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1 Product Monogrph Pulished y

2 INDICATION AND LIMITATION OF USE JARDIANCE is indicted s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus. JARDIANCE is not recommended for ptients with type 1 dietes or for the tretment of dietic ketocidosis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS JARDIANCE should not e used in ptients with history of serious hypersensitivity to JARDIANCE or in ptients with severe renl impirment, end-stge renl disese, or dilysis. WARNINGS AND PRECAUTIONS Hypotension JARDIANCE cuses intrvsculr volume contrction. Symptomtic hypotension my occur fter inititing JARDIANCE prticulrly in ptients with renl impirment, the elderly, in ptients with low systolic lood pressure, nd in ptients on diuretics. Before inititing JARDIANCE, ssess for volume contrction nd correct volume sttus if indicted. Monitor for signs nd symptoms of hypotension fter inititing therpy. Impirment in Renl Function JARDIANCE increses serum cretinine nd decreses egfr. Renl function should e evluted prior to inititing JARDIANCE nd periodiclly therefter. More frequent monitoring is recommended with egfr elow 60 ml/min/1.73 m 2. The risk of impired renl function with JARDIANCE is incresed in elderly ptients nd ptients with moderte renl impirment. JARDIANCE should e discontinued in ptients with persistent egfr less thn 45 ml/min/1.73 m 2. Hypoglycemi with Concomitnt Use with Insulin nd Insulin Secretgogues Insulin nd insulin secretgogues re known to cuse hypoglycemi. The use of JARDIANCE with these gents cn increse the risk of hypoglycemi. A lower dose of insulin or the insulin secretgogue my e required to reduce the risk of hypoglycemi when used in comintion with JARDIANCE. Genitl Mycotic Infections JARDIANCE increses the risk for genitl mycotic infections. Ptients with history of chronic or recurrent genitl mycotic infections were more likely to develop these infections. Monitor nd tret s pproprite. Urinry Trct Infections JARDIANCE increses the risk for urinry trct infections. Monitor nd tret s pproprite. Incresed Low-Density Lipoprotein Cholesterol (LDL-C) Increses in LDL-C cn occur with JARDIANCE. Monitor nd tret s pproprite. Mcrovsculr Outcomes There hve een no clinicl studies estlishing conclusive evidence of mcrovsculr risk reduction with JARDIANCE or ny other ntidietic drug. ADVERSE REACTIONS The most common dverse rections (>5%) ssocited with plceo nd JARDIANCE 10 mg nd 25 mg were urinry trct infections (7.6%, 9.3%, 7.6%, respectively) nd femle genitl mycotic infections (1.5%, 5.4%, 6.4%, respectively). When JARDIANCE ws dministered with insulin or sulfonylure, the incidence of hypoglycemic events ws incresed. DRUG INTERACTIONS Codministrtion of JARDIANCE with diuretics resulted in incresed urine volume nd frequency of voids, which might enhnce the potentil for volume depletion. USE IN SPECIAL POPULATIONS Pregnncy There re no dequte nd well-controlled studies of JARDIANCE in pregnnt women. JARDIANCE should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus. Nursing Mothers It is not known if JARDIANCE is excreted in humn milk. Becuse of the potentil for serious dverse rections in nursing infnts from JARDIANCE, discontinue nursing or discontinue JARDIANCE. Geritric Use JARDIANCE is expected to hve diminished efficcy in elderly ptients with renl impirment. The incidence of volume depletion-relted dverse rections nd urinry trct infections incresed in ptients 75 yers treted with JARDIANCE. JARPROFISI Plese see full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

3 PUBLISHING STAFF EDITOR-IN-CHIEF Fred M. Eckel, RPh, MS, ScD (Hon) VICE PRESIDENT, GROUP EDITORIAL DIRECTOR Be Riemschneider MANAGING EDITOR Kirk McKy SENIOR EDITOR Ktie Eder ASSOCIATE EDITOR Eileen Oldfield ASSOCIATE EDITOR Aimee Simone PHARMACY LAW EDITOR Joseph L. Fink III, BSPhrm, JD PUBLISHER Ashley Hennessy Tlmo SENIOR CREATIVE DIRECTOR: PRINT/DIGITAL Jennifer Lynn SENIOR VICE PRESIDENT OF OPERATIONS AND CLINICAL AFFAIRS Jeff Prescott, PhrmD, RPh SENIOR DIRECTOR OF SCIENTIFIC AFFAIRS Mryjo Dixon, RPh, MBA QUALITY ASSURANCE EDITOR Dvid Alliks MARKETING & PARTNERSHIP MANAGER Eline Chu SALES & MARKETING COORDINATOR Grce Rhee ADVERTISING REPRESENTATIVES Kristen Ashukin Crmel Burke-Bonesso Anthony Costell Mike Glicr DIGITAL ADVERTISING John Hydrusko MAIN NUMBER: OPERATIONS & FINANCE CONTROLLER: Jonthn Fisher, CPA ASSISTANT CONTROLLER Leh Bitz, CPA ACCOUNTANT: Amy Wheeler CORPORATE CHAIRMAN AND CEO Mike Hennessy VICE CHAIRMAN Jck Lepping PRESIDENT Tighe Blzier CHIEF FINANCIAL OFFICER Neil Glsser, CPA/CFE EXECUTIVE VICE PRESIDENT AND GENERAL MANAGER John Mglione VICE PRESIDENT OF HUMAN RESOURCES Rich Weismn VICE PRESIDENT OF EDUCATION Dvid Heckrd VICE PRESIDENT/EXECUTIVE CREATIVE DIRECTOR Jeff Brown This JARDIANCE Product Monogrph ws developed y Phrmcy Times, with editoril nd finncil support provided y Boehringer Ingelheim Phrmceuticls, Inc, nd Eli Lilly nd Compny. 2 Aout Type 2 Dietes Mellitus 2 Tretment of Type 2 Dietes Mellitus 3 Aout JARDIANCE 3 Role of the Phrmcist 16 Summry 16 References 17 Full Prescriing Informtion for JARDIANCE INDICATION AND LIMITATION OF USE Product Monogrph JARDIANCE is indicted s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus. JARDIANCE is not recommended for ptients with type 1 dietes or for the tretment of dietic ketocidosis. CONTRAINDICATIONS JARDIANCE should not e used in ptients with history of serious hypersensitivity to JARDIANCE or in ptients with severe renl impirment, end-stge renl disese, or dilysis. Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

