AST elevtion 61% 9% 33% 0% Hypoklemi 18% 4% 10% 1% Hypophosphtemi 28% 5% 25% 6% ALK-positive metsttic NSCLC- Study 2 The sfety nlysis popultion in Study 2 included 934 ptients with ALK-positive metsttic NSCLC who received XALKORI in clinicl tril. The medin durtion of tretment ws 23 weeks. Dosing interruptions nd reductions due to tretment-relted dverse events occurred in 23% nd 12% of ptients, respectively. The rte of tretment-relted dverse events resulting in permnent discontinution ws 5%. The most common dverse rections ( 25%) included vision disorder (55%), nuse (51%), vomiting (46%), dirrhe (46%), edem (39%), constiption (38%), nd ftigue (26%). Description of selected dverse drug rections Vision disorders Vision disorders, most commonly visul impirment, photopsi, blurred vision, or vitreous floters, occurred in 691 (56%) ptients cross clinicl trils (n=1225). The mjority (99%) of these ptients hd Grde 1 or 2 visul dverse rections. Across clinicl studies, one ptient hd tretment-relted grde 3 vision bnormlity. Bsed on the Visul Symptom Assessment Questionnire (VSAQ-ALK), ptients treted with XALKORI in Study 1 reported higher incidence of visul disturbnces compred to ptients treted with chemotherpy. The onset of vision disorders generlly strted within the first week of drug dministrtion. The mjority of ptients on the XALKORI rm in Study 1 (> 50%) reported visul disturbnces; these visul disturbnces occurred t frequency of 4-7 dys ech week, lsted up to 1 minute, nd hd mild or no impct (scores 0 to 3 out of mximum score of 10) on dily ctivities s cptured in ptient questionnire. Neuropthy Neuropthy, most commonly sensory in nture, occurred in 235 (19%) of 1225 ptients. Most events (95%) were Grde 1 or Grde 2 in severity. Renl Cysts Renl cysts occurred in 7 (4%) ptients treted with XALKORI nd 1 (1%) ptient treted with chemotherpy in Study 1. The mjority of renl cysts in XALKORI-treted ptients were complex. Locl cystic invsion beyond the kidney occurred, in some cses with imging chrcteristics suggestive of bscess formtion. However, cross clinicl trils no renl bscesses were confirmed by microbiology tests. 7 DRUG INTERACTIONS 7.1 Drugs Tht My Increse Crizotinib Plsm Concentrtions Codministrtion of crizotinib with strong CYP3A inhibitors increses crizotinib plsm concentrtions [see Clinicl Phrmcology (12.3)]. Avoid concomitnt use of strong CYP3A inhibitors, including but not limited to tznvir, clrithromycin, indinvir, itrconzole, ketoconzole, nefzodone, nelfinvir, ritonvir, squinvir, telithromycin, trolendomycin, nd voriconzole. Avoid grpefruit or grpefruit juice which my lso increse plsm concentrtions of crizotinib. Exercise cution with concomitnt use of moderte CYP3A inhibitors. 7.2 Drugs Tht My Decrese Crizotinib Plsm Concentrtions Codministrtion of crizotinib with strong CYP3A inducers decreses crizotinib plsm concentrtions [see Clinicl Phrmcology (12.3)]. Avoid concomitnt use of strong CYP3A inducers, including but not limited to crbmzepine, phenobrbitl, phenytoin, rifbutin, rifmpin, nd St. John s Wort. 7.3 Drugs Whose Plsm Concentrtions My Be Altered By Crizotinib Crizotinib inhibits CYP3A both in vitro nd in vivo [see Clinicl Phrmcology (12.3)]. Avoid concomitnt use of CYP3A substrtes with nrrow therpeutic rnge, including but not limited to lfentnil, cyclosporine, dihydroergotmine, ergotmine, fentnyl, pimozide, quinidine, sirolimus, nd tcrolimus in ptients tking XALKORI. If concomitnt use of these CYP3A substrtes with nrrow therpeutic rnge is required in ptients tking XALKORI, dose reductions of the CYP3A substrtes my be required due to dverse rections. