達格列凈片F(xiàn)ARXIGA(dapagliflozin)FDA藥品說明書翻譯

FULLPRESCRIBINGINFORMATIONINDICATIONSANDUSAGE適應(yīng)癥和用途FARXIGA(dapagliflozin)isindicatedasanadjuncttodietandexercisetoimproveglycemiccontrolinadultswithtype2diabetesmellitus[seeClinicalStudies(14)].本藥用于配合飲食控制和運動改善2型糖尿病患者的血糖控制。LimitationofUse使用限制FARXIGAisnotrecommendedforpatientswithtype1diabetesmellitusorforthetreatmentofdiabeticketoacidosis.本藥不適用于1型糖尿病或糖尿病酮癥酸中毒患者。DOSAGEANDADMINISTRATION用法用量RecommendedDosing推薦劑量TherecommendedstartingdoseofFARXIGAis5mgoncedaily,takeninthemorning,withorwithoutfood.InpatientstoleratingFARXIGA5mgoncedailywhorequireadditionalglycemiccontrol,thedosecanbeincreasedto10mgoncedaily.推薦起始劑量為一次5mg,—日1次，早晨服用，可與或不與食物同服。對本藥一次 5mg,一日1次劑量耐受且須更多血糖擴指著，可增至一次 10mg，一日1次。Inpatientswithvolumedepletion,correctingthisconditionpriortoinitiationofFARXIGAisrecommended[seeWarningsandPrecautions(5.1),UseinSpecificPopulations(8.5,8.6),andPatientCounselingInformation(17)].血容量減少患者，推薦用藥前應(yīng)先糾正血容量減少。PatientswithRenalImpairment腎功能不全時劑量AssessmentofrenalfunctionisrecommendedpriortoinitiationofFARXIGAtherapyandperiodicallythereafter.建議在開始使用本藥前及使用期間定期評估腎功能。2FARXIGAshouldnotbeinitiatedinpatientswithaneGFRlessthan60mL/min/1.73m.腎小球濾過率v60ml/(min/1.73m2)患者不得開始用藥。Nodoseadjustmentisneededinpatientswithmildrenalimpairment(eGFRof60mL/min/1.73morgreater).輕度腎功能損害者[腎小球濾過率＞60ml/(min/1.73m2)]無需調(diào)整劑量。2FARXIGAshouldbediscontinuedwheneGFRispersistentlylessthan60mL/min/1.73m[seeWarningsandPrecautions(5.2)andUseinSpecificPopulations(8.6)].腎小球濾過率持續(xù)v60ml/(min/1.73m2)時應(yīng)停藥。?l”?l”5”engravFARXIGA5mgtabletsareyellow,biconvex,round,film-coatedtabletswithonesideand“1427”engravedontheotherside.FARXIGA10mgtabletsareyellow,biconvex,diamond-shaped,film-coatedtabletswithengravedononesideand “1428”engravedontheotherside.達格列凈片(1)5mg。(2)10mg。CONTRAINDICATIONS禁忌癥HistoryofaserioushypersensitivityreactiontoFARXIGA[seeAdverseReactions(6.1)].Severerenalimpairment,end-stagerenaldisease(ESRD),orpatientsondialysis[seeUseinSpecificPopulations(8.6)].對本藥有嚴(yán)重過敏史者。重度腎功能損害、晚期腎病患者。透析患者。WARNINGSANDPRECAUTIONS警告和注意事項5.1Hypotension低血壓FARXIGAcausesintravascularvolumecontraction.SymptomatichypotensioncanoccurafterinitiatingFARXIGA[seeAdverseReactions(6.1)]particularlyinpatientswithimpairedrenal2function(eGFRlessthan60mL/min/1.73m),elderlypatients,orpatientsonloopdiuretics.BeforeinitiatingFARXIGAinpatientswithoneormoreofthesecharacteristics,volumestatusshouldbeassessedandcorrected.Monitorforsignsandsymptomsofhypotensionafterinitiatingtherapy.本藥可引起血管收縮，開始用藥后可出現(xiàn)癥狀性低血壓。尤其腎功能損害者[(腎小球濾過率v60ml/(min/1.73m2)]、老年患者、使用髓袢利尿藥的患者。以上患者開始使用本藥前應(yīng)先評估并糾正血容量狀況。用藥后應(yīng)監(jiān)測低血壓跡象和癥狀。ImpairmentinRenalFunction腎功能損害FARXIGAincreasesserumcreatinineanddecreaseseGFR.Elderlypatientsandpatientswithimpairedrenalfunctionmaybemoresusceptibletothesechanges.AdversereactionsrelatedtorenalfunctioncanoccurafterinitiatingFARXIGA[seeAdverseReactions(6.1)].RenalfunctionshouldbeevaluatedpriortoinitiationofFARXIGAandmonitoredperiodicallythereafter本藥可增加血清肌酸酐并降低腎小球濾過率。老年患者和腎功能損害者對此類作用更為敏感。