TRULICITY TRU-0003-USPI _TRU-0002-MG , 8 X 10.5 PRINTER VERSION 1 OF 8

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescriing informtion for. (dulglutide) injection, for sucutneous use Initil U.S. Approvl: 2014 WARNING: RISK OF THYROID CCELL TUMORS See full prescriing informtion for complete oxed wrning. Dulglutide cuses thyroid Ccell tumors in rts. It is unknown whether cuses thyroid C cell tumors, including medullry thyroid crcinom (MTC), in humns s the humn relevnce of dulglutideinduced rodent thyroid Ccell tumors hs not een determined (5.1, 13.1). is contrindicted in ptients with personl or fmily history of MTC nd in ptients with Multiple Endocrine Neoplsi syndrome type 2 (MEN 2). Counsel ptients regrding the potentil risk of MTC nd symptoms of thyroid tumors (4.1, 5.1). RECENT MAJOR CHANGES BOXED WARNING: RISK OF THYROID CCELL TUMORS 03/2015 INDICATIONS AND USAGE Limittions of Use (1.1) 03/2015 WARNINGS AND PRECAUTIONS Risk of Thyroid Ccell Tumors (5.1) 03/2015 INDICATIONS AND USAGE is glucgonlike peptide (GLP1) receptor gonist indicted s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus. Limittions of Use: Not recommended s firstline therpy for ptients indequtely controlled on diet nd exercise (1, 5.1). Hs not een studied in ptients with history of pncretitis. Consider nother ntidietic therpy (1, 5.2). Not for tretment of type 1 dietes mellitus or dietic ketocidosis. Not for ptients with preexisting severe gstrointestinl disese. Hs not een studied in comintion with sl insulin. DOSAGE AND ADMINISTRATION Administer once weekly t ny time of dy (2.1). Inject sucutneously in the domen, thigh, or upper rm (2.1). Initite t sucutneously once weekly. Dose cn e incresed to once weekly for dditionl glycemic control (2.1). If dose is missed dminister within 3 dys of missed dose (2.1). DOSAGE FORMS AND STRENGTHS Injection: /0.5 ml solution in singledose pen (3) Injection: /0.5 ml solution in singledose pen (3) Injection: /0.5 ml solution in singledose prefilled syringe (3) Injection: /0.5 ml solution in singledose prefilled syringe (3) CONTRAINDICATIONS is contrindicted in ptients with personl or fmily history of medullry thyroid crcinom or in ptients with Multiple Endocrine Neoplsi syndrome type 2 (4.1, 5.1, 13.1). is contrindicted in ptients with prior serious hypersensitivity rection to or ny of the product components (4.2, 5.4). WARNINGS AND PRECAUTIONS Thyroid Ccell Tumors: See Boxed Wrning (5.1). Pncretitis: Hs een reported in clinicl trils. Discontinue promptly if pncretitis is suspected. Do not restrt if pncretitis is confirmed. Consider other ntidietic therpies in ptients with history of pncretitis (5.2). Hypoglycemi: When is used with n insulin secretgogue (e.g., sulfonylure) or insulin, consider lowering the dose of the sulfonylure or insulin to reduce the risk of hypoglycemi (5.3). Hypersensitivity Rections: Discontinue if suspected. Monitor nd tret promptly per stndrd of cre until signs nd symptoms resolve (5.4). Renl Impirment: Monitor renl function in ptients with renl impirment reporting severe dverse gstrointestinl rections (5.5). Mcrovsculr outcomes: There hve een no studies estlishing conclusive evidence of mcrovsculr risk reduction with or ny other ntidietic drug (5.7). ADVERSE REACTIONS The most common dverse rections, reported in 5% of ptients treted with re: nuse, dirrhe, vomiting, dominl pin, nd decresed ppetite (6.1). To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t LillyRx ( ) or FDA t FDA 1088 or DRUG INTERACTIONS Dulglutide slows gstric emptying nd my impct sorption of concomitntly dministered orl medictions (7.1, 12.3). USE IN SPECIFIC POPULATIONS Pregnncy: my cuse fetl hrm; only use if potentil enefit justifies potentil risk to fetus (). Nursing Mothers: Discontinue nursing or discontinue (8.3). Renl Impirment: No dosge djustment recommended. Monitor renl function in ptients with renl impirment reporting severe dverse gstrointestinl rections (5.5, 8.7). See 17 for PATIENT COUNSELING INFORMATION nd FDApproved Mediction Guide Revised: 03/2015 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID CCELL TUMORS 1 INDICATIONS AND USAGE 1.1 Limittions of Use 2 DOSAGE AND ADMINISTRATION 2.1 Dosge 2.2 Concomitnt Use with n Insulin Secretgogue (e.g., Sulfonylure) or with Insulin 2.3 Dosge in Ptients with Renl Impirment 2.4 Importnt Administrtion Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Medullry Thyroid Crcinom 4.2 Hypersensitivity 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid Ccell Tumors 5.2 Pncretitis 5.3 Hypoglycemi with Concomitnt Use of Insulin Secretgogues or Insulin 5.4 Hypersensitivity Rections (dulglutide) injection, for sucutneous use TRU0003USPI Renl Impirment 5.6 Severe Gstrointestinl Disese 5.7 Mcrovsculr Outcomes 6 ADVERSE REACTIONS 6.1 Clinicl Studies Experience 7 DRUG INTERACTIONS 7.1 Orl Medictions 8 USE IN SPECIFIC POPULATIONS Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Heptic Impirment 8.7 Renl Impirment 8.8 Gstropresis 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics (dulglutide) injection, for sucutneous use TRU0003USPI Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, nd Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Monotherpy 14.2 Comintion Therpy 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION * Sections or susections omitted from the full prescriing informtion re not listed (dulglutide) injection, for sucutneous use TRU0003USPI TRU0003USPI _TRU0002MG , 8 X 10.5 PRINTER VERSION 1 OF 8

2 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID CCELL TUMORS In mle nd femle rts, dulglutide cuses doserelted nd tretmentdurtiondependent increse in the incidence of thyroid Ccell tumors (denoms nd crcinoms) fter lifetime exposure. It is unknown whether cuses thyroid Ccell tumors, including medullry thyroid crcinom (MTC), in humns s humn relevnce of dulglutideinduced rodent thyroid Ccell tumors hs not een determined [see Wrnings nd Precutions (5.1), nd Nonclinicl Toxicology (13.1)]. is contrindicted in ptients with personl or fmily history of MTC nd in ptients with Multiple Endocrine Neoplsi syndrome type 2 (MEN 2). Counsel ptients regrding the potentil risk of MTC with use of nd inform them of symptoms of thyroid tumors (e.g., mss in the neck, dysphgi, dyspne, persistent horseness). Routine monitoring of serum clcitonin or using thyroid ultrsound is of uncertin vlue for erly detection of MTC in ptients treted with [see Contrindictions (4.1) nd Wrnings nd Precutions (5.1)]. 