Specilty Phrmcy Distriution Network for IBRANCE (plocicli), INLYTA (xitini), XALKORI (crizotini), BOSULIF (osutini), nd SUTENT (sunitini mlte) Option Contct the specilty phrmcy directly (See next pge for list of specilty phrmcies.) Contct the specilty phrmcy directly to fill the prescription if one of the following pplies: Your office knows the ptient s specilty phrmcy Your ptient knows tht the specilty phrmcy is covered in his/her pln nd tht the phrmcy is in the tretment network Your office uses specilty phrmcy tht is in the ptient s network SPECIALTY PHARMACY ORDERING PROCESS The provider s office Sumits prescriptions to the specilty phrmcy vi: Sumits ny supporting documenttion to the pyer The specilty phrmcy Verifies the ptient s coverge Helps with prior uthoriztion, if required Cn help ptients seek co-py ssistnce Schedules shipment of product to the ptient s home Bills the pyer for the cost of the product Bills the ptient for remining co-py/coinsurnce Option If option is not pplicle, contct Pfizer Ptient Support Pfizer Ptient Support helps eligile ptients get ccess to their Pfizer medicines y offering rnge of prescription ssistnce services. Pfizer Ptient Support helps insured ptients find n pproprite specilty phrmcy For uninsured nd underinsured ptients, Pfizer Ptient Support cn provide eligile ptients with free medicine for up to months Visit the Pfizer provider portl for the Ptient Assistnce Progrm t www.pfizerpap.com to egin the enrollment process for new ptients nd to mnge existing ones, or cll --- Mondy to Fridy, m to pm ET. IBRANCE, INLYTA, XALKORI, BOSULIF, nd SUTENT ARE NOT ville through trditionl retil phrmcies. Pfizer Ptient Support is joint progrm of Pfizer Inc. nd the Pfizer Ptient Assistnce Foundtion. Pfizer Ptient Support is prt of Pfizer s Glol Socil Investments portfolio. For more informtion, plese visit www.pfizer.com/responsiility. Plese see full Prescriing Informtion, including BOXED WARNING nd Mediction Guide, for SUTENT, on susequent pges. Plese see full Prescriing Informtion for ll products t www.pfizerpro.com.
IBRANCE (plocicli), INLYTA (xitini), XALKORI (crizotini), BOSULIF (osutini), nd SUTENT (sunitini mlte) ville through these specilty phrmcies AcriHelth www.crihelth.com Tel: () 9- Fx: () 9- Mondy Fridy, m pm (ET) Sturdy, 9 m pm (ET) Accredo Helth Group, Inc. www.ccredo.com Tel: () - Fx: () - Mondy Fridy, m pm (ET) Sturdy, m pm (ET) Advnced Cre Scripts www.cs-rx.com Tel: () 9- Fx: () 9- Mondy Fridy, m pm (ET) Aetn Specilty Phrmcy www.etnspeciltyphrmcy.com Tel: () -9 Fx: () 9- Mondy Fridy, m pm (ET) Alertsons Sfewy Specilty Cre www.lertsons.com/speciltycre Tel: () - Fx: () - Mondy Fridy, m pm (PT) AllinceRx Wlgreens Prime www.llincerxwp.com Tel: () - Fx: () - Mondy Fridy, m pm (ET) Sturdy, 9 m pm (ET) Avell Specilty Phrmcy www.vell.com Tel: () -9 Fx: () - Mondy Fridy, m pm* Sturdy, 9: m : pm* *Arizon time. Biologics, Inc. www.iologicsinc.com Tel: () - Fx: () - Mondy Fridy, 9 m pm (ET) BioPlus Specilty Phrmcy www.ioplusrx.com Tel: () 9- Fx: () 9-9 Mondy Fridy, m pm (ET) Sturdy Sundy, m pm (ET) BriovRx www.riovrx.com Tel: () BRIOVA (-) Fx: () -9 Mondy Fridy, : m pm (ET) Sturdy, 9 m pm (ET) Crdinl Helth Specilty Phrmcy (f.k.. OncoSourceRx) www.oncosourcerx.com Tel: () -9 Fx: () -9 Mondy Fridy, m pm (ET) CreMed Phrmceuticl Services www.cremedsp.com Tel: () - Fx: () - Mondy Fridy, 9 m pm (ET) Cign www.cign.com Tel: () - Fx: () - Mondy Sundy, hours CVS Cremrk Specilty Phrmcy www.cvscremrkspeciltyrx.com Tel: () - Fx: () - Mondy Fridy, : m 9 pm (ET) Diplomt Specilty Phrmcy www.diplomtphrmcy.com Tel: () 9-9 Fx: () - Mondy Fridy, 9 m pm (ET) Sturdy, 9 m pm (ET) EnvisionSpecilty www.envisionspecilty.com Tel: () -9 Fx: () 9- Mondy Fridy, m pm (ET) Sturdy, m : pm (ET) Exctus Phrmcy Solutions www.exctusrx.com Tel: () -9 Fx: () -9 Mondy Thursdy, m pm (ET) Fridy, m pm (ET) Humn Specilty Phrmcy www.humnphrmcy.com/specilty.cmd Tel: () - Fx: () -9 Mondy Fridy, m pm (ET) Sturdy, m pm (ET) Kroger Specilty Phrmcy www.krogerspeciltyphrmcy.com Tel: () -9 Fx: () - Mondy Fridy, m pm (ET) Onco Oncology Phrmcy www.onco.com Tel: () - Fx: () - Mondy Fridy, m pm (ET) Sturdy, 9 m pm (ET) OncologyRx Cre Advntge www.mycredvntge.com Tel: () 9- Fx: () -99 Mondy Fridy, 9 m pm (ET) US Bioservices www.usioservices.com Tel: () - Fx: () 99- Mondy Fridy, m pm (ET) Plese see full Prescriing Informtion, including BOXED WARNING nd Mediction Guide, for SUTENT, on susequent pges. Plese see full Prescriing Informtion for ll products t www.pfizerpro.com. PP-ONC-USA-- Pfizer Inc. All rights reserved. Decemer
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use SUTENT sfely nd effectively. See full prescriing informtion for SUTENT. SUTENT (sunitini mlte) cpsules, for orl use Initil U.S. Approvl: WARNING: HEPATOTOXICITY See full prescriing informtion for complete oxed wrning. Heptotoxicity hs een oserved in clinicl trils nd postmrketing experience. Heptotoxicity my e severe, nd in some cses ftl. Monitor heptic function nd interrupt, reduce, or discontinue dosing s recommended [see Wrnings nd Precutions (.)]. ------------------------------------ RECENT MAJOR CHANGES ------------------------------------ Boxed Wrning / Indictions nd Usge, Adjuvnt Tretment of Renl Cell Crcinom (RCC) (.) / Dosge nd Administrtion, Recommended Dose for Adjuvnt Tretment of RCC (.) / Dosge nd Administrtion, Dose Modifiction (.) / Wrnings nd Precutions () / ------------------------------------- INDICATIONS AND USAGE ------------------------------------ SUTENT is kinse inhiitor indicted for: the tretment of gstrointestinl stroml tumor (GIST) fter disese progression on or intolernce to imtini mesylte. (.) the tretment of dvnced renl cell crcinom (RCC). (.) the djuvnt tretment of dult ptients t high risk of recurrent RCC following nephrectomy. (.) the tretment of progressive, well-differentited pncretic neuroendocrine tumors (pnet) in ptients with unresectle loclly dvnced or metsttic disese. (.) --------------------------------- DOSAGE AND ADMINISTRATION --------------------------------- GIST nd Advnced RCC: mg orlly once dily, with or without food, weeks on tretment followed y weeks off. (.) Adjuvnt RCC: mg orlly once dily, with or without food, weeks on tretment followed y weeks off for nine -week cycles. (.) pnet:. mg orlly once dily, with or without food, continuously without scheduled off-tretment period. (.) Dose Modifiction: Dose interruptions nd/or dose djustments of. mg recommended sed on individul sfety nd tolerility. (.) ------------------------------- DOSAGE FORMS AND STRENGTHS ------------------------------- Cpsules:. mg, mg,. mg, mg () --------------------------------------- CONTRAINDICATIONS --------------------------------------- None () --------------------------------- WARNINGS AND PRECAUTIONS --------------------------------- Heptotoxicity, including ftl liver filure, hs een oserved. Monitor liver function tests efore initition of tretment, during ech cycle of tretment, nd s cliniclly indicted. Interrupt SUTENT for Grde or drug-relted heptic dverse rections nd discontinue if there is no resolution. Do not restrt SUTENT if ptients experience severe chnges in liver function tests or hve signs nd symptoms of liver filure. (.) Crdiovsculr events including myocrdil ischemi, myocrdil infrction, left ventriculr ejection frction declines to elow the lower limit of norml nd crdic filure including deth hve occurred. Monitor ptients for signs nd symptoms of congestive hert filure. Discontinue SUTENT for clinicl mnifesttions of congestive hert filure. (.) Prolonged QT intervls nd Torsde de Pointes hve een oserved. Monitor ptients t higher risk for developing QT intervl prolongtion. Consider monitoring of electrocrdiogrms nd electrolytes. (.) Hypertension my occur. Monitor lood pressure nd tret s needed. (.) Hemorrhgic events, including tumor-relted hemorrhge, nd viscus perfortion (oth with ftl events) hve occurred. Perform seril complete lood counts nd physicl exmintions. (.) Cses of Tumor Lysis Syndrome (TLS) (some ftl) hve een reported primrily in ptients with RCC nd GIST with high tumor urden. Monitor these ptients closely nd tret s cliniclly indicted. (.) Thromotic microngiopthy (TMA), including thromotic thromocytopenic purpur nd hemolytic uremic syndrome, sometimes leding to renl filure or ftl outcome, hs een reported. Discontinue SUTENT in ptients developing TMA. (.) Proteinuri, including renl filure or ftl outcome, hs occurred. Monitor urine protein. Interrupt tretment for -hour urine protein grms. Discontinue for repet episodes of protein grms despite dose reductions or nephrotic syndrome. (.) Necrotizing fsciitis, erythem multiforme, Stevens-Johnson syndrome (SJS), nd toxic epiderml necrolysis (TEN) (some ftl) hve occurred. Discontinue SUTENT if these events occur. (.9) Thyroid dysfunction my occur. Ptients with signs nd/or symptoms suggestive of hypothyroidism or hyperthyroidism should hve lortory monitoring of thyroid function performed nd e treted s per stndrd medicl prctice. (.) Hypoglycemi my occur. Check lood glucose levels regulrly nd ssess if ntidietic drug dose modifictions re required. (.) Osteonecrosis of the jw hs een reported. Consider preventive dentistry prior to tretment with SUTENT. If possile, void invsive dentl procedures, prticulrly in ptients receiving intrvenous isphosphonte therpy. (.) Wound Heling: Impired wound heling hs occurred with SUTENT. Temporry interruption of therpy with SUTENT is recommended in ptients undergoing mjor surgicl procedures. (.) Emryo-Fetl Toxicity: Cn cuse fetl hrm. Advise ptients of potentil risk to fetus nd to use effective contrception. (.,.,.) --------------------------------------- ADVERSE REACTIONS --------------------------------------- The most common dverse rections ( ) re ftigue/stheni, dirrhe, mucositis/ stomtitis, nuse, decresed ppetite/norexi, vomiting, dominl pin, hnd-foot syndrome, hypertension, leeding events, dysgeusi/ltered tste, dyspepsi, nd thromocytopeni. () To report SUSPECTED ADVERSE REACTIONS, contct Pfizer Inc t ---9 or FDA t --FDA- or www.fd.gov/medwtch. --------------------------------------- DRUG INTERACTIONS --------------------------------------- CYPA Inhiitors: Consider dose reduction of SUTENT when dministered with strong CYPA inhiitors. (.) CYPA Inducers: Consider dose increse of SUTENT when dministered with CYPA inducers. (.) --------------------------------- USE IN SPECIFIC POPULATIONS --------------------------------- Lcttion: Advise women not to restfeed. (.) See for PATIENT COUNSELING INFORMATION nd FDA pproved ptient leling. Revised: /
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: HEPATOTOXICITY INDICATIONS AND USAGE. Gstrointestinl Stroml Tumor (GIST). Advnced Renl Cell Crcinom (RCC). Adjuvnt Tretment of Renl Cell Crcinom (RCC). Advnced Pncretic Neuroendocrine Tumors (pnet) DOSAGE AND ADMINISTRATION. Recommended Dose for GIST nd RCC. Recommended Dose for Adjuvnt Tretment of RCC. Recommended Dose for pnet. Dose Modifiction DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Heptotoxicity. Crdiovsculr Events. QT Intervl Prolongtion nd Torsde de Pointes. Hypertension. Hemorrhgic Events nd Viscus Perfortion. Tumor Lysis Syndrome (TLS). Thromotic Microngiopthy. Proteinuri.9 Dermtologic Toxicities. Thyroid Dysfunction. Hypoglycemi. Osteonecrosis of the Jw (ONJ). Wound Heling. Emryo-Fetl Toxicity ADVERSE REACTIONS. Clinicl Trils Experience. Postmrketing Experience DRUG INTERACTIONS. CYPA Inhiitors. CYPA Inducers. In Vitro Studies of CYP Inhiition nd Induction USE IN SPECIFIC POPULATIONS. Pregnncy. Lcttion. Femles nd Mles of Reproductive Potentil. Peditric Use. Geritric Use. Heptic Impirment. Renl Impirment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechnism of Action. Phrmcokinetics. Crdic Electrophysiology NONCLINICAL TOXICOLOGY. Crcinogenesis, Mutgenesis, Impirment of Fertility CLINICAL STUDIES. Gstrointestinl Stroml Tumor. Renl Cell Crcinom. Pncretic Neuroendocrine Tumors HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION * Sections or susections omitted from the full prescriing informtion re not listed. FULL PRESCRIBING INFORMATION WARNING: HEPATOTOXICITY Heptotoxicity hs een oserved in clinicl trils nd postmrketing experience. Heptotoxicity my e severe, nd in some cses, ftl. Monitor heptic function nd interrupt, reduce, or discontinue dosing s recommended [see Wrnings nd Precutions (.)]