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1. 2
2. o B ARE EN
3. 14 2 GE BERR BARDA ENDOSO BRET 15 DPP 4 GLP 1 PA
4. O eo 1 Sug 1 2 1 1 1 4 20
5. DPP 4 GLP 1 LY2189265 dulaglutide 1 7 1 1 7 p hi 3 3
6. v4 32 LY2189265 1 7 fi dulaglutide zi E En FS Sat 1 7 3 awe A UR
7. AT LY2189265 1 7 dulaglutide R 1 7 2 6 7 3 8 4
8. Vo Boi BECE D do 5 B VAI BR Ae EME PUSE 2 ANS DAR O KAMEN 3 2015 3 5 2013 3 5 2 mg Lois 25 LY2189265 dulaglutide 1 7 3 1 7 AT S ug 300 10 ng 300 100 mL
9. 30 5c 24 LY2189265 1 7 dulaglutide p hi R 1 7 2 10 10 1 1 0 3 1 0 2 3 if X5 CA
10. 35 al M YE En p LY2189265 1 7 fi dulaglutide 1 7 3 2 015 0 1 ae 2 IN I BER SEEN Ses AST 5 175 GOT ALT GPT DEAR SU B bie We Aen ps i aA DER
11. 30 mL min HR 3 4 4 5 1 5 DB T 1 _ 2 RETRE SRR DS
12. LY2189265 dulaglutide 1 5 1 5 2 2 2 1 GLP 1 11
13. 27 AL LY2189265 1 7 dulaglutide 1 7 3 1 1 2 2 MES THE LATEST 1 0
14. SU E Ee 3 4 DL RUE DO ERAT E Ea 13 3 se MA 4 ERE MIHE REO HITOS A Bl cbr Que
15. 31 1 12 Pharmacol 2007 63 2 206 215 2011 21 27 Diabetes Frontier 2013 24 6 695 701 2011 37 50 006 49 12 919 927 BEA 2013 56 8 08 4399 1 74 2012 63 13 LY2189265 1 12 dulaglutide
16. LY2189265 dulaglutide 1 8 R 0 75 mg OW 1 2 II GBDP GBDY GBDQ 0 75 mg 1 8 2 2 2 GBDP GBDY GBDQ GBDP II 32 26
17. AL OF CB HEH GLP 1 8 0107 1 26 1 7 9 9 10 Qmd GLP 1
18. PAZ Wu FEET DMG MRE OO SE 238850 DNE 3 Gr C 3e 5 Hol Me 5 1 5 1 pn ESIR PR k Wn Hmm S TE Jg ot SH ime A G HH BI A E FER Wd Ie FE E
19. te t 23 LY2189265 1 7 dulaglutide p hi R 1 7 2 9 9 1 1 1 AAMT JIS T 3226 2 1 ni a 2 A E VED ARA CASE 1H o 2 Es Q 1
20. 6 1 t 4 55 Al Ce BIB 1 0 75 mg O 71 21 INR FRODE RR I 1 0 75 mg 4 MKD 2 0 ERE LEMS B cef
21. 3 2 25 R m 9 Et ATU amm i 3 2 S 1 General Information COME Eli Lilly and ENZ AMA Company 3 2 8 2 Manufacture COM FRA Eli Lilly and Company Lilly Kinsale Ireland 3 2 S 3 Characterisation COMER Eli Lilly and Company 3 2 S 4 Control of Drug Substance COMER Eli Lilly and Company Lilly Kinsale Ireland 3 2 8 5 Reference Standards or COM EA Eli Lilly and Materials Company 3 2 S 6 Container Closure System COM FRA Eli Lilly and Company 32 8 7 Stability 2008 Eli Lilly and Company Lilly Kinsale Ireland 3 2 P der zs ETE hera sae s 32 P 1 Description and Composition OMIT Eli Lilly and ES of the Drug Product Company 3 2 P 2 Pharmaceutical Development CM BH Eli Lilly and
22. 1 2 2 nil LY2189265 1 10 ER dulaglutide 2 CHO 1 2 o
23. GE ju a ee aa A et gee Mm Ey 184 GE Company Core Data Sheet CCDS E 1 11 GRIEF 606 i IZE 59 9 4 25 HAT a LY2189265 dulaglutide 6 lies 607 1 8 DY 9 4 25 Mm 1 2
24. 9X MC GBCR ESE BU 9X MC GBC AFR 9X MC GBCPE 9X MC GBC ERES 9X MC GBC 9X MC GBDW H9X MC GBCH 25 LY2189265 1 12 dulaglutide R st SES aae 9X MC GBDN Hg H9X JE GBDQ 5 3 7 3
25. 2 fet E E AMERO Te DEA A NN po Ms Eg BRAR 2
26. 1 BUE EA 2 13 30 ug 1 2 1 100 pg 23 RA BR PIEDRA CROT AERO SUE 2 t EE STA
27. v VN DRA av LY2189265 1 7 dulaglutide 1 7 2 1 1 1 1
28. 2012 44 4 425 435 RU 1 6 dulaglutide FJLU Ver 4 BOTE 0 75 mg 1 6 i LY2189265 L6 dulaglutide n seg A BT aussen POR NRI EVA 1 1 6 LY2189265 1 6 dulaglutide 1 6 EU 1 6 1 EU Trulicity n
29. 26 ZIM ONE BAL IC J I C CR eH 3 57 5 C 1H E v gv D E 6 hos 93 3 GLP 1 5 TasH2 HE J 9
30. 10 9 E i IIA TA Sz S LR HR p nr 7 10 a 1 1 3 72
31. 30 LY2189265 1 7 fi dulaglutide zi M E En FS Natt R 1 7 3 3 3 SE AES js e BUT 3 Af Wm PE nac es hae w p