1 INDICATIONS AND USAGE is indicted s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus. 1.1 Limittions of Use is not recommended s firstline therpy for ptients who hve indequte glycemic control on diet nd exercise ecuse of the uncertin relevnce of rodent Ccell tumor findings to humns. Prescrie only to ptients for whom the potentil enefits outweigh the potentil risk [see Wrnings nd Precutions (5.1)]. hs not een studied in ptients with history of pncretitis [see Wrnings nd Precutions (5.2)]. Consider other ntidietic therpies in ptients with history of pncretitis. should not e used in ptients with type 1 dietes mellitus or for the tretment of dietic ketocidosis. is not sustitute for insulin. hs not een studied in ptients with severe gstrointestinl disese, including severe gstropresis. The use of is not recommended in ptients with preexisting severe gstrointestinl disese [see Wrnings nd Precutions (5.6)] The concurrent use of nd sl insulin hs not een studied. 2 DOSAGE AND ADMINISTRATION 2.1 Dosge The recommended inititing dose of is once weekly. The dose my e incresed to once weekly for dditionl glycemic control. The mximum recommended dose is once weekly. Administer once weekly, ny time of dy, with or without food. should e injected sucutneously in the domen, thigh, or upper rm. If dose is missed, instruct ptients to dminister s soon s possile if there re t lest 3 dys (72 hours) until the next scheduled dose. If less thn 3 dys remin efore the next scheduled dose, skip the missed dose nd dminister the next dose on the regulrly scheduled dy. In ech cse, ptients cn then resume their regulr once weekly dosing schedule. The dy of weekly dministrtion cn e chnged if necessry s long s the lst dose ws dministered 3 or more dys efore. 2.2 Concomitnt Use with n Insulin Secretgogue (e.g., Sulfonylure) or with Insulin When inititing, consider reducing the dosge of concomitntly dministered insulin secretgogues (e.g., sulfonylures) or insulin to reduce the risk of hypoglycemi [see Wrnings nd Precutions (5.3)]. 2.3 Dosge in Ptients with Renl Impirment is recommended in ptients with renl impirment including endstge renl disese (ESRD). Monitor renl function in ptients with renl impirment reporting severe dverse gstrointestinl rections. [see Wrning nd Precutions (5.5), Use in Specific Popultions (8.7), Clinicl Phrmcology (12.3)]. 2.4 Importnt Administrtion Instructions Prior to initition of, ptients should e trined y their helthcre professionl on proper injection technique. Trining reduces the risk of dministrtion errors such s improper injection site, needle sticks, nd incomplete dosing. Refer to the ccompnying Instructions for Use for complete dministrtion instructions with illustrtions. The instructions cn lso e found t When using with insulin, instruct ptients to dminister s seprte injections nd to never mix the products. It is cceptle to inject nd insulin in the sme ody region ut the injections should not e djcent to ech other. When injecting in the sme ody region, dvise ptients to use different injection site ech week. must not e dministered intrvenously or intrmusculrly. solution should e visully inspected for prticulte mtter nd discolortion prior to dministrtion. 3 DOSAGE FORMS AND STRENGTHS Injection: /0.5 ml or solution in singledose pen Injection: /0.5 ml solution in singledose pen Injection: /0.5 ml solution in singledose prefilled syringe Injection: /0.5 ml solution in singledose prefilled syringe 4 CONTRAINDICATIONS 4.1 Medullry Thyroid Crcinom is contrindicted in ptients with personl or fmily history of medullry thyroid crcinom (MTC) or in ptients with Multiple Endocrine Neoplsi syndrome type 2 (MEN 2) [see Wrnings nd Precutions (5.1)]. 4.2 Hypersensitivity is contrindicted in ptients with prior serious hypersensitivity rection to dulglutide or to ny of the product components [see Wrnings nd Precutions (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid Ccell Tumors In mle nd femle rts, dulglutide cuses doserelted nd tretmentdurtiondependent increse in the incidence of thyroid C cell tumors (denoms nd crcinoms) fter lifetime exposure [see Nonclinicl Toxicology (13.1)]. Glucgonlike peptide (GLP 1) receptor gonists hve induced thyroid C cell denoms nd crcinoms in mice nd rts t cliniclly relevnt exposures. It is unknown whether will cuse thyroid Ccell tumors, including medullry thyroid crcinom (MTC), in humns, s the humn relevnce of dulglutideinduced rodent thyroid Ccell tumors hs not een determined. One cse of MTC ws reported in ptient treted with. This ptient hd pretretment clcitonin levels pproximtely 8 times the upper limit of norml (ULN). Cses of MTC in ptients treted with lirglutide, nother GLP1 receptor gonist, hve een reported in the postmrketing period; the dt in these reports re insufficient to estlish or exclude cusl reltionship etween MTC nd GLP1 receptor gonist use in humns. is contrindicted in ptients with personl or fmily history of MTC or in ptients with MEN 2. Counsel ptients regrding the potentil risk for MTC with the use of nd inform them of symptoms of thyroid tumors (e.g. mss in the neck, dysphgi, dyspne, persistent horseness). Routine monitoring of serum clcitonin or using thyroid ultrsound is of uncertin vlue for erly detection of MTC in ptients treted with. Such monitoring my increse the risk of unnecessry procedures, due to the low test specificity for serum clcitonin nd high ckground incidence of thyroid disese. Significntly elevted serum clcitonin vlue my indicte MTC nd ptients with MTC usully hve clcitonin vlues >50 ng/l. If serum clcitonin is mesured nd found to e elevted, the ptient should e further evluted. Ptients with thyroid nodules noted on physicl exmintion or neck imging should lso e further evluted. 5.2 Pncretitis In Phse 2 nd Phse 3 clinicl studies, 12 (3.4 cses per 1000 ptient yers) pncretitis relted dverse rections were reported in ptients exposed to versus 3 in nonincretin comprtors (2.7 cses per 1000 ptient yers). An nlyses of djudicted events reveled 5 cses of confirmed pncretitis in ptients exposed to (1.4 cses per 1000 ptient yers) versus 1 cse in nonincretin comprtors (0.88 cses per 1000 ptient yers). After initition of, oserve ptients crefully for signs nd symptoms of pncretitis, including persistent severe dominl pin. If pncretitis is suspected, promptly discontinue. If pncretitis is confirmed, should not e restrted. hs not een evluted in ptients with prior history of pncretitis. Consider other ntidietic therpies in ptients with history of pncretitis. 5.3 Hypoglycemi with Concomitnt Use of Insulin Secretgogues or Insulin The risk of hypoglycemi is incresed when is used in comintion with insulin secretgogues (e.g., sulfonylures) or insulin. Ptients my require lower dose of sulfonylure or insulin to reduce the risk of hypoglycemi in this setting [see Adverse Rections (6.1)]. 