. INDICATIONS AND USAGE. Gstrointestinl Stroml Tumor (GIST) SUTENT is indicted for the tretment of gstrointestinl stroml tumor fter disese progression on or intolernce to imtini mesylte.. Advnced Renl Cell Crcinom (RCC) SUTENT is indicted for the tretment of dvnced renl cell crcinom.. Adjuvnt Tretment of Renl Cell Crcinom (RCC) SUTENT is indicted for the djuvnt tretment of dult ptients t high risk of recurrent RCC following nephrectomy.. Advnced Pncretic Neuroendocrine Tumors (pnet) SUTENT is indicted for the tretment of progressive, well-differentited pncretic neuroendocrine tumors in ptients with unresectle loclly dvnced or metsttic disese. DOSAGE AND ADMINISTRATION. Recommended Dose for GIST nd Advnced RCC The recommended dose of SUTENT for gstrointestinl stroml tumor (GIST) nd dvnced renl cell crcinom (RCC) is one mg orl dose tken once dily, on schedule of weeks on tretment followed y weeks off (Schedule /). SUTENT my e tken with or without food.. Recommended Dose for Adjuvnt Tretment of RCC The recommended dose of SUTENT for the djuvnt tretment of RCC is mg tken orlly once dily, on schedule of weeks on tretment followed y weeks off (Schedule /), for nine week cycles. SUTENT my e tken with or without food.. Recommended Dose for pnet The recommended dose of SUTENT for pncretic neuroendocrine tumors (pnet) is. mg tken orlly once dily continuously without scheduled off-tretment period. SUTENT my e tken with or without food.. Dose Modifiction Dose interruption nd/or dose modifiction in. mg increments or decrements is recommended sed on individul sfety nd tolerility. The mximum dose dministered in the pnet study ws mg dily. In the djuvnt RCC study, the minimum dose dministered ws. mg. Strong CYPA inhiitors such s ketoconzole my increse sunitini plsm concentrtions. Selection of n lternte concomitnt mediction with no or miniml enzyme inhiition potentil is recommended. A dose reduction for SUTENT to minimum of. mg (GIST nd RCC) or mg (pnet) dily should e considered if SUTENT must e codministered with strong CYPA inhiitor [see Drug Interctions (.) nd Clinicl Phrmcology (.)]. CYPA inducers such s rifmpin my decrese sunitini plsm concentrtions. Selection of n lternte concomitnt mediction with no or miniml enzyme induction potentil is recommended. A dose increse for SUTENT to mximum of. mg (GIST nd RCC) or. mg (pnet) dily should e considered if SUTENT must e codministered with CYPA inducer. If dose is incresed, the ptient should e monitored crefully for toxicity [see Drug Interctions (.) nd Clinicl Phrmcology (.)]. DOSAGE FORMS AND STRENGTHS. mg cpsules Hrd geltin cpsule with ornge cp nd ornge ody, printed with white ink Pfizer on the cp nd STN. mg on the ody. mg cpsules Hrd geltin cpsule with crmel cp nd ornge ody, printed with white ink Pfizer on the cp nd STN mg on the ody.. mg cpsules Hrd geltin cpsule with yellow cp nd yellow ody, printed with lck ink Pfizer on the cp nd STN. mg on the ody. mg cpsules Hrd geltin cpsule with crmel top nd crmel ody, printed with white ink Pfizer on the cp nd STN mg on the ody. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS. Heptotoxicity SUTENT cn cuse severe heptotoxicity, resulting in liver filure or deth. Liver filure occurred t n incidence of < in clinicl trils. Liver filure signs include jundice, elevted trnsminses nd/or hyperiliruinemi in conjunction with encephlopthy, cogulopthy, nd/or renl filure. Monitor liver function tests (lnine minotrnsferse [ALT], sprtte minotrnsferse [AST], nd iliruin) efore initition of tretment, during ech cycle of tretment, nd s cliniclly indicted. Interrupt SUTENT for Grde or drug relted heptic dverse rections nd discontinue if there is no resolution. Do not restrt SUTENT if ptients susequently experience severe chnges in liver function tests or hve other signs nd symptoms of liver filure. Sfety in ptients with ALT or AST >. x upper limit of norml (ULN) or, if due to liver metstses, >. x ULN hs not een estlished.
. Crdiovsculr Events Discontinue SUTENT in the presence of clinicl mnifesttions of congestive hert filure (CHF). Interrupt SUTENT nd/or reduce the dose in ptients without clinicl evidence of CHF who hve n ejection frction of > ut < elow seline or elow the lower limit of norml if seline ejection frction is not otined. In ptients without crdic risk fctors seline evlution of ejection frction should e considered. Crefully monitor ptients for clinicl signs nd symptoms of CHF while receiving SUTENT. Bseline nd periodic evlutions of left ventriculr ejection frction (LVEF) should lso e considered while these ptients re receiving SUTENT. Crdiovsculr events, including hert filure, crdiomyopthy, myocrdil ischemi, nd myocrdil infrction, some of which were ftl, hve een reported. In ptients treted with SUTENT (N=) for GIST, dvnced RCC, djuvnt tretment of RCC nd pnet, of ptients experienced hert filure; of the ptients with hert filure were reported s recovered. Ftl crdic filure ws reported in < of ptients. In the djuvnt tretment of RCC study, ptients in ech rm experienced decresed ejection frction meeting Grde CTCAE criteri (LVEF - nd -9 decrese from seline). No ptients hd Grde - decrese in ejection frction. The ejection frctions of three ptients in the SUTENT rm nd ptients in the plceo rm did not return to or seline y the time of lst mesurement. No ptients who received SUTENT were dignosed with CHF. Ptients who presented with crdic events within months prior to SUTENT dministrtion, such s myocrdil infrction (including severe/unstle ngin), coronry/peripherl rtery ypss grft, symptomtic CHF, cererovsculr ccident or trnsient ischemic ttck, or pulmonry emolism were excluded from SUTENT clinicl studies. It is unknown whether ptients with these concomitnt conditions my e t higher risk of developing drug-relted left ventriculr dysfunction.. QT Intervl Prolongtion nd Torsde de Pointes SUTENT cn cuse QT intervl prolongtion in dose-dependent mnner, which my led to n incresed risk for ventriculr rrhythmis including Torsde de Pointes. Torsde de Pointes hs een oserved in <. of SUTENT-exposed ptients. Monitor ptients with history of QT intervl prolongtion, ptients who re tking ntirrhythmics, or ptients with relevnt pre-existing crdic disese, rdycrdi, or electrolyte disturnces. When using SUTENT, periodic monitoring with on-tretment electrocrdiogrms nd electrolytes (mgnesium, potssium) should e considered. Concomitnt tretment with strong CYPA inhiitors my increse sunitini plsm concentrtions nd dose reduction of SUTENT should e considered [see Dosge nd Administrtion (.)].. Hypertension Monitor ptients for hypertension nd tret s needed with stndrd ntihypertensive therpy. In cses of severe hypertension, temporry suspension of SUTENT is recommended until hypertension is controlled. In ptients treted with SUTENT (N=) in GIST, dvnced RCC, djuvnt tretment of RCC nd pnet, 9 of ptients experienced hypertension. Grde hypertension ws reported in of ptients, nd Grde hypertension ws reported in. of ptients.. Hemorrhgic Events nd Viscus Perfortion Hemorrhgic events reported through postmrketing experience, some of which were ftl, hve included GI, respirtory, tumor, urinry trct, nd rin hemorrhges. In ptients treted with SUTENT (N=) for GIST, dvnced RCC, djuvnt tretment of RCC nd pnet, of ptients experienced hemorrhgic events, nd. of ptients experienced Grde or event. Epistxis ws the most common hemorrhgic dverse