用藥后可能出現(xiàn)與腎功能相關(guān)的不良反應(yīng)，開始使用本藥前及使用期間應(yīng)定期評估腎功能。HypoglycemiawithConcomitantUsewithInsulinandInsulinSecretagogues低血糖(與胰島素和胰島素促泌劑合用時)Insulinandinsulinsecretagoguesareknowntocausehypoglycemia.FARXIGAcanincreasetheriskofhypoglycemiawhencombinedwithinsulinoraninsulinsecretagogue[seeAdverseReactions(6.1)].Therefore,alowerdoseofinsulinorinsulinsecretagoguemayberequiredtominimizetheriskofhypoglycemiawhentheseagentsareusedincombinationwithFARXIGA.已知胰島素和胰島素促泌劑可引起低血糖。本藥與以上兩種藥物合用時發(fā)生低血糖的風(fēng)險增加。合用時可能需降低胰島素或胰島素促泌劑的劑量，以降低低血糖風(fēng)險。GenitalMycoticInfections生殖器霉菌感染FARXIGAincreasestheriskofgenitalmycoticinfections.Patientswithahistoryofgenitalmycoticinfectionsweremorelikelytodevelopgenitalmycoticinfections[seeAdverseReactions(6.1)].Monitorandtreatappropriately.本藥增加發(fā)生生殖器霉菌感染的風(fēng)險。有生殖器霉菌感染病史的患者更易出現(xiàn)。應(yīng)進行適當(dāng)?shù)谋O(jiān)測和治療。IncreasesinLow-DensityLipoproteinCholesterol(LDL-C)低密度脂蛋白(LDL-C)升高IncreasesinLDL-CoccurwithFARXIGA[seeAdverseReactions(6.1)].MonitorLDL-CandtreatperstandardofcareafterinitiatingFARXIGA.本藥可使LDL-C升高，開始用藥后應(yīng)監(jiān)測LDL-C并進行標(biāo)準(zhǔn)治療。BladderCancer膀胱癌Across22clinicalstudies,newlydiagnosedcasesofbladdercancerwerereportedin10/6045patients(0.17%)treatedwithFARXIGAand1/3512patient(0.03%)treatedwithplacebo/comparator.Afterexcludingpatientsinwhomexposuretostudydrugwaslessthanoneyearatthetimeofdiagnosisofbladdercancer,therewere4caseswithFARXIGAandnocaseswithplacebo/comparator.Bladdercancerriskfactorsandhematuria(apotentialindicatorofpreexistingtumors)werebalancedbetweentreatmentarmsatbaseline.ThereweretoofewcasestodeterminewhethertheemergenceoftheseeventsisrelatedtoFARXIGA.22項臨床試驗中，有0.17%(10/6045)使用本藥和0.03%(1/3512)使用安慰劑患者出現(xiàn)新近診斷的膀胱癌的報道。排除診斷為膀胱癌時用藥不足一年的患者，有 4例使用本藥患者出現(xiàn)膀胱癌(使用安慰劑患者0例)。開始用藥時在治療組中評估膀胱癌風(fēng)險因素和血尿 (已存在腫瘤的潛在指標(biāo))，評估人數(shù)過少無法確定膀胱癌是否與本藥相關(guān)。ThereareinsufficientdatatodeterminewhetherFARXIGAhasaneffectonpre-existingbladdertumors.Consequently,FARXIGAshouldnotbeusedinpatientswithactivebladdercancer.Inpatientswithpriorhistoryofbladdercancer,thebenefitsofglycemiccontrolversusunknownrisksforcancerrecurrencewithFARXIGAshouldbeconsidered.尚無充分的數(shù)據(jù)確定本藥對已存在的膀胱癌是否有作用。故活動期膀胱癌患者不得用藥。有膀胱癌病史者，用藥時應(yīng)權(quán)衡血糖控制與復(fù)發(fā)的未知風(fēng)險。MacrovascularOutcomes大血管病變TherehavebeennoclinicalstudiesestablishingconclusiveevidenceofmacrovascularriskreductionwithFARXIGAoranyotherantidiabeticdrug.尚無本藥或其他任一抗糖尿病藥降低大血管病變風(fēng)險的臨床試驗證據(jù)。ADVERSEREACTIONS不良反應(yīng)Thefollowingimportantadversereactionsaredescribedbelowandelsewhereinthelabeling:下列重要不良反應(yīng)已在說明書其他章節(jié)討論：Hypotension[seeWarningsandPrecautions(5.1)]ImpairmentinRenalFunction[seeWarningsandPrecautions(5.2)]HypoglycemiawithConcomitantUsewithInsulinandInsulinSecretagogues[seeWarningsandPrecautions(5.3)]GenitalMycoticInfections[seeWarningsandPrecautions(5.4)]IncreasesinLow-DensityLipoproteinCholesterol(LDL-C)[seeWarningsandPrecautions(5.5)]BladderCancer[seeWarningsandPrecautions(5.6)]低血壓、腎功能損害、低血糖 (與胰島素和胰島素促泌劑合用時 )、生殖器霉菌感染、LDL-C升高、膀胱癌。6.1ClinicalTrialsExperience臨床試驗經(jīng)驗Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinclinicalpractice.由于臨床試驗是在各種不同條件下進行的，觀察到的不良反應(yīng)發(fā)生率不能直接與其他臨床試驗中的發(fā)生率相比較，可能也不能反應(yīng)臨床實踐中觀察到的發(fā)生率。Poolof12Placebo-ControlledStudiesforFARXIGA5and10mg12項本藥5mg、10mg安慰劑對照試驗合并數(shù)據(jù)ThedatainTable1isderivedfrom12placebo-controlledstudiesrangingfrom12to24weeks.In4studiesFARXIGAwasusedasmonotherapy,andin8studiesFARXIGAwasusedasadd-ontobackgroundantidiabetictherapyorascombinationtherapywithmetformin[seeClinicalStudies(14)].表1中的數(shù)據(jù)來源于12項安慰劑對照試驗，試驗時長 12-24周。其中4項為本藥單藥治療，另外8項為本藥加入標(biāo)準(zhǔn)糖尿病治療方案或與二甲雙胍合用。Thesedatareflectexposureof2338patientstoFARXIGAwithameanexposuredurationof21weeks.Patientsreceivedplacebo(N=1393),FARXIGA5mg(N=1145),orFARXIGA10mg(N=1193)oncedaily.Themeanageofthepopulationwas55yearsand2%wereolderthan75yearsofage.Fiftypercent(50%)ofthepopulationweremale;81%wereWhite,14%wereAsian,and3%wereBlackorAfricanAmerican.Atbaseline,thepopulationhaddiabetesforanaverageof6years,hadameanhemoglobinA1c(HbA1c)of8.3%,and21% hadestablishedmicrovascularcomplicationsofdiabetes.Baselinerenalfunctionwasnormalormildlyimpairedin92%ofpatients2andmoderatelyimpairedin8%ofpatients(meaneGFR86mL/min/1.73m ).試驗數(shù)據(jù)中，2338名患者接受本藥治療，平均暴露時間為 21周。其中安慰劑組1393名患者、本藥5mg組1145名患者、本藥10mg組1193名患者，患者均接受一日1次用藥。受試者平均年齡55歲，其中2%>75歲。50%為男性，81%為白種人，14%為亞洲人，3%為黑人或非暨美國人。基線水平，受試者患病平均年數(shù)為 6年，糖化血紅蛋白(HbA1c)平均值為8.3%，其中21%受試者出現(xiàn)糖尿病微血管并發(fā)癥。 92%受試者腎功能正常或出現(xiàn)輕度腎功能損害， 8%受試者出現(xiàn)中度腎功能損害，平均腎小球濾過率為 86ml/(min/1.73m2)oTable1showscommonadversereactionsassociatedwiththeuseofFARXIGA.Theseadversereactionswerenotpresentatbaseline,occurredmorecommonlyonFARXIGAthanonplacebo,andoccurredinatleast2%ofpatientstreatedwitheitherFARXIGA5mgorFARXIGA10mg.本藥的常見不良反應(yīng)見表 1。這些不良反應(yīng)并不是在基線時出現(xiàn)，本藥較安慰劑更為常見發(fā)生程度，在本藥5mg或10mg組中發(fā)生率>2%Table1:AdverseReactionsinPlacebo-ControlledStudiesReportedin 訟％ofPatientsTreatedwithFARXIGA表1安慰劑對照試驗中本藥發(fā)生率 >2%勺不良反應(yīng)AdverseReaction不良反應(yīng)%ofPatients患者百分比Poolof12Placebo-ControlledStudies12項安慰劑對照試驗PlaceboN=1393FARXIGA5mgN=1145FARXIGA10mgN=1193Femalegenitalmycoticinfections*女性生殖器霉菌感染Nasopharyngitis鼻咽炎Urinarytractinfections?尿道感染Backpain背痛Increasedurination?排尿增加Malegenitalmycoticinfections男性生殖器霉菌感染§Nausea惡心Influenza流行性感冒Dyslipidemia血脂異常Constipation便秘Discomfortwithurination排尿不適Paininextremity四肢疼痛1.42.01.7*Genitalmycoticinfectionsineludethefollowingadversereactions,listedinorderoffrequencyreportedforfemales:vulvovaginalmycoticinfection,vaginalinfection,vulvovaginalcandidiasis,vulvovaginitis,genitalinfection,genitalcandidiasis,fungalgenitalinfection,vulvitis,genitourinarytractinfection,vulvalabscess,andvaginitisbacterial.(Nforfemales:Placebo=677,FARXIGA5mg=581,FARXIGA10mg=598).*女性生殖器霉菌感染包括以下不良反應(yīng) (按發(fā)生率排序)：外陰陰道霉菌感染、陰道感染、外陰陰道念珠菌病、外陰陰道炎、生殖感染、生殖器念珠菌病、生殖器真菌感染、外陰炎、泌尿生殖道感染、外陰膿腫、細(xì)菌性陰道炎。?Urinarytractinfectionsincludethefollowingadversereactions,listedinorderoffrequencyreported:urinarytractinfection,cystitis,Escherichiaurinarytractinfection,genitourinarytractinfection,pyelonephritis,trigonitis,urethritis,kidneyinfection,andprostatitis.?