4 Jrdince (empgliflozin) Tlets Product Monogrph ABOUT TYPE 2 DIABETES MELLITUS In the United Sttes, the prevlence of dietes incresed from 4.7% to 11.2% in men nd from 5.7% to 8.7% in women from to After djustment for ge, rce/ethnicity, nd ody mss index, the prevlence of dietes incresed in men (6.2% to 9.6%) ut not women (7.6% to 7.5%). 1 According to estimtes from the Centers for Disese Control nd Prevention (CDC) pulished in 2014, 9.3% of the US popultion hs dietes, including 4.1% of dults ged 20 to 44 yers, 16.2% of dults ged 45 to 64 yers, nd 25.9% of those 65 yers nd older. In dults, type 2 dietes ccounts for out 90% to 95% of ll dignosed cses of dietes. 2 Type 2 dietes disproportiontely ffects older individuls nd certin minority popultions (eg, Africn Americns, Hispnics/Ltinos, Americn Indins, some Asins, nd Ntive Hwiins or other Pcific Islnders). 2 Other risk fctors for the development of type 2 dietes include fmily history of dietes, excess weight (ody mss index [BMI] 25 kg/m 2 ), physicl inctivity, history of gesttionl dietes, hypertension (lood pressure 140/90 mm Hg), low high-density lipoprotein cholesterol (HDL-C) level (<35 mg/dl), polycystic ovrin syndrome, nd history of crdiovsculr disese. 3 The centrl components of type 2 dietes pthogenesis involve insulin resistnce nd norml insulin secretion, stemming from comintion of fctors tht include genetic susceptiility nd oesity. 4 As insulin resistnce nd hyperinsulinemi progress, the ody s -cells my lose the ility to produce insulin in sufficient quntities, resulting in hyperglycemi. 2,4 According to the Americn Dietes Assocition (ADA), the dignosis of dietes is sed on glycted hemogloin (A1C) of 6.5% or higher, fsting plsm glucose (FPG) of 126 mg/ dl or higher (fter no cloric intke for t lest 8 hours), 2-hour plsm glucose of 200 mg/dl or higher during n orl glucose tolernce test, or rndom plsm glucose of 200 mg/dl or higher in ptient who is exhiiting clssic symptoms of hyperglycemi or hyperglycemic crisis. 3 TREATMENT OF TYPE 2 DIABETES MELLITUS Tretment gols re individulized for ech ptient sed on severl fctors, including ge, the presence of comorid conditions, durtion of dietes, life expectncy, nd the risk of hypoglycemi nd other tretment-relted dverse events. The ADA recommends lowering A1C to less thn 7% for mny nonpregnnt dults or less thn 6.5% for helthy ptients without concurrent illness nd t low hypoglycemic risk. In those ptients with history of severe hypoglycemi, limited life expectncy, dvnced microvsculr or mcrovsculr complictions, nd extensive comorid conditions, less stringent A1C gol of less thn 8% is recommended. 3 Guidelines from the Americn Assocition of Clinicl Endocrinologists (AACE) stte tht n A1C of 6.5% or less is considered optiml; however, s with the ADA guidelines, the AACE recommendtions stress tht the A1C gol must e individulized, sed on the forementioned fctors. 5 Mny ntihyperglycemic therpies with vrying mechnisms of ction re ville to mnge type 2 dietes; using comintion of therpies tht hve complementry mechnisms of ction might e necessry to chieve nd mintin glycemic control. 5 Minimizing the risk of hypoglycemi nd the risk of weight gin re priorities when using phrmcologic therpy. The efficcy of tretment should e monitored frequently until stle (ie, every 3 months). 5 According to the ADA guidelines, if ptient does not chieve glycemic control fter 3 months of monotherpy with single orlly dministered ntihyperglycemic gent, second gent should e dded. Triple therpy is recommended if A1C gols re not met fter 3 months on dul therpy. 3 Ptients should lso e monitored for dverse events nd comorid conditions. 5 All ptients with type 2 dietes should e counseled on lifestyle chnges, including helthy eting, weight control, nd physicl ctivity. One of the most recently developed clsses of tretments for type 2 dietes is the sodium glucose co-trnsporter 2 (SGLT2) inhiitor, which exerts its lood glucose lowering effects y inhiiting the resorption of glucose in the kidneys. 6,7 The kidney is involved in glucose homeostsis vi gluconeogenesis nd resorption of glucose. 6 Sodium glucose co-trnsporters in the kidney re responsile for regulting 2 Novemer 2014 Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

5 Jrdince (empgliflozin) Tlets Product Monogrph the resorption of glucose following plsm filtrtion. 6,7 ABOUT JARDIANCE The SGLT2 inhiitor JARDIANCE (empgliflozin) ws pproved y the FDA in August 2014 for the tretment of dults with type 2 dietes s n djunct to diet nd exercise. JARDIANCE is not recommended for ptients with type 1 dietes or for the tretment of dietic ketocidosis. 8 Plese see full Prescriing Informtion for JARDIANCE on pges 17 to 26. Role of the Phrmcist As helthcre professionls who re redily ccessile in the community setting, phrmcists ply key role in disseminting importnt informtion to ptients nd others out type 2 dietes nd mngement options, including JARDIANCE. As such, it is especilly importnt for the phrmcist to gin n understnding of the mechnism of ction, sfety profile, nd efficcy profile of JARDIANCE. Phrmcists should lso e fmilir with informtion regrding the use of JARDIANCE in pproprite ptients nd specil popultions. Contrindictions JARDIANCE is contrindicted in ptients with history of serious hypersensitivity rections nd in ptients with severe renl impirment, with end-stge renl disese (ESRD), or on dilysis. 8 Pregnncy/Lcttion The use of JARDIANCE hs not een evluted in pregnnt women, nd JARDIANCE should only e used during pregnncy if the potentil enefit justifies the potentil risk to the fetus. Although it is not known if JARDIANCE is excreted in humn milk, ecuse of the potentil for serious dverse rections in nursing infnts from JARDIANCE, decision should e mde whether to discontinue nursing or to discontinue JARDIANCE, Figure 1. The Structurl Formul of JARDIANCE 8 HO HO O OH OH tking into ccount the importnce of the drug to the mother. 8 Peditric Ptients The sfety nd effectiveness of JARDIANCE in peditric ptients (ged <18 yers) hve not een estlished. 8 Dosge nd Administrtion In pproprite ptients, the recommended dose of JARDIANCE is 10 mg once dily, tken in the morning with or without food. The dose cn e incresed to 25 mg once dily in ptients tolerting JARDIANCE. No chnge in JARDIANCE dosge is recommended sed on ge. JARDIANCE my e used in ptients with heptic impirment. In ptients with volume depletion, correcting this condition prior to initition of JARDIANCE is recommended. 8 Monitoring JARDIANCE increses serum cretinine nd decreses estimted glomerulr filtrtion rte (egfr). Renl function should e evluted prior to inititing JARDIANCE nd periodiclly therefter. Ptients with n egfr less thn 45 ml/min/1.73 m 2 should not e treted with JARDIANCE. Likewise, if t ny time during tretment with JARDIANCE the egfr flls persistently elow 45 ml/min/1.73 m 2, tretment with JARDIANCE should e discontinued. More frequent monitoring is recommended for ptients with moderte renl impirment nd elderly ptients. 8 Phrmcists should dvise ptients to seek medicl ttention if they develop signs or symptoms of hypotension, Cl O O hypoglycemi, genitl mycotic infection (GMI), or urinry trct infection (UTI). In ddition to monitoring ptients for the forementioned dverse events, phrmcists should remind physicins to monitor for incresed levels of low-density lipoprotein cholesterol (LDL-C) in ptients tking JARDIANCE. 8 Description JARDIANCE tlets contin empgliflozin, n SGLT2 inhiitor. The chemicl nme of empgliflozin is D-Glucitol,1,5-nhydro-1-C-[4-chloro- 3-[[4-[[(3S)-tetrhydro-3-furnyl] oxy]phenyl]methyl]phenyl]-, (1S). Its moleculr formul is C 23 H 27 ClO 7 nd the moleculr weight is The structurl formul is shown in Figure 1. 