达格列净片FARXIGA(dapagliflozin)FDA药品说明书翻译

FULLPRESCRIBINGINFORMATIONINDICATIONSANDUSAGE适应症和用途FARXIGA(dapagliflozin)isindicatedasanadjuncttodietandexercisetoimproveglycemiccontrolinadultswithtype2diabetesmellitus[seeClinicalStudies(14)].本药用于配合饮食控制和运动改善2型糖尿病患者的血糖控制。LimitationofUse使用限制FARXIGAisnotrecommendedforpatientswithtype1diabetesmellitusorforthetreatmentofdiabeticketoacidosis.本药不适用于1型糖尿病或糖尿病酮症酸中毒患者。DOSAGEANDADMINISTRATION用法用量RecommendedDosing推荐剂量TherecommendedstartingdoseofFARXIGAis5mgoncedaily,takeninthemorning,withorwithoutfood.InpatientstoleratingFARXIGA5mgoncedailywhorequireadditionalglycemiccontrol,thedosecanbeincreasedto10mgoncedaily.推荐起始剂量为一次5mg,—日1次，早晨服用，可与或不与食物同服。对本药一次 5mg,一日1次剂量耐受且须更多血糖扩指着，可增至一次 10mg，一日1次。Inpatientswithvolumedepletion,correctingthisconditionpriortoinitiationofFARXIGAisrecommended[seeWarningsandPrecautions(5.1),UseinSpecificPopulations(8.5,8.6),andPatientCounselingInformation(17)].血容量减少患者，推荐用药前应先纠正血容量减少。PatientswithRenalImpairment肾功能不全时剂量AssessmentofrenalfunctionisrecommendedpriortoinitiationofFARXIGAtherapyandperiodicallythereafter.建议在开始使用本药前及使用期间定期评估肾功能。2FARXIGAshouldnotbeinitiatedinpatientswithaneGFRlessthan60mL/min/1.73m.肾小球滤过率v60ml/(min/1.73m2)患者不得开始用药。Nodoseadjustmentisneededinpatientswithmildrenalimpairment(eGFRof60mL/min/1.73morgreater).轻度肾功能损害者[肾小球滤过率＞60ml/(min/1.73m2)]无需调整剂量。2FARXIGAshouldbediscontinuedwheneGFRispersistentlylessthan60mL/min/1.73m[seeWarningsandPrecautions(5.2)andUseinSpecificPopulations(8.6)].肾小球滤过率持续v60ml/(min/1.73m2)时应停药。«l”«l”5”engravFARXIGA5mgtabletsareyellow,biconvex,round,film-coatedtabletswithonesideand“1427”engravedontheotherside.FARXIGA10mgtabletsareyellow,biconvex,diamond-shaped,film-coatedtabletswithengravedononesideand “1428”engravedontheotherside.达格列净片(1)5mg。(2)10mg。CONTRAINDICATIONS禁忌症HistoryofaserioushypersensitivityreactiontoFARXIGA[seeAdverseReactions(6.1)].Severerenalimpairment,end-stagerenaldisease(ESRD),orpatientsondialysis[seeUseinSpecificPopulations(8.6)].对本药有严重过敏史者。重度肾功能损害、晚期肾病患者。透析患者。WARNINGSANDPRECAUTIONS警告和注意事项5.1Hypotension低血压FARXIGAcausesintravascularvolumecontraction.SymptomatichypotensioncanoccurafterinitiatingFARXIGA[seeAdverseReactions(6.1)]particularlyinpatientswithimpairedrenal2function(eGFRlessthan60mL/min/1.73m),elderlypatients,orpatientsonloopdiuretics.BeforeinitiatingFARXIGAinpatientswithoneormoreofthesecharacteristics,volumestatusshouldbeassessedandcorrected.Monitorforsignsandsymptomsofhypotensionafterinitiatingtherapy.本药可引起血管收缩，开始用药后可出现症状性低血压。尤其肾功能损害者[(肾小球滤过率v60ml/(min/1.73m2)]、老年患者、使用髓袢利尿药的患者。以上患者开始使用本药前应先评估并纠正血容量状况。