GEFTINAT吉非替尼片劑說明書全文(中英對照翻譯

1、$)edai PeiUon$: In populalion based data analyses no rclatioiuhips wre identified bciwocn predicted steady state irough concentrution and patent age. body urighr gender ethnicity or crcininc clearance. Fediatne; There arc nopharnucokincuc data in pcduiric patients.For (he use only of a Canocr SpccuU

2、rt or 2 Hospital of 汕 lnsutulion|GEFTINAT*(Ccniinib Tablets IPiCompo sitionEach film coated ubici conums: Gcliiinib IP 250 mgDESCRIPTIONGKFTINAT (gcfltinib ubicis IP) contain 250 mg of gcliiinib IP and arc availaUc as reddish brown film-voaicd tablets cngracd with GEFTINAT 0(1 one side and 250 on an

3、other side lor daity orul administrution, Gdllinib i& an anilinoquinazoliiK with the cbcmicat name 4-Quinazotin ami IK. N-J7-mcihoxy-6-|3-l-inopholml propoxy). Il has ihc molecular formula C22H24C1F4O3a relative molecular mass of 446,9 and u a white-colored powder. Gefitinib b a free base.CLINICAL P

4、HARMACOLOGYMcclunism of Action: The mechanism of ihc cUnicat antiiumor acdoti of gefitinib is not fully charMlcrized. Ccliiinib inhibits the iiMraccItular phosphorylation of numerous tyrosine kinases associaicd wiih traiumcmtvanc cell surface nxxpior including ihc lyro&inc kinases associMcd with ihc

5、 cpidcnnal powih factor rcccpiof (EGFRTK). EGFR Is expressed on the cell surface of many normal celts and cancer cells. No clinical studies have been perform tiui demonstrate a cotTcUUon between EGFR rcccpior expression and response to gcfiimih.PharmacokiiKdcs: Gcfltinib k absorbed slowly aficroral

6、adminisiraiion with mean bioavditabiljty of 60%, Elimination is by metabolism primarily CYP3A41 and excretion in feces. The Emin獨iai bathlife is about 48 hours. Daily oral adminisiraiion of jcfiliiUb 10 cancer paiients resulted in a 2 fold accumulation compared 10 single dose ddministrution, Steady

7、stale plasma conccmrations arc achieved within IObys.Absorpdon and Disiribuiion:Cdiiinib is slowly dMorbed. with peak plasma levels occurring 37 hciuni after doting and mean oral bigwibbiiny of 60%. Bioavailahility js not significantly altered by food. Gcfltinib is extensively disiributed thmuglKMU

8、the with a mean sicady stale volume of distritxuion of I400L following iniravcnous adminisiraiion. In vitro binding of gcfhinib to human plasma proteins (serum aibumm and ahacid glycoprotcini is 90% and is independent of drug conccncraiions.Metabolism and Elimindiion: Gcfltinib undergoes extensive h

9、epatic mciabolistn in humans, prcdominanily by CYP3A4. Three sites of bioiransformatjon have been identified: metabolism of the N-propoxy morpholino-dcmcihyUtion of the mcthoxy-subMiiucni on the quinazoliM. and oxidadvc dcnuoruidiion of the tulo$cn/cd phenyl group, nvc nwubotil” were identified in h

10、uman pbsma. Only Mcsmchyl 踽fiimib exposure comparable lo gdiiinik Although this mcidboliic has similar ECFR-TK activity to gcliiinib in the isoUicd enzyme assay, it had only I/I4 of the potency of gcHiinib in one of the cell- based assays.Ccliimib ii ekared primarily by the live乙 with total plasma c

11、karancc and diminadon tulfdife values of 595 mL/min and 48 hours, rcspeciiwly. after iMmvenous adminhmUon. Excrciion is prcdominanily via the feces (86% with rnul elimination of drug and metabolites accounting for leu than 4除 of the Administered dose.Hepatic Impairment: The influence of bepatk metas

12、tases with cicvaiion of scrum a平artatc aminotransferase iaST/SGOTL alkaline phosphat磁. and bilirubin has been evaluated in Salients with normal (14 paiknut mcxicraicly clcvaicd (B paiientsi 4站 severely ckvuicd(4 potienut of one or more of ihese biochemical parameicrs, BKicnis with mcxlcraicly and se