5.4 Hypersensitivity Rections Systemic hypersensitivity rections were oserved in ptients receiving in clinicl trils [see Adverse Rections (6.1)]. If hypersensitivity rection occurs, the ptient should discontinue nd promptly seek medicl dvice. 5.5 Renl Impirment In ptients treted with GLP1 receptor gonists, there hve een postmrketing reports of cute renl filure nd worsening of chronic renl filure, which my sometimes require hemodilysis. Some of these events were reported in ptients without known underlying renl disese. A mjority of reported events occurred in ptients who hd experienced nuse, vomiting, dirrhe, or dehydrtion. Becuse these rections my worsen renl function, use cution when inititing or esclting doses of in ptients with renl impirment. Monitor renl function in ptients with renl impirment reporting severe dverse gstrointestinl rections [see Dosge nd Administrtion (2.3), Use in Specific Popultions (8.7)]. 5.6 Severe Gstrointestinl Disese Use of my e ssocited with gstrointestinl dverse rections, sometimes severe [see Adverse Rections (6.1)]. hs not een studied in ptients with severe gstrointestinl disese, including severe gstropresis, nd is therefore not recommended in these ptients. 5.7 Mcrovsculr Outcomes There hve een no clinicl studies estlishing conclusive evidence of mcrovsculr risk reduction with or ny other ntidietic drug. 6 ADVERSE REACTIONS The following serious rections re descried elow or elsewhere in the prescriing informtion: Risk of Thyroid Ccell Tumors [see Wrnings nd Precutions (5.1)] Pncretitis [see Wrnings nd Precutions (5.2)] Hypoglycemi with Concomitnt Use of Insulin Secretgogues or Insulin [see Wrnings nd Precutions (5.3)] Hypersensitivity rections [see Wrnings nd Precutions (5.4)] Renl impirment [see Wrnings nd Precutions (5.5)] Severe Gstrointestinl Disese [see Wrnings nd Precutions (5.6)] 6.1 Clinicl Studies Experience Becuse clinicl studies re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl studies of drug cnnot e directly compred to rtes in the clinicl studies of nother drug nd my not reflect the rtes oserved in prctice. Pool of Plceocontrolled Trils The dt in Tle 1 re derived from the plceocontrolled trils [see Clinicl Studies (14)]. These dt reflect exposure of 1670 ptients to nd men durtion of exposure to of 23.8 weeks. Across the tretment rms, the men ge of ptients ws 56 yers, 1% were 75 yers or older nd 53% were mle. The popultion in these studies ws 69% White, 7% Blck or Africn Americn, 13% Asin; 30% were of Hispnic or Ltino ethnicity. At seline, the popultion hd dietes for n verge of 8.0 yers nd hd men HA1c of 8.0%. At seline, 2.5% of the popultion reported retinopthy. estimted renl function ws norml or mildly impired (egfr 60mL/min/1.73 m 2 ) in 96.0% of the pooled study popultions. Tle 1 shows common dverse rections, excluding hypoglycemi, ssocited with the use of in the pool of plceocontrolled trils. These dverse rections were not present t seline, occurred more commonly on thn on plceo, nd occurred in t lest 5% of ptients treted with. (dulglutide) injection, for sucutneous use TRU0003USPI (dulglutide) injection, for sucutneous use TRU0003USPI TRU0003USPI _TRU0002MG , 8 X 10.5 PRINTER VERSION 2 OF 8

3 Adverse Rection Tle 1: Adverse Rections in PlceoControlled Trils Reported in 5% of Treted Ptients Plceo (N=568) % Trulicity (N=836) % Trulicity (N=834) % Nuse Dirrhe Vomiting Adominl Pin c Decresed Appetite Dyspepsi Ftigue d Includes dirrhe, fecl volume incresed, frequent owel movements. Includes retching, vomiting, vomiting projectile. c Includes dominl discomfort, dominl pin, dominl pin lower, dominl pin upper, dominl tenderness, gstrointestinl pin. d Includes ftigue, stheni, mlise. Note: Percentges reflect the numer of ptients tht reported t lest 1 tretment emergent occurrence of the dverse rection. Gstrointestinl Adverse Rections In the pool of plceocontrolled trils, gstrointestinl dverse rections occurred more frequently mong ptients receiving thn plceo (plceo 21.3%, 31.6%, 41.0%). More ptients receiving (1.3%) nd (3.5%) discontinued tretment due to gstrointestinl dverse rections thn ptients receiving plceo (0.2%). Investigtors grded the severity of gstrointestinl dverse rections occurring on nd of s mild in 58% nd 48% of cses, respectively, moderte in 35% nd 42% of cses, respectively, or severe in 7% nd 11% of cses, respectively. In ddition to the rections in Tle 1, the following dverse rections were reported more frequently in treted ptients thn plceo (frequencies listed, respectively, s: plceo; ; ): constiption (0.7%, 3.9%, 3.7%), fltulence (1.4%, 1.4%, 3.4%), dominl distension (0.7%, 2.9%, 2.3%), gstroesophgel reflux disese (0.5%, 1.7%, 2.0%), nd eructtion (0.2%, 0.6%, 1.6%). Pool of Plceo nd ActiveControlled Trils The occurrence of dverse rections ws lso evluted in lrger pool of ptients with type 2 dietes prticipting in 6 plceo nd ctivecontrolled trils evluting the use of s monotherpy nd ddon therpy to orl medictions or insulin.[see Clinicl Studies (14)]. In this pool, totl of 3342 ptients with type 2 dietes were treted with for men durtion of 52 weeks. The men ge of ptients ws 56 yers, 2% were 75 yers or older nd 51% were mle. The popultion in these studies ws 71% White, 7% Blck or Africn Americn, 11% Asin; 32% were of Hispnic or Ltino ethnicity. At seline, the popultion hd dietes for n verge of 8.2 yers nd hd men HA1c of %. At seline, 5.2% of the popultion reported retinopthy. estimted renl function ws norml or mildly impired (egfr 60 ml/min/1.73 m 2 ) in 95.7% of the popultion. In the pool of plceo nd ctivecontrolled trils, the types nd frequency of common dverse rections, excluding hypoglycemi, were similr to those listed in Tle 1. Other Adverse Rections Hypoglycemi Tle 2 summrizes the incidence of documented symptomtic ( 70 mg/dl glucose threshold) nd severe hypoglycemi in the plceocontrolled clinicl studies. Tle 2: Incidence (%) of Documented Symptomtic nd Severe Hypoglycemi Adverse Rections in PlceoControlled Trils Plceo Addon to Metformin (26 weeks) N=177 N=302 N=304 Documented symptomtic 1.1% 2.6% 5.6% Severe Addon to Metformin + Pioglitzone (26 weeks) N=141 N=280 N=279 Documented symptomtic 1.4% 4.6% 5.0% Severe Hypoglycemi ws more frequent when ws used in comintion with sulfonylure or insulin [see Wrnings nd Precutions (5.3)]. Documented symptomtic hypoglycemi occurred in 39% nd 40% of ptients when nd, respectively, ws codministered with sulfonylure. Severe hypoglycemi occurred in 0% nd 0.7% of ptients when nd, respectively, ws