用药后应监测低血压迹象和症状。ImpairmentinRenalFunction肾功能损害FARXIGAincreasesserumcreatinineanddecreaseseGFR.Elderlypatientsandpatientswithimpairedrenalfunctionmaybemoresusceptibletothesechanges.AdversereactionsrelatedtorenalfunctioncanoccurafterinitiatingFARXIGA[seeAdverseReactions(6.1)].RenalfunctionshouldbeevaluatedpriortoinitiationofFARXIGAandmonitoredperiodicallythereafter本药可增加血清肌酸酐并降低肾小球滤过率。老年患者和肾功能损害者对此类作用更为敏感。用药后可能出现与肾功能相关的不良反应，开始使用本药前及使用期间应定期评估肾功能。HypoglycemiawithConcomitantUsewithInsulinandInsulinSecretagogues低血糖(与胰岛素和胰岛素促泌剂合用时)Insulinandinsulinsecretagoguesareknowntocausehypoglycemia.FARXIGAcanincreasetheriskofhypoglycemiawhencombinedwithinsulinoraninsulinsecretagogue[seeAdverseReactions(6.1)].Therefore,alowerdoseofinsulinorinsulinsecretagoguemayberequiredtominimizetheriskofhypoglycemiawhentheseagentsareusedincombinationwithFARXIGA.已知胰岛素和胰岛素促泌剂可引起低血糖。本药与以上两种药物合用时发生低血糖的风险增加。合用时可能需降低胰岛素或胰岛素促泌剂的剂量，以降低低血糖风险。GenitalMycoticInfections生殖器霉菌感染FARXIGAincreasestheriskofgenitalmycoticinfections.Patientswithahistoryofgenitalmycoticinfectionsweremorelikelytodevelopgenitalmycoticinfections[seeAdverseReactions(6.1)].Monitorandtreatappropriately.本药增加发生生殖器霉菌感染的风险。有生殖器霉菌感染病史的患者更易出现。应进行适当的监测和治疗。IncreasesinLow-DensityLipoproteinCholesterol(LDL-C)低密度脂蛋白(LDL-C)升高IncreasesinLDL-CoccurwithFARXIGA[seeAdverseReactions(6.1)].MonitorLDL-CandtreatperstandardofcareafterinitiatingFARXIGA.本药可使LDL-C升高，开始用药后应监测LDL-C并进行标准治疗。BladderCancer膀胱癌Across22clinicalstudies,newlydiagnosedcasesofbladdercancerwerereportedin10/6045patients(0.17%)treatedwithFARXIGAand1/3512patient(0.03%)treatedwithplacebo/comparator.Afterexcludingpatientsinwhomexposuretostudydrugwaslessthanoneyearatthetimeofdiagnosisofbladdercancer,therewere4caseswithFARXIGAandnocaseswithplacebo/comparator.Bladdercancerriskfactorsandhematuria(apotentialindicatorofpreexistingtumors)werebalancedbetweentreatmentarmsatbaseline.ThereweretoofewcasestodeterminewhethertheemergenceoftheseeventsisrelatedtoFARXIGA.22项临床试验中，有0.17%(10/6045)使用本药和0.03%(1/3512)使用安慰剂患者出现新近诊断的膀胱癌的报道。排除诊断为膀胱癌时用药不足一年的患者，有 4例使用本药患者出现膀胱癌(使用安慰剂患者0例)。开始用药时在治疗组中评估膀胱癌风险因素和血尿 (已存在肿瘤的潜在指标)，评估人数过少无法确定膀胱癌是否与本药相关。ThereareinsufficientdatatodeterminewhetherFARXIGAhasaneffectonpre-existingbladdertumors.Consequently,FARXIGAshouldnotbeusedinpatientswithactivebladdercancer.Inpatientswithpriorhistoryofbladdercancer,thebenefitsofglycemiccontrolversusunknownrisksforcancerrecurrencewithFARXIGAshouldbeconsidered.尚无充分的数据确定本药对已存在的膀胱癌是否有作用。故活动期膀胱癌患者不得用药。有膀胱癌病史者，用药时应权衡血糖控制与复发的未知风险。