尿道感染包括以下不良反應(yīng) (按發(fā)生率排序)：尿道感染、膀胱炎、大腸埃希菌型尿路感染、泌尿生殖道感染、腎盂腎炎、膀胱三角炎、尿道炎、腎臟感染、前列腺炎。?Increasedurinationincludesthefollowingadversereactions,listedinorderoffrequencyreported:pollakiuria,polyuria,andurineoutputincreased.?排尿增加包括以下不良反應(yīng) (按發(fā)生率排序)：尿頻、多尿、尿量增加?！霨enitalmycoticinfectionsincludethefollowingadversereactions,listedinorderoffrequencyreportedformales:balanitis,fungalgenitalinfection,balanitiscandida,genitalcandidiasis,genitalinfectionmale,penileinfection,balanoposthitis,balanoposthitisinfective,genitalinfection,posthitis.(Nformales:Placebo=716,FARXIGA5mg=564,FARXIGA10mg=595).§男性生殖器霉菌感染包括以下不良反應(yīng) (按發(fā)生率排序)：龜頭炎、生殖器真菌感染、龜頭念珠菌病、生殖器念珠菌病、男性生殖器感染、陰莖感染、龜頭包皮炎、感染性龜頭包皮炎、生殖感染、包皮炎。Poolof13Placebo-ControlledStudiesforFARXIGA10mg13項本藥10mg安慰劑對照試驗合并數(shù)據(jù)ThesafetyandtolerabilityofFARXIGA10mgwasalsoevaluatedinalargerplacebo-controlledstudypool.Thispoolcombined13placebo-controlledstudies,including3monotherapystudies,9add-ontobackgroundantidiabetictherapystudies,andaninitialcombinationwithmetforminstudy.Acrossthese13studies,2360patientsweretreatedoncedailywithFARXIGA10mgforameandurationofexposureof22weeks.Themeanageofthepopulationwas59yearsand4%wereolderthan75years.Fifty-eightpercent(58%)ofthepopulationweremale;84%wereWhite,9%wereAsian,and3%wereBlackorAfricanAmerican.Atbaseline,thepopulationhaddiabetesforanaverageof9years,hadameanHbA1cof8.2%,and30%hadestablishedmicrovasculardisease.Baselinerenalfunctionwasnormalormildlyimpairedin88%ofpatientsandmoderatelyimpaired2in11%ofpatients(meaneGFR82mL/min/1.73m).本藥10mg的安全性和耐受性在一項大型安慰劑對照合并研究中進行評估。這項合并對照研究包括13項臨床試驗，其中3項為本藥單藥治療，另外9項為本藥加入標(biāo)準(zhǔn)糖尿病治療方案或用藥初期與二甲雙胍合用。試驗數(shù)據(jù)中， 2360名患者接受本藥10mg治療，一日1次，患者平均暴露時間為22周。受試者平均年齡59歲，其中4%>75歲。58%為男性，84%為白種人，9%為亞洲人，3%為黑人或非暨美國人?；€水平，受試者患病平均年數(shù)為 9年，HbA1c平均值為8.2%，其中30%受試者出現(xiàn)糖尿病微血管并發(fā)癥。 88%受試者腎功能正?；虺霈F(xiàn)輕度腎功能損害，11%受試者出現(xiàn)中度腎功能損害，平均腎小球濾過率為 82ml/(min/1.73m2)。VolumeDepletion血容量不足FARXIGAcausesanosmoticdiuresis,whichmayleadtoreductionsinintravascularvolume.Adversereactionsrelatedtovolumedepletion(includingreportsofdehydration,hypovolemia,

orthostatichypotension,orhypotension)areshowninTable2forthe12-studyand13-study,short-term,placebo-controlledpools[seeWarningsandPrecautions(5.1)].本藥可引起滲透性利尿，降低血容量。 12項和13項短期、安慰劑對照合并數(shù)據(jù)中與血容量不足(包括脫水、血容量減少、直立性低血壓、低血壓的報道 )相關(guān)的不良反應(yīng)見表2。Table2:AdverseReactionsofVolumeDepletion*inClinicalStudieswithFARXIGA表2本藥臨床試驗中血容量不足的不良反應(yīng)Poolof12Placebo-ControlledStudies12項安慰劑對照試驗Poolof13Placebo-ControlledStudies13項安慰劑對照試驗PlaceboFARXIGA5mgFARXIGA10mgPlaceboFARXIGA10mgOverallpopulationN(%)總患病人數(shù)N=13935(0.4%)N=11457(0.6%)N=11939(0.8%)N=229517(0.7%)N=236027(1.1%)PatientSubgroupn(%) 疾病人群Patientsonloopdiuretics使用髓袢利尿劑者n=551(1.8%)n=400n=313(9.7%)n=2674(1.5%)n=2366(2.5%)PatientswithmoderaterenalimpairmentwitheGFR>30and<602mL/min/1.73m中度腎功能損害者，腎小球濾過率>30ml/(min/1.73n2),v60ml/(min/1.73m2)n=1072(1.9%)n=1071(0.9%)n=891(1.1%)n=2684(1.5%)n=2655(1.9%)Patients >65yearso年齡>6歲者:ag2761(0.4%)n=2161(0.5%)n=2043(1.5%)n=7116(0.8%)n=66511(1.7%)*Volumedepletionincludesreportsofdehydration,hypovolemia,orthostatichypotension,orhypotension.