32. Na M A o 1 EAE KETE dbi thax 2
33. INR HMG CoA ETRE AUC ES VAL IG 40 Crax BS 28 MEL StS AE FL tnx 4 Ege B man w E JE 1 1 MS y J E S Buen 4i cok mE IE REE FENDA MIN ARA B
34. 1t F FOH 2 INR 1 HMG CoA 11 AUC 40 HOLE Cs 28 F UL tnax 4 Syk INR
35. 2 3 FAL HERRE o oe
36. amp 14 24 s Ie IRK AL Ye oe A AVRAVIV TAI bik
37. CHO 2 7 LY2189265 1 10 dulaglutide 2 EE CO y lt gt 1 2 HBOS o LL 3
38. p hi LY2189265 1 7 dulaglutide 1 7 1 1 1 1 1 eee iud WEE OOBETEREO DABRE 2 3 4 Rs md IRU 2 one HEU 25433 43342 14 018 G
39. 88 1 2 ue p hi LY2189265 1 7 dulaglutide R 1 7 1 9 1 1 JIS T 3226 2 12 A DEA TWH J
40. 2 2 0 2 fg
41. la ine SGLT2 E pi or MAO TENE BEBE FEA DINOS OI 7 VOW 4 5 5
42. 2 7 2 2 2 2 1 2 QTc QT QTc 0 1 12 0 mg 0 75 1 5 mg 1 seamless Index II II II imu FESTA L FE GBCF 4 GBCF GBDA GBDB GBDD HH
43. 42 r 5 1 20 hg 1 LARS Li amp amp OAs POR RE E AUC D 117 ff CHEE Sf Ik
44. gt 1 1 13 1 Eee en cet E 1 1 GLP 1 2 ae 2 3 GLP 1
45. PRE A LY2189265 1 7 dulaglutide R 1 7 2 20 ug 1 2 mg 1 1578 Us 4 10 ug 1 1 1 15 ng 1 1 H1l 20 ug 1 20 hg 1 a
46. 57 56 53 23 20 20 ERTI Y URRY LY2189265 1 10 dulaglutide 1 0 75smg 2 0 75 mg 1 Bic m EDR fit 1 1
47. CER 4 5 5 BEOTI EB REPO ERA WE MERRE DR 9 1
48. o Y rot o CHO A C 3 4 5 amp 6 1 7 2 1 2 3 4 Do
49. 4 DPP 4 DPP 4 GLP 1 t 2011 ib et al 2012 E DPP 4 E E Exendin 4 2013 5 HbAlc Helodema suspectum DW LEE FRASER VT 6 9 7 0 E 2
50. 2 Veris GBCZ LY2189265 1 5 dulaglutide 1 5 2 6 1 2 II GBCZ GBCZ IT 12 2 0 25 0 5 0 75 mg 1 12 HbAlc p lt 0 001 HbAlc
51. za ul 1 5 2 6 1 3 Ill GBDP GBDY GBDQ GBDP I 32 26 AU XEBIRZTVEGAABR FEBRES 2 0 75 mg 1 1 1 1 1 0 75 mg 1 26 HbAlc
52. 11 2 ERORE DIBE 3 12 4 5 1 2
53. 1 10 ug 1 26 1 E 1 4 80 1 LY2189265 1 7 dulaglutide p hi R 1 7 3 1 60 1 1 mL 1 ug 1 H 2
54. 2 i n AL LY2189265 1 7 dulaglutide 1 7 2 2 2 STE GLP 1
55. ED 2 E 1 LY2189265 dulagl
56. 296 288 224 77 8 AP 33 Bil 11 1 48 146 50 7 HD 75 ffi 26 0 41 7 2 4 14 2 32 2 0 7 11 1 31 10 8 2 0 7 26 9 0 t ERE Chor 1 1 1 OGRA E um Rio JR mir AA 160 2 6 180 uc 1 84 1 4 Bil 0 5 1 16 RAR pue b puce
57. 1 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys NH Hse Gy hehe Ter Ser p Lear Lees m Mec heu Cares D 10 li Val Arg Leu Phu The Gla Try Lava Lao Asu Ule Gly Pru Ser Ber Gly Ala Pru Pru A 1 3 n Perser NH E 1 Gm 300 pg TENA 1 2 6 mg TE 1 2 mg 2
58. I Hi af REEL D se PEERS COMME oni aR E I DS PEAR PLE ED CR DIES 33 LY2189265 1 7 dulaglutide p hi R 1 7 3 4
59. em scenic ua abe ye x mA diua cumma Gne RE 5 3 7 3 1 ERRA i RARO SE D El Lym TAR H9X MC GBCM 5 3 7 3 2 z HZ H9X EW GBDO 5 3 7 3 3 x EE ER H9X MC GBDW 26 LY2189265 dulaglutide 53 34 HERA RS 5 3 7 3 5 5 3 7 3 6 5 3 7 3 7 5 3 7 3 8 5 3 7 3 8 1 5 3 7 3 9 5 3 7 3 10 5 3 7 3 11 5 3 7 3 12 5 3 7 3 13 5 3 7 3 14 5 3 7 3 15 5 3 7 3 16 5 3 7 3 17 5 3 7 3 18 9X MC GBCC T 9X MC GBCA T FRASERIN 9X MC GBCD T ESTA E RRA SEB 9X JE GBCZARR T HERA ERRED H9X JE GBDP 26 9X JE GBDP T ERA E RRA BUE Di 5230 9X JE GBDY T RETA EERE RJE 9X MC GBCJ T I FS Tg EERE SLE Bi 9X MC
60. 3 e 9 YO LE VERA OTHER 110 DIAS
61. Wo uy Ng 1 2 ES HEIL pte JN Jin PERA MV lt a Q 6 4 1 2 VEDA Y 5 AX 2 8 C
62. 29 A LY2189265 1 7 dulaglutide R 1 7 3 7 6 CUTE e EL J Ik 7 J VE
63. 12 0 9 mg 1 1 ERE 1 D wA vv vv
64. 3 4 MK ina 5 RE ait iat H R 28 A LY2189265 1 7 dulaglutide