codministered with sulfonylure. Documented symptomtic hypoglycemi occurred in 85% nd 80% of ptients when nd, respectively, ws codministered with prndil insulin. Severe hypoglycemi occurred in 2.4% nd 3.4% of ptients when nd, respectively, ws codministered with prndil insulin. Hert Rte Increse nd Tchycrdi Relted Adverse Rections. nd resulted in men increse in hert rte (HR) of 24 ets per minute (pm). The longterm clinicl effects of the increse in HR hve not een estlished [see Wrnings nd Precutions (5.7)]. Adverse rections of sinus tchycrdi were reported more frequently in ptients exposed to. Sinus tchycrdi ws reported in 3.0%, 2.8%, nd 5.6% of ptient treted with plceo, nd, respectively. Persistence of sinus tchycrdi (reported t more thn 2 visits) ws reported in 0.2%, 0.4% nd 1.6% of ptients treted with plceo, nd, respectively. Episodes of sinus tchycrdi, ssocited with concomitnt increse from seline in hert rte of 15 ets per minute, were reported in 0.7%, 1.3% nd 2.2% of ptient treted with plceo, nd, respectively. Immunogenicity Across four Phse 2 nd five Phse 3 clinicl studies, 64 (1.6%) treted ptients developed ntidrug ntiodies (ADAs) to the ctive ingredient in (i.e., dulglutide). Of the 64 dulglutidetreted ptients tht developed dulglutide ADAs, 34 ptients (0.9% of the overll popultion) hd dulglutideneutrlizing ntiodies, nd 36 ptients (0.9% of the overll popultion) developed ntiodies ginst ntive GLP1. The detection of ntiody formtion is highly dependent on the sensitivity nd specificity of the ssy. Additionlly, the oserved incidence of ntiody (including neutrlizing ntiody) positivity in n ssy my e influenced y severl fctors including ssy methodology, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, the incidence of ntiodies to dulglutide cnnot e directly compred with the incidence of ntiodies of other products. Hypersensitivity Systemic hypersensitivity dverse rections sometimes severe (e.g., severe urticri, systemic rsh, fcil edem, lip swelling) occurred in 0.5% of ptients on in the four Phse 2 nd five Phse 3 studies. Injectionsite Rections In the plceocontrolled studies, injectionsite rections (e.g., injectionsite rsh, erythem) were reported in 0.5% of treted ptients nd in 0.0% of plceotreted ptients. PR Intervl Prolongtion nd Adverse Rections of First Degree Atrioventriculr (AV) Block A men increse from seline in PR intervl of 23 milliseconds ws oserved in treted ptients in contrst to men decrese of 0.9 millisecond in plceotreted ptients. The dverse rection of first degree AV lock occurred more frequently in ptients treted with thn plceo (0.9%, 1.7% nd 2.3% for plceo, nd, respectively). On electrocrdiogrms, PR intervl increse to t lest 220 milliseconds ws oserved in 0.7%, 2.5% nd 3.2% of ptients treted with plceo, nd, respectively. Amylse nd Lipse Increse Ptients exposed to hd men increses from seline in lipse nd/or pncretic mylse of 14% to 20%, while plceotreted ptients hd men increses of up to 3%. 7 DRUG INTERACTIONS 7.1 Orl Medictions slows gstric emptying nd thus hs the potentil to reduce the rte of sorption of concomitntly dministered orl medictions. Cution should e exercised when orl medictions re concomitntly dministered with. Drug levels of orl medictions with nrrow therpeutic index should e dequtely monitored when concomitntly dministered with. In clinicl phrmcology studies, did not ffect the sorption of the tested, orlly dministered medictions to cliniclly relevnt degree [see Clinicl Phrmcology (12.3)]. 8 USE IN SPECIFIC POPULATIONS Pregnncy Pregnncy Ctegory C There re no dequte nd wellcontrolled studies of in pregnnt women. The risk of irth defects, loss, or other dverse outcomes is incresed in pregnncies complicted y hyperglycemi nd my e decresed with good metolic control. It is essentil for ptients with dietes to mintin good metolic control efore conception nd throughout pregnncy. should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus. In rts nd rits, dulglutide dministered during the mjor period of orgnogenesis produced fetl growth reductions nd/or skeletl nomlies nd ossifiction deficits in ssocition with decresed mternl weight nd food consumption ttriuted to the phrmcology of dulglutide. In pregnnt rts given sucutneous doses of 0.49, 1.63, or 4.89 mg/kg dulglutide on Gesttion Dys 6, 9, 12, nd 15 (orgnogenesis), reduced fetl weights ssocited with decresed mternl food intke nd decresed weight gin ttriuted to the phrmcology of dulglutide were oserved t 1.63 mg/kg, systemic exposure 14 fold the MRHD sed on AUC. Irregulr skeletl ossifictions nd increses in post implnttion loss lso were oserved t 4.89 mg/kg, systemic exposure 44 fold the MRHD sed on AUC. No developmentl dverse effects were oserved t 4fold the MRHD sed on AUC. In pregnnt rits given sucutneous doses of 0.04, 0.12, or 0.41 mg/kg dulglutide on Gesttion Dys 7, 10, 13, 16, nd 19 (orgnogenesis), fetl skeletl mlformtions of the vertere nd/or ris were oserved in conjunction with decresed mternl food intke nd decresed weight gin ttriuted to the phrmcology of dulglutide t 0.41 mg/kg, systemic exposure 13 fold the MRHD sed on AUC. No developmentl dverse effects were oserved t 4fold the MRHD sed on AUC. In prentlpostntl study in F 0 mternl rts given sucutneous doses of 0.2, 0.49, or 1.63 mg/kg every third dy from implnttion through lcttion, F 1 pups from F 0 mternl rts given 1.63 mg/kg dulglutide hd sttisticlly significntly lower men ody weight from irth through postntl dy 63 for mles nd postntl dy 84 for femles. F 1 offspring from F 0 mternl rts receiving 1.63 mg/kg dulglutide hd decresed forelim nd hindlim grip strength nd mles hd delyed lnopreputil seprtion. Femles hd decresed strtle response. These physicl findings my relte to the decresed size of the offspring reltive to controls s they ppered t erly postntl ssessments ut were not oserved t lter ssessment. F 1 femle offspring of the F 0 mternl rts given 1.63 mg/kg of dulglutide hd longer men escpe time nd higher men numer of errors reltive to concurrent control during 1 of 2 trils in the memory evlution portion of the Biel wter mze. These findings occurred in conjunction with decresed F 0 mternl food intke nd decresed weight gin ttriuted to the phrmcologic ctivity t 1.63 mg/kg, systemic exposure 16 fold the MRHD sed on AUC. The humn relevnce of these memory deficits in the F 1 femle rts is not known. 8.3 Nursing Mothers It is not known whether is excreted in humn milk. Becuse mny drugs re excreted in humn milk nd ecuse of the potentil for clinicl dverse rections from in nursing infnts, decision should e mde whether to discontinue nursing or to discontinue, tking into ccount the importnce of the drug to the mother. 8.4 Peditric Use Sfety nd effectiveness of hve not een estlished in peditric ptients. is not recommended for use in peditric ptients younger thn 18 yers. 8.5 Geritric Use In the pool of plceo nd ctivecontrolled trils [see Adverse Rections (6.1)], 620 (18.6%) treted ptients were 65 yers of ge nd over nd 65 treted ptients (1.9%) ptients were 75 yers of ge nd over. No overll differences in sfety or efficcy were detected etween these ptients nd younger ptients, ut greter sensitivity of some older individuls cnnot e ruled out. (dulglutide) injection, for sucutneous use TRU0003USPI (dulglutide) injection, for sucutneous use TRU0003USPI TRU0003USPI _TRU0002MG , 8 X 10.5 PRINTER VERSION 3 OF 8