*血容量不足包括脫水、血容量減少、直立性低血壓、低血壓的報道。ImpairmentofRenalFunction 腎功能損害UseofFARXIGAwasassociatedwithincreasesinserumcreatinineanddecreasesineGFR(seeTable3).Inpatientswithnormalormildlyimpairedrenalfunctionatbaseline,serumcreatinineandeGFRreturnedtobaselinevaluesatWeek24.Renal-relatedadversereactions,includingrenalfailureandbloodcreatinineincrease,weremorefrequentinpatientstreatedwithFARXIGA(seeTable4).Elderlypatientsandpatientswithimpairedrenalfunctionweremoresusceptibletotheseadversereactions(seeTable4).SustaineddecreasesineGFRwere2seeninpatientswithmoderaterenalimpairment(eGFR30tolessthan60mL/min/1.73m ).本藥可增加血清肌酸酐并降低腎小球濾過率 (見表3)。基線腎功能正?；蜉p度腎功能損害者，用藥24周后血清肌酸酐和腎小球濾過率水平回至基線值。 使用本藥患者出現(xiàn)與腎相關(guān)的不良反應(yīng)(包括腎衰竭和血清肌酸酐升高 )頻率更高(見表4)。老年患者和腎功能損害者對此類作用更為敏感(見表4)。中度腎功能損害者［腎小球濾過率〉30ml/(min/1.73m2),v60ml/(min/1.73m2)］曾出現(xiàn)持續(xù)的腎小球濾過率降低。

Table3:ChangesinSerumCreatinineandeGFRAssociatedwithFARXIGAinthePoolof12Placebo-ControlledStudiesandModerateRenalImpairmentStudy表3本藥12周臨床試驗中和中度腎功能損害試驗中血清肌酸酐、腎小球濾過率改變Pnnlnf12Plactho-ControlledStudieNPlaceboN=13?3FARXIGA5mgN=114*FARXIGA10mgN=119SBaselineMeanSerumCYeatinine(mg/dL)0.8530.6600.B47eGFR.(mL/miiifL73tn2)853甌了Week1CliangeSerumCYealinine(mg/dL)-0.0030.0290.041eGFR. m2)0.4-2.9-4AWeek24ChangeSerumCre?linine-0.005-0.0010.001eGFR(inL/nMiy1.73m2)0.8080.3ModerateRensilImp?imientStudyPlucebuN=84FARXIGA5mgN=83FARXIGA10mgN-85BaselineMeanSerumCYeatiniiie1.46L531.52eGKR(mL/minl.73m2)45.644.243.9Week1CbansjeSerumCYeatiijiiie(mg-^dLj0.010.130.1BeGFR(mL/uiinl.73in2)0.5-3.E-5.5Week14ChangeSerumCicatinine(mg/dL)0.02o.os0.16eGFR.fmL/niinl.73tn2)0.0370-7AWeek52ChangeSerumCTealinint(mg/dL)0A00.060丄5eGFR(niL/iniii1.73m2)-2.6-4.2~3表3復(fù)制出來樣式太亂，鑒于內(nèi)容較簡單，故直接截圖了。Table4:ProportionofPatientswithatLeastOneRenalImpairment-RelatedAdverseReaction表4至少有一項腎功能損害相關(guān)不良反應(yīng)的患者比例Poolof6Placebo-ControlledStudies(upto104weeks)*6項安慰劑對照試驗(至104周)Poolof9Placebo-ControlledStudies(upto104weeks)?9項安慰劑對照試驗(至104周)BaselineCharacteristic基線特征PlaceboFARXIGA5mgFARXIGA10mgPlaceboFARXIGA10mgOverallpopulationPatients(%)withatleastoneevent出現(xiàn)至少一項不良反應(yīng)的總患病人數(shù)n=78513(1.7%)n=76714(1.8%)n=85916(1.9%)n=195682(4.2%)n=2026136(6.7%)65yearsofageandolderPatients(%)withatleastoneevent出現(xiàn)至少一項不良反應(yīng)的》6歲的患者n=1904(2.1%)n=1625(3.1%)n=1596(3.8%)n=65552(7.9%)n=62087(14.0%)eGFR >30and <60mL/min/1.73m2Patients(%)withatleastoneevent出現(xiàn)至少一項不良反應(yīng)的腎小球濾過率>30ml/(min/1.73m2),<60ml/(min/1.73m)的患者n=775(6.5%)n=887(8.0%)n=759(12.0%)n=24940(16.1%)n=25171(28.3%)65yearsofageandolderandeGFR >30and <60mL/min/1.73m2Patients(%)withatleastoneevent出現(xiàn)至少一項不良反應(yīng)的>6歲，且腎小球濾過率>30ml/(min/1.73n2), <60ml/(min/1.73m)的患者n=412(4.9%)n=433(7.0%)n=354(11.4%)n=14127(19.1%)n=13447(35.1%)*Subsetofpatientsfromthepoolof12placebo-controlledstudieswithIong-termextensions.*患者來源于12項安慰劑對照試驗的長期擴展。?Subsetofpatientsfromthepoolof13placebo-controlledstudieswithIong-termextensions.?患者來源于13項安慰劑對照試驗的長期擴展。