65. PT INR 2015 5 FE 8 8 LY2189265 dulaglutide 1 7 2 1 7 AER AT 300 ug 2 mg 2mg 2013 6 A 28 2012 3 30 2 mg 2015 3 2 mg 10
66. 1 1 5 mg LC 2 RUE 2 7 3 1 3 1 1 0 mg Il fH GBCZ J 0 2 75 mg LY2189265 18 R dulaglutide GBCZ 2 F 0 25 0 5 0 75 mg 1 12 0 75 mg HbAlc 3 0 75 mg Old 1
67. 4 MEAN ga w E PE Apo DPP 4 Hiro 4 h ii MANS MAO B EZ 4
68. C 1 0 75 mg O 12 o rasH2 E PRRI ENED PIRR 1 RD SIZED Te II ADA 1 4 13 010 3 3 100 E 3 0 100 2 XJ bees D BEE O do 2 XE 2 EY H PT INR
69. TAGES is pis S 5 3 2 5 3 2 3 PUT MES te Hz IE E m A BR 5 3 2 3 1 LY2189265 Metabolism COM Eli Lilly and Company Lilly Corporate Center 5 3 3 PK 5332 BA AH SPKAUMMS SIME XL ERE REA Ee bh Hh sh ei EE aria sara Quen 5 3332 H9X JE 20 WA GBCB 2 Safety Tolerability M Pharmacokinetics and Pharmacodynamics of LY2189265 after Single Subcutaneous Dose in Japanese Patients with Type 2 Diabetes Mellitus 53322 H9X JE 20 EUH GBCL Safety Tolerability Pharmacokinetics and Pharmacodynamics of LY2189265 after Multiple Subcutaneous Doses in Japanese Patients with Type 2 Diabetes Mellitus Ee 17 LY2189265 1 12 dulaglutide
70. 2 GLP 1 qub M 3 3 HE RI deii 3 4 o
71. LY2189265 1 5 dulaglutide 1 5 15 4 LY2189265 1 GLP 1 CHO GLP 1 G4 IgG4 Fc 4 DPP GLP 1 GLP 1 GLP 1 7 37 90 GLP 1 I
72. 3 2 361 81 180 0 75 me 1 1 1 26 26 HbAlc 1 44 0 05 0 90 0 05 HbAlc 0 54 95 0 67 0 41 95 0 4 FE 70 mg dL IA AMAR 47 181 Bil 26 0 86 180 47 8 26
73. D N AUC eg Ce Era ED E CL F VF ng hr mL ng mL hr hr L hr L 1 i 4630 37 7 71 7 31 33 12 0 95 2 6 11 6730 51 6 48 0 1313 0 111 192 3 32 30 24 0 72 5 107 189 32 19 CLF V F c i 1 K 2 3 N 9 2 487 152 65 AMERO 65 7 9 5 5 9 D 2
74. INR 2 10 SHAN 0B
75. a BEBE TRO Ra A AU AC ARS 1 ll dd 2 PUn pd GLP 1 E Brie 3 i GLP 1 o Es
76. m E SEE en AL LY2189265 1 7 dulaglutide 1 7 1 2 RK OH Hj EZ Elo AERA LL 2
77. 100 mg kg 20 mg kg BERS 10 mg kg 4 112 n S d St EC S gt n XE S c S s tat St Ya c LY2189265 1 10 dulaglutide RERE f B HE f Be OS Do BE WEE D gt KIE To FA et REY Ze HEE ft BR Ok HR OD Yk gt BERMEO 2 917 272 29 7
78. GBDQ II 32 2 ER 10 LY2189265 1 5 dulaglutide o SU o GI TZD 0 75 mg 1 HbAlc 14 52 LOCF p lt 0 001 HbAlc 26 LOCF 1 93 0 09 SU 1 58 0 11 52 LOCF 1 69 0 13 TZD
79. v ffe AML CO ACTH GB Ute arfar RIL BET HETE RETO ER Lbs LAE EAT De
80. E NN w Ea og
81. Bl A H eo o E 4 fX CAL CHO A C 5 it 6 CHO 1 7 CHO 2 LY2189265 112 dulaglutide FJLU Ver 4 BOTE 0 75 mg 112 LY2189265 1 12 dulaglutide 1 12 3 3 32
82. 13 14 p hi LY2189265 1 7 dulaglutide R 1 7 1
83. ed O REX d is 3 wc c ERHSOC ec o da MM aki 3 o ITA FSA MINA PC oe 5 is redu SUERA yr E vera n uu XB YA Y vA RUE co 3 DPP 4
84. LY2189265 1 10 dulaglutide 1 1 2 3 MO iC 5 74 ARE an Beo toi n oem HA e Em MEM MIN ik SM 5540 35510 pH EE REC EE c BEM gu c m AN E 7 EE 57 0777 4 8 ME 2 757 4 9 MAT y 774405 247 16601 NEN M E Es GE 10 MEN gt E 11 Wl D 1 10 HSK SRS OMEBARHO Ld dulagl
85. 7 1 5 LY2189265 18 R dulaglutide 18 2 a E 1 8 2 1 2 1 8 2 2 2 0709 1 22 7 9 2 L H9X JE GBCZ 2 II H9X JE GBDP H9X JE GBDY H9X JE GBDQ 4 Pil H9X JE GBCZ GBCZ