4 8.6 Heptic Impirment There is limited clinicl experience in ptients with mild, moderte, or severe heptic impirment. Therefore, should e used with cution in these ptient popultions. In clinicl phrmcology study in sujects with vrying degrees of heptic impirment, no cliniclly relevnt chnge in dulglutide phrmcokinetics (PK) ws oserved [see Clinicl Phrmcology (12.3)]. 8.7 Renl Impirment In the four Phse 2 nd five Phse 3 rndomized clinicl studies, t seline, 50 (1.2%) treted ptients hd mild renl impirment (egfr 60 ut <90 ml/min/1.73 m 2 ), 171 (4.3%) treted ptients hd moderte renl impirment (egfr 30 ut <60 ml/min/1.73 m 2 ) nd no treted ptients hd severe renl impirment (egfr <30 ml/min/1.73 m 2 ). No overll differences in sfety or effectiveness were oserved reltive to ptients with norml renl function, though conclusions re limited due to smll numers. In clinicl phrmcology study in sujects with renl impirment including endstge renl disese (ESRD), no cliniclly relevnt chnge in dulglutide PK ws oserved [see Clinicl Phrmcology (12.3)]. There is limited clinicl experience in ptients with severe renl impirment or ESRD. should e used with cution, nd if these ptients experience dverse gstrointestinl side effects, renl function should e closely monitored [see Dosge nd Administrtion (2.3), Wrning nd Precutions (5.5), Clinicl Phrmcology (12.3)]. 8.8 Gstropresis Dulglutide slows gstric emptying. hs not een studied in ptients with preexisting gstropresis. 10 OVERDOSAGE Overdoses hve een reported in clinicl studies. Effects ssocited with these overdoses were primrily mild or moderte gstrointestinl events (e.g., nuse, vomiting) nd nonsevere hypoglycemi. In the event of overdose, pproprite supportive cre (including frequent plsm glucose monitoring) should e initited ccording to the ptient s clinicl signs nd symptoms. 11 DESCRIPTION contins dulglutide, humn GLP 1 receptor gonist. The molecule is fusion protein tht consists of 2 identicl, disulfidelinked chins, ech contining n N terminl GLP 1 nlog sequence covlently linked to the Fc portion of modified humn immunogloulin G4 (IgG4) hevy chin y smll peptide linker nd is produced using mmmlin cell culture. The GLP 1 nlog portion of dulglutide is 90% homologous to ntive humn GLP 1 (737). Structurl modifictions were introduced in the GLP 1 prt of the molecule responsile for interction with the enzyme dipeptidylpeptidse IV (DPP 4). Additionl modifictions were mde in n re with potentil T cell epitope nd in the res of the IgG4 Fc prt of the molecule responsile for inding the highffinity Fc receptors nd hlfntiody formtion. The overll moleculr weight of dulglutide is pproximtely 63 kilodltons. is cler, colorless, sterile solution. Ech 0.5 ml of solution contins or of dulglutide. Ech singledose pen or prefilled syringe contins 0.5 ml of solution nd the following excipients: citric cid nhydrous (0.07 mg), mnnitol (23.2 mg), polysorte 80 (0.10 mg), trisodium citrte dihydrte (1.37 mg), in wter for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action contins dulglutide, which is humn GLP 1 receptor gonist with 90% mino cid sequence homology to endogenous humn GLP 1 (737). Dulglutide ctivtes the GLP 1 receptor, memrneound cellsurfce receptor coupled to denylyl cyclse in pncretic et cells. Dulglutide increses intrcellulr cyclic AMP (camp) in et cells leding to glucosedependent insulin relese. Dulglutide lso decreses glucgon secretion nd slows gstric emptying Phrmcodynmics lowers fsting glucose nd reduces postprndil glucose (PPG) concentrtions in ptients with type 2 dietes mellitus. The reduction in fsting nd postprndil glucose cn e oserved fter single dose. Fsting nd Postprndil Glucose In clinicl phrmcology study in dults with type 2 dietes mellitus, tretment with once weekly resulted in reduction of fsting nd 2hour PPG concentrtions, nd postprndil serum glucose incrementl AUC, when compred to plceo (25.6 mg/dl,59.5 mg/dl, nd 197 mg h/dl, respectively); these effects were sustined fter 6 weeks of dosing with the dose. First nd SecondPhse Insulin Secretion Both firstnd secondphse insulin secretion were incresed in ptients with type 2 dietes treted with compred with plceo. Insulin nd Glucgon Secretion stimultes glucosedependent insulin secretion nd reduces glucgon secretion. Tretment with nd once weekly incresed fsting insulin from seline t Week 26 y nd pmol/l, respectively, nd Cpeptide concentrtion y 0.09 nd 0.07 nmol/l, respectively, in Phse 3 monotherpy study. In the sme study, fsting glucgon concentrtion ws reduced y 1.71 nd 2.05 pmol/l from seline with nd, respectively. Gstric Motility Dulglutide cuses dely of gstric emptying. The dely is lrgest fter the first dose nd diminishes with susequent doses. Crdic Electrophysiology (QTc) The effect of dulglutide on crdic repolriztion ws tested in thorough QTc study. Dulglutide did not produce QTc prolongtion t suprtherpeutic doses of 4 nd 7 mg Phrmcokinetics The phrmcokinetics of dulglutide is similr etween helthy sujects nd ptients with type 2 dietes mellitus. Following sucutneous dministrtion, the time to mximum plsm concentrtion of dulglutide t stedystte rnges from 24 to 72 hours, with medin of 48 hours. After multipledose dministrtion of to stedy stte, the men pek plsm concentrtion (C mx ) nd totl systemic exposure (AUC) of dulglutide were 114 ng/ml (rnge 56 to 231 ng/ml) nd 14,000 ng*h/ml (rnge 6940 to 26,000 ng*h/ml), respectively; ccumultion rtio ws pproximtely Stedystte plsm dulglutide concentrtions were chieved etween 2 nd 4 weeks following once weekly dministrtion. Site of sucutneous dministrtion (domen, upper rm, nd thigh) hd no sttisticlly significnt effect on the exposure to dulglutide. Asorption The men solute iovilility of dulglutide following sucutneous dministrtion of single nd doses ws 65% nd 47%, respectively. Distriution The men volumes of distriution fter sucutneous dministrtion