ThesafetyofFARXIGAwasevaluatedinastudyofpatientswithmoderaterenalimpairment2(eGFR30tolessthan60mL/min/1.73m )[seeClinicalStudies(14)].Inthisstudy13patientsexperieneedbonefracturesfortreatmentdurationsupto104weeks.Nofracturesoccurredintheplacebogroup,5occurredintheFARXIGA5mggroup,and8occurredintheFARXIGA10mggroup.Eightofthese13fractureswereinpatientswhohadabaselineeGFRof30to452mL/min/1.73m.Elevenofthe13fractureswerereportedwithinthefirst52weeks.Therewasnoapparentpatternwithrespecttotheanatomicsiteoffracture.本藥的安全性通過一項在中度 腎功能損害者 [腎小球濾過率〉30ml/(min/1.73m2),<60ml/(min/1.73m2)]中的試驗評估。在這項試驗中， 13名患者用藥104周期間出現(xiàn)骨折，安慰劑組未出現(xiàn)骨折。出現(xiàn)骨折的 13名患者中：5名為本藥5mg組，8名為本藥10mg組；8名為基線腎小球濾過率30-45ml/(min/1.73m2)；11名用藥52周內(nèi)出現(xiàn)骨折。骨折的位置無固定模式。Hypoglycemia低血糖Thefrequencyofhypoglycemiabystudy[seeClinicalStudies(14)]isshowninTable5.HypoglycemiawasmorefrequentwhenFARXIGAwasaddedtosulfonylureaorinsulin[seeWarningsandPrecautions(5.3)].試驗中低血糖的發(fā)生率見表 5，本藥與磺酰脲或胰島素合用時候更易發(fā)生低血糖。Table5:IncideneeofMajor*andMinor?HypoglycemiainPlacebo-ControlledStudies表5安慰劑對照試驗中低血壓的主要和小幅度發(fā)生率PlaceboFARXIGA5mgFARXIGAlUmgMoncrtlierapy*(24weeks)N=75NR4N=7DMaj&r[n(%)]000Minor[n(%)]000Add-ontoMetTcrmiii*(24wteks^N=137213了N=135Major[n(%)]D00Minor[n(%)]D2(1-5)1(0.7)ActiveControlAdd-ontoMetforminversusGlipizide(52weeks)N=40S-ar[n(%)]3(0.7)—0Minor[n(%)]147(36.0)—Add-ontodimepiridei*(24weeks)N=146N=151M超ur[n(%)]00CMinor[n(%)]缸5.5)Add-ontoPiogUcaztHie*(24weeks)N=139N=141N=14OM商or[n(%)]D00Minor[n(%)]D3(2-00Add-ontoDPP4inhibitor(24week^fN=226■N=225Majnr[n蹩)]D一Minar[n(K)]Xl-3)-4(1⑥FlaccoFARXIGA5mgFARXIGA10mgAdd-ontoInsulinwitliarwithoutotherOADs^(24weeks)N=197N=212Major[n(S4)]1(05)1(GO1SMinor[n(%)]67(34.0)92(43.4)79(40.3)表5復(fù)制出來樣式太亂，鑒于內(nèi)容較簡單，故直接截圖了。*Majorepisodesofhypoglycemiaweredefinedassymptomaticepisodesrequiringexternnal(thirdparty)assistaneeduetosevereimpairmentinconsciousnessorbehaviorwithacapillaryorplasmaglucosevalue<54mg/dLandpromptrecoveryafterglucoseorglucagonadministration.*低血糖主要發(fā)作定義為出現(xiàn)意識或行為嚴(yán)重?fù)p害 (伴毛細(xì)血管或血漿葡萄糖值v54mg/dl)后需外界(第三方)協(xié)助的有癥狀發(fā)作，發(fā)作在使用葡萄糖或胰高血糖素后迅速恢復(fù)。?Minorepisodesofhypoglycemiaweredefinedaseitherasymptomaticepisodewithacapillaryorplasmaglucosemeasurement<63mg/dLregardlessofneedforexternalassistanee,oranasymptomaticcapillaryorplasmaglucosemeasurement<63mg/dLthatdoesnotqualifyasamajorepisode.?低血糖小幅度發(fā)作定義為伴毛細(xì)血管或血漿葡萄糖值v 63mg/dl無需外界協(xié)助的有癥狀發(fā)作，或伴毛細(xì)血管或血漿葡萄糖值v 63mg/dI未評價為主要發(fā)作的無癥狀發(fā)作。?OAD=oralantidiabetictherapyOAD=口服抗糖尿病藥療法GenitalMycoticInfections 生殖器霉菌感染GenitalmycoticinfectionsweremorefrequentwithFARXIGAtreatment.Genitalmycoticinfectionswerereportedin0.9%ofpatientsonplacebo,5.7%onFARXIGA5mg,and4.8%onFARXIGA10mg,inthe12-studyplacebo-controlledpool.Discontinuationfromstudyduetogenitalinfectionoccurredin0%ofplacebo-treatedpatientsand0.2% ofpatientstreatedwithFARXIGA10mg.Infectionsweremorefrequentlyreportedinfemalesthaninmales(seeTable1).Themostfrequentlyreportedgenitalmycoticinfectionswerevulvovaginalmycoticinfectionsinfemalesandbalanitisinmales.Patientswithahistoryofgenitalmycoticinfectionsweremorelikelytohaveagenitalmycoticinfectionduringthestudythanthosewithnopriorhistory(10.0%,23.1%,and25.0%versus0.8%,5.9%,and5.0%onplacebo,FARXIGA5mg,andFARXIGA10mg,respectively）.