86. 5 3 3 3 PK Ys ES FR th UA tics ee aio deso Dr SEE Sanh 5 3 3 3 1 H9X MC n E TNR DASS GBCM Pharmacokinetics of 2 Dulaglutide in Subjects with Impaired Renal Function 5 3 3 3 2 H9X MC n EAR GBCT n A Study to Evaluate the 208 c Pharmacokinetics Pharmacodynamics Safety and Tolerability of LY2189265 in Elderly Patients with Type 2 Diabetes Mellitus 5 3 3 3 3 H9X EW 2010114 EAR GBDO A Single Dose Pharmacokinetic 2011 11 Study of Dulaglutide in Subjects with Varying Degrees of Hepatic Impairment 5 3 3 4 PK WTAE R an MISS 5 3 3 4 1 H9X MC 2011 9 DATE GBCR Effect of Dulaglutide 2011 11 LY2189265 on the Pharmacokinetics of Digoxin in Healthy Subjects 5 3 3 4 2 H9X MC 2011 3 GBCO lt Pharmacokinetic and 2011 8 Pharmacodynamic Effect of Dulaglutide on Lisinopril in Subjects with Hypertension and Metoprolol in Healthy Subjects 5 3 3 4 3
87. CESK AA E EU ERRE GLP 1 5 2 5 1 eG Cli 2 8 C E TK UT te GLP 1 SAK I OZ in vivo SLT y Sedes E EIES HEK 293
88. 1 1 1 1 L 2 6 2 1 TUMOR 2 BRE 3 DBE AEETI 4 MARE PRAT H 5 6 7 8 BEBE TEH 2 LEST 2 HE A FERRETA 3 ERA 2 3
89. 0 3 6 0 mg HEL CRAY 1 0 mg H 3 0 mg 2 7 4 5 9 6 1 2 DV cm WW 1 0 L5 mg F 1 0 mg 2 7 4 5 9 6 1 0 GBCL 1 1 23 2 7 4 2 3 mg EDS
90. 2 rj 2 NGS 6 9 4 etal 2006 2014 2 et al 2013 SU TZD
91. 22 p hi LY2189265 1 7 dulaglutide 1 7 2 6 6 1 T HERE banus de 22 ug kg e 2mg 1 1 Ws 49 5 1 20 ug 1 1
92. 1 TID IHRE UK liz 2 FERE AER BS bw RE Z IL ASE tH AEN VESPA SNS ENE E E ir EH MER 12 X A E 27 OP 4 8
93. Es 9 w ETHIE TEK E 2 Es 3 8
94. 19 p hi LY2189265 1 7 dulaglutide 1 7 2 4 4 2 II FARR ARR ICS II YC BAA 250 2 672 2 672 1 225 45 8 818 635 f 23 8 556 426 fi 52 1 JE 293 11 0 231 A 8 6 HERE 1614 19 7 104 ff 250 12 7 62 7 6 175 70 0 Hp 5 FER 55 Bil 6 7 88 49 6 0 43 5 3 35 2 41
95. 24 2013 56 8 543 550 Available at http www mhlw go jp file 04 Houdouhappyou 10904750 Kenkoukyoku Gantaisakukenkouzoushinka 0000032813 pdf 2013 Accessed June 27 2014 12 18 2008 4399 71 74 F 2014 2015 2014 2013 Available at http www jds or jp common fckeditor editor filemanager connectors php transfer php file uid000025_6B756D616D6F746F323031332E706466 Accessed June 27 2014 MERA 2012 63 13 13 22
96. GBDP COLO M RN III 3 GBDP PROAT e gt gt gt o MI gt lt gt 7007 A cov c mE OB Ren Oe Chor GBDQ ARICA MN LY2189265 1 5 dulaglutide IO sco MIS p 1 5 2 6 1 5 1 1 5 1 2 5 1 S X 1 5 1 CREE H9X JE GBCB 2 SER B ir 2
97. GLP 1 zl ATL 5 O PARAS RAE 0 Er BOM BEDS peck d SEA EAR SICHERER 6 GLP 1 6 7 8 GLP 1 7
98. 0 75 mg HbAlc 4 52 p 0 001 52 HbAlc 0 75 mg 1 39 0 00 0 75 mg 1 55 0 12 1 19 0 08 0 75 mg 95 0 20 0 39 0 01 0 75 mg p 0 040 26 0 75 mg 56 1 157 280 Bil 55 5 76 137 Pil 55 7 39 70 fil 52 0 75 mg
99. E C C LY2189265 dulaglutide 1 CN GLP 1 ed Biel 2 2 pu
100. H gt i 82723138 1 0 75 mg 1 1 8 R 2 I GBCB GBCL IL GBDP GBDY GBDO E Urbi ies 1 Em 1 II fH 0 75 mg Bre HA BOT HEN 3 HE GBCB 2
101. ELT 0 75 mg 1 Kl 155 EMA European Medicines Agency 2006 Scientific discussion BYETTA exenatide Available at http www emea europa eu docs en_GB document_library EPAR_ Scientific Discussion human 000698 WC500051842 pdf Accessed August 6 2013 EMA European Medicines Agency 2012 Summary of Product Characteristics LYXUMIA lixisenatide Available at http www ema europa eu docs en GB document library EPAR Product Information human 002445 W C500140401 pdf Accessed August 14 2013 FDA United States Food and Drug Administration 2010 Summary basis of approval VICTOZA liraglutide rDNA injection NDA 022341 Pharmacology Review Parts 1 3 Available at 14 LY2189265 1 5 dulaglutide http www accessdata fda gov drugsatfda docs nda 2010 022341s000TOC cfm Accessed August 6 2013 FDA United States Food and Drug Administration 2012 Summary basis of approval BYDUREON exenatide extended release for injectable suspension NDA 022200 pharmacology review Available at http www accessdata fda gov drugsatfda docs nda 2012 0222000rig1s000TOC cfm Accessed August 6 2013 Glaesner W Vick AM Millican R Ellis B Tschang SH