8 Empgliflozin is white to yellowish, non-hygroscopic powder. It is very slightly solule in wter, springly solule in methnol, slightly solule in ethnol nd cetonitrile, solule in 50% cetonitrile/wter, nd prcticlly insolule in toluene. 8 Ech film-coted tlet of JARDIANCE contins 10 mg or 25 mg of empgliflozin (free se) nd the inctive ingredients lctose monohydrte, microcrystlline cellulose, hydroxypropyl cellulose, croscrmellose sodium, colloidl silicon dioxide, nd mgnesium sterte. In ddition, the film coting contins the inctive ingredients hypromellose, titnium dioxide, tlc, polyethylene glycol, nd yellow ferric oxide. 8 Clinicl Phrmcology Indictions nd Usge JARDIANCE is indicted s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus. JARDIANCE is not recommended for ptients with type 1 dietes mellitus or for the tretment of dietic ketocidosis. 8 Mechnism of Action Empgliflozin is n inhiitor of SGLT2, which is the predominnt Novemer Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

6 Jrdince (empgliflozin) Tlets Product Monogrph trnsporter responsile for the resorption of glucose from the glomerulr filtrte ck into the circultion. By inhiiting SGLT2, empgliflozin reduces renl resorption of filtered glucose nd lowers the renl threshold for glucose, therey incresing urinry glucose excretion. 8 Hypotension JARDIANCE cuses intrvsculr volume contrction. Symptomtic hypotension my occur fter inititing JARDIANCE prticulrly in ptients with renl impirment, the elderly, in ptients with low systolic lood pressure, nd in ptients on diuretics. Before inititing JARDIANCE, ssess for volume contrction nd correct volume sttus if indicted. Monitor for signs nd symptoms of hypotension fter inititing therpy nd increse monitoring in clinicl situtions where volume contrction is expected. 8 Phrmcodynmics Urinry Glucose Excretion In ptients with type 2 dietes, urinry glucose excretion incresed immeditely following dose of JARDIANCE nd ws mintined t the end of 4-week tretment period, verging pproximtely 64 grms per dy with 10 mg empgliflozin nd 78 grms per dy with 25 mg JARDIANCE once dily. 8 Urinry Volume In 5-dy study, the men 24-hour urine volume increse from seline ws 341 ml on dy 1 nd 135 ml on dy 5 of tretment with empgliflozin 25 mg once dily. 8 Crdic Electrophysiology In rndomized, plceo-controlled, ctive-comprtor, crossover study, 30 helthy sujects were dministered single orl dose of JARDIANCE 25 mg, JARDIANCE 200 mg (8 times the mximum dose), moxifloxcin, nd plceo. No increse in corrected QT intervl ws oserved with either 25 mg or 200 mg empgliflozin. 8 Phrmcokinetics Asorption The phrmcokinetics of empgliflozin hs een chrcterized in helthy volunteers nd ptients with type 2 dietes, nd no cliniclly relevnt differences were noted etween the 2 popultions. After orl dministrtion, pek plsm concentrtions (C mx ) of empgliflozin were reched t 1.5 hours postdose. Therefter, plsm concentrtions declined in iphsic mnner with rpid distriution phse nd reltively slow terminl phse. The stedystte men plsm re under the curve () nd C mx were 1870 nmol h/l nd 259 nmol/l, respectively, with 10 mg empgliflozin once dily, nd 4740 nmol h/l nd 687 nmol/l, respectively, with 25 mg empgliflozin once dily. Systemic exposure of empgliflozin incresed in dose-proportionl mnner in the therpeutic dose rnge. The single-dose nd stedy-stte phrmcokinetic prmeters of empgliflozin were similr, suggesting liner phrmcokinetics with respect to time. 8 Administrtion of 25 mg empgliflozin fter intke of high-ft nd high-clorie mel resulted in slightly lower exposure; decresed y pproximtely 16% nd C mx decresed y pproximtely 37%, compred with dministrtion under fsting conditions. The oserved effect of food on empgliflozin phrmcokinetics ws not considered cliniclly relevnt, nd empgliflozin my e dministered with or without food. 8 Distriution The pprent stedy-stte volume of distriution ws estimted to e 73.8 L, sed on popultion phrmcokinetic nlysis. Following dministrtion of n orl [ 14 C]-empgliflozin solution to helthy sujects, the red lood cell prtitioning ws pproximtely 36.8%, nd plsm protein inding ws 86.2%. 8 Metolism No mjor metolites of empgliflozin were detected in humn plsm, nd the most undnt metolites were 3 glucuronide conjugtes (2-O-, 3-O-, nd 6-O-glucuronide). Systemic exposure of ech metolite ws less thn 10% of totl drug-relted mteril. In vitro studies suggested tht the primry route of metolism of empgliflozin in humns is glucuronidtion y the uridine 5 -diphospho-glucuronosyltrnsferses (UGTs) UGT2B7, UGT1A3, UGT1A8, nd UGT1A9. 8 Elimintion The pprent terminl elimintion hlflife of empgliflozin ws estimted to e 12.4 h, nd pprent orl clernce ws 10.6 L/h, sed on the popultion phrmcokinetic nlysis. Following once-dily dosing, up to 22% ccumultion, with respect to plsm, ws oserved t stedy stte, which ws consistent with empgliflozin hlf-life. Following dministrtion of n orl [ 14 C]-empgliflozin solution to helthy sujects, pproximtely 95.6% of the drug-relted rdioctivity ws eliminted in feces (41.2%) nd urine (54.4%). The mjority of drug-relted rdioctivity recovered in feces ws unchnged prent drug, nd pproximtely one-hlf of drug-relted rdioctivity excreted in urine ws unchnged prent drug. 8 Specific Popultions Renl Impirment In ptients with mild (egfr: 60 to <90 ml/min/1.73 m 2 ), moderte (egfr: 30 to <60 ml/min/1.73 m 2 ), nd severe (egfr: <30 ml/min/1.73 m 2 ) renl impirment nd ptients with kidney filure/esrd, the of empgliflozin incresed y pproximtely 18%, 20%, 66%, nd 48%, respectively, compred with individuls with norml renl function. Pek plsm levels of empgliflozin were similr in ptients with moderte renl impirment nd kidney filure/esrd compred with ptients with norml renl function. Pek plsm levels of empgliflozin were roughly 20% higher in ptients with mild nd severe renl impirment compred with individuls with norml 4 Novemer 2014 Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