使用本藥患者更易出現(xiàn)生殖器霉菌感染。 在12項安慰劑對照試驗的已有報道中， 出現(xiàn)生殖器霉菌感染患者比例，安慰劑組為 0.9%、本藥5mg組為5.7%、本藥10mg組為4.8%。由于生殖器霉菌感染停藥患者比例，安慰劑組為 0%、本藥10mg組為0.2%。報道中女性感染較男性感染更為常見（見表1），最為常見的生殖器霉菌感染為女性外陰陰道霉菌感染、男性龜頭炎。試驗中有生殖器霉菌感染病史的患者更易出現(xiàn)感染。HypersensitivityReactions過敏反應(yīng)Hypersensitivityreactions（e.g.,angioedema,urticaria,hypersensitivity）werereportedwithFARXIGAtreatment.Acrosstheclinicalprogram,seriousanaphylacticreactionsandseverecutaneousadversereactionsandangioedemawerereportedin0.2%ofcomparator-treatedpatientsand0.3%ofFARXIGA-treatedpatients.Ifhypersensitivityreactionsoccur,discontinueuseofFARXIGA;treatperstandardofcareandmonitoruntilsignsandsymptomsresolve.使用本藥治療有出現(xiàn)過敏反應(yīng)（如血管神經(jīng)性水腫、過敏）的報道。臨床研究中，出現(xiàn)嚴(yán)重過敏反應(yīng)、嚴(yán)重皮膚不良反應(yīng)、血管神經(jīng)水腫患者的比例，對照組為 0.2%、使用本藥組為0.3%。如出現(xiàn)過敏反應(yīng)，應(yīng)停藥并進行對癥治療及監(jiān)測，直至跡象和癥狀解決。LaboratoryTests實驗室測試IncreaseinHematocrit血細(xì)胞比容升高Inthepoolof13placebo-controlledstudies,increasesfrombaselineinmeanhematocritvalueswereobservedinFARXIGA-treatedpatientsstartingatWeek1andcontinuinguptoWeek16,whenthemaximummeandifferencefrombaselinewasobserved.AtWeek24,themeanchangesfrombaselineinhematocritwere-0.33%intheplacebogroupand2.30%intheFARXIGA10mggroup.ByWeek24,hematocritvalues>55%werereportedin0.4%ofplacebo-treatedpatientsand1.3%ofFARXIGA10mg-treatedpatients.13項安慰劑對照試驗合并數(shù)據(jù)顯示，患者用藥 1周后出現(xiàn)血細(xì)胞比容平均值較基線水平升高且繼續(xù)持續(xù)升高。第16周時血細(xì)胞比容平均值較基線差異最大。 第24周時，血細(xì)胞比容平均值較基線的變化，安慰劑組為-0.33%、本藥10mg組為2.30%。截至第24周，血細(xì)胞比容〉55%的患者比例，安慰劑組為0.4%、本藥10mg組為1.3%。IncreaseinSerumInorganicPhosphorus血清無機磷升高Inthepoolof13placebo-controlledstudies,increasesfrombaselineinmeanserumphosphoruslevelswerereportedatWeek24inFARXIGA-treatedpatientscomparedwithplacebo-treatedpatients（meanincreaseof0.13versus-0.04mg/dL,respectively）.Higherproportionsofpatientswithmarkedlaboratoryabnormalitiesofhyperphosphatemia（ -65yearsor>5.6mg/dLforage1>5.1mg/dLforage >66years）werereportedonFARXIGAatWeekver^0d91.7%forplaceboandFARXIGA10mg,respectively）.13項安慰劑對照試驗合并數(shù)據(jù)顯示， 與使用安慰劑相比，患者用藥24周后出現(xiàn)血清無機磷平均值較基線水平升高（安慰劑組為-0.04mg/dl，本藥為0.13mg/dl）。用藥24周后，使用本藥患者出現(xiàn)高磷血癥（實驗室檢測數(shù)據(jù)17-65歲者》5.6mg/dl,>66歲者》5.1mg/dl）患者比例更高（安慰劑組為0.9%、本藥10mg組為1.7%）。IncreaseinLow-DensityLipoproteinCholesterolLDL-C升高Inthepoolof13placebo-controlledstudies,changesfrombaselineinmeanlipidvalueswerereportedinFARXIGA-treatedpatientscomparedtoplacebo-treatedpatients.MeanpercentchangesfrombaselineatWeek24,were0.0%versus2.5%fortotalcholesteroland-1.0%versus2.9%forLDLcholesterol,intheplaceboandFARXIGA10mggroups,respectively.13項安慰劑對照試驗合并數(shù)據(jù)顯示， 與使用安慰劑相比，使用本藥患者出現(xiàn)LDL-C較基線水平升高。第24時，LDL-C平均變化值，安慰劑組總膽固醇為0.0%、低密度脂蛋白膽固醇為-1.0%,本藥10mg組總膽固醇為2.5%、低密度脂蛋白膽固醇為2.9%。8USEINSPECIFICPOPULATIONS特殊人群用藥Pregnancy妊娠期婦女PregnancyCategoryC妊娠分級：C級Therearenoadequateandwell-controlledstudiesofFARXIGAinpregnantwomen.Basedonresultsofreproductiveanddevelopmentaltoxicitystudiesinanimals,dapagliflozinmayaffectrenaldevelopmentandmaturation.Inajuvenileratstudy,increasedincidenceand/orseverityofrenalpelvicandtubulardilatationswereevidentatthelowesttesteddosewhichwasapproximately15timesclinicalexposurefroma10mgdose.