102. HH T 26 HbAlc 0 75 mg 1 44 0 05 0 90 0 05 26 0 75 mg HbAlc 95 0 54 0 67 0 41 95 YO 0 4 F 0 75 mg 0 75 mg p lt 0 001 26 0 75 mg 75 1 136 181 61 7 111 180 0 75 mg
103. 24 73 5 Bil 6 8 E 3 4 1 IEA 1 1 4 RE 1 1 0 7 ERK A gia ex m HE EA E by EN E BE Dpr Hy NERIS E
104. A LY2189265 1 7 dulaglutide R 1 7 2 41 co UL fibi v Sus qd 15 16 17 D
105. MARIO RIAL RO A NN a ce PEE E OMB ee E EE July 33 xz aN EE 12 a N LT PI 13 CCDS 13 1 3 72 3 72 1 OO 3
106. 6 1 cd 2 6 1 m cR 2 3 23 cm BEL CHE 4 3 1 2 8 C 2 dec DBR NS 4 RIFE 1 2 es 30 2 H
107. 0 75 mg RREE REB a jouit 4 x 48 ASA t tmax 1 F HbAlc 3 0 25 0 5 0 75 mg 1 a E 12 AUC HE Cu 2 0 035 mg En Be 5 2 145 12 0 75 mg 1 35 0 09 0 18 0 09 0 75mg p 0 001 TE
108. 30 C C 1 0 75 mg DOME PURO 12 rasH2 iil V Nat a 6 II ADA 1 4 13 910 2 24 0 75 mg 1 1 5 2 8 C 18 RAKE R CROT REE RRA PERO AREA GENTE ZIT TOD REREAD AUC 90
109. i 13 5 5 BUE A T it 6 ik 7 HE OO b 2 8 H
110. 2 26 HbAlc 0 75 mg H 1 JERA 1 1 1 0 75 mg 0 75 mg 1 0 75 mg 1 26 HbAlc 0 75 mg 1 43 0 05 BIET 0 14 0 10 1 33 0 07 0 75 mg HbAlc
111. 7 4 DAS 9 AA BY FRED SW R 8 1 2 MR EH LE Ob BE Do 10 es
112. 1 0 3 0 6 0 mg 1 0 mg 3 0 mg E 88 GBCL FF 1 0 1 5 mg E 3 GE tmax 7 38 1 lh FEA FIERA KRE KORIE E 2 1 0 1 5 mg IH 1785 EE GBCZ 9 1 QT QTc AR 1 5 2 1 GBCB 2 I GBCZ
113. 52 C LC C C amp dzvcwv 2523 BER E HOX JE GBCB LY2189265 dulaglutide 1 5 2 6 1 20 Lik GBDT loj 1 5 2 6 1 1 148 GBCB I
114. 0 48 0 17 kg 0 945 0 17 kg 2 0 75 mg 1 32 HbAlc 32 1 19 0 01 70 mg dL ELT SEO N HbAlc D Ai ple 131 1 67 0 09 33 6 ce 65 1 65 0 11 6 2
115. I Sig MAO BB h h 4 B
116. 21 LY2189265 dulaglutide R 1 7 2 1 7 AA zi E En un Sat 2 E E 3 5 1 5 LY ARTI FA FS TEE DEV BAY DE 2 5 1 5 1 HEAR SS FAR
117. Hie 1 m HE Bob MEREHANA 4 WAR Wis TBZ FED 3 d Um coy L BERTI E ee SABE SAR ARA TRE DRA E ur WED IR PR T pgs DEEN DAA L Hd AM vg IE ALT GPT AST GOT 354 Ou HAE st Es NS UH m 1 Ea
118. 0 75 mg 29 8 54 181 2 2 4 180 0 75 mg p lt 0 001 0 75 mg 5 E zwi Hu LY2189265 dulaglutide GBDQ EX a GD 0 75 mg 4 II 32 PE M OVE 2 0 75 mg p lt 0 05 1
119. GLP 1 0427 1 Pa ERE 22 4 27 16 LY2189265 dulaglutide 18 R J zn Hx DPP 4 3f E lt 2 IW et FS 72151 IE R BOIL IVS OMA OME 3 EZ a 2 3 SERE BERR
120. A cou E Le 2 8 C 14 30 a as E AR Hii 3 202 ET 1
121. 9X MC GBCC l EESE CEKA TIERE BE UR E FER 24 23 GF Mila BERE FIERA CEE FEES BAR A THETA ELAR IL We THE LY2189265 dulaglutide 1 5 2 6 2 EA 20 2 1 5
122. 917 272 il CASA 1 29 7 57 0 75 mg 149 6 2 3E 56 6 1 534 5 8 E gt 2 1 7 3 pesos 8 1 DP
123. ELT 8 0 75 mg 1 XE in EIC gt 9 1 03 m 10 1 1