7 Jrdince (empgliflozin) Tlets Product Monogrph renl function. Popultion phrmcokinetic nlysis showed tht the pprent orl clernce of empgliflozin decresed with decrese in egfr, leding to n increse in drug exposure. However, the frction of empgliflozin tht ws excreted unchnged in urine nd urinry glucose excretion declined with decrese in egfr. 8 Heptic Impirment In sujects with mild, moderte, nd severe heptic impirment ccording to the Child-Pugh clssifiction, of empgliflozin incresed y pproximtely 23%, 47%, nd 75% nd C mx incresed y pproximtely 4%, 23%, nd 48%, respectively, compred with sujects with norml heptic function. 8 Effects of Age, BMI, Gender, nd Rce Bsed on the popultion phrmcokinetic nlysis, ge, BMI, gender, nd rce (Asins vs primrily whites) do not hve cliniclly meningful effect on the phrmcokinetics of empgliflozin. 8 Peditric Studies chrcterizing the phrmcokinetics of empgliflozin in peditric ptients hve not een performed. 8 Drug Interctions In Vitro Assessment of Drug Interctions In vitro dt suggest tht the primry route of metolism of empgliflozin in humns is glucuronidtion vi UGT2B7, UGT1A3, UGT1A8, nd UGT1A9. Empgliflozin does not inhiit, inctivte, or induce cytochrome P450 (CYP450) isoforms. Empgliflozin lso does not inhiit UGT1A1. Therefore, no effect of empgliflozin is nticipted on concomitntly dministered drugs tht re sustrtes of the mjor CYP450 isoforms or UGT1A1. The effect of UGT induction (eg, induction y rifmpicin or ny other UGT enzyme inducer) on empgliflozin exposure hs not een evluted. 8 Empgliflozin is sustrte for P-glycoprotein (P-gp) nd rest cncer resistnce protein (BCRP), ut it does not inhiit these efflux trnsporters t therpeutic doses. Bsed on in vitro studies, empgliflozin is considered unlikely to cuse interctions with drugs tht re P-gp sustrtes. Empgliflozin is sustrte of the humn uptke trnsporters orgnic nion trnsporter (OAT) OAT3, OATP1B1, nd OATP1B3, ut not OAT1 nd OCT2. Empgliflozin does not inhiit ny of these humn uptke trnsporters t cliniclly relevnt plsm concentrtions, nd therefore no effect of empgliflozin is nticipted on concomitntly dministered drugs tht re sustrtes of these uptke trnsporters. 8 Codministrtion of JARDIANCE with diuretics resulted in incresed urine volume nd frequency of voids, which might enhnce the potentil for volume depletion. 8 Insulin nd insulin secretgogues re known to cuse hypoglycemi. The use of JARDIANCE with these gents cn increse the risk of hypoglycemi. A lower dose of insulin or the insulin secretgogue my e required to reduce the risk of hypoglycemi when use in comintion with JARDIANCE. 8 In Vivo Assessment of Drug Interctions No dose djustment of JARDIANCE is recommended when codministered with commonly prescried medicinl products sed on results of the descried phrmcokinetic studies. Empgliflozin phrmcokinetics were similr with nd without codministrtion of metformin, glimepiride, pioglitzone, sitgliptin, lingliptin, wrfrin, verpmil, rmipril, simvsttin, hydrochlorothizide, or torsemide in helthy volunteers. The oserved increses in overll exposure () of empgliflozin following codministrtion with gemfirozil, rifmpicin, or proenecid re not cliniclly relevnt. In sujects with norml renl function, codministrtion of empgliflozin with proenecid resulted in 30% decrese in the frction of empgliflozin excreted in urine without ny effect on 24-hour urinry glucose excretion. The relevnce of this oservtion to ptients with renl impirment is unknown. Empgliflozin hd no cliniclly relevnt effect on the phrmcokinetics of metformin, glimepiride, pioglitzone, sitgliptin, lingliptin, wrfrin, digoxin, rmipril, simvsttin, hydrochlorothizide, torsemide, or orl contrceptives when codministered in helthy volunteers. 8 Nonclinicl Toxicology Crcinogenesis Crcinogenesis ws evluted during 2-yer studies conducted in CD-1 mice nd Wistr rts. Empgliflozin did not increse the incidence of tumors in femle rts dosed t 100, 300, or 700 mg/kg/dy (up to 72 times the exposure from the mximum clinicl dose of 25 mg). In mle rts, hemngioms of the mesenteric lymph node were incresed significntly t 700 mg/kg/dy (pproximtely 42 times the exposure from 25-mg clinicl dose). Empgliflozin did not increse the incidence of tumors in femle mice dosed t 100, 300, or 1000 mg/kg/dy (up to 62 times the exposure from 25-mg clinicl dose). Renl tuule denoms nd crcinoms were oserved in mle mice t 1000 mg/kg/dy, which is pproximtely 45 times the mximum clinicl dose of 25 mg. 8 Mutgenesis Empgliflozin ws not mutgenic or clstogenic with or without metolic ctivtion ccording to the in vitro Ames cteril mutgenicity ssy, the in vitro L5178Y tk +/- mouse lymphom cell ssy, or n in vivo micronucleus ssy in rts. 8 Impirment of Fertility Empgliflozin hd no effects on mting, fertility, or erly emryonic development in treted mle or femle rts up to the high dose of 700 mg/kg/dy (pproximtely 155 times the 25-mg clinicl dose in mles nd femles). 8 How Supplied nd Storge JARDIANCE tlets re ville in Novemer Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

8 Jrdince (empgliflozin) Tlets Product Monogrph Tle 1. Results t Week 24 From Plceo-controlled Monotherpy Study of JARDIANCE 8 JARDIANCE 10 mg N = 224 JARDIANCE 25 mg N = 224 Plceo N = 228 A1C (%) Bseline (men) Chnge from seline (djusted men) Difference from plceo (djusted men) (97.5% confidence intervl [CI]) 0.7 ( 0.9, 0.6) 0.9 ( 1.0, 0.7) Ptients [n (%)] chieving A1C <7% 72 (35%) 88 (44%) 25 (12%) FPG (mg/dl) c Bseline (men) Chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) 31 ( 37, 26) 36 ( 42, 31) Body Weight Bseline (men) in kg % chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) 2.5 ( 3.1, 1.9) -2.8 ( 3.4, 2.2) Modified intent to tret (mitt) popultion. Lst oservtion on study crried forwrd (LOCF) ws used to impute missing dt t Week 24. At Week 24, 9.4%, 9.4%, nd 30.7% ws imputed for ptients rndomized to JARDIANCE 10 mg, JARDIANCE 25 mg, nd plceo, respectively. Anlysis of covrince (ANCOVA) derived P< (A1C: ANCOVA model includes seline A1C, tretment, renl function, nd region. Body weight nd FPG: sme model used s for A1C ut dditionlly including seline ody weight/seline FPG, respectively.) c FPG (mg/dl); for JARDIANCE 10 mg, n = 223, for JARDIANCE 25 mg, n = 223, nd for plceo, n = mg nd 25-mg strengths s follows 8 : 10-mg tlets: ple yellow, round, iconvex nd evel-edged, filmcoted tlets deossed with S 10 on one side nd the Boehringer A1C (%) Men Chnge From Bseline Ingelheim compny symol on the other side. 25-mg tlets: ple yellow, ovl, iconvex film-coted tlets, deossed with S 25 on one side nd the Figure 2. Plceo-controlled Monotherpy Study: Adjusted Men A1C Chnge t Ech Time Point (Completers) nd t Week 24 (mitt Popultion) LOCF 8, Plceo (N = 185) p Empgliflozin 10 mg (N = 206) Empgliflozin 25 mg (N = 202) Boehringer Ingelheim compny symol on the other side. Dispense in well-closed continer s defined in the United Sttes Phrmcopei (USP). Store t 25 C (77 F); excursions permitted to 15 C to 30 C (59 F 86 F). 8 Clinicl Studies JARDIANCE hs een studied s monotherpy nd in comintion with metformin, sulfonylure, pioglitzone, nd insulin. JARDIANCE hs lso een studied in ptients with type 2 dietes with mild or moderte renl impirment. In ptients with type 2 dietes, tretment with JARDIANCE reduced A1C compred with plceo p p p p p Genitl Mycotic Infections JARDIANCE increses the risk for genitl mycotic infections. Ptients with history of chronic or recurrent genitl mycotic infections were more likely to develop these infections. Monitor nd tret s pproprite. Bseline 6 12 Week Wk 24 (mitt) LOCF = lst oservtion on study crried forwrd; mitt = modified intent to tret. Men chnge from seline djusted for seline A1C, geogrphic region, nd egfr t seline. Urinry Trct Infections JARDIANCE increses the risk for urinry trct infections. Monitor nd tret s pproprite. 6 Novemer 2014 Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