rection nd gstrointestinl hemorrhge ws the most common Grde event. Tumor-relted hemorrhge hs een oserved in ptients treted with SUTENT. These events my occur suddenly, nd in the cse of pulmonry tumors, my present s severe nd life-thretening hemoptysis or pulmonry hemorrhge. Cses of pulmonry hemorrhge, some with ftl outcome, hve een oserved in clinicl trils nd hve een reported in postmrketing experience in ptients treted with SUTENT for metsttic RCC, GIST, nd metsttic lung cncer. SUTENT is not pproved for use in ptients with lung cncer. Clinicl ssessment of hemorrhgic events should include seril complete lood counts (CBCs) nd physicl exmintions. Serious, sometimes ftl, gstrointestinl complictions including gstrointestinl perfortion, hve een reported in ptients with intr-dominl mlignncies treted with SUTENT.. Tumor Lysis Syndrome (TLS) Cses of TLS, some ftl, occurred in clinicl trils nd hve een reported in postmrketing experience, primrily in ptients with RCC or GIST treted with SUTENT. Ptients generlly t risk of TLS re those with high tumor urden prior to tretment. Monitor these ptients closely nd tret s cliniclly indicted.. Thromotic Microngiopthy Thromotic microngiopthy (TMA), including thromotic thromocytopenic purpur nd hemolytic uremic syndrome, sometimes leding to renl filure or ftl outcome, occurred in clinicl trils nd in postmrketing experience of SUTENT s monotherpy nd dministered in comintion with evcizum. Discontinue SUTENT in ptients developing TMA. Reversl of the effects of TMA hs een oserved fter tretment ws discontinued.. Proteinuri Proteinuri nd nephrotic syndrome hve een reported. Some of these cses hve resulted in renl filure nd ftl outcomes. Monitor ptients for the development or worsening of proteinuri. Perform seline nd periodic urinlyses during tretment, with follow up mesurement of hour urine protein s cliniclly indicted. Interrupt SUTENT nd dose reduce for -hour urine protein grms. Discontinue SUTENT for ptients with nephrotic syndrome or repet episodes of urine protein grms despite dose reductions. The sfety of continued SUTENT tretment in ptients with moderte to severe proteinuri hs not een systemticlly evluted..9 Dermtologic Toxicities Severe cutneous rections hve een reported, including cses of erythem multiforme (EM), Stevens-Johnson syndrome (SJS), nd toxic epiderml necrolysis (TEN), some of which were ftl. If signs or symptoms of EM, SJS, or TEN (e.g., progressive skin rsh often with listers or mucosl lesions) re present, discontinue SUTENT tretment. If dignosis of SJS or TEN is suspected, SUTENT tretment must not e re-strted. Necrotizing fsciitis, including ftl cses, hs een reported in ptients treted with SUTENT, including of the perineum nd secondry to fistul formtion. Discontinue SUTENT in ptients who develop necrotizing fsciitis.. Thyroid Dysfunction Bseline lortory mesurement of thyroid function is recommended nd ptients with hypothyroidism or hyperthyroidism should e treted s per stndrd medicl prctice prior to the strt of SUTENT tretment. All ptients should e oserved closely for signs nd symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, nd thyroiditis, while on SUTENT tretment. Ptients with signs nd/or symptoms suggestive of thyroid dysfunction should hve lortory monitoring of thyroid function performed nd e treted s per stndrd medicl prctice. Cses of hyperthyroidism, some followed y hypothyroidism, hve een reported in clinicl trils nd through postmrketing experience.. Hypoglycemi SUTENT cn result in symptomtic hypoglycemi, which my led to loss of consciousness, or require hospitliztion. Hypoglycemi hs occurred in clinicl trils in of the ptients treted with SUTENT for dvnced RCC nd GIST nd in pproximtely of the ptients treted with SUTENT for pnet. In the djuvnt tretment of RCC study, no ptients on SUTENT experienced hypoglycemi. For ptients eing treted with SUTENT for pnet, pre-existing normlities in glucose homeostsis were not present in ll ptients who experienced hypoglycemi. Reductions in lood glucose levels my e worse in dietic ptients. Check lood glucose levels regulrly during nd fter discontinution of tretment with SUTENT. Assess if ntidietic drug dosge needs to e djusted to minimize the risk of hypoglycemi.. Osteonecrosis of the Jw (ONJ) ONJ hs een oserved in clinicl trils nd hs een reported in postmrketing experience in ptients treted with SUTENT. Concomitnt exposure to other risk fctors, such s isphosphontes or dentl disese, my increse the risk of osteonecrosis of the jw. Consider preventive dentistry prior to tretment with SUTENT. If possile, void invsive dentl procedures while on SUTENT tretment, prticulrly in ptients receiving intrvenous isphosphonte therpy.. Wound Heling Cses of impired wound heling hve een reported during SUTENT therpy. Temporry interruption of SUTENT therpy is recommended for precutionry resons in ptients undergoing mjor surgicl procedures. There is limited clinicl experience regrding the timing of reinitition of therpy following mjor surgicl intervention. Therefore, the decision to resume SUTENT therpy following mjor surgicl intervention should e sed upon clinicl judgment of recovery from surgery.. Emryo-Fetl Toxicity Bsed on findings from niml studies nd its mechnism of ction, SUTENT cn cuse fetl hrm when dministered to pregnnt womn. Administrtion of sunitini to pregnnt rts nd rits during the period of orgnogenesis resulted in tertogenicity t pproximtely. nd. times the clinicl systemic exposure (AUC) t the recommended dily doses (RDD) of mg/dy, respectively. Advise pregnnt women of the potentil risk to fetus. Advise femles of reproductive potentil to use effective contrception during tretment with SUTENT nd for weeks following the finl dose [see Clinicl Phrmcology (.) nd Use in Specific Popultions (.,.)]. ADVERSE REACTIONS The following serious dverse rections re discussed in greter detil in other sections of the leling. Heptotoxicity [see Wrnings nd Precutions (.)] Crdiovsculr Events [see Wrnings nd Precutions (.)] QT Intervl Prolongtion nd Torsde de Pointes [see Wrnings nd Precutions (.)] Hypertension [see Wrnings nd Precutions (.)] Hemorrhgic Events [see Wrnings nd Precutions (.)] Tumor Lysis Syndrome (TLS) [see Wrnings nd Precutions (.)] Thromotic Microngiopthy [see Wrnings nd Precutions (.)] Proteinuri [see Wrnings nd Precutions (.)] Dermtologic Toxicities [see Wrnings nd Precutions (.9)] Thyroid Dysfunction [see Wrnings nd Precutions (.)] Hypoglycemi [see Wrnings nd Precutions (.)] Osteonecrosis of the Jw (ONJ) [see Wrnings nd Precutions (.)] Wound Heling [see Wrnings nd Precutions (.)]
. Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in prctice. The dt descried in the Wrnings nd Precutions reflect exposure to SUTENT (N = ) in GIST, dvnced RCC, djuvnt tretment of RCC, nd pnet [see Wrnings nd Precutions (.,.)]. In this dtse, the most common dverse rections ( ) re ftigue/ stheni, dirrhe, mucositis/stomtitis, nuse, decresed ppetite/norexi, vomiting, dominl pin, hnd-foot syndrome, hypertension, leeding events, dysgeusi/ltered tste, dyspepsi, nd thromocytopeni. The dt elow reflect exposure to SUTENT in 9 ptients who prticipted in the tretment phse of rndomized trils of GIST (n=), dvnced RCC (n=), djuvnt tretment of RCC (n=), nd pnet (n=) [see Clinicl Studies (.,.,.)]. Gstrointestinl Stroml Tumor (GIST) The sfety of SUTENT ws evluted in Study, rndomized, doule-lind, plceocontrolled tril in which previously treted ptients with GIST received SUTENT mg dily on Schedule / (n=) or plceo (n=). Medin durtion of linded study tretment ws cycles for ptients on SUTENT (men:.; rnge: 9) nd cycle (men;.; rnge: -) for ptients on plceo t the time of the interim nlysis. Dose reductions occurred in ptients () on SUTENT nd none on plceo. Dose interruptions occurred in 9 ptients (9) on SUTENT nd ptients () on plceo. The rtes of tretment emergent, nonftl dverse rections resulting in permnent discontinution were nd in the SUTENT nd plceo groups, respectively. Most tretment-emergent dverse rections in oth study rms were Grde or in severity. Grde or tretment-emergent dverse rections were reported in versus of ptients on SUTENT versus plceo, respectively, in the doule-lind tretment phse of the tril. Tle compres the incidence of common ( ) tretment-emergent dverse rections for ptients receiving SUTENT nd reported more commonly in ptients receiving SUTENT thn in ptients receiving plceo. Tle. Adverse Rections Reported in Study in of GIST Ptients Who Received SUTENT in the Doule-Blind Tretment Phse nd More Commonly Thn in Ptients Given Plceo* GIST SUTENT (N=) Plceo (N=) All Grdes Grde - All Grdes Grde - Adverse Rection Any Adverse Rection 9 9 Gstrointestinl Dirrhe Mucositis/stomtitis Constiption 9 Crdic Hypertension Dermtology Skin discolortion Rsh Hnd-foot syndrome Neurology Altered tste Musculoskeletl Mylgi/lim pin 9 9 Metolism/Nutrition Anorexi Astheni 9 * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: GIST=gstrointestinl stroml tumor; N=numer of ptients. Includes decresed ppetite. In the doule-lind tretment phse of GIST Study, orl pin other thn mucositis/ stomtitis occurred in ptients () on SUTENT versus () on plceo. Hir color chnges occurred in ptients () on SUTENT versus () on plceo. Alopeci ws oserved in ptients () on SUTENT versus () on plceo. Tle provides common ( ) tretment-emergent lortory normlities. Tle. Lortory Anormlities Reported in Study in of GIST Ptients Who Received SUTENT or Plceo in the Doule-Blind Tretment Phse* GIST SUTENT (N=) Plceo (N=) Lortory Prmeter All Grdes* Grde -*, All Grdes* Grde -*, Any () () Gstrointestinl AST/ALT Lipse Alkline phosphtse Amylse Totl iliruin Indirect iliruin 9 Crdic Decresed LVEF Renl/Metolic Cretinine Potssium decresed Sodium incresed Hemtology Neutrophils Lymphocytes Pltelets Hemogloin * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: ALT=lnine minotrnsferse; AST=sprtte minotrnsferse; GIST=gstrointestinl stroml tumor; LVEF=left ventriculr ejection frction; N=numer of ptients. Grde lortory normlities in ptients on SUTENT included lkline phosphtse (), lipse (), cretinine (), potssium decresed (), neutrophils (), hemogloin (), nd pltelets (). Grde lortory normlities in ptients on plceo included mylse (), lipse (), nd hemogloin (). After n interim nlysis, the study ws unlinded nd ptients on the plceo rm were given the opportunity to receive open-lel SUTENT tretment [see Clinicl Studies (.)]. For ptients rndomized to the SUTENT rm, including 9 who received SUTENT in oth the doule-lind nd open-lel tretment phses, the medin durtion of SUTENT tretment ws cycles (men:.; rnge: ). For the ptients who ultimtely received open-lel SUTENT tretment, medin durtion of study tretment ws cycles (men:.; rnge: ) from the time of the unlinding. A totl of ptients () required dosing interruptions, nd totl of ptients () required dose reductions. The incidence of tretment emergent dverse rections resulting in permnent discontinution ws. The most common Grde or tretment-relted dverse rections experienced y ptients receiving SUTENT in the open-lel tretment phse were ftigue (), hypertension (), stheni (), dirrhe (), hnd-foot syndrome (), nuse (), dominl pin (), norexi (), mucositis (), vomiting (), nd hypothyroidism (). Advnced Renl Cell Crcinom (RCC) The sfety of SUTENT ws evluted in Study, doule-lind, ctive-controlled tril in which previously untreted ptients with loclly dvnced or metsttic RCC received SUTENT mg dily on Schedule / (n=) or IFN-α 9 million Interntionl Units (MIU) (n=). The medin durtion of tretment ws. months (rnge:..) for SUTENT tretment nd. months (rnge:..) for IFN- tretment. Dose interruptions occurred in ptients () on SUTENT nd ptients (9) on IFN-. Dose reductions occurred in 9 ptients () on SUTENT nd 9 ptients () on IFN-. Discontinution rtes due to dverse rections were for SUTENT nd for IFN-. Most tretment-emergent dverse rections in oth study rms were Grde or in severity. Grde or tretment-emergent dverse rections were reported in versus of ptients on SUTENT versus IFN, respectively. Tle compres the incidence of common ( ) tretment emergent dverse rections for ptients receiving SUTENT versus IFN.