124. LY2189265 dulaglutide GBC A Phase 2 3 Placebo Controlled Efficacy and Safety Study of Once Weekly Subcutaneous LY2189265 Compared to Sitagliptin in Patients with Type 2 Diabetes Mellitus on Metformin H9X MC 2010 2 A Randomized Placebo 2012475 Controlled Comparison of the Effects of Two Doses of LY2189265 or Exenatide on Glycemic Control in Patients with Type 2 Diabetes on Stable Doses of Metformin and Pioglitazone AWARD 1 Assessment of Weekly AdministRation of LY2189265 in Diabetes 1 H9X MC ES GBDB A Randomized Open Label 201244114 Parallel Arm Noninferiority Comparison of the Effects of Two Doses of LY2189265 and Insulin Glargine on Glycemic Control in Patients with Type 2 Diabetes on Stable Doses of Metformin and Glimepiride AWARD 2 Assessment of Weekly AdministRation of LY2189265 in Diabetes 2 H9X MC GBDC The Impact of LY2189265 versus Metformin on Glycemic Control in Early Type 2 Diabetes Mellitus AWARD 3 Assessment of Weekly AdministRation of LY2189265 in Diabetes 3 H9X MC GBDD The Impact of LY2189265 F9 Versus Insulin Glargine Both in Combination with Insulin Lispro for the Treatment to Target of Type 2 Diabetes Mellit
125. 9 ES HA LY2189265 18 R dulaglutide 52 0 75 mg 0 75 ms AEA 66 1 185 280 fil 68 6 94 137 75 7 53 70 56 5 35 62 AN 0 75 mg 0 75 mg 5 0 75 mg 0 75 mg 3 4
126. 2 Cd od jr cops aM e J A LY2189265 1 7 dulaglutide R 1 7 1 10 1 24 C
127. PESIMA L2 34 A LY2189265 1 7 dulaglutide 1 7 3 AA aL 2 BRE EA CC EH ow NO HRA IZ EY WR SONAS EA 3 HARE BEES 23 amp DION KK aes PND o de Ag ERX 0 7 P
128. 0 75 mg GRE 2 zu AX SU o GI TZD 44 3 58 131 17 66 36 6 26 71 Bil 9 9 39 394 21 65 23 8 gt HE 9 496 FEX HbAlc 1 52 ao E 0 7 mg 1 11 LY2189265 dulaglutide 1 8 3 2 H GBCZ
129. 2 mg ti AO LAS HIRE 1 1162 l 8 2 2 84 3 3 2 61 3 2 C C
130. ARI DEE N AUC Co tma hr 90 90 90 1 mg 1 1 22 22 0 88 0 64 1 00 0 85 0 92 0 59 0 70 0 73 1 73 Y ABB 2221 1 05 094 002 1000 mg LOL 1 08 1087 1 031 _ 0 50 0 531 4 2221 1 00 1 04 0 02 2 0 96 1 03 0 96 1 14 0 50 0 09 3 mg 1 7 1 8 8 0 89 0 50 2 15 0 83 0 95 0 43 0 59 1 02 3 97 7 4 86 E ONE XT e AT 097 1000 mg 9 1 05 1 23 0 82 1 14 0 00 1 48 4 86 105 097 049 2 0 97 1 14 0 82 1 14 0 03 1 02 1 5 mg 1 1 23 22 1 06 0 95 0 50 0 91 1 24 0 81 1 12 1 00 0 00 5 40 mg 4 23718 108 lee 70302 7 L00 0 89 1 24 0 86 1 21 1 00 1 00 20719 1 19 1 32 1 00 100 mg 1 11 1 28 1 20 1 45 0 00 3 00 ME AA A PA AA pa PERE ele eens dete tet S 28 25 0 99 0 78 4 02 A AA PA PA 0 96 1 01 074 083 3 00 5 00 R 28 25 0 99 0 86 5 50 0 96 1 02 0 82 0 90 4 00 8 00 2 12 1
131. 16 4 31 2 mg 12 4 27 10 8 1 1 1 EXE 1 Eia LK 18 ERTR EE DE ud EN MA RM WES y eus A TEA LN oe ER EE TH Do BA KR amp 6 ip Bai DPP 4 eee
132. 17 05 20 ys E E 36 UR 2 8 C 14 ICH in vitro in vivo E lies AMERICA RE E 1 in vitro fa D JE ER 1 in vitro TU TI Xx LY2189265 dulaglutide 1 1 5 2 5 2 15 EF ax
133. 68 pg kg UE AUC 2mg 1 4 6 BUTS VE OIL TER SE REO 5 4 32 T en w DE 0 3 mg kg 2 mg 1 1 TWH FOPMERREO 1 748 3 1 NE E ear 3 mg kg 2 mg 1 o ao HEHE BY 10 9 R
134. LY2189265 dulaglutide 4 2 1 1 7 4 2 1 1 8 4 2 1 1 9 4 2 1 1 10 OAAX03 Evaluation of the Activity of Subcutaneously Administered 2189265 G8E22 L IgG4mEIK in Normal Cynomolgus Monkeys in the Fasting State and During an Intravenous Glucose Tolerance Test IVGTT bTDRO3 Assessment of the Dose Dependency of Insulinotropic Activity of LY2189265 ina Stepped Glucose Infusion SGI Model in Sprague Dawley Rats 6180 702 Effect of LY2189265 on Glucodynamics Insulinotropics in Normal Cynomolgus Monkeys Subjected to Repeat Graded Intravenous Glucose Infusions 6180 773 Repeat Dose Effect of LY2189265 on Glucodynamics Insulinotropics in Normal Cynomolgus Monkeys Subjected to Graded Intravenous Glucose Infusions 4213 4 2 1 3 1 4 2 1 3 2 LLYOS 07 LY2189265 In Vitro Effect on hERG Current Ix Expressed in Human Embryonic Kidney HEK Cells 010 08 Cardiovascular Telemetry Study in Conscious Cynomolgus Monkeys Administered LY2189265 by Subcutaneous Injection 2 ED EliLilly and Company OESTE Eli Lilly and Company OE gg CO Eli Lilly and Company OE D Eli Lilly and Company J