of nd to stedy stte were pproximtely 19.2 L (rnge 14.3 to 26.4 L) nd 17.4 L (rnge 9.3 to 33 L), respectively. Metolism Dulglutide is presumed to e degrded into its component mino cids y generl protein ctolism pthwys. Elimintion The men pprent clernce t stedy stte of dulglutide is pproximtely L/h for the dose, nd L/h for the dose. The elimintion hlflife of dulglutide for oth doses is pproximtely 5 dys. Specific Popultions of dulglutide is needed sed on ge, gender, rce, ethnicity, ody weight, or renl or heptic impirment. The effects of intrinsic fctors on the PK of dulglutide re shown in Figure 1. Intrinsic Fctor PK Rtio nd 90%CI Recommendtion Weight = 70 kg AUC Weight = 120 kg AUC Age >= 65 yers old AUC Age >= 75 yers old AUC Femle AUC Hispnic AUC Asin AUC Blck AUC Renl Impirment mild AUC moderte AUC severe AUC ESRD AUC Heptic Impirment mild AUC moderte AUC severe AUC Rtio Reltive to Reference Arevitions: AUC = re under the timeconcentrtion curve; CI = confidence intervl; C mx = mximum concentrtion; ESRD = endstge renl disese; PK = phrmcokinetics. Note: Reference vlues for weight, ge, gender, nd rce comprisons re 93 kg, 56 yers old, mle, nd white, respectively; reference groups for renl nd heptic impirment dt re sujects with norml renl nd heptic function from the respective clinicl phrmcology studies. The weight vlues shown in the plot (70 nd 120 kg) re the 10 th nd 90 th percentiles of weight in the Phse 3 PK popultion. Figure 1: Impct of intrinsic fctors on dulglutide phrmcokinetics. Renl Dulglutide systemic exposure ws incresed y 20, 28, 14 nd 12% for mild, moderte, severe, nd ESRD renl impirment sugroups, respectively, compred to sujects with norml renl function. The corresponding vlues for increse in C mx were 13, 23, 20 nd 11%, respectively (Figure 1). [see Dosge nd Administrtion (2.3), Wrning nd Precutions (5.5), Use in Specific Popultion (8.7)]. Heptic Dulglutide systemic exposure decresed y 23, 33 nd 21% for mild, moderte nd severe heptic impirment groups, respectively, compred to sujects with norml heptic function, nd C mx ws decresed y similr mgnitude (Figure 1). [see Use in Specific Popultion (8.6)]. Drug Interctions The potentil effect of codministered medictions on the PK of dulglutide nd vicevers ws studied in severl single nd multipledose studies in helthy sujects, ptients with type 2 dietes mellitus, nd ptients with hypertension. Potentil for Dulglutide to Influence the Phrmcokinetics of Other Drugs Dulglutide slows gstric emptying nd, s result, my reduce the extent nd rte of sorption of orlly codministered medictions. In clinicl phrmcology studies, dulglutide did not ffect the sorption of the tested orlly dministered medictions to ny cliniclly relevnt degree. Phrmcokinetic (PK) mesures indicting the mgnitude of these interctions re presented in Figure 2. is recommended for ny of the evluted codministered medictions. Codministered Drug PK Rtio nd 90%Cl Recommendtion Lisinopril AUC Metoprolol AUC Digoxin AUC Norelgestromin AUC Ethinylestrdiol AUC Atorvsttin AUC Metformin AUC Acetminophen AUC SWrfrin AUC Rwrfrin AUC Sitgliptin AUC Rtio Reltive to Reference Arevitions: AUC = re under the timeconcentrtion curve; CI = confidence intervl; C mx = mximum concentrtion; PK = phrmcokinetics. Note: Reference group is codministered mediction given lone. Figure 2: Impct of dulglutide on the phrmcokinetics of codministered medictions. (dulglutide) injection, for sucutneous use TRU0003USPI (dulglutide) injection, for sucutneous use TRU0003USPI TRU0003USPI _TRU0002MG , 8 X 10.5 PRINTER VERSION 4 OF 8

5 Potentil for Codministered Drugs to Influence the Phrmcokinetics of Dulglutide In clinicl phrmcology study, the codministrtion of single dose of dulglutide () with stedystte sitgliptin (100 mg) cused n increse in dulglutide AUC nd C mx of pproximtely 38% nd 27%, which is not considered cliniclly relevnt. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, nd Impirment of Fertility A 2yer crcinogenicity study ws conducted with dulglutide in mle nd femle rts t doses of 0.05, 0.5, 1.5, nd 5.0 mg/kg (0.5, 7, 20, nd 58fold the MRHD of once weekly sed on AUC) dministered y sucutneous injection twice weekly. In rts, dulglutide cused doserelted nd tretmentdurtiondependent increse in the incidence of thyroid C cell tumors (denoms nd/or crcinoms) compred to controls, t 7fold the MRHD sed on AUC. A sttisticlly significnt increse in C cell denoms ws oserved in rts receiving dulglutide t 0.5 mg/kg). Numericl increses in thyroid C cell crcinoms occurred t 5 mg/kg (58 times the MRHD sed on AUC) nd were considered to e tretmentrelted despite the sence of sttisticl significnce. A 6month crcinogenicity study ws conducted with dulglutide in rsh2 trnsgenic mice t doses of 0.3, 1.0, nd 3.0 mg/kg dministered y sucutneous injection twice weekly. Dulglutide did not produce incresed incidences of thyroid C cell hyperplsi or neoplsi t ny dose. Dulglutide is recominnt protein; no genotoxicity studies hve een conducted. Humn relevnce of thyroid Ccell tumors in rts is unknown nd could not e determined y clinicl studies or nonclinicl studies [see Boxed Wrning nd Wrnings nd Precutions (5.1)]. In fertility nd erly emryonic development studies in mle nd femle rts, no dverse effects of dulglutide on sperm morphology, mting, fertility, conception, nd emryonic survivl were oserved t up to 16.3 mg/kg (130 fold the MRHD sed on AUC). In femle rts, n increse in the numer of femles with prolonged diestrus nd doserelted decrese in the men numer of corpor lute, implnttion sites, nd vile emryos were oserved t 4.9 mg/kg ( 32fold the MRHD sed on AUC), which occurred in the presence of decresed mternl food consumption nd ody weight gin Animl Toxicology nd/or Phrmcology Zucker dietic ftty (ZDF) rts were given 0.5, 1.5, or 5.0 mg/kg/twice weekly of dulglutide (3, 8, nd 30 fold the MRHD sed on AUC) for 3 months. Increses of 12% to 33% in totl nd pncretic mylse, ut not lipse, were oserved t ll doses without microscopic pncretic inflmmtory correltes in individul nimls. Other chnges in the dulglutidetreted nimls included incresed interloulr ductl epithelium without ctive ductl cell prolifertion ( 0.5 mg/kg), incresed cinr trophy with/without inflmmtion ( /kg), nd incresed neutrophilic inflmmtion of the cinr pncres (5 mg/kg). Tretment of monkeys for 12 months with 5 mg/kg/twice weekly of dulglutide (nerly 500 fold the MRHD sed on AUC) demonstrted no evidence of pncretic inflmmtion or pncretic intrepithelil neoplsi. In 4 of 19 monkeys on dulglutide tretment, there ws n increse in golet cells within the pncretic ducts, ut no differences from the control group in totl mylse or lipse t study termintion. There were no prolifertive chnges in the thyroid C cells. 