尚未在妊娠期婦女中進行充分、嚴(yán)格的對照試驗，基于動物生殖毒性試驗結(jié)果，本藥可能影響腎臟的發(fā)育和成熟。在一項大鼠幼崽研究中，給予最低測試劑量 （約為人類臨床暴露量10mg的15倍）可出現(xiàn)明顯的腎盂炎和食道擴張發(fā)生率增加和 （或）加重。Theseoutcomesoccurredwithdrugexposuresduringperiodsofanimaldevelopmentthatcorrelatewiththelatesecondandthirdtrimestersofhumanpregnancy.Duringpregnancy,considerappropriatealternativetherapies,especiallyduringthesecondandthirdtrimesters.FARXIGAshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.Inajuveniletoxicitystudy,whendapagliflozinwasdoseddirectlytoyoungratsfrompostnatalday（PND）21untilPND90atdosesof1,15,or75mg/kg/day,increasedkidneyweightsandrenalpelvicandtubulardilatationswerereportedatalllevels.Exposureatthelowesttesteddosewas15timesthemaximumclinicaldose,basedonAUC.Therenalpelvicandtubulardilatationsobservedinjuvenileanimalsdidnotfullyreversewithintheapproximate1-monthrecoveryperiod.這些在動物發(fā)育期間使用藥物暴露量出現(xiàn)的結(jié)果，與人類妊娠中期、妊娠晚期相關(guān)。妊娠期間，應(yīng)采取替代療法，尤其妊娠中期、妊娠晚期。本藥僅在利大于弊的情況下方可用于妊娠期婦女。在一項大鼠幼崽毒性研究中，給予本藥劑量為一日1mg/kg、15mg/kg、75mg/kg（于出生后21-90日期間），所有劑量組出現(xiàn)腎臟重量增加、腎盂炎、食道擴張。給予的最低測試劑量以曲線下面積（AUC）計，約為人類最大臨床暴露量的15倍。在幼崽中出現(xiàn)的腎盂炎、食管擴張并未在1個月恢復(fù)期間完全恢復(fù)。Inaprenatalandpostnataldevelopmentstudy,maternalratsweredosedfromgestationday6throughlactationday21atdosesof1,15,or75mg/kg/day,andpupswereindirectlyexposedinuteroandthroughoutlactation.Increasedincidenceorseverityofrenalpelvicdilatationwasobservedinadultoffspringoftreateddamsat75mg/kg/day（maternalandpupdapagliflozinexposureswere1415timesand137times,respectively,thehumanvaluesattheclinicaldose）.Dose-relatedreductionsinpupbodyweightswereobservedatdoses >1mg/kg/day（approximately>19imestheclinicaldose）.Noadverseeffectsondevelopmentalendpointswerenotedat1mg/kg/day,orapproximately19timestheclinicaldose.在一項大鼠出生前和出生后發(fā)育研究中，妊娠大鼠從妊娠第 6日到哺乳第21日，給予本藥劑量為一日1mg/kg、15mg/kg、75mg/kg，幼崽在子宮內(nèi)及哺乳期間間接暴露于本藥。使用每日75mg/kg組（妊娠大鼠暴露量相當(dāng)于人類治療暴露量的 1415倍，幼崽暴露量相當(dāng)于人類治療暴露量的137倍）中，成年后代出現(xiàn)腎盂炎和食道擴張發(fā)生率增加或加重。所有組 （約為臨床劑量》19倍）中幼崽出現(xiàn)與劑量相關(guān)的體重降低。每日 1mg/kg組（約為臨床劑量的19倍）中，未見發(fā)育相關(guān)不良反應(yīng)。Inembryo-fetaldevelopmentstudiesinratsandrabbits,dapagliflozinwasadministeredforintervalscoincidingwiththefirsttrimesterperiodoforganogenesisinhumans.Nodevelopmentaltoxicitieswereobservedinrabbitsatanydosetested.Inrats,dapagliflozinwasneitherembryolethalnorteratogenicatdosesupto75mg/kg/dayor1441timesthemaximumclinicaldoseof10mg.Athigherdosesinrats,malformationsofbloodvessels,ribs,vertebra,manubria,andskeletalvariationsinfetusesat>150mg/kgor2344timesthe10mgclinicaldosewereobserved在一項大鼠、家兔胚胎-胎仔發(fā)育研究中，間隔給予本藥以保持與人類妊娠前期器官形成期一致。家兔任一劑量組未見生殖毒性。大鼠給予本藥劑量達一日75mg/kg(相當(dāng)于最大臨床暴露量10mg的1441倍)時未見致畸作用。大鼠使用更高劑量 (》150mg/kg，相當(dāng)于臨床劑量10mg的2344倍)時出現(xiàn)血管、肋骨、椎骨、胸骨柄畸形，以及胎仔骨骼變化。NursingMothers哺乳期婦女ItisnotknownwhetherFARXIGAisexcretedinhumanmilk.Dapagliflozinisexcretedinratmilkreachinglevels0.49timesthatfoundinmaternalplasma.Datainjuvenileratsdirect