135. TM VAY AD ABRE CNI AL Pis e ye 4 VA gt I MIE PRAA GLP 1 a 3 4 A MI EERE SRL ioe 3 4 SN Beak Wiens E KP ROCA 2
136. s zi M E En un Sat LY2189265 17 HA dulaglutide 1 7 2 3 3 seas mer lr re e Pr man man 2
137. 0 25 0 5 0 75 mg p lt 0 001 0 25 0 5 0 75 mg ZW 1 12 OK PR 0 75 mg HbAlc GBDP GBDY GBDO 0 75 mg
138. 6 PEI 1 5 2 5 3 SEN EE ES LES 1 6 9 rasH2 GLP 1 HER POE D FE SE Y 1 E JV TER
139. E ADCC II 2 7 4 4 2 HH GI GLP 1 g QT QTc RIB sux 20 E QT QTc 2 7 4 5 9 7 RUE QT QTc RV QTc GLP 1 Id E 30 C
140. 0 75 mg 6 2 7 4 2 1 1 1 a GBDY II 26 F SU 2 26 HbAlc SU 0 75 mg 1 1 1 Y 0 75 mg E 26
141. 1 4 275 IgG4 Fc 2 16 30 57 63 64 Gly Glu Gly Pro Ala Ala AN LAB SAID 5 PEA SIV 275 2 63 000 1 1 3mL P 0 75 mg 18 0 mg 2 2 2 0 75
142. PT ee B Me aA ex 31 zi E En p Yat LY2189265 1 7 fi dulaglutide 1 7 3 awe AEI R N B 12 E PEELE AM
143. WHERE Wa ur iE B sin HER s HB E PE JER AI EE
144. 0 75 mg URGE 1 RKA RIE ERRA 0 75 mg 1 0 9mg 1 1 GER 26 280 TIVE BBE 2 487 137 PA CARRE 70 1 8 R EEE GLP 1 IgG4 Fc DPP 4 2 B GLP 1 cAMP dj 59
145. 2 1H e 5 cs 6 1 A DS 3 1 2 8 C zs Y 2 3 cm 2 4 1H m Te 30 C 1 2 8 C 1 AFTER WERFT S Z
146. 2010 10 27 2008 1 30 2008 9 H 25 2014 6 belt The Phe Thr Ser syr Ler Surkys tlr Meth 1 10 4 Yal T Lea Phe De Gly Try Lew Lys Aen Gly Gly Pro Ser Ser Gl Aa ro Io Ai Vries NH Ej 8 3 35 GIVEQCCTSI CSLYQLENYC G FVNQHLCGSH LVEALYLVCG ERGFFYTPKT RR ERA 1 bm 300 ug 1 Gm 7 300 2 te
147. EN vM 1 3 N dE HbAlc Clinical Utility za 1 6 uu LY2189265 1 5 dulaglutide 1 29 Exendin 4 GLP 1 e GLP 1 2 0 75 mg
148. 5 3 5 3 1 5311 BA The Effect of Injection Site on the Relative Bioavailability of LY2189265 in Subjects with Low and High Body Mass Index H9X MC 2011 2 GBDR A Study to Evaluate the Safety 2011 8 Tolerability and Absolute Bioavailability of Subcutaneous Dulaglutide 5312 BA BE T EMO e ET one rem dida dial GREdoKEHEA o Pl 5 3 1 2 1 H9X MC 2012 3 E EA GBDT s Comparative Pharmacokinetics 2012 6 of Dulaglutide after Administration via an Auto injector and a Manual Syringe in Healthy Subjects 5 3 1 4 HARO se ES A z ouk doi GREKERE
149. D 4 3 o al 4 FAD 5
150. SOIT PJP 272 29 7 1 002 37 6 2 6 379 fil 699 4 6 1 53 5 8 37 8 85 95 4 8 5 63 Bil 74 6 3 1 1 Bbi ON EE EER A 3 JR BF BA El TR RR HM DE DEN DPP 4
151. 0 75 ms 1 43 0 05 BEET 0 14 0 10 1 33 0 07 0 75 mg HbAlc 9 1 57 1 79 135 p lt 0 001 0 75 mg 0 75 mg 95 0 10 0 27 0 07 95 0 4 LY2189265 1 5 dulaglutide 0 75 mg 95 0
152. 1 BU 0 75 mg 1 5 mg 75 0 75 mg 1 LY2189265 dulaglutide 1 6 R 1 6 1 2015 2
153. 2 2 1 9 1 3 Se BRIA BH AST
154. en 10 A DESEE E
155. 9 1 57 1 79 1 35 p lt 0 001 0 75 mg 0 75 mg 95 0 10 0 27 0 07 95 0 4 0 75 mg 95 BRAS 0 F 0 75 mg HbAlc 4 52 52 HbAlc 0 75 mg a EO
156. Gu VES 4 3 c 2 2 3 4
157. o 6 DERE DER LEAN AS ATES A O E TAN H PEREZ O NEAR 4 4 8
158. 4 G ana e HTA 5 puc 1 2 GLP 1 3 4 5 aida
159. RIA MATA AE cw DPP 4 SGLT2 HAT SBA ii o gU NIH oy ov Bm 0 Hof S TUS B
160. e 2 EU 2 0 75 mg 1 1 5 mg 1 1 5 mg 1 1
161. 2 5 6 TZD SU 2 154 G HAZ JAN 1 rare PG 0 75 mg 0 5mL 2