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory D [see Wrnings nd Precutions (5.5)] XALKORI cn cuse fetl hrm when dministered to pregnnt womn bsed on its mechnism of ction. There re no dequte nd well-controlled studies of XALKORI in pregnnt women. In nonclinicl studies in rts, crizotinib ws embryotoxic nd fetotoxic t exposures similr to those observed in humns t the recommended clinicl dose of 250 mg twice dily. Crizotinib ws dministered to pregnnt rts nd rbbits during orgnogenesis to study the effects on embryo-fetl development. Postimplnttion loss ws incresed t doses 50 mg/kg/dy (pproximtely 0.6 times the AUC t the recommended humn dose) in rts. No tertogenic effects were observed in rts t doses up to the mternlly toxic dose of 200 mg/kg/dy (pproximtely 2.7 times the AUC t the recommended humn dose) or in rbbits t doses of up to 60 mg/kg/dy (pproximtely 1.6 times the AUC t the recommended humn dose), though fetl body weights were reduced t these doses. Advise women of childbering potentil to void becoming pregnnt while receiving XALKORI. Women of childbering potentil who re receiving this drug, or prtners of women of childbering potentil receiving this drug, should use dequte contrceptive methods during therpy nd for t lest 90 dys fter completing therpy. If this drug is used during pregnncy, or if the ptient or their prtner becomes pregnnt while tking this drug, pprise the ptient of the potentil hzrd to fetus. 8.3 Nursing Mothers It is not known whether XALKORI is excreted in humn milk. Becuse mny drugs re excreted in humn milk nd becuse of the potentil for serious dverse rections in nursing infnts from XALKORI, consider whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother. 8.4 Peditric Use The sfety nd efficcy of XALKORI in peditric ptients hs not been estblished. Decresed bone formtion in growing long bones ws observed in immture rts t 150 mg/kg/dy following once dily dosing for 28 dys (pproximtely 5.4 times the AUC in dult ptients t the recommended humn dose). Other toxicities of potentil concern to peditric ptients hve not been evluted in juvenile nimls. 8.5 Geritric Use Of XALKORI treted ptients in Study 1, 27 (16%) were 65 yers or older, in Study 2, 152 (16%) were 65 yers or older, nd in Study 3, 16 (13%) were 65 yers or older. No overll differences in sfety or effectiveness were observed between these ptients nd younger ptients. 8.6 Heptic Impirment XALKORI hs not been studied in ptients with heptic impirment. As crizotinib is extensively metbolized in the liver, heptic impirment is likely to increse plsm crizotinib concentrtions. Clinicl studies excluded ptients with AST or ALT greter thn 2.5 x ULN, or greter thn 5 x ULN, if due to liver metstses. Ptients with totl bilirubin greter thn 1.5 x ULN were lso excluded. Therefore, use cution in ptients with heptic impirment [see Clinicl Phrmcology (12.3)]. 8.7 Renl Impirment No strting dose djustment is needed for ptients with mild (cretinine clernce [CLcr] 60-89 ml/min) or moderte (CLcr 30-59 ml/min) renl impirment bsed on popultion phrmcokinetic nlysis. Incresed exposure to crizotinib occurred in ptients with severe renl impirment (CLcr <30 ml/min) not requiring dilysis. Administer XALKORI t dose of 250 mg tken orlly once dily in ptients with severe renl impirment not requiring dilysis [see Dosge nd Administrtion (2.2) nd Clinicl Phrmcology (12.3)]. 10 OVERDOSAGE There hve been no known cses of XALKORI overdose. There is no ntidote for XALKORI. 11 DESCRIPTION XALKORI (crizotinib) is n orl receptor tyrosine kinse inhibitor. The moleculr formul for crizotinib is C 21 H 22 Cl 2 FN 5 O. The moleculr weight is 450.34 Dltons. Crizotinib is described chemiclly s (R)- 3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrzol-4-yl]pyridin-2-mine. The chemicl structure of crizotinib is shown below: Crizotinib is white to ple-yellow powder with pk of 9.4 (piperidinium ction) nd 5.6 (pyridinium ction). The solubility of crizotinib in queous medi decreses over the rnge ph 1.6 to ph 8.2 from greter thn 10 mg/ml to less thn 0.1 mg/ml. The log of the distribution coefficient (octnol/wter) t ph 7.4 is 1.65. XALKORI cpsules re supplied s printed hrd-shell cpsules contining 250 mg or 200 mg of crizotinib together with colloidl silicon dioxide, microcrystlline cellulose, nhydrous dibsic clcium phosphte, sodium strch glycolte, mgnesium sterte, nd hrd geltin cpsule shells s inctive ingredients. The pink opque cpsule shell components contin geltin, titnium dioxide, nd red iron oxide. The white opque cpsule shell components contin geltin, nd titnium dioxide. The printing ink contins shellc, propylene glycol, strong mmoni solution, potssium hydroxide, nd