MacrovascularOutcomes大血管病变TherehavebeennoclinicalstudiesestablishingconclusiveevidenceofmacrovascularriskreductionwithFARXIGAoranyotherantidiabeticdrug.尚无本药或其他任一抗糖尿病药降低大血管病变风险的临床试验证据。ADVERSEREACTIONS不良反应Thefollowingimportantadversereactionsaredescribedbelowandelsewhereinthelabeling:下列重要不良反应已在说明书其他章节讨论：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)]低血压、肾功能损害、低血糖 (与胰岛素和胰岛素促泌剂合用时 )、生殖器霉菌感染、LDL-C升高、膀胱癌。6.1ClinicalTrialsExperience临床试验经验Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinclinicalpractice.由于临床试验是在各种不同条件下进行的，观察到的不良反应发生率不能直接与其他临床试验中的发生率相比较，可能也不能反应临床实践中观察到的发生率。Poolof12Placebo-ControlledStudiesforFARXIGA5and10mg12项本药5mg、10mg安慰剂对照试验合并数据ThedatainTable1isderivedfrom12placebo-controlledstudiesrangingfrom12to24weeks.In4studiesFARXIGAwasusedasmonotherapy,andin8studiesFARXIGAwasusedasadd-ontobackgroundantidiabetictherapyorascombinationtherapywithmetformin[seeClinicalStudies(14)].表1中的数据来源于12项安慰剂对照试验，试验时长 12-24周。其中4项为本药单药治疗，另外8项为本药加入标准糖尿病治疗方案或与二甲双胍合用。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 ).试验数据中，2338名患者接受本药治疗，平均暴露时间为 21周。其中安慰剂组1393名患者、本药5mg组1145名患者、本药10mg组1193名患者，患者均接受一日1次用药。受试者平均年龄55岁，其中2%>75岁。50%为男性，81%为白种人，14%为亚洲人，3%为黑人或非暨美国人。基线水平，受试者患病平均年数为 6年，糖化血红蛋白(HbA1c)平均值为8.3%，其中21%受试者出现糖尿病微血管并发症。 92%受试者肾功能正常或出现轻度肾功能损害， 8%受试者出现中度肾功能损害，平均肾小球滤过率为 86ml/(min/1.73m2)oTable1showscommonadversereactionsassociatedwiththeuseofFARXIGA.Theseadversereactionswerenotpresentatbaseline,occurredmorecommonlyonFARXIGAthanonplacebo,andoccurredinatleast2%ofpatientstreatedwitheitherFARXIGA5mgorFARXIGA10mg.本药的常见不良反应见表 1。这些不良反应并不是在基线时出现，本药较安慰剂更为常见发生程度，在本药5mg或10mg组中发生率>2%Table1:AdverseReactionsinPlacebo-ControlledStudiesReportedin 訟％ofPatientsTreatedwithFARXIGA表1安慰剂对照试验中本药发生率 >2%勺不良反应AdverseReaction不良反应%ofPatients患者百分比Poolof12Placebo-ControlledStudies12项安慰剂对照试验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恶心Influenza流行性感冒Dyslipidemia血脂异常Constipation便秘Discomfortwithurination排尿不适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应 (按发生率排序)：外阴阴道霉菌感染、阴道感染、外阴阴道念珠菌病、外阴阴道炎、生殖感染、生殖器念珠菌病、生殖器真菌感染、外阴炎、泌尿生殖道感染、外阴脓肿、细菌性阴道炎。?Urinarytractinfectionsincludethefollowingadversereactions,listedinorderoffrequencyreported:urinarytractinfection,cystitis,Escherichiaurinarytractinfection,genitourinarytractinfection,pyelonephritis,trigonitis,urethritis,kidneyinfection,andprostatitis.?尿道感染包括以下不良反应 (按发生率排序)：尿道感染、膀胱炎、大肠埃希菌型尿路感染、泌尿生殖道感染、肾盂肾炎、膀胱三角炎、尿道炎、肾脏感染、前列腺炎。?Increasedurinationincludesthefollowingadversereactions,listedinorderoffrequencyreported:pollakiuria,polyuria,andurineoutputincreased.?排尿增加包括以下不良反应 (按发生率排序)：尿频、多尿、尿量增加。