9 Jrdince (empgliflozin) Tlets Product Monogrph Tle 2. Results t Week 24 From Plceo-controlled Study for JARDIANCE Used in Comintion With 8 JARDIANCE 10 mg + N = 217 JARDIANCE 25 mg + N = 213 Plceo + N = 207 A1C (%) Bseline (men) Chnge from seline (djusted men) Difference from plceo + metformin (djusted men) (95% CI) 0.6 ( 0.7, 0.4) 0.6 ( 0.8, 0.5) Ptients [n (%)] chieving A1C <7% 75 (38%) 74 (39%) 23 (13%) FPG (mg/dl) c Bseline (men) Chnge from seline (djusted men) Difference from plceo + metformin (djusted men) Body Weight Bseline men in kg % chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) 2.0 ( 2.6, 1.4) 2.5 ( 3.1, 1.9) Modified intent to tret (mitt) popultion. Lst oservtion on study crried forwrd (LOCF) ws used to impute missing dt t Week 24. At Week 24, 9.7%, 14.1%, nd 24.6% ws imputed for ptients rndomized to JARDIANCE 10 mg, JARDIANCE 25 mg, nd plceo, respectively. ANCOVA P< (A1C: ANCOVA model includes seline A1C, tretment, renl function, nd region. Body weight nd FPG: sme model used s for A1C ut dditionlly including seline ody weight/seline FPG, respectively.) c FPG (mg/dl): for JARDIANCE 10 mg, n = 216, for JARDIANCE 25 mg, n = 213, nd for plceo, n = 207. The reduction in A1C for JARDIANCE compred with plceo ws oserved cross sugroups including gender, rce, geogrphic region, seline BMI, nd durtion of disese. 8 Monotherpy A totl of 986 ptients with type 2 dietes prticipted in doule-lind, plceo-controlled study to evlute the efficcy nd sfety of JARDIANCE monotherpy. Tretment-nïve ptients with indequtely controlled type 2 dietes entered 2-week, open-lel, plceo run-in period. At the end of the run-in period, ptients who remined Incresed Low-Density Lipoprotein Cholesterol (LDL-C) Increses in LDL-C cn occur with JARDIANCE. Monitor nd tret s pproprite. Mcrovsculr Outcomes There hve een no clinicl studies estlishing conclusive evidence of mcrovsculr risk reduction with JARDIANCE or ny other ntidietic drug. indequtely controlled nd hd n A1C etween 7% nd 10% were rndomized to plceo, JARDIANCE 10 mg, JARDIANCE 25 mg, or reference comprtor. 8 At Week 24, tretment with JARDIANCE 10 mg or 25 mg dily provided sttisticlly significnt reductions in A1C (P<0.0001), FPG, nd ody weight compred with plceo (Tle 1 8 nd Figure 2 8 ). 8 At Week 24, the systolic lood pressure (SBP) ws sttisticlly significntly reduced compred with plceo y 2.6 mm Hg (plceo-djusted, P=0.0231) in ptients rndomized to 10 mg of JARDIANCE nd y 3.4 mm Hg (plceo-corrected, P=0.0028) in ptients rndomized to 25 mg of JARDIANCE. 8 JARDIANCE is not indicted for weight loss or ntihypertensive therpy. Chnges in ody weight nd lood pressure were secondry endpoints. Comintion Therpy Add-on Comintion Therpy With A totl of 637 ptients with type 2 dietes prticipted in doulelind, plceo-controlled study to evlute the efficcy nd sfety of JARDIANCE in comintion with metformin. Ptients with type 2 dietes indequtely controlled on t lest 1500 mg of metformin per dy entered n open-lel, 2-week, plceo run-in period. At the end of the run-in period, ptients who remined indequtely controlled nd hd n A1C etween 7% nd 10% were rndomized to plceo, JARDIANCE 10 mg, or JARDIANCE 25 mg. 8 At Week 24, tretment with JARDIANCE 10 mg or 25 mg dily provided sttisticlly significnt reductions in A1C (P<0.0001), FPG, nd ody weight compred with plceo (Tle 2). 8 At Week 24, the SBP ws sttisticlly significntly reduced compred with plceo y 4.1 mm Hg (plceo-corrected, P<0.0001) for JARDIANCE 10 mg nd 4.8 mm Hg (plceo-corrected, P<0.0001) for JARDIANCE 25 mg. 8 JARDIANCE is not indicted for weight loss or ntihypertensive therpy. Chnges in ody weight nd lood pressure were secondry endpoints. Novemer Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

10 Jrdince (empgliflozin) Tlets Product Monogrph Tle 3. Results t Week 24 From Plceo-controlled Study for JARDIANCE in Comintion With nd Sulfonylure 8 JARDIANCE10 mg + + SU N = 225 A1C (%) JARDIANCE 25 mg + + SU N = 216 Plceo + + SU N = 225 Bseline (men) Chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) 0.6 ( 0.8, 0.5) 0.6 ( 0.7, 0.4) -- Ptients [n (%)] chieving A1C <7% 55 (26%) 65 (32%) 20 (9%) FPG (mg/dl) c Bseline (men) Chnge from seline (djusted men) Difference from plceo (djusted men) Body Weight Bseline men in kg % chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) 2.4 ( 3.0, 1.8) 2.7 ( 3.3, 2.1) Modified intent to tret (mitt) popultion. Lst oservtion on study crried forwrd (LOCF) ws used to impute missing dt t week 24. At Week 24, 17.8%, 16.7%, nd 25.3% ws imputed for ptients rndomized to JARDIANCE 10 mg, JARDIANCE 25 mg, nd plceo, respectively. ANCOVA P< (A1C: ANCOVA model includes seline A1C, tretment, renl function, nd region. Body weight nd FPG: sme model used s for A1C ut dditionlly including seline ody weight/seline FPG, respectively.) c FPG (mg/dl): for JARDIANCE 10 mg, n = 225, for JARDIANCE 25 mg, n = 215, for plceo, n = 224. Add-on Comintion Therpy With nd Sulfonylure A totl of 666 ptients with type 2 dietes prticipted in doule-lind, plceo-controlled study to evlute the efficcy nd sfety of JARDIANCE in comintion with metformin plus sulfonylure. Ptients with indequtely controlled type 2 dietes on t lest 1500 mg per dy of metformin nd sulfonylure entered 2-week, openlel, plceo run-in period. At the end of the run-in period, ptients who remined indequtely controlled nd hd n A1C etween 7% nd 10% were rndomized to plceo, JARDIANCE 10 mg, or JARDIANCE 25 mg. 8,9 Tretment with JARDIANCE 10 mg or 25 mg dily provided sttisticlly significnt reductions in A1C (P<0.0001), FPG, nd ody weight compred with plceo (Tle 3). 