blck iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action Crizotinib is n inhibitor of receptor tyrosine kinses including ALK, Heptocyte Growth Fctor Receptor (HGFR, c-met), ROS1 (c-ros), nd Recepteur d Origine Nntis (RON). Trnsloctions cn ffect the ALK gene resulting in the expression of oncogenic fusion proteins. The formtion of ALK fusion proteins results in ctivtion nd dysregultion of the gene s expression nd signling which cn contribute to incresed cell prolifertion nd survivl in tumors expressing these proteins. Crizotinib demonstrted concentrtion-dependent inhibition of ALK, ROS1, nd c-met phosphoryltion in cell-bsed ssys using tumor cell lines nd demonstrted ntitumor ctivity in mice bering tumor xenogrfts tht expressed EML4- or NPM-ALK fusion proteins or c-met. 12.2 Phrmcodynmics Crdic Electrophysiology The QT intervl prolongtion potentil of crizotinib ws ssessed in ll ptients who received XALKORI 250 mg twice dily. Seril ECGs in triplicte were collected following single dose nd t stedy stte to evlute the effect of crizotinib on QT intervls. Sixteen of 1167 ptients (1.4%) were found to hve QTcF (corrected QT by the Friderici method) greter thn or equl to 500 msec nd 51 of 1136 ptients (4.4%) hd n increse from bseline QTcF greter thn or equl to 60 msec by utomted mchine-red evlution of ECG. A phrmcokinetic/phrmcodynmic nlysis suggested concentrtion-dependent increse in QTcF [see Wrnings nd Precutions (5.3)].
12.3 Phrmcokinetics Absorption Following single orl dose, crizotinib ws bsorbed with medin time to chieve pek concentrtion of 4 to 6 hours. Following crizotinib 250 mg twice dily, stedy stte ws reched within 15 dys nd remined stble, with medin ccumultion rtio of 4.8. Stedy-stte systemic exposure (C min nd AUC) ppered to increse in greter thn dose proportionl mnner over the dose rnge of 200-300 mg twice dily. The men bsolute biovilbility of crizotinib ws 43% (rnge: 32% to 66%) following single 250 mg orl dose. A high-ft mel reduced crizotinib AUC inf nd C mx by pproximtely 14%. XALKORI cn be dministered with or without food [see Dosge nd Administrtion (2.2)]. Distribution The geometric men volume of distribution (Vss) of crizotinib ws 1,772 L following intrvenous dministrtion of 50 mg dose, indicting extensive distribution into tissues from the plsm. Binding of crizotinib to humn plsm proteins in vitro is 91% nd is independent of drug concentrtion. In vitro studies suggested tht crizotinib is substrte for P-glycoprotein (P-gp). The blood-to-plsm concentrtion rtio is pproximtely 1. Metbolism Crizotinib is predominntly metbolized by CYP3A4/5. The primry metbolic pthwys in humns were oxidtion of the piperidine ring to crizotinib lctm nd O-delkyltion, with subsequent Phse 2 conjugtion of O-delkylted metbolites. Elimintion Following single doses of crizotinib, the men pprent plsm terminl hlf-life of crizotinib ws 42 hours in ptients. Following the dministrtion of single 250 mg rdiolbeled crizotinib dose to helthy subjects, 63% nd 22% of the dministered dose ws recovered in feces nd urine, respectively. Unchnged crizotinib represented pproximtely 53% nd 2.3% of the dministered dose in feces nd urine, respectively. The men pprent clernce (CL/F) of crizotinib ws lower t stedy stte (60 L/h) fter 250 mg twice dily thn tht fter single 250 mg orl dose (100 L/h), which ws likely due to utoinhibition of CYP3A by crizotinib fter multiple dosing. Drug Interctions CYP3A inhibitors: Codministrtion of single 150 mg orl dose of crizotinib with ketoconzole (200 mg twice dily), strong CYP3A inhibitor, incresed crizotinib AUC inf nd C mx vlues by pproximtely 3.2-fold nd 1.4-fold, respectively, compred to crizotinib lone. However, the mgnitude of effect of CYP3A inhibitors on stedy-stte crizotinib exposure hs not been evluted [see Drug Interctions (7.1)]. CYP3A inducers: Codministrtion of single 250 mg orl dose of crizotinib with rifmpin (600 mg once dily), strong CYP3A inducer, decresed crizotinib AUC inf nd C mx by 82% nd 69%, respectively, compred to crizotinib lone. However, the mgnitude of effect of CYP3A inducers on stedy-stte crizotinib exposure hs not been evluted [see Drug