14 CLINICAL STUDIES hs een studied s monotherpy nd in comintion with metformin, metformin nd sulfonylure, metformin nd thizolidinedione, nd prndil insulin with or without metformin. The studies evluted the use of nd. Uptitrtion ws not performed in ny of the trils; ptients were initited nd mintined on either or for the durtion of the trils. In ptients with type 2 dietes mellitus, produced reductions from seline in HA1c compred to plceo. No overll differences in glycemic effectiveness were oserved cross demogrphic sugroups (ge, gender, rce/ethnicity, durtion of dietes) Monotherpy In 52week doulelind study (26 week primry endpoint), 807 ptients indequtely treted with diet nd exercise, or with diet nd exercise nd one ntidietic gent used t sumximl dose, were rndomized to once weekly, once weekly, or metformin 1500 to 2000 mg/dy following two week wshout. Seventyfive percent (75%) of the rndomized popultion were treted with one ntidietic gent t the screening visit. Most ptients previously treted with n ntidietic gent were receiving metformin (~90%) t medin dose of 1000 mg dily nd pproximtely 10% were receiving sulfonylure. Ptients hd men ge of 56 yers nd men durtion of type 2 dietes of 3 yers. Fortyfour percent were mle. The White, Blck nd Asin rce ccounted for 74%, 7% nd 8% of the popultion, respectively. Twentynine percent of the study popultion were from the US. Tretment with nd once weekly resulted in reduction in HA1c from seline t the 26 week primry timepoint (Tle 3). The difference in oserved effect size etween nd, respectively, nd metformin excluded the prespecified noninferiority mrgin of 0.4%. Tle 3: Results t Week 26 in Tril of s Monotherpy 26Week Primry Time Point Metformin mg IntenttoTret (ITT) Popultion (N) HA1c (%) (Men) HA1c Fsting Serum Glucose (mg/dl) (Men) Body Weight (kg) (Men) (men) Arevition: HA1c = hemogloin A1c. Sujects included in the nlysis re suset of the ITT popultion tht hd t lest one postseline ssessment. The primry nlysis included 265 individuls in ech of the tretment rms. Intenttotret popultion. Lst oservtion crried forwrd (LOCF) ws used to impute missing dt. Dt postonset of rescue therpy re treted s missing. At Week 26, primry efficcy ws missing for 10%, 12% nd 14% of individuls rndomized to, nd metformin, respectively Comintion Therpy Addon to Metformin In this 104week plceocontrolled, doulelind study (52week primry endpoint), 972 ptients were rndomized to plceo, once weekly, once weekly, or sitgliptin 100 mg/dy (fter 26 weeks, ptients in the plceo tretment group received linded sitgliptin 100 mg/dy for the reminder of the study), ll s ddon to metformin. Rndomiztion occurred fter n 11week ledin period to llow for metformin titrtion period, followed y 6week glycemic stiliztion period. Ptients hd men ge of 54 yers; men durtion of type 2 dietes of 7 yers; 48% were mle; rce: White, Blck nd Asin were 53%, 4% nd 27%, respectively; nd 24% of the study popultion were in the US. At the 26 week plceocontrolled time point, the HA1c chnge ws 0.1%, 1.0%, 1.2%, nd 0.6% for plceo,,, nd sitgliptin, respectively. The percentge of ptients who chieved HA1c <7.0% ws 22%, 56%, 62%, 39% for plceo,,, nd sitgliptin, respectively. At 26 weeks, there ws men weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, nd 1.4 kg for plceo,,, nd sitgliptin, respectively. There ws men reduction of fsting glucose of 9 mg/dl, 35 mg/dl, 41 mg/dl, nd 18 mg/dl for plceo,,, nd sitgliptin, respectively. Tretment with nd once weekly resulted in sttisticlly significnt reduction in HA1c compred to plceo (t 26 weeks) nd compred to sitgliptin (t 26 nd 52), ll in comintion with metformin (Tle 4 nd Figure 4). Tle 4: Results t Week 52 of Compred to Sitgliptin used s AddOn to Metformin 52Week Primry Time Point Sitgliptin 100 mg IntenttoTret (ITT) Popultion (N) HA1c (%) (Men) Difference from sitgliptin (95% CI) 0.5 (0.7, 0.3) 0.7 (0.9, 0.5) Percentge of ptients HA1c <7.0% 49 ## 59 ## 33 Fsting Plsm Glucose (mg/dl) (Men) Difference from sitgliptin (95% CI) Body Weight (kg) (Men) (men) Difference from sitgliptin (95% CI) (22, 9) (1.8, 0.6) (33, 20) (2.1, 0.9) Arevitions: HA1c = hemogloin A1c. All ITT ptients rndomized fter the dosefinding portion of the study. Lst oservtion crried forwrd (LOCF) ws used to impute missing dt. At Week 52 primry efficcy ws missing for 15%, 19%, nd 20% of individuls rndomized to, nd sitgliptin, respectively. Lestsqures (LS) men djusted for seline vlue nd other strtifiction fctors. Sujects included in the nlysis re suset of the ITT popultion tht hd t lest one postseline ssessment. The primry nlysis included 276, 277, nd 270 individuls rndomized to, nd sitgliptin, respectively. Multiplicity djusted 1sided pvlue <0.001, for superiority of compred to sitgliptin, ssessed only for HA1c. ## p<0.001 compred to sitgliptin, ssessed only for HA1c <7.0%. Sitgliptin 100 mg (dulglutide) injection, for sucutneous use TRU0003USPI (dulglutide) injection, for sucutneous use TRU0003USPI LS Men HA1c (%) Weeks PostRndomiztion Numer of sujects with oserved dt Plceo Sitgliptin Plceo Wk 52 LOCF Men chnge from seline djusted for seline HA1c nd country. Figure 3: Adjusted Men HA1c Chnge t ech Time Point (ITT, MMRM) nd t Week 52 (ITT, LOCF) Addon to Metformin nd Thizolidinedione In this 52week plceocontrolled study (26week primry endpoint), 976 ptients were rndomized to plceo, once weekly, once weekly, or exentide 10 mcg BID, ll s ddon to mximlly tolerted doses of metformin ( 1500 mg per dy) nd pioglitzone (up to 45 mg per dy). Exentide tretment group ssignment ws openlel while the tretment ssignments to plceo, TRU0003USPI _TRU0002MG , 8 X 10.5 PRINTER VERSION 5 OF 8