§Genitalmycoticinfectionsincludethefollowingadversereactions,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应 (按发生率排序)：龟头炎、生殖器真菌感染、龟头念珠菌病、生殖器念珠菌病、男性生殖器感染、阴茎感染、龟头包皮炎、感染性龟头包皮炎、生殖感染、包皮炎。Poolof13Placebo-ControlledStudiesforFARXIGA10mg13项本药10mg安慰剂对照试验合并数据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).本药10mg的安全性和耐受性在一项大型安慰剂对照合并研究中进行评估。这项合并对照研究包括13项临床试验，其中3项为本药单药治疗，另外9项为本药加入标准糖尿病治疗方案或用药初期与二甲双胍合用。试验数据中， 2360名患者接受本药10mg治疗，一日1次，患者平均暴露时间为22周。受试者平均年龄59岁，其中4%>75岁。58%为男性，84%为白种人，9%为亚洲人，3%为黑人或非暨美国人。基线水平，受试者患病平均年数为 9年，HbA1c平均值为8.2%，其中30%受试者出现糖尿病微血管并发症。 88%受试者肾功能正常或出现轻度肾功能损害，11%受试者出现中度肾功能损害，平均肾小球滤过率为 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)].本药可引起渗透性利尿，降低血容量。 12项和13项短期、安慰剂对照合并数据中与血容量不足(包括脱水、血容量减少、直立性低血压、低血压的报道 )相关的不良反应见表2。Table2:AdverseReactionsofVolumeDepletion*inClinicalStudieswithFARXIGA表2本药临床试验中血容量不足的不良反应Poolof12Placebo-ControlledStudies12项安慰剂对照试验Poolof13Placebo-ControlledStudies13项安慰剂对照试验PlaceboFARXIGA5mgFARXIGA10mgPlaceboFARXIGA10mgOverallpopulationN(%)总患病人数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使用髓袢利尿剂者n=551(1.8%)n=400n=313(9.7%)n=2674(1.5%)n=2366(2.5%)PatientswithmoderaterenalimpairmentwitheGFR>30and<602mL/min/1.73m中度肾功能损害者，肾小球滤过率>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年龄>6岁者:ag2761(0.4%)n=2161(0.5%)n=2043(1.5%)n=7116(0.8%)n=66511(1.7%)*Volumedepletionincludesreportsofdehydration,hypovolemia,orthostatichypotension,orhypotension.*血容量不足包括脱水、血容量减少、直立性低血压、低血压的报道。ImpairmentofRenalFunction 肾功能损害UseofFARXIGAwasassociatedwithincreasesinserumcreatinineanddecreasesineGFR(seeTable3).Inpatientswithnormalormildlyimpairedrenalfunctionatbaseline,serumcreatinineandeGFRreturnedtobaselinevaluesatWeek24.Renal-relatedadversereactions,includingrenalfailureandbloodcreatinineincrease,weremorefrequentinpatientstreatedwithFARXIGA(seeTable4).Elderlypatientsandpatientswithimpairedrenalfunctionweremoresusceptibletotheseadversereactions(seeTable4).SustaineddecreasesineGFRwere2seeninpatientswithmoderaterenalimpairment(eGFR30tolessthan60mL/min/1.73m ).本药可增加血清肌酸酐并降低肾小球滤过率 (见表3)。基线肾功能正常或轻度肾功能损害者，用药24周后血清肌酸酐和肾小球滤过率水平回至基线值。 使用本药患者出现与肾相关的不良反应(包括肾衰竭和血清肌酸酐升高 )频率更高(见表4)。老年患者和肾功能损害者对此类作用更为敏感(见表4)。中度肾功能损害者［肾小球滤过率〉30ml/(min/1.73m2),v60ml/(min/1.73m2)］曾出现持续的肾小球滤过率降低。

Table3:ChangesinSerumCreatinineandeGFRAssociatedwithFARXIGAinthePoolof12Placebo-ControlledStudiesandModerateRenalImpairmentStudy表3本药12周临床试验中和中度肾功能损害试验中血清肌酸酐、肾小球滤过率改变Pnnlnf12Plactho-ControlledStudieNPlaceboN=13?3FARXIGA5mgN=114*FARXIGA10mgN=119SBaselineMeanSerumCYeatinine(mg/dL)0.8530.6600.B47eGFR.(mL/miiifL73tn2)853瓯了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复制出来样式太乱，鉴于内容较简单，故直接截图了。