Interctions (7.2)]. Gstric ph elevting medictions: In helthy subjects, codministrtion of single 250 mg orl dose of crizotinib following dministrtion of esomeprzole 40 mg dily for 5 dys did not result in cliniclly relevnt chnge in crizotinib exposure (AUC inf decresed by 10% nd no chnge in C mx ). CYP3A substrtes: Codministrtion of crizotinib (250 mg twice dily for 28 dys) in ptients incresed the AUC inf of orl midzolm 3.7-fold compred to midzolm lone, suggesting tht crizotinib is moderte inhibitor of CYP3A [see Drug Interctions (7.3)]. Other CYP substrtes: In vitro studies suggest tht clinicl drug-drug interctions s result of crizotinib-medited inhibition of the metbolism of substrtes for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 re unlikely to occur. Crizotinib is n inhibitor of CYP2B6 in vitro. Therefore, crizotinib my increse plsm concentrtions of codministered drugs tht re predominntly metbolized by CYP2B6. An in vitro study suggests tht clinicl drug-drug interctions s result of crizotinib-medited induction of the metbolism of substrtes for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A re unlikely to occur. UGT substrtes: In vitro studies suggest tht clinicl drug-drug interctions s result of crizotinibmedited inhibition of the metbolism of drugs tht re substrtes for UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 re unlikely to occur. Substrtes of trnsporters: Crizotinib inhibited P-glycoprotein (P-gp) in vitro t cliniclly relevnt concentrtions. Therefore, crizotinib hs the potentil to increse plsm concentrtions of codministered drugs tht re substrtes of P-gp. Crizotinib inhibited the heptic uptke trnsporter, orgnic ction trnsporter 1 (OCT1), nd renl uptke trnsporter, orgnic ction trnsporter 2 (OCT2), in vitro t cliniclly relevnt concentrtions. Therefore, crizotinib hs the potentil to increse plsm concentrtions of codministered drugs tht re substrtes of OCT1 or OCT2. Crizotinib did not inhibit the humn heptic uptke trnsport proteins OATP1B1 or OATP1B3, or the renl uptke trnsport proteins OAT1 or OAT3 in vitro t cliniclly relevnt concentrtions. Effect on other trnsport proteins: Crizotinib did not inhibit the heptic efflux bile slt export pump trnsporter (BSEP) in vitro t cliniclly relevnt concentrtions. Specific Popultions Heptic Impirment: As crizotinib is extensively metbolized in the liver, heptic impirment is likely to increse plsm crizotinib concentrtions. However, XALKORI hs not been studied in ptients with heptic impirment. Clinicl studies excluded ptients with ALT or AST greter thn 2.5 x ULN or greter thn 5 x ULN if due to liver metstses. Ptients with totl bilirubin greter thn 1.5 x ULN were lso excluded [see Use in Specific Popultions (8.6)]. The popultion phrmcokinetic nlysis using the dt from Studies 1, 2 nd 3 suggested tht bseline totl bilirubin (0.1 to 2.1 mg/dl) or AST levels (7 to 124 U/L) did not hve cliniclly relevnt effect on the exposure of crizotinib. Renl impirment: The phrmcokinetics of crizotinib were evluted using popultion phrmcokinetic nlysis in ptients with mild (CLcr 60-89 ml/min, N=433) nd moderte (CLcr 30-59 ml/min, N=137) renl impirment enrolled in Studies 1, 2, nd 3. Mild or moderte renl impirment hs no cliniclly relevnt effect on the exposure of crizotinib. A study ws conducted in 7 ptients with severe renl impirment (CLcr <30 ml/min) who did not require dilysis nd 8 ptients with norml renl function (CLcr 90 ml/min). All ptients received single 250 mg orl dose of XALKORI. The men AUC inf for crizotinib incresed by 79% nd the men C mx incresed by 34% in ptients with severe renl impirment compred to those with norml renl function. Similr chnges in AUC inf nd C mx were observed for the ctive metbolite of crizotinib [see Dosge nd Administrtion (2.2) nd Use in Specific Popultions (8.7)]. Ethnicity: No cliniclly relevnt difference in the exposure of crizotinib between Asin ptients (N=523) nd non-asin ptients (N=691). Age: Age hs no effect on the exposure of crizotinib bsed on the popultion phrmcokinetic nlysis from Studies 1, 2 nd 3. Body weight nd gender: No cliniclly relevnt effect of body weight or gender on the exposure of crizotinib bsed on the popultion phrmcokinetic nlysis from Studies 1, 2 nd 3. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Crcinogenicity studies with crizotinib hve not been conducted. Crizotinib ws genotoxic in n in vitro micronucleus ssy in Chinese Hmster Ovry cultures, in n in vitro humn lymphocyte chromosome berrtion ssy, nd in in vivo rt bone mrrow micronucleus ssys. Crizotinib ws not mutgenic in vitro in the bcteril reverse muttion (Ames) ssy. No specific studies with crizotinib hve been conducted in nimls to evlute the effect on fertility; however, crizotinib is considered to hve the potentil to impir reproductive function nd fertility in humns bsed on findings in repet-dose toxicity studies in the rt. Findings observed in the mle reproductive trct included testiculr pchytene spermtocyte degenertion in rts given greter thn or equl to 50 mg/kg/dy for 28 dys (greter thn 1.7 times the AUC t the recommended humn dose). Findings observed in the femle reproductive trct included single-cell necrosis of ovrin follicles of rt given 500 mg/kg/dy (pproximtely 10 times the recommended humn dily dose on mg/m 2 bsis) for 3 dys. 14 CLINICAL STUDIES ALK-positive metsttic NSCLC-Study 1 The efficcy nd sfety of XALKORI s monotherpy for the tretment of 347 ptients with metsttic ALK-positive NSCLC, previously treted with one pltinum-bsed chemotherpy regimen, ws demonstrted in rndomized, multicenter, open-lbel, ctive-controlled study (Study 1). The mjor efficcy outcome ws progression-free survivl (PFS) s ssessed by independent rdiology review (IRR). Additionl efficcy outcomes included objective response rte (ORR) s ssessed by IRR nd overll survivl (OS). Ptients were rndomized to receive XALKORI 250 mg orlly twice dily (n=173) or chemotherpy (n=174). Chemotherpy consisted of pemetrexed 500 mg/m 2 (if pemetrexed nïve; n=99) or docetxel 75 mg/m 2 (n=72) intrvenously (IV) every 21 dys. Ptients in both tretment rms continued tretment until documented disese progression, intolernce to therpy, or the investigtor determined tht the ptient ws no longer experiencing clinicl benefit. Rndomiztion ws strtified by ECOG performnce sttus (0-1, 2), brin metstses (present, bsent), nd prior EGFR tyrosine kinse inhibitor tretment (yes, no). Ptients were required to hve ALK-positive NSCLC s identified by the FDA-pproved ssy, Vysis ALK Brek-Aprt FISH Probe Kit, prior to rndomiztion. A totl of 112 (64%) ptients rndomized to the chemotherpy rm subsequently received XALKORI fter disese progression. The demogrphic chrcteristics of the overll study popultion were 56% femle, medin ge of 50 yers, bseline ECOG performnce sttus 0 (39%) or 1 (52%), 52% White nd 45% Asin, 4% current smokers, 33% pst-smokers, nd 63% never smokers. The disese chrcteristics were metsttic disese in t lest 95% of ptients nd t lest 93% of ptients tumors were clssified s denocrcinom histology. Study 1 demonstrted sttisticlly significnt improvement in PFS in the ptients treted with XALKORI. Tble 5 nd Figure 1 summrize the efficcy results. Tble 5. ALK-Positive Metsttic NSCLC - Efficcy Results XALKORI Chemotherpy (N=173) (N=174) Progression-free Survivl (Bsed on IRR) Number of Events (%) 100 (58%) 127 (73%) Progressive Disese 84 (49%) 119 (68%) Deth 16 (9%) 8 (5%) Medin, Months (95% CI) 7.7 (6.0, 8.8) 3.0 (2.6, 4.3) HR (95% CI) b 0.49 (0.37,0.64) P-vlue c <0.001 Overll Survivl d Number of Events (%) 49 (28%) 47 (27%) Medin, Months (95% CI) 20.3 (18.1,NR) 22.8 (18.6,NR) HR (95% CI) b 1.02 (0.68,1.54) P-vlue c 0.54 Tumor Responses (Bsed on IRR) Objective Response Rte % (95% CI) 65% (58, 72) 20% (14, 26) CR, n (%) 1 (0.6%) 0 PR, n (%) 112 (65%) 34 (20%) P-vlue e <0.001 Durtion of Response Medin, Months (95% CI) 7.4 (6.1, 9.7) 5.6 (3.4, 8.3) HR = Hzrd Rtio; CI = confidence intervl; NR = not reched; CR = complete response; PR = prtil response For pemetrexed, the medin PFS ws 4.2 months. For docetxel, the medin PFS ws 2.6 months. b Bsed on the Cox proportionl hzrds strtified nlysis c Bsed on the strtified Log-rnk test d Interim OS nlysis conducted t 40% of totl events required for finl nlysis e Bsed on the strtified Cochrn-Mntel-Henszel test