8,9 JARDIANCE is not indicted for weight loss. Chnge in ody weight ws secondry endpoint. Active-controlled Study Versus Glimepiride in Comintion With The efficcy of JARDIANCE ws evluted in doule-lind, glimepiride-controlled study in 1545 ptients with type 2 dietes with insufficient glycemic control despite metformin therpy. Ptients with indequte glycemic control nd n A1C etween 7% nd 10% fter 2-week run-in period were rndomized to glimepiride or JARDIANCE 25 mg. 8,10 At Week 52, JARDIANCE 25 mg nd glimepiride lowered A1C nd FPG (Tle 4, 8 Figure 3 8 ). 8,10 The difference in oserved effect size etween JARDIANCE 25 mg nd glimepiride excluded the prespecified non-inferiority mrgin of 0.3%. The men dily dose of glimepiride ws 2.7 mg nd the mximl pproved dose in the United Sttes is 8 mg per dy. At Week 52, the djusted men chnge from seline in SBP in the JARDIANCE group ws 3.6 mm Hg compred with 2.2 mm Hg for glimepiride. The difference etween tretment groups for SBP ws sttisticlly significnt (P<0.0001). 8,10 Add-on Comintion Therpy With Pioglitzone With or Without A totl of 498 ptients with type 2 dietes prticipted in doule-lind, plceo-controlled study to evlute the efficcy nd sfety of JARDIANCE in comintion with pioglitzone, with or without metformin. Ptients with indequtely controlled type 2 dietes on metformin t dose of t lest 1500 mg per dy nd pioglitzone t dose of t lest 30 mg per dy entered 2-week, open-lel, plceo run-in period. Ptients with indequte glycemic control nd n A1C etween 7% nd 10% fter the run-in period were rndomized to plceo, JARDIANCE 10 mg, or JARDIANCE 25 mg. 8,11 Hypoglycemi with Concomitnt Use with Insulin nd Insulin Secretgogues Insulin nd insulin secretgogues re known to cuse hypoglycemi. The use of JARDIANCE with these gents cn increse the risk of hypoglycemi. A lower dose of insulin or the insulin secretgogue my e required to reduce the risk of hypoglycemi when used in comintion with JARDIANCE. 8 Novemer 2014 Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

11 Jrdince (empgliflozin) Tlets Product Monogrph Adverse Rections The most common dverse rections (>5%) ssocited with plceo nd JARDIANCE 10 mg nd 25 mg were urinry trct infections (7.6%, 9.3%, 7.6%, respectively) nd femle genitl mycotic infections (1.5%, 5.4%, 6.4%, respectively). When JARDIANCE ws dministered with insulin or sulfonylure, the incidence of hypoglycemic events ws incresed. Tretment with JARDIANCE 10 mg or 25 mg dily resulted in sttisticlly significnt reductions in A1C (P<0.0001), FPG, nd ody weight compred with plceo (Tle 5, pge 10). 8,11 JARDIANCE is not indicted for weight loss. Chnge in ody weight ws secondry endpoint. Add-on Comintion With Insulin With or Without nd/or Sulfonylures A totl of 494 ptients with type 2 dietes indequtely controlled on insulin, or insulin in comintion with orl drugs, prticipted in doule-lind, plceo-controlled study to evlute the efficcy of JARDIANCE s ddon therpy to insulin over 78 weeks. Ptients on sl insulin (eg, insulin glrgine, insulin detemir, or NPH insulin) with or without metformin nd/or sulfonylure ckground therpy entered 2-week, plceo run-in period. Following the run-in period, ptients with indequte glycemic control were rndomized to the ddition of JARDIANCE 10 mg, JARDIANCE 25 mg, or plceo. Ptients were mintined on stle dose of insulin prior to enrollment, during the run-in period, nd during the first 18 weeks of tretment. For the remining 60 weeks, insulin could e djusted. The men totl dily insulin dose t seline in the JARDIANCE 10 mg, 25 mg, nd plceo groups ws 45 IU, 48 IU, nd 48 IU, respectively. 8 JARDIANCE used in comintion with insulin (with or without metformin nd/or sulfonylure) provided Tle 4. Results t Week 52 From n Active-controlled Study Compring JARDIANCE With Glimepiride s Add-on Therpy in Ptients Indequtely Controlled on 8 JARDIANCE 25 mg + A1C (%) sttisticlly significnt reductions in A1C nd FPG compred with plceo fter oth 18 nd 78 weeks of tretment N = 765 Glimepiride + N = 780 Bseline (men) Chnge from seline (djusted men) Difference from glimepiride (djusted men) (97.5% CI) FPG (mg/dl) c 0.07 ( 0.15, 0.01) -- Bseline (men) Chnge from seline (djusted men) 19 9 Body Weight Bseline men in kg % chnge from seline (djusted men) Difference from comprtor (djusted men) (95% CI) 5.9 d ( 6.3, 5.5) -- Modified intent to tret (mitt) popultion. Lst oservtion on study crried forwrd (LOCF) ws used to impute dt missing t Week 52. At Week 52 dt were imputed for 15.3% nd 21.9% of ptients rndomized to JARDIANCE 25 mg nd glimepiride, respectively. Non-inferior, ANCOVA model P< (A1C: ANCOVA model includes seline A1C, tretment, renl function, nd region). c FPG (mg/dl): for JARDIANCE 25 mg, n = 764, for plceo, n = 779. d ANCOVA P< (Body weight nd FPG: sme model used s for A1C ut dditionlly including seline ody weight/ seline FPG, respectively.) A1C (%) Men Chnge From Bseline (Tle 6, pge 11). 8 JARDIANCE 10 mg or 25 mg dily lso resulted in sttisticlly significntly greter percent Figure 3. Active-controlled Study: Adjusted Men A1C Chnge t Ech Time Point (Completers) nd t Week 52 (mitt Popultion) LOCF 8, Glimepiride + (N=700) Empgliflozin 25 mg + (N=693) Bseline Wk 52 Week (mitt) LOCF = lst oservtion on study crried forwrd; mitt = modified intent to tret. Men chnge from seline djusted for seline A1C, geogrphic region, nd egfr t seline. Novemer Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

12 Jrdince (empgliflozin) Tlets Product Monogrph Tle 5. Results of Plceo-controlled Study for JARDIANCE in Comintion Therpy With Pioglitzone 8 JARDIANCE 10 mg + Pioglitzone N = 165 JARDIANCE 25 mg + Pioglitzone N = 168 Plceo + Pioglitzone N = 165 A1C (%) Bseline (men) Chnge from seline (djusted men) Difference from plceo + pioglitzone (djusted men) (95% CI) 0.5 ( 0.7, 0.3) 0.6 ( 0.8, 0.4) Ptients [n (%)] chieving A1C <7% 36 (24%) 48 (30%) 12 (8%) FPG (mg/dl) c Bseline (men) Chnge from seline (djusted men) Difference from plceo + pioglitzone (djusted men) (97.5% CI) Body Weight 23 ( 31.8, 15.2) 28 ( 36.7, 20.2) Bseline men in kg % chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) ( 3.4, 1.8) 2.4 ( 3.2, 1.6) Modified intent to tret (mitt) popultion. Lst oservtion on study crried forwrd (LOCF) ws used to impute missing dt t Week 24. At Week 24, 10.9%, 8.3%, nd 20.6% ws imputed for ptients rndomized to JARDIANCE 10 mg, JARDIANCE 25 mg, nd plceo, respectively. ANCOVA P< (A1C: ANCOVA model includes seline A1C, tretment, renl function, nd ckground mediction. Body weight nd FPG: sme model used s for A1C ut dditionlly including seline ody weight/seline FPG, respectively.) c FPG (mg/dl): for JARDIANCE 10 mg, n = 163. ody weight reduction compred with plceo. 