Table4:ProportionofPatientswithatLeastOneRenalImpairment-RelatedAdverseReaction表4至少有一项肾功能损害相关不良反应的患者比例Poolof6Placebo-ControlledStudies(upto104weeks)*6项安慰剂对照试验(至104周)Poolof9Placebo-ControlledStudies(upto104weeks)?9项安慰剂对照试验(至104周)BaselineCharacteristic基线特征PlaceboFARXIGA5mgFARXIGA10mgPlaceboFARXIGA10mgOverallpopulationPatients(%)withatleastoneevent出现至少一项不良反应的总患病人数n=78513(1.7%)n=76714(1.8%)n=85916(1.9%)n=195682(4.2%)n=2026136(6.7%)65yearsofageandolderPatients(%)withatleastoneevent出现至少一项不良反应的》6岁的患者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出现至少一项不良反应的肾小球滤过率>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出现至少一项不良反应的>6岁，且肾小球滤过率>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.*患者来源于12项安慰剂对照试验的长期扩展。?Subsetofpatientsfromthepoolof13placebo-controlledstudieswithIong-termextensions.?患者来源于13项安慰剂对照试验的长期扩展。ThesafetyofFARXIGAwasevaluatedinastudyofpatientswithmoderaterenalimpairment2(eGFR30tolessthan60mL/min/1.73m )[seeClinicalStudies(14)].Inthisstudy13patientsexperieneedbonefracturesfortreatmentdurationsupto104weeks.Nofracturesoccurredintheplacebogroup,5occurredintheFARXIGA5mggroup,and8occurredintheFARXIGA10mggroup.Eightofthese13fractureswereinpatientswhohadabaselineeGFRof30to452mL/min/1.73m.Elevenofthe13fractureswerereportedwithinthefirst52weeks.Therewasnoapparentpatternwithrespecttotheanatomicsiteoffracture.本药的安全性通过一项在中度 肾功能损害者 [肾小球滤过率〉30ml/(min/1.73m2),<60ml/(min/1.73m2)]中的试验评估。在这项试验中， 13名患者用药104周期间出现骨折，安慰剂组未出现骨折。出现骨折的 13名患者中：5名为本药5mg组，8名为本药10mg组；8名为基线肾小球滤过率30-45ml/(min/1.73m2)；11名用药52周内出现骨折。骨折的位置无固定模式。Hypoglycemia低血糖Thefrequencyofhypoglycemiabystudy[seeClinicalStudies(14)]isshowninTable5.HypoglycemiawasmorefrequentwhenFARXIGAwasaddedtosulfonylureaorinsulin[seeWarningsandPrecautions(5.3)].试验中低血糖的发生率见表 5，本药与磺酰脲或胰岛素合用时候更易发生低血糖。Table5:IncideneeofMajor*andMinor?HypoglycemiainPlacebo-ControlledStudies表5安慰剂对照试验中低血压的主要和小幅度发生率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复制出来样式太乱，鉴于内容较简单，故直接截图了。*Majorepisodesofhypoglycemiaweredefinedassymptomaticepisodesrequiringexternnal(thirdparty)assistaneeduetosevereimpairmentinconsciousnessorbehaviorwithacapillaryorplasmaglucosevalue<54mg/dLandpromptrecoveryafterglucoseorglucagonadministration.*低血糖主要发作定义为出现意识或行为严重损害 (伴毛细血管或血浆葡萄糖值v54mg/dl)后需外界(第三方)协助的有症状发作，发作在使用葡萄糖或胰高血糖素后迅速恢复。?Minorepisodesofhypoglycemiaweredefinedaseitherasymptomaticepisodewithacapillaryorplasmaglucosemeasurement<63mg/dLregardlessofneedforexternalassistanee,oranasymptomaticcapillaryorplasmaglucosemeasurement<63mg/dLthatdoesnotqualifyasamajorepisode.?