Tle. Adverse Rections Reported in Study in of Ptients With RCC Who Received SUTENT or IFN-* Tretment-Nïve RCC SUTENT (N=) IFN-α (N=) Adverse Rection All Grdes Grde - All Grdes Grde - Any Adverse Rection 99 99 Constitutionl Ftigue Astheni Fever Weight decresed Chills Chest Pin Influenz like illness < < < Gstrointestinl Dirrhe Nuse Mucositis/stomtitis Vomiting Dyspepsi Adominl pin c Constiption Dry mouth GERD/reflux esophgitis Fltulence Orl pin Glossodyni Hemorrhoids Crdic Hypertension Edem peripherl Ejection frction decresed Dermtology Rsh Hnd-foot syndrome Skin discolortion/yellow skin Dry skin Hir color chnges Alopeci Erythem Pruritus Neurology Altered tste d Hedche Dizziness Musculoskeletl Bck pin Arthrlgi Pin in extremity/lim discomfort 9 9 9 Endocrine Hypothyroidism Respirtory Cough Dyspne Nsophryngitis Orophryngel pin Upper respirtory trct infection Metolism/Nutrition Anorexi e Hemorrhge/Bleeding Bleeding, ll sites f Psychitric Insomni Depression g < * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: ARs=dverse rections; IFN=interferon ; N=numer of ptients; RCC=renl cell crcinom. Grde ARs in ptients on SUTENT included ck pin (), rthrlgi (<), dyspne (<), stheni (<), ftigue (<), lim pin (<) nd rsh (<). Grde ARs in ptients on IFN-α included dyspne (), ftigue (), dominl pin (<), nd depression (<). c Includes flnk pin. d Includes geusi, hypogeusi, nd dysgeusi. e Includes decresed ppetite. f Includes ptient with Grde gstric hemorrhge. g Includes depressed mood. < < < < < < < < < < < 9 9 9 < < < < < < < < Tretment-emergent Grde - lortory normlities re presented in Tle. Tle. Lortory Anormlities Reported in Study in of Tretment-Nïve RCC Ptients Who Received SUTENT or IFN- Tretment-Nïve RCC SUTENT (N=) IFN- (N=) All Grdes* Grde -*, All Grdes* Grde -*, Lortory Prmeter Gstrointestinl AST ALT Lipse Alkline phosphtse Amylse Totl iliruin Indirect iliruin Renl/Metolic Cretinine < < Cretine kinse 9 Uric cid Clcium decresed Phosphorus Alumin Glucose incresed Sodium decresed Glucose decresed < Potssium incresed Clcium incresed < Potssium decresed < Sodium incresed Hemtology Neutrophils 9 9 Hemogloin 9 9 Pltelets 9 Lymphocytes Leukocytes * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: ALT=lnine minotrnsferse; AST=sprtte minotrnsferse; IFN=interferon ; N=numer of ptients; RCC=renl cell crcinom. Grde lortory normlities in ptients on SUTENT included uric cid (), lipse (), neutrophils (), lymphocytes (), hemogloin (), pltelets (), mylse (), ALT (<), cretine kinse (<), cretinine (<), glucose incresed (<), clcium decresed (<), phosphorous (<), potssium incresed (<), nd sodium decresed (<). Grde lortory normlities in ptients on IFN- included uric cid (), lymphocytes (), lipse (), neutrophils (), mylse (<), clcium incresed (<), glucose decresed (<), potssium incresed (<), nd hemogloin (<). Long-Term Sfety in RCC The long-term sfety of SUTENT in ptients with metsttic RCC ws nlyzed cross 9 completed clinicl studies conducted in the first-line, evcizum-refrctory, nd cytokine-refrctory tretment settings. The nlysis included 9 ptients, of whom () were treted for t lest yers nd () for t lest yers. Prolonged tretment with SUTENT did not pper to e ssocited with new types of dverse rections. There ppered to e no increse in the yerly incidence of dverse rections t lter time points. Hypothyroidism incresed during the second yer of tretment with new cses reported up to yer. Adjuvnt Tretment of RCC The sfety of SUTENT ws evluted in S-TRAC, rndomized, doule-lind, plceocontrolled tril in which ptients who hd undergone nephrectomy for RCC received SUTENT mg dily (n=) on Schedule / or plceo (n=). The medin durtion of tretment ws. months (rnge:..9) for SUTENT nd. months (rnge:..) for plceo. Permnent discontinution due to n dverse rection occurred in of ptients on SUTENT nd on plceo. Adverse rections leding to permnent discontinution in > of ptients include hnd-foot syndrome nd ftigue/stheni. Dosing interruptions or delys occurred in () nd () ptients on SUTENT nd plceo, respectively. One hundred forty ptients (.) out of ptients in the SUTENT rm nd ptients () out of ptients in the plceo rm hd dose reductions.