13、verely cicvaicd biochemical Hwr abnormalities tud ndnib pharmacokinetics similar 10 individual wiihoui tiver abnonnalitics isec PRECAlEONS scciionxRenat Impairmcm: No clinic at siudies ttcre conducted with Gdliinib in patknu with sewrely compromised renal funciion iscc PRECAUTIONS section), Gcfidnib

14、 and iis metabolites arc no( signilicantly excreted via tbe kidney i4XDtu-Dnig liMcraciions: In human liver mkrosomc siudics. cfiiimb had no inhibitory effect on CYPlAl CYP2C9. and CYP3A4 xUvW” at conccMraiions ranging from 2-5000 ng/ mk Al ihc highcM concemrion siudicd 5000 ng/mL) gcfitinib inhibit

15、ed CYP2C19 by 24嘆 and CYP2D6 by 43%. Exposure to metoprolol a substralc of CYP2O6. was I IK readied by 3g when ii was given in combinatixi with gcliiinib tuic (to maintain ibc gastric pH abow pH 5.0reduced mean gcliiinib AUC by 44% (see P RECAVTIONS-Drug Inicracdons scclkm).International Normatized

16、Ratio (INRi elevations and/or bleeding even恬 have been reported in some paiients taking wMfarin while on Gcfltinib tbempy. Palknts uking warfarin should be moniiorcd regularly for changes in proihmmbin lime or INR (sec PRECAlTTIONS-Dtug Inicrdclions and ADVERSE REACTIONS scctiotutClinical Studies: N

17、on-Small Celt Lung Cancer n-small cell lung cancer whose disease 血 pregressed after at Icasi tuo prior chcmoihcrupy regimens including a platinum drug and docetaxel Gcfltinib was taken mcc daily ai appraximcly ihc same time each day. Two hundred and sixteen luiients received kndmk 102 (47%I and H4 (

18、53除 J receiving 250 mg and SOO mg daily dose顯 rcspcciiwly, Siudy patkm demofTAphies and disease cturacicristics arc summarized in Table L Forty-one pcrccM of the paUcncs tud received two prior ircwmcni Fcgimcns. 33% three prior treatment regimens, and 25% four or more prior trvaiment regimens. Effec

19、li、vnc“ of Gcfidnib as third line tberupy was dctermiiKd in the 142 evatuabk paiients with documcnicd disease prossion on platinum and docciaxcl therapies who had had unxccpublc toxicit)- on ihcsc agents.Table 1: Demographic and Disease Characicrisdc Gdiiinib DoseCharactcrisdc250 tng/day500 mgZday N

20、=7tt%)Age Groupyears4365)434H54)Female2845168)6282)No (Never smoked)2H32)MU8Baseline WHO PcrfcHrmancc Suius014121)9(I2I3655)53(701215(23)148Noi Recorded1(KOITumor HistologySquamous9(14H(I4Adenocarcinoma47(71150166Undiffcrmiaicd他4Lar CellJ2Squamous and Adenocarcinoma37Nol RecordedOlO)2Cuncm Disease S

21、tatusLocally AdvancedH(I75(7)McUMaliC837H93)Table 2 show s tumor rcqxmsc and response duration. The owrali response tm for the 250 and 500 mg doses combined was 10.6% (95% Cl: 6%. 168怪 Response rales appeared lo be highly variable in subgroups of ihc trvaicd populaiion: 5.1% f4/79 in mal”. 17 J% 11/

22、63 in females. 465f IOS) in prcvioits orcitrrcm smokers. 29.4% UO/54) in nonsmokers. 12.4% 12/97) with Renocardnofna hisiology. and 6,7% 45wiih oihcr NSCLC histologies. Similar differences in response ttrre seen in a mutiinatioiul study in patients who had received I or 2 prior chemotherapy repmend

23、ai least I of whkh wm pIdUnunbbased. In respondent, the medun time from diagnosis lo siudy randomization was 16.7 months angc 8io 34 nxmthsbTable 2 : Efficacy ResultsObjociivc Tumor Response Rate(% 95% ClM&ian Durion of Objeedve Rcponsc( months) Range (month引250 mg tN=66) 13.6500 mg (N=76)Z9Combined