低血糖小幅度发作定义为伴毛细血管或血浆葡萄糖值v 63mg/dl无需外界协助的有症状发作，或伴毛细血管或血浆葡萄糖值v 63mg/dI未评价为主要发作的无症状发作。?OAD=oralantidiabetictherapyOAD=口服抗糖尿病药疗法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）.使用本药患者更易出现生殖器霉菌感染。 在12项安慰剂对照试验的已有报道中， 出现生殖器霉菌感染患者比例，安慰剂组为 0.9%、本药5mg组为5.7%、本药10mg组为4.8%。由于生殖器霉菌感染停药患者比例，安慰剂组为 0%、本药10mg组为0.2%。报道中女性感染较男性感染更为常见（见表1），最为常见的生殖器霉菌感染为女性外阴阴道霉菌感染、男性龟头炎。试验中有生殖器霉菌感染病史的患者更易出现感染。HypersensitivityReactions过敏反应Hypersensitivityreactions（e.g.,angioedema,urticaria,hypersensitivity）werereportedwithFARXIGAtreatment.Acrosstheclinicalprogram,seriousanaphylacticreactionsandseverecutaneousadversereactionsandangioedemawerereportedin0.2%ofcomparator-treatedpatientsand0.3%ofFARXIGA-treatedpatients.Ifhypersensitivityreactionsoccur,discontinueuseofFARXIGA;treatperstandardofcareandmonitoruntilsignsandsymptomsresolve.使用本药治疗有出现过敏反应（如血管神经性水肿、过敏）的报道。临床研究中，出现严重过敏反应、严重皮肤不良反应、血管神经水肿患者的比例，对照组为 0.2%、使用本药组为0.3%。如出现过敏反应，应停药并进行对症治疗及监测，直至迹象和症状解决。LaboratoryTests实验室测试IncreaseinHematocrit血细胞比容升高Inthepoolof13placebo-controlledstudies,increasesfrombaselineinmeanhematocritvalueswereobservedinFARXIGA-treatedpatientsstartingatWeek1andcontinuinguptoWeek16,whenthemaximummeandifferencefrombaselinewasobserved.AtWeek24,themeanchangesfrombaselineinhematocritwere-0.33%intheplacebogroupand2.30%intheFARXIGA10mggroup.ByWeek24,hematocritvalues>55%werereportedin0.4%ofplacebo-treatedpatientsand1.3%ofFARXIGA10mg-treatedpatients.13项安慰剂对照试验合并数据显示，患者用药 1周后出现血细胞比容平均值较基线水平升高且继续持续升高。第16周时血细胞比容平均值较基线差异最大。 第24周时，血细胞比容平均值较基线的变化，安慰剂组为-0.33%、本药10mg组为2.30%。截至第24周，血细胞比容〉55%的患者比例，安慰剂组为0.4%、本药10mg组为1.3%。IncreaseinSerumInorganicPhosphorus血清无机磷升高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项安慰剂对照试验合并数据显示， 与使用安慰剂相比，患者用药24周后出现血清无机磷平均值较基线水平升高（安慰剂组为-0.04mg/dl，本药为0.13mg/dl）。用药24周后，使用本药患者出现高磷血症（实验室检测数据17-65岁者》5.6mg/dl,>66岁者》5.1mg/dl）患者比例更高（安慰剂组为0.9%、本药10mg组为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项安慰剂对照试验合并数据显示， 与使用安慰剂相比，使用本药患者出现LDL-C较基线水平升高。第24时，LDL-C平均变化值，安慰剂组总胆固醇为0.0%、低密度脂蛋白胆固醇为-1.0%,本药10mg组总胆固醇为2.5%、低密度脂蛋白胆固醇为2.9%。8USEINSPECIFICPOPULATIONS特殊人群用药Pregnancy妊娠期妇女PregnancyCategoryC妊娠分级：C级Therearenoadequateandwell-controlledstudiesofFARXIGAinpregnantwomen.Basedonresultsofreproductiveanddevelopmentaltoxicitystudiesinanimals,dapagliflozinmayaffectrenaldevelopmentandmaturation.Inajuvenileratstudy,increasedincidenceand/orseverityofrenalpelvicandtubulardilatationswereevidentatthelowesttesteddosewhichwasapproximately15timesclinicalexposurefroma10mgdose.尚未在妊娠期妇女中进行充分、严格的对照试验，基于动物生殖毒性试验结果，本药可能影响肾脏的发育和成熟。在一项大鼠幼崽研究中，给予最低测试剂量 （约为人类临床暴露量10mg的15倍）可出现明显的肾盂炎和食道扩张发生率增加和 （或）加重。