Tle compres the incidence of common ( ) tretment-emergent dverse rections for ptients receiving SUTENT versus plceo. Tle. Adverse Rections Reported in S-TRAC in of Ptients With RCC Who Received SUTENT nd More Commonly Thn in Ptients Given Plceo* Adjuvnt Tretment of RCC SUTENT (N=) Plceo (N=) Adverse Rection All Grdes Grde - All Grdes Grde - Any Adverse Rection 99 Constitutionl Ftigue/Astheni Loclized edem Pyrexi < < < Gstrointestinl Mucositis/Stomtitis Dirrhe Nuse Dyspepsi Adominl pin c Vomiting Constiption Crdic Hypertension d Edem/Peripherl edem Dermtology Hnd-foot syndrome Hir color chnges Rsh e Skin discolortion/yellow skin Dry skin Neurology Altered tste f Hedche Musculoskeletl Pin in extremity Arthrlgi 9 9 9 Endocrine Hypothyroidism/TSH incresed < Metolism/Nutrition Anorexi/Decresed ppetite 9 < Hemorrhge/Bleeding Bleeding events, ll sites g < < * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: ARs=dverse rections; N=numer of ptients; RCC=renl cell crcinom. Includes edem loclized, fce edem, eyelid edem, perioritl edem, swelling fce, nd eye edem. Includes mucosl inflmmtion, stomtitis pthous ulcer, mouth ulcertion, tongue ulcertion, orophryngel pin nd orl pin. c Includes dominl pin, dominl pin lower, nd dominl pin upper. d Includes hypertension, lood pressure incresed, lood pressure systolic incresed, lood pressure distolic incresed, nd hypertensive crisis. e Includes dermtitis, dermtitis psorisiform, exfolitive rsh, genitl rsh, rsh, rsh erythemtous, rsh folliculr, rsh generlized, rsh mculr, rsh mculoppulr, rsh ppulr, nd rsh pruritic. f Includes geusi, hypogeusi, nd dysgeusi. g Includes epistxis, gingivl leeding, rectl hemorrhge, hemoptysis, nl hemorrhge, upper gstrointestinl hemorrhge, hemturi. Grde dverse rections in ptients on SUTENT included hnd-foot syndrome (), ftigue (<), dominl pin (< ), stomtitis (<), nd pyrexi (< ). Grde dverse rections in ptients on plceo included stheni (<) nd hypertension (<). Grde - lortory normlities tht occurred in of ptients receiving SUTENT include neutropeni (), thromocytopeni (), leukopeni (), lymphopeni (), elevted lnine minotrnsferse (), elevted sprtte minotrnsferse (), hyperglycemi (), nd hyperklemi (). Advnced Pncretic Neuroendocrine Tumors (pnet) The sfety of SUTENT ws evluted in Study, rndomized, doule-lind, plceocontrolled tril in which ptients with progressive pnet received SUTENT. mg dily continuous dosing (n=) or plceo (n=). The medin numer of dys on tretment ws 9 dys (rnge: - dys) for ptients on SUTENT nd dys (rnge: - dys) for ptients on plceo. Nineteen ptients () on SUTENT nd ptients () on plceo were on study for > yer. Dose interruptions occurred in ptients () on SUTENT nd ptients () on plceo. Dose reductions occurred in ptients () on SUTENT nd 9 ptients () on plceo. Discontinution rtes due to dverse rections were for SUTENT nd for plceo. Most tretment-emergent dverse rections in oth study rms were Grde or in severity. Grde or tretment-emergent dverse rections were reported in versus of ptients on SUTENT versus plceo, respectively. Tle compres the incidence of common ( ) tretment-emergent dverse rections for ptients receiving SUTENT nd reported more commonly in ptients receiving SUTENT thn in ptients receiving plceo. < < < < < 9 < < < Tle. Adverse Rections Reported in the pnet Study in of Ptients Who Received SUTENT nd More Commonly Thn in Ptients Given Plceo* pnet SUTENT (N=) Plceo (N=) Adverse Rection All Grdes Grde - All Grdes Grde - Any Adverse Rection 99 9 Constitutionl Astheni Ftigue Weight decresed Gstrointestinl Dirrhe Stomtitis/orl syndromes Nuse Adominl pin c Vomiting Dyspepsi 9 9 Crdic Hypertension Dermtology Hir color chnges Hnd-foot syndrome Rsh Dry skin Neurology Dysgeusi Hedche 9 Musculoskeletl Arthrlgi Psychitric Insomni Hemorrhge/Bleeding Bleeding events d Epistxis * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: N=numer of ptients; pnet=pncretic neuroendocrine tumors. Grde dverse rections in ptients on SUTENT included ftigue (). Includes phthous stomtitis, gingivl pin, gingivitis, glossitis, glossodyni, mouth ulcertion, orl discomfort, orl pin, tongue ulcertion, mucosl dryness, mucosl inflmmtion, nd dry mouth. c Includes dominl discomfort, dominl pin, nd dominl pin upper. d Includes hemtemesis, hemtochezi, hemtom, hemoptysis, hemorrhge, melen, nd metrorrhgi. Tle provides common ( ) tretment-emergent lortory normlities. Tle. Lortory Anormlities Reported in the pnet Study in of Ptients Who Received SUTENT pnet SUTENT Plceo N All Grdes* Grde -*, N 9 9 All Grdes* 9 Grde -*, Lortory Prmeter Gstrointestinl AST incresed ALT incresed Alkline phosphtse incresed Totl iliruin incresed Amylse incresed Lipse incresed Renl/Metolic Glucose incresed Alumin decresed 9 Phosphorus decresed Clcium decresed 9 Sodium decresed 9 Cretinine incresed Glucose decresed Potssium decresed Mgnesium decresed 9 9 Potssium incresed Hemtology Neutrophils decresed Hemogloin decresed Pltelets decresed Lymphocytes decresed * Common Terminology Criteri for Adverse Events (CTCAE), version.. Arevitions: ALT=lnine minotrnsferse; AST=sprtte minotrnsferse; N=numer of ptients; pnet=pncretic neuroendocrine tumors. Grde lortory normlities in ptients on SUTENT included cretinine (), lipse (), glucose decresed (), glucose incresed (), neutrophils (), ALT (), AST (), pltelets (), potssium incresed (), nd totl iliruin (). Grde lortory normlities in ptients on plceo included cretinine (), lkline phosphtse (), glucose incresed (), nd lipse ().
Venous Thromoemolic Events In ptients treted with SUTENT (N=) for GIST, dvnced RCC, djuvnt tretment of RCC nd pnet,. of ptients experienced venous thromoemolic event;. Grde -. Reversile Posterior Leukoencephlopthy Syndrome There hve een reports (<), some ftl, of ptients presenting with seizures nd rdiologicl evidence of reversile posterior leukoencephlopthy syndrome (RPLS). Ptients with seizures nd signs/symptoms consistent with RPLS, such s hypertension, hedche, decresed lertness, ltered mentl functioning, nd visul loss, including corticl lindness, should e controlled with medicl mngement including control of hypertension. Temporry suspension of SUTENT is recommended; following resolution, tretment my e resumed t the discretion of the treting helthcre provider. Pncretic Function Pncretitis ws oserved in ptients () receiving SUTENT for tretment-nïve RCC compred to ptient (<) receiving IFN-. In tril of ptients receiving djuvnt tretment for RCC, ptient (<) on SUTENT nd none on plceo experienced pncretitis. Pncretitis ws oserved in ptient () receiving SUTENT for pnet nd ptient () receiving plceo.. Postmrketing Experience The following dverse rections hve een identified during post-pprovl use of SUTENT. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. Blood nd lymphtic system disorders: hemorrhge ssocited with thromocytopeni*. Suspension of SUTENT is recommended; following resolution, tretment my e resumed t the discretion of the treting helthcre provider. Gstrointestinl disorders: esophgitis. Heptoiliry disorders: cholecystitis, prticulrly clculous cholecystitis. Immune system disorders: hypersensitivity rections, including ngioedem. Infections nd infesttions: serious infection (with or without neutropeni)*. The infections most commonly oserved with SUTENT tretment include respirtory, urinry trct, skin infections, nd sepsis/septic shock. Musculoskeletl nd connective tissue disorders: fistul formtion, sometimes ssocited with tumor necrosis nd/or regression*; myopthy nd/or rhdomyolysis with or without cute renl filure*. Ptients with signs or symptoms of muscle toxicity should e mnged s per stndrd medicl prctice. Renl nd urinry disorders: renl impirment nd/or filure*. Respirtory disorders: pulmonry emolism*. Skin nd sucutneous tissue disorders: pyoderm gngrenosum, including positive dechllenges. Vsculr disorders: rteril thromoemolic events*. The most frequent events included cererovsculr ccident, trnsient ischemic ttck, nd cererl infrction. *including some ftlities. DRUG INTERACTIONS. CYPA Inhiitors Strong CYPA inhiitors such s ketoconzole my increse sunitini plsm concentrtions. Selection of n lternte concomitnt mediction with no or miniml enzyme inhiition potentil is recommended. Concurrent dministrtion of SUTENT with the strong CYPA inhiitor, ketoconzole, resulted in 9 nd increses in the comined (sunitini + primry ctive metolite) C mx nd AUC - vlues, respectively, fter single dose of SUTENT in helthy volunteers. Codministrtion of SUTENT with strong inhiitors of the CYPA fmily (e.g., ketoconzole, itrconzole, clrithromycin, tznvir, indinvir, nefzodone, nelfinvir, ritonvir, squinvir, telithromycin, voriconzole) my increse sunitini concentrtions. Grpefruit my lso increse plsm concentrtions of sunitini. A dose reduction for SUTENT should e considered when it must e codministered with strong CYPA inhiitors [see Dosge nd Administrtion (.)].. CYPA Inducers CYPA inducers such s rifmpin my decrese sunitini plsm concentrtions. Selection of n lternte concomitnt mediction with no or miniml enzyme induction potentil is recommended. Concurrent dministrtion of SUTENT with the strong CYPA inducer, rifmpin, resulted in nd reduction in the comined (sunitini + primry ctive metolite) C mx nd AUC - vlues, respectively, fter single dose of SUTENT in helthy volunteers. Codministrtion of SUTENT with inducers of the CYPA fmily (e.g., dexmethsone, phenytoin, crmzepine, rifmpin, rifutin, rifpentin, phenoritl, St. John s Wort) my decrese sunitini concentrtions. St. John s Wort my decrese sunitini plsm concentrtions unpredictly. Ptients receiving SUTENT should not tke St. John s Wort concomitntly. A dose increse for SUTENT should e considered when it must e codministered with CYPA inducers [see Dosge nd Administrtion (.)].. In Vitro Studies of CYP Inhiition nd Induction In vitro studies indicted tht sunitini does not induce or inhiit mjor CYP enzymes. The in vitro studies in humn liver microsomes nd heptocytes of the ctivity of CYP isoforms CYPA, CYPA, CYPB, CYPC, CYPC9, CYPC9, CYPD, CYPE, CYPA/, nd CYPA9/ indicted tht sunitini nd its primry ctive metolite re unlikely to hve ny cliniclly relevnt drug-drug interctions with drugs tht my e metolized y these enzymes. USE IN SPECIFIC POPULATIONS. Pregnncy Risk Summry Bsed on niml reproduction studies nd its mechnism of ction, SUTENT cn cuse fetl hrm when dministered to pregnnt womn [see Clinicl Phrmcology (.)]. There re no ville dt in pregnnt women to inform drug-ssocited risk. In niml developmentl nd reproductive toxicology studies, orl dministrtion of sunitini to pregnnt rts nd rits throughout orgnogenesis resulted in tertogenicity (emryolethlity, crniofcil nd skeletl mlformtions) t. nd. times the AUC in ptients dministered the recommended dily doses (RDD), respectively (see Dt). Advise pregnnt women or femles of reproductive potentil of the potentil hzrd to fetus. The ckground risk of mjor irth defects nd miscrrige for the indicted popultions re unknown. However, the estimted ckground risk in the United Sttes (U.S.) generl popultion of mjor irth defects is nd of miscrrige is of cliniclly recognized pregnncies. Dt Animl Dt In femle fertility nd erly emryonic development study, femle rts were dministered orl sunitini (.,., mg/kg/dy) for dys prior to mting nd for dys fter mting. Emryolethlity ws oserved t mg/kg/dy (pproximtely times the AUC in ptients dministered the RDD of mg/dy). In emryo-fetl developmentl toxicity studies, orl sunitini ws dministered to pregnnt rts (.,.,, mg/kg/dy) nd rits (.,,, mg/kg/dy) during the period of orgnogenesis. In rts, emryolethlity nd skeletl mlformtions of the ris nd vertere were oserved t the dose of mg/kg/dy (pproximtely. times the systemic exposure [comined AUC of sunitini + primry ctive metolite] in ptients dministered the RDD). No dverse fetl effects were oserved in rts t doses mg/kg/dy (pproximtely times the AUC in ptients dministered the RDD). In rits, emryolethlity ws oserved t mg/kg/dy (pproximtely times the AUC in ptients dministered the RDD), nd crniofcil mlformtions (cleft lip nd cleft plte) were oserved t mg/kg/dy (pproximtely. times the AUC in ptients dministered the RDD of mg/dy). Sunitini (.,, mg/kg/dy) ws evluted in pre- nd postntl development study in pregnnt rts. Mternl ody weight gins were reduced during gesttion nd lcttion t doses mg/kg/dy (pproximtely. times the AUC in ptients dministered the RDD). At mg/kg/dy (pproximtely times the AUC in ptients dministered the RDD), reduced neonte ody weights were oserved t irth nd persisted in the offspring of oth sexes during the prewening period nd in mles during postwening period. No dverse developmentl effects were oserved t doses mg/kg/dy.. Lcttion There is no informtion regrding the presence of sunitini nd its metolites in humn milk. Sunitini nd its metolites were excreted in rt milk t concentrtions up to -fold higher thn in plsm (see Dt). Becuse of the potentil for serious dverse rections in restfed infnts from SUTENT, dvise lctting womn not to restfeed during tretment with SUTENT nd for t lest weeks fter the lst dose. Dt Animl Dt In lctting femle rts dministered mg/kg, sunitini nd its metolites were excreted in milk t concentrtions up to fold higher thn in plsm.. Femles nd Mles of Reproductive Potentil Bsed on niml reproduction studies nd its mechnism of ction, SUTENT cn cuse fetl hrm when dministered to pregnnt womn [see Pregnncy (.) nd Clinicl Phrmcology (.)]. Pregnncy Testing Femles of reproductive potentil should hve pregnncy test efore tretment with SUTENT is strted. Contrception Femles Advise femles of reproductive potentil to use effective contrception during tretment with SUTENT nd for t lest weeks fter the lst dose. Mles Bsed on findings in niml reproduction studies, dvise mle ptients with femle prtners of reproductive potentil to use effective contrception during tretment with SUTENT nd for weeks fter the lst dose. Infertility Bsed on findings in nimls, mle nd femle fertility my e compromised y tretment with SUTENT [see Nonclinicl Toxicology (.)].. Peditric Use The sfety nd efficcy of SUTENT in peditric ptients hve not een estlished. Physel dysplsi ws oserved in cynomolgus monkeys with open growth pltes treted for months ( month dosing,, mg/kg/dy; cycles of dosing.,.,. mg/kg/dy) with sunitini t doses tht were >. times the RDD sed on systemic exposure (AUC). In developing rts treted continuously for months (.,., nd. mg/kg) or cycles (.,., nd. mg/kg/dy), one normlities consisted of thickening of the epiphysel crtilge of the femur nd n increse of frcture of the tii