8 JARDIANCE is not indicted for weight loss. Chnge in ody weight ws secondry endpoint. Renl Impirment A totl of 738 ptients with type 2 dietes nd seline egfr less thn 90 ml/ min/1.73 m 2 prticipted in rndomized, doule-lind, plceo-controlled, prllel-group study to evlute the efficcy nd sfety of JARDIANCE in ptients with type 2 dietes nd renl impirment. The tril popultion comprised 290 ptients with mild renl impirment (egfr 60 to <90 ml/min/1.73 m 2 ), 374 ptients with moderte renl impirment (egfr 30 to <60 ml/min/1.73 m 2 ), nd 74 with severe renl impirment (egfr <30 ml/min/1.73 m 2 ). A totl of 194 ptients with moderte renl impirment hd seline egfr of 30 to less thn 45 ml/min/1.73 m 2 nd 180 ptients hd seline egfr of 45 to less thn 60 ml/ min/1.73 m 2. 8 At Week 24, JARDIANCE 25 mg provided sttisticlly significnt reduction in A1C reltive to plceo in ptients with mild to moderte renl impirment (Tle 7). 8 A sttisticlly significnt reduction reltive to plceo ws lso oserved with JARDIANCE 25 mg in ptients with either mild ( 0.7 [95% CI: 0.9 to 0.5]) or moderte ( 0.4 [95% CI: 0.6 to 0.3]) renl impirment nd with JARDIANCE 10 mg in ptients with mild ( 0.5 [95% CI: 0.7 to 0.3]) renl impirment. The glucose-lowering efficcy of JARDIANCE 25 mg decresed with decresing level of renl function in the mild-to-moderte rnge. Lest squre men A1C chnges t 24 weeks were 0.6%, 0.5%, nd 0.2% for those with seline egfr of 60 to less thn 90 ml/min/1.73 m 2, 45 to less thn 60 ml/min/1.73 m 2, nd 30 to less thn 45 ml/min/1.73 m 2, respectively. For plceo, lest squre men A1C chnges t 24 weeks were 0.1%, 0.1%, nd 0.2% for ptients with seline egfr of 60 to less thn 90 ml/min/1.73 m 2, 45 to less thn 60 ml/min/1.73 m 2, nd 30 to less thn 45 ml/min/1.73 m 2, respectively. For ptients with severe renl impirment, the nlyses of chnges in A1C nd FPG showed no discernile tretment effect of JARDIANCE 25 mg compred with plceo. 8 Wrnings nd Precutions Hypotension JARDIANCE cuses intrvsculr volume contrction. Symptomtic hypotension my occur fter inititing JARDIANCE, prticulrly in ptients with renl impirment, the elderly, ptients with low SBP, nd ptients on diuretics. Before inititing JARDIANCE, ptients should e ssessed for volume Impirment in Renl Function JARDIANCE increses serum cretinine nd decreses egfr. Renl function should e evluted prior to inititing JARDIANCE nd periodiclly therefter. More frequent monitoring is recommended with egfr elow 60 ml/min/1.73 m 2. The risk of impired renl function with JARDIANCE is incresed in elderly ptients nd ptients with moderte renl impirment. JARDIANCE should e discontinued in ptients with persistent egfr less thn 45 ml/min/1.73 m Novemer 2014 Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

13 Jrdince (empgliflozin) Tlets Product Monogrph Tle 6. Results t Week 18 nd 78 for Plceo-controlled Study for JARDIANCE in Comintion With Insulin 8 A1C (%) JARDIANCE 10 mg + Insulin N = 169 contrction, nd volume sttus should e corrected if indicted. Ptients should e monitored for signs nd symptoms of hypotension fter inititing therpy nd monitoring should e incresed in clinicl situtions where volume contrction is expected. 8 Impirment in Renl Function JARDIANCE increses serum cretinine nd decreses egfr. The risk of impired renl function with JARDIANCE is incresed in elderly ptients nd ptients with moderte renl impirment. More frequent monitoring of renl function is recommended in these ptients. Renl function should e evluted prior to inititing JARDIANCE nd periodiclly therefter. 8 Hypoglycemi With Concomitnt Use With Insulin nd Insulin Secretgogues Insulin nd insulin secretgogues re known to cuse hypoglycemi. The 18 weeks (no insulin djustment) JARDIANCE 25 mg + Insulin N = 155 Plceo + Insulin N = 170 risk of hypoglycemi is incresed when JARDIANCE is used in comintion with insulin secretgogues (eg, sulfonylure) or insulin. Therefore, lower dose of the insulin secretgogue or insulin my e required to reduce the risk of hypoglycemi when used in comintion with JARDIANCE. 8 Genitl Mycotic Infections JARDIANCE increses the risk for GMIs. Ptients with history of chronic or recurrent GMIs were more likely to 78 weeks (djustle insulin dose fter 18 weeks) JARDIANCE 10 mg + Insulin N = 169 JARDIANCE 25 mg + Insulin N = 155 Bseline (men) Chnge from seline (djusted men) Difference from plceo (djusted men) (97.5% CI) 0.6 ( 0.8, 0.4) 0.7 ( 0.9, 0.5) 0.5 ( 0.7, 0.3) 0.7 ( 0.9, 0.5) Ptients (%) chieving A1C <7% FPG (mg/dl) Bseline (men) Chnge from seline (djusted men, SE) Difference from plceo (djusted men) (95% CI) Body Weight Plceo + Insulin N = (3.2) 19.1 (3.3) 10.4 (3.1) 10.1 (3.2) 15.2 (3.4) 2.8 (3.2) 28.2 ( 37.0, 19.5) 29.5 ( 38.4, 20.6) 12.9 c ( 21.9, 3.9) 17.9 ( 27.0, 8.8) Bseline men in kg % chnge from seline (djusted men) Difference from plceo (djusted men) (95% CI) SE = stndrd error. 1.7 d ( 3.0, 0.5) 1.3 e ( 2.5, 0.0) 3.0 ( 4.4, 1.7) 3.0 ( 4.4, 1.6) Modified intent to tret (mitt) popultion. Lst oservtion on study crried forwrd (LOCF) ws used to impute missing dt t Weeks 18 nd 78. At Week 18, 21.3%, 30.3%, nd 21.8% ws imputed for ptients rndomized to JARDIANCE 10 mg, JARDIANCE 25 mg, nd plceo, respectively. At Week 78, 32.5%, 38.1%, nd 42.4% ws imputed for ptients rndomized to JARDIANCE 10 mg, JARDIANCE 25 mg, nd plceo, respectively. ANCOVA P< (A1C: ANCOVA model includes seline A1C, tretment, nd geogrphic region; FPG: mixed effect model repet mesurement (MMRM) model includes seline FPG, seline A1C, tretment, geogrphic region, visit, nd visit y tretment interction. Body weight: MMRM model includes seline ody weight, seline A1C, tretment, geogrphic region, visit, nd visit y tretment interction.) c P= d P= e P= develop GMIs. Ptients should e monitored nd treted s pproprite. 8 Urinry Trct Infections JARDIANCE increses the risk for UTIs. Ptients should e monitored nd treted s pproprite. 8 Incresed Low-density Lipoprotein Cholesterol Increses in LDL-C cn occur with JARDIANCE. Ptients should e monitored nd treted s pproprite. 8 Tle 7. Results t Week 24 (LOCF) of Plceo-controlled Study for JARDIANCE in Ptients With Type 2 Dietes nd Renl Impirment 8 A1C Mild nd Moderte Impirment JARDIANCE 25 mg Numer of ptients n = 284 Comprison vs plceo (djusted men) (95% CI) 0.5 ( 0.6, 0.4) LOCF = lst oservtion on study crried forwrd. P< (A1C: ANCOVA model includes seline A1C, tretment, renl function, nd ckground mediction). egfr 30 to <90 ml/min/1.73 m 2 modified intent to tret (mitt) popultion. LOCF ws used to impute missing dt t Week 24. At Week 24, 24.6% nd 26.2% ws imputed for ptients rndomized to JARDIANCE 25 mg nd plceo, respectively. Novemer Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.