24、 lN=42i 10.66,4-24,310-16.46XM6.8&94.6-18.6+4,544O67.04,4.I8.6tAliablc Plicnts+=4414 arc cmgoingNon-Smatl Cell Lung Cancer iNSCLO: Sludi” of Firsi-linc Trcaimeni inreceive Gefitinib 250 mg daily. Ccfiiinib 500 mg daily, or placebo inCombination wiih Chcmoibcrapy- Ttvo large trials were coixhicicd in

25、 chcmothcrapy-naivc patients with stage 111 and IV noibsnull cell lung cancer Two tbotuand one hundred thirty patients were randomized to combination wiih pidtinum-based chemotbery rtgimcRs. The chemotherapies pven in these firsblinc triab were gcmcitabmc and cis-plaiinum (N=lccthv response rates i&

26、oc CLINICAL PHARMACOLOGY - Clinical Studies scviioni. There arc no coMFoltcd trials dcmonMraiin d clinical bcncfiL such as improvcmcni in disc-rcled sympioms or increased survival.Results from iwo brjc. controlled, randomized triaU in firs tine trcaimcnt of non-small cell lung cancer showed no bendl

27、l from adding GEFTINAT to doubkl. platinum-based chcmoUKwpy. Therefore, GEFTINAT is nol indicated 仙 use in ihis scuinCONTRAINDICATIONSGEFTINAT is contruindkMcd in paiicnts with severe hypcrscnsiiiniy to gefitinib or to any other component of GEFTINAT-WARNINGS Pulmonary Tbxkiiy Cases of inicrsiitiat

28、lung disease (ILDi have been observed in patents receiving Gefitinib al an ovcrali inckknee of about 1%. Approximately 13 oi the eases have been faial. The reported incidence of HD was about 2% in the JajuiKsc jXMihmarkcting experience, about 0.3% in approximaicly 23.000 patients trvaicd wiih Gefitm

29、ib in 3 US expanded ccc pmgram and aboix in the studies of (irsNinc use in NSCLC ibut with similar rates in both trcaiment and placebo groups), Repons hag described the adgrse Ctni as imcrstiiial pneumonia, pneumonitis and alwoUlb. FMicnu o伽 prcscni with ihc acute onset of dyspnea, somciimcs aswciai

30、cd wiih cough or lowgra(k fever, often becoming severe within a short lime and requiring hospiudizalion, ILD has occurred in paticnu who have Foccivcd prior radiation therapy (31 餐 of reported cascsi. prior chemotherapy (57% of rqxmcd paticnu). and no previous therapy (12% of rcpon&l eases). Paiknis

31、 wiih concurrem idiqMlhic pulmonary fibrosis who$c condidon worsens while receiving Gcliiinib have been observed to an increased monaliiy companxl u those without concutTCM idiopathic putmonary fibrosis.In the cvcM of acme onset or worsening of pulmcmary symptoms dyspnea, cough, fcvert Gefitinib ihc

32、rapy should be inicmipied and aprompi mvettigaiion of these symploms should occur. H iMcrMidal lung disease is conHxmcd. iqriaidy iscc PRECAVTlONS-bfofmaiion for Palkms. ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION-Dosa Adjitstmcni scciionsKPregnancy CaicgOQ Dmg/kg from the beginning of organogen

33、esis to ihc end of weaning gaw birth, ihcre was 3 rcduciion in the number of offspring bom alive. This cITcci was more xvem dt 20 mg/kg and was accompanied by high ncouial monaliiy so(m after panuntion. In this study a dose oi 1 mg/kg caused no adverse effects.In rabbils. a dose of 20 mg/kday (240 m

34、”m2 aboui twice theGdiiinib may C3usc fcul harm when administered to a prcgnaiu woman. A single dose study m rs showed ihat gcliiinib crosses ihc ptacenu after an oral do&c of 5 mg/kj 30 mg/mZ . aboui 1/5 ihc recommended human dose on a ing/m2 basis). When pregnant ruts were treated with 5 recommend

35、ed dose in humans on 1 mm2 basis) caused reduced fetal ucighl. There arc no adcqiuic and wcU-controIlcd studies in prcgiuni women using Gefitinib. If Gefitinib is used during prcnancy or if ihc paiicnt becomes premnant while receiving this drug, she should be apprised of the poicneial hazard to the

36、fetus ar poicnual risk far loss of the pregnancy.AdwrscEvcMPRECAUTIONSFkpaloccnichyAsymp sccre or pcrstMcnt diarrhea. luusea. anorexia, or vomiling. as these have sometimes been associated with dchydmiion:2 an onset ar worsening of pulmonary sympcewm. jc shortiks of breath or cough:3aii eye irrition