6 , nd were linded. After 26 weeks, ptients in the plceo tretment group were rndomized to either once weekly or once weekly to mintin study lind. Rndomiztion occurred fter 12week ledin period; during the initil 4 weeks of the ledin period, ptients were titrted to mximlly tolerted doses of metformin nd pioglitzone; this ws followed y n 8week glycemic stiliztion period prior to rndomiztion. Ptients rndomized to exentide strted t dose of 5 mcg BID for 4 weeks nd then were esclted to 10 mcg BID. Ptients hd men ge of 56 yers; men durtion of type 2 dietes of 9 yers; 58% were mle; rce: White, Blck nd Asin were 74%, 8% nd 3%, respectively; nd 81% of the study popultion were in the US. Tretment with nd once weekly resulted in sttisticlly significnt reduction in HA1c compred to plceo (t 26 weeks) nd compred to exentide t 26 weeks (Tle 5 nd Figure 4). Over the 52week study period, the percentge of ptients who required glycemic rescue ws 8.9% in the once weekly + metformin nd pioglitzone tretment group, 3.2% in the once weekly + metformin nd pioglitzone tretment group, nd 8.7% in the exentide BID + metformin nd pioglitzone tretment group. Tle 5: Results t Week 26 of Compred to Plceo nd Exentide, All s AddOn to Metformin nd Thizolidinedione Plceo 26Week Primry Time Point Exentide 10 mcg BID IntenttoTret (ITT) Popultion (N) HA1c (%) (Men) Difference from plceo (95% CI) Difference from exentide (95% CI) (1.0, 0.7) 0.3 (0.4, 0.2) (1.2, 0.9) 0.5 (0.7, 0.4) Percentge of ptients HA1c <7.0% 43 66**, ## 78**, ## 52 Fsting Serum Glucose (mg/dl) (Men) Difference from plceo (95% CI) Difference from exentide (95% CI) Body Weight (kg) (Men) (men) Difference from plceo (95% CI) Difference from exentide (95% CI) (36, 23) 10 (15, 5) (1.8, 0.3) 1.3 (0.6, 1.9) (45, 31) 18 (24, 13) (3.3, 1.8) 0.2 (0.9, 0.4) Arevitions: BID = twice dily; HA1c = hemogloin A1c. Intenttotret popultion. Lst oservtion crried forwrd (LOCF) ws used to impute missing dt. Dt postonset of rescue therpy re treted s missing. At Week 26, primry efficcy ws missing for 23%, 10%, 7% nd 12% of individuls rndomized to plceo,,, nd exentide, respectively. Lestsqures (LS) men djusted for seline vlue nd other strtifiction fctors. Sujects included in the nlysis re suset of the ITT popultion tht hd t lest one postseline ssessment. Multiplicity djusted 1sided pvlue <0.001, for superiority of compred to plceo, ssessed only for HA1c. Multiplicity djusted 1sided pvlue <0.001, for superiority of compred to exentide, ssessed only for HA1c. Sujects included in the nlysis re suset of the ITT popultion tht hd t lest one postseline ssessment. The primry nlysis included 119, 269, 271 nd 266 individuls rndomized to plceo,,, nd exentide, respectively. ** p<0.001 compred to plceo, ssessed only for HA1c <7.0%. ## p<0.001 compred to exentide, ssessed only for HA1c <7.0%. LS Men HA1c (%) Weeks PostRndomiztion Numer of sujects with oserved dt Plceo Exentide 276 Men chnge from seline djusted for seline HA1c nd country. Exentide Plceo Wk 26 LOCF Figure 4: Adjusted Men HA1c Chnge t Ech Time Point (ITT) nd t Week 26 (ITT) LOCF Addon to Metformin nd Sulfonylure In this 78week (52week primry endpoint) openlel comprtor study (doulelind with respect to dose ssignment), 807 ptients were rndomized to once weekly, once weekly, or insulin glrgine once dily, ll s ddon to mximlly tolerted doses of metformin nd glimepiride. Rndomiztion occurred fter 10week ledin period; during the initil 2 weeks of the ledin period, ptients were titrted to mximlly tolerted doses of metformin nd glimepiride. This ws followed y 6 to 8week glycemic stiliztion period prior to rndomiztion. Ptients rndomized to insulin glrgine were strted on dose of 10 U once dily. Insulin glrgine dose djustments occurred twice weekly for the first 4 weeks of tretment sed on selfmesured fsting plsm glucose (FPG), followed y once weekly titrtion through Week 8 of study tretment, utilizing n lgorithm tht trgeted fsting plsm glucose of <100 mg/dl. Only 24% of ptients were titrted to gol t the 52 week primry endpoint. The dose of glimepiride could e reduced or discontinued fter rndomiztion (t the discretion of the investigtor) in the event of persistent hypoglycemi. The dose of glimepiride ws reduced or discontinued in 28%, 32%, nd 29% of ptients rndomized to,, nd glrgine. Ptients hd men ge of 57 yers; men durtion of type 2 dietes of 9 yers; 51% were mle; rce: White, Blck nd Asin were 71%, 1% nd 17%, respectively; nd 0% of the study popultion were in the US. Tretment with once weekly resulted in reduction in HA1c from seline t 52 weeks when used in comintion with metformin nd sulfonylure (Tle 6). The difference in oserved effect size etween nd, respectively, nd glrgine in this tril excluded the prespecified noninferiority mrgin of 0.4%. Tle 6: Results t Week 52 of Compred to Insulin Glrgine, Both s Addon to Metformin nd Sulfonylure 52Week Primry Time Point (dulglutide) injection, for sucutneous use TRU0003USPI (dulglutide) injection, for sucutneous use TRU0003USPI Insulin Glrgine IntenttoTret (ITT) Popultion (N) HA1c (%) (Men) Fsting Serum Glucose (mg/dl) (Men) Difference from insulin glrgine. Adjusted men (95% CI) Body Weight (kg) (Men) (men) Difference from insulin. Adjusted men (95% CI) (9, 23) (3.4, 2.2) (2, 12) (3.9, 2.7) 0.6 Arevitions: HA1c = hemogloin A1c. Intenttotret popultion. Lst oservtion crried forwrd (LOCF) ws used to impute missing dt. Dt postonset of rescue therpy re treted s missing. At Week 52, primry efficcy ws missing for 17%, 13% nd 12% of individuls rndomized to, nd glrgine, respectively. Lestsqures (LS) men djusted for seline vlue nd other strtifiction fctors. Sujects included in the nlysis re suset of the ITT popultion tht hd t lest one postseline ssessment. The primry nlysis included 267, 263 nd 259 individuls rndomized to,, nd glrgine, respectively. Addon to Prndil Insulin, with or without Metformin In this 52week (26week primry endpoint) openlel comprtor study (doulelind with respect to dose ssignment), 884 ptients on 1 or 2 insulin injections per dy were enrolled. Rndomiztion occurred fter 9week ledin period; during the initil 2 weeks of the ledin period, ptients continued their prestudy insulin regimen ut could e initited nd/or uptitrted on metformin, sed on investigtor discretion; this ws followed y 7 week glycemic stiliztion period prior to rndomiztion. At rndomiztion, ptients discontinued their prestudy insulin regimen nd were rndomized to once weekly, once weekly, or insulin glrgine once dily, ll in comintion with prndil insulin lispro 3 times dily, with or without metformin. Insulin lispro ws titrted in ech rm sed on preprndil nd edtime glucose, nd insulin glrgine ws titrted to fsting plsm glucose gol of <100 mg/dl. Only 36% of ptients rndomized to glrgine were titrted to the fsting glucose gol t the 26 week primry timepoint. Ptients hd men ge of 59 yers; men durtion of type 2 dietes of 13 yers; 54% were mle; rce: White, Blck nd Asin were 79%, 10% nd 4%, respectively; nd 33% of the study popultion were in the US. Tretment with nd once weekly resulted in reduction in HA1c from seline. The difference in oserved effect size etween nd, respectively, nd glrgine in this tril excluded the prespecified noninferiority mrgin of 0.4%. Tle 7: Results t Week 26 of Compred to Insulin Glrgine, Both in Comintion with Insulin Lispro 26Week Primry Time Point Insulin Glrgine IntenttoTret (ITT) Popultion (N) HA1c (%) (Men) TRU0003USPI _TRU0002MG , 8 X 10.5 PRINTER VERSION 6 OF 8