14 Jrdince (empgliflozin) Tlets Product Monogrph Hypoglycemi with Concomitnt Use with Insulin nd Insulin Secretgogues Insulin nd insulin secretgogues re known to cuse hypoglycemi. The use of JARDIANCE with these gents cn increse the risk of hypoglycemi. A lower dose of insulin or the insulin secretgogue my e required to reduce the risk of hypoglycemi when used in comintion with JARDIANCE. Mcrovsculr Outcomes There hve een no clinicl studies estlishing conclusive evidence of mcrovsculr risk reduction with JARDIANCE or ny other ntidietic drug. 8 Adverse Rections Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred with rtes in the clinicl trils of nother drug nd might not reflect the rtes oserved in prctice. 8 Pool of Plceo-controlled Trils Evluting JARDIANCE 10 mg nd 25 mg The dt in Tle 8 8 re derived from pool of four 24-week plceocontrolled trils nd 18-week dt from plceo-controlled tril with insulin. JARDIANCE ws used s monotherpy in 1 tril nd s ddon therpy in 4 trils. These dt reflect exposure of 1976 ptients to JARDIANCE with men exposure durtion of pproximtely 23 weeks. Ptients received plceo (N = 995), JARDIANCE 10 mg (N = 999), or JARDIANCE 25 mg (N = 977) once dily. The men ge of the popultion ws 56 yers, nd 3% were older thn 75 yers. More thn hlf (55%) of the popultion ws mle; 46% ws white, 50% ws Asin, nd 3% ws lck or Africn Americn. At seline, 57% of the popultion hd hd dietes for more thn 5 yers nd hd men A1C of 8%. Estlished microvsculr complictions of dietes t seline included dietic nephropthy (7%), retinopthy (8%), or neuropthy (16%). Bseline renl function ws norml or mildly impired in 91% of ptients nd modertely impired in 9% of ptients (men egfr 86.8 ml/min/1.73 m 2 ). 8 Tle 8 8 shows common dverse rections (excluding hypoglycemi) ssocited with the use of JARDIANCE. The dverse rections were not present t seline, occurred more commonly with JARDIANCE thn with plceo, nd occurred in 2% or more of ptients treted with JARDIANCE 10 mg or JARDIANCE 25 mg. Thirst (including polydipsi) ws reported in 0%, 1.7%, nd 1.5% of ptients in the plceo, JARDIANCE 10 mg, nd JARDIANCE 25 mg groups, respectively. 8 Volume Depletion JARDIANCE cuses n osmotic diuresis, which my led to intrvsculr volume contrction nd dverse rections relted to volume depletion. In the pool of 5 plceo-controlled clinicl trils, dverse rections relted to volume depletion (eg, decresed [multory] lood pressure, decresed SBP, dehydrtion, hypotension, hypovolemi, orthosttic hypotension, nd syncope) were reported y 0.3%, 0.5%, nd 0.3% of ptients treted with plceo, JARDIANCE 10 mg, nd JARDIANCE 25 mg, respectively. JARDIANCE my increse the risk of hypotension in ptients t risk for volume contrction. 8 Incresed Urintion In the pool of 5 plceo-controlled Tle 8. Adverse Rections (Excluding Hypoglycemi) Reported in 2% of Ptients Treted With JARDIANCE nd Greter Thn Plceo in Pooled Plceo-controlled Clinicl Studies of JARDIANCE Monotherpy or Comintion Therpy 8 Numer (%) of Ptients Plceo N = 995 JARDIANCE 10 mg N = 999 JARDIANCE 25 mg N = 977 Urinry trct infection 7.6% 9.3% 7.6% Femle genitl mycotic infections 1.5% 5.4% 6.4% Upper respirtory trct infection 3.8% 3.1% 4.0% Incresed urintion c 1.0% 3.4% 3.2% Dyslipidemi 3.4% 3.9% 2.9% Arthrlgi 2.2% 2.4% 2.3% Mle genitl mycotic infections d 0.4% 3.1% 1.6% Nuse 1.4% 2.3% 1.1% Predefined dverse event grouping, including, ut not limited to, urinry trct infection, symptomtic cteriuri, cystitis. Femle genitl mycotic infections include the following dverse rections: vulvovginl mycotic infection, vginl infection, vulvitis, vulvovginl cndidisis, genitl infection, genitl cndidisis, genitl infection fungl, genitourinry trct infection, vulvovginitis, cervicitis, urogenitl infection fungl, vginitis cteril. Percentges clculted with the numer of femle sujects in ech group s denomintor: plceo (N = 481), JARDIANCE 10 mg (N = 443), JARDIANCE 25 mg (N = 420). c Predefined dverse event grouping, including, ut not limited to, polyuri, pollkiuri, nd nocturi. d Mle genitl mycotic infections include the following dverse rections: lnoposthitis, lnitis, genitl infections fungl, genitourinry trct infection, lnitis cndid, scrotl scess, penile infection. Percentges clculted with the numer of mle sujects in ech group s denomintor: plceo (N = 514), JARDIANCE 10 mg (N = 556), JARDIANCE 25 mg (N = 557) Novemer 2014 Plese see Importnt Sfety Informtion out JARDIANCE on inside cover nd full Prescriing Informtion nd Ptient Informtion on pges 17 to 26.