37、: or.4) any other new sympiom (see WARNINGS- Pulmonary Tbxicii)； ADVERSE REACTIONS and DOSAGE AND ADMIN ISTRATION-Dosagc Adjiutmeni sediemWbmen of childbearing potcmial must be advised to 鼻void becoming prcgnani (see WARNINGS-Prcgnancy Caicgofj- D).Iug InicraciionsSubstances ihal arc induces of CVP3

38、A4 activity increase the mcubolism cif gcliiinib and decrease its plasma conccntratioiu. In patents receiving a potent CYP3A4 inducer such “ nfampkin or phenytoin, a dose increase lo 500 mg daily should be considered in the absence of severe adverse drug reaction, and cKmcal response and adverse eve

39、nts should be carefully nxMiiiorcdsee CLINICAL PHARMACOLOGY- PlunnacokiiKUc SDrug-Drug Inicruciions and IXSAGE AND ADM IN-1 STRATI ON- ga 共 AdjuMmcni sectiem Entcmaiional NwnuliMd fUlki (1NR elevations and/or bleeding evenb have been reported in some patknis ukin warfarin while on GefUinib therapy.

40、Patients taking warfaiin should be monitored regularly for changes in prothrombin time or INR iscc CLINICAL PHARMACOLOGY-Phaxmacokincdcs-Dnig-Drug Intcracdons and ADVERSE REACTIONS wxikwishSubstances lhal arc potent mhibiior of CYP3A4 activity leg. kctoconazolc and ibxonazokdecrease 趺fiUnih metaboli

41、sm and increase gdllinib plasma conccMra-tions. This increase may be ctinicatly rckvani as expcrienccs arc related to dose and exposure: therefore, caudon should be lucd when administering CYP3A4 inhibitors with GEFTINAT (see CLINICAL PHARMACOLOGY-Pharmacokinciics-Onig-Drug Intcracdons and ADVERSE R

42、EACTIONS scctionsi.Drugs that cause Msnifkani susuined elevation in gastric pH (hiMamix H 2 -rccqxor aiuajomsls such 3$ raniUdinc or cimcddinc) may reduce plasma conccnirations of Gefitinib and therefore poicncially may reduce crtkacy(scc CLINICAL PHARMACOLOGY- DaigDaij liMcractions seciiooi.Carcino

43、genesis. MuugencMs. ImpairmcM of Fertility Gefitinib has been tested for genotoxicity in a series of in vitro Ibacicrial muuiion. mouse lymphoma, and human lymphocyte) assays and an in vivo mi mkronuckus tesL Under the condiiions of these assays, gcfiiimb did noi cause gene lie damage.Cardnojcmci導 s

44、tudies have not been conducted with gefitinib.PregnancyPregnancy Catcgoiy D (see WARNINGS and PRECaCTIONS- Informatioo for Patients sections).Nursing Mothersh is not known whether Gefitinib Is excreted in human milk. Following oral administrion of carbon-14 Labeled gefitinib lo rats 14 days po口panum

45、. cohccm祕ions of 總dioKCivity in milk wre hi火r than in blood. Levels of gcfidnib and lU metabolites were I l-io-l9-fo(d higher in milk than in blood, after oral cxpmufc of lactaiin rals lo a dose of 5 mg/kg. Because many (kugs art excreted in human milk and because of the pmcndal for serious advez rc

46、aclions in nursing infants, women should be advised against brvdslJceding while receiving Gefitinib ibcrupy.Pediatric VseSafely and cffccdvencss of Cdiimib in pediathe pclients tuw no( been sludbcd.Geriatric UseOf ihc toul number of juiients panicipating in triaU of second- and third-line Gefitinib

47、ircatmciM of NSCLC. 65% were aged 64 years or kss. 30,5欣 ttcrc aged 65 lo 74 years, and S除 of patknu were aged 75 years or older No differences in safety or efficacy were observed bciwocn younger and older pienu.Paiicnts with Severe Renal ImpairmemThe ciicci of severe renal impairmcm on the pturmacokinciic of gcfidnib IS not known, Putknis wiih severe roul impairmcni should be treked wiih cautiaiients who received ihc 250 mgZday dose of Gefitinib monoihcrapy for trvaimcm of NSCLC. Onl