Theseoutcomesoccurredwithdrugexposuresduringperiodsofanimaldevelopmentthatcorrelatewiththelatesecondandthirdtrimestersofhumanpregnancy.Duringpregnancy,considerappropriatealternativetherapies,especiallyduringthesecondandthirdtrimesters.FARXIGAshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.Inajuveniletoxicitystudy,whendapagliflozinwasdoseddirectlytoyoungratsfrompostnatalday（PND）21untilPND90atdosesof1,15,or75mg/kg/day,increasedkidneyweightsandrenalpelvicandtubulardilatationswerereportedatalllevels.Exposureatthelowesttesteddosewas15timesthemaximumclinicaldose,basedonAUC.Therenalpelvicandtubulardilatationsobservedinjuvenileanimalsdidnotfullyreversewithintheapproximate1-monthrecoveryperiod.这些在动物发育期间使用药物暴露量出现的结果，与人类妊娠中期、妊娠晚期相关。妊娠期间，应采取替代疗法，尤其妊娠中期、妊娠晚期。本药仅在利大于弊的情况下方可用于妊娠期妇女。在一项大鼠幼崽毒性研究中，给予本药剂量为一日1mg/kg、15mg/kg、75mg/kg（于出生后21-90日期间），所有剂量组出现肾脏重量增加、肾盂炎、食道扩张。给予的最低测试剂量以曲线下面积（AUC）计，约为人类最大临床暴露量的15倍。在幼崽中出现的肾盂炎、食管扩张并未在1个月恢复期间完全恢复。Inaprenatalandpostnataldevelopmentstudy,maternalratsweredosedfromgestationday6throughlactationday21atdosesof1,15,or75mg/kg/day,andpupswereindirectlyexposedinuteroandthroughoutlactation.Increasedincidenceorseverityofrenalpelvicdilatationwasobservedinadultoffspringoftreateddamsat75mg/kg/day（maternalandpupdapagliflozinexposureswere1415timesand137times,respectively,thehumanvaluesattheclinicaldose）.Dose-relatedreductionsinpupbodyweightswereobservedatdoses >1mg/kg/day（approximately>19imestheclinicaldose）.Noadverseeffectsondevelopmentalendpointswerenotedat1mg/kg/day,orapproximately19timestheclinicaldose.在一项大鼠出生前和出生后发育研究中，妊娠大鼠从妊娠第 6日到哺乳第21日，给予本药剂量为一日1mg/kg、15mg/kg、75mg/kg，幼崽在子宫内及哺乳期间间接暴露于本药。使用每日75mg/kg组（妊娠大鼠暴露量相当于人类治疗暴露量的 1415倍，幼崽暴露量相当于人类治疗暴露量的137倍）中，成年后代出现肾盂炎和食道扩张发生率增加或加重。所有组 （约为临床剂量》19倍）中幼崽出现与剂量相关的体重降低。每日 1mg/kg组（约为临床剂量的19倍）中，未见发育相关不良反应。Inembryo-fetaldevelopmentstudiesinratsandrabbits,dapagliflozinwasadministeredforintervalscoincidingwiththefirsttrimesterperiodoforganogenesisinhumans.Nodevelopmentaltoxicitieswereobservedinrabbitsatanydosetested.Inrats,dapagliflozinwasneitherembryolethalnorteratogenicatdosesupto75mg/kg/dayor1441timesthemaximumclinicaldoseof10mg.Athigherdosesinrats,malformationsofbloodvessels,ribs,vertebra,manubria,andskeletalvariationsinfetusesat>150mg/kgor2344timesthe10mgclinicaldosewereobserved在一项大鼠、家兔胚胎-胎仔发育研究中，间隔给予本药以保持与人类妊娠前期器官形成期一致。家兔任一剂量组未见生殖毒性。大鼠给予本药剂量达一日75mg/kg(相当于最大临床暴露量10mg的1441倍)时未见致畸作用。大鼠使用更高剂量 (》150mg/kg，相当于临床剂量10mg的2344倍)时出现血管、肋骨、椎骨、胸骨柄畸形，以及胎仔骨骼变化。NursingMothers哺乳期妇女ItisnotknownwhetherFARXIGAisexcretedinhumanmilk.Dapagliflozinisexcretedinratmilkreachinglevels0.49timesthatfoundinmaternalplasma.Datainjuvenileratsdirect