162. ER gt NE 14 pi WERL Ele irj OIL IF Hx e X 30 C 18 1 2 G RP 3 CCDS 1 2 10 C 0 75 mg 1 H C PR ue E 165 II
163. MES MAO SAIS BERE TF TER 23 8 DOT MAE to 1 DHAR 1 Hof S TUS v I a DPP 4 SGLT2 X iif Y Z
164. SU a GI TZD GBDO ECS HbAlc 14 52 LOCF GBDP GBDY GBDQ F 0 75 mg GBDP 0 75 mg 1 66 1 85 5 34 bpm 0 75 mg 2 7 4 2 0 75 mg od
165. 0709 1 II 589 Aci GBCB GBCL 6 0 mg 2 Zub 1 5 J C Bin 48 PEA Ea HE I GBCL 22 7 bw 9 i GBCC 1 GBCC GBDT I II 8 E
166. Me MA OR SEE Cv A s S LAS ICE Sx C BE dip ote SR Do 3 4 4 1 1 100 ug 10 2 2 ED IEEE e OAE cM EN 3 4 d 2 juu 4 1 a
167. s dude o LIME RA JG RSR RAIDERS JEO ASA OE FA Cet Clk BE Zby c E REO E to DT EN o EH ICO CH BATX PARIO OU AC a 1 3 1
168. zu HX 1 1 II GBDP 0 75 mg 48 GBDP 7 7 2 7 2 3 6 1 2 0 75 mg Oi 7 2 FAIR B 1 1 2 II GLP 1 Hsc ELT 4 5 1 2
169. 10 11 12 EE len 13 2 14 LY2189265 18 dulaglutide 15 16 17 18 19 20 21 22 Terauchi et al Endocrine Journal 61 10 949 2014 23 2 II GBDY 24 2 II GBD
170. 13 1 REE DARE 3 72 3 4 3 2 72 1 2 1 3 72 LY2189265 18 dulaglutide
171. 2 I GBDP GBDY GBDO 0 75 mg GBDP 26 HbAlc 0 75 mg DH 1 FF 0 75 mg HbAlc 4 52 52 HbAlc 0 75 mg SU GBDY 26 HbAlc 0 75 mg OFF 1 0 75 mg
172. H9X MC GBCP H9X MC GBCQ H9X MC GBCS H9X MC GBDW H9X MC GBCC H9X MC GBCA H9X MC GBCH H9X MC GBCI H9X MC GBCD H9X EW GBDM H9X JE GBCZ H9X JE GBDP 26 Ti H9X JE GBDP 32 H9X JE GBDY H9X MC GBCJ H9X MC GBCK H9X MC GBDN H9X MC GBCF H9X MC GBDA H9X MC GBDB IM S 24 LY2189265 1 12 dulaglutide RRR E ji H9X MC GBDD H9X JE GBDQ
173. Company 3 2 P 3 Manufacture COMER Eli Lilly and Ey Compan 3 2 P 4 Control of Excipients COME Eli Lilly and Company 3 2 P 5 Control of Drug Product COM BH Eli Lilly and Company 3 2 P 6 Reference Standards or COME Eli Lilly and 15 Materials Company 3 2 P 7 Container Closure System CMT BH Eli Lilly and Company 3 2 P 8 Stability CONF Eli Lilly and Company LY2189265 dulaglutide 3 2A 3 2 A 1 Facilities and Equipment 3 2 A 2 Adventitious Agents Safety Evaluation 3 2 R 3 2 R Regional Information 4 4 4 2 4 2 1 4 2 1 1 ae 4 2 1 1 1 BTDR225 In Vitro Binding Activity of Dulaglutide LY2189265 4 2 1 1 2 bTDROl In Vitro Activity of LY2189265 4 2 1 1 3 DBT56 LY2189265 Glucose Dependently Stimulates Insulin Secretion from Rodent and Primate Pancreatic Islets Through Interaction with the GLP 1 Receptor 4 2 1 1 4 bTDRO4 In Vitro Evaluation of ADCC Effector Functions of LY2189265 and Related Proteins 4 2 1 1 5 bTDR224 In Si
174. H9X MC GBCJ The Effect of Dose Titration of LY2189265 GLP 1 analog IV Fc in Overweight and Obese Patients with Type 2 Diabetes Mellitus The EGO Study H9X MC GBCK Assessment of Dose Dependent Effects of LY2189265 on Glycemic Control in Patients with Type 2 Diabetes Treated only with Lifestyle Interventions H9X MC GBDN The Effect of LY2189265 on Blood Pressure and Heart Rate as Assessed by Ambulatory Blood Pressure Monitoring in Patients with Type 2 Diabetes Mellitus 2009 12 2010 12 2012 4 2014 5 26 Data cutoff dra 2012 4 2014475 2012 6 2013 7 2008 4 2009 1 2008 11 2010 1 2010 6 2012 1 21 1 12 EA HU HW HU HUS HUS ESI
175. TE Vx Hut PEREZ do 2 v NEU e
176. 2013 LY2189265 dulaglutide 1 5 1 5 2 3 1 5 1 PEI LS dulaglutide 1 5 1 LY2189265 dulaglutide 1 5 2 4 2007 4 24 3 E RUE gt zn 4 1138 1525 JEM Es OS 65 C LAF 2 1 5 ER 48
177. 30 lt lt sS0mLmm 8 lt 30mLmmn 8 G 8 15mg 5 11 Child Pugh A 6 Child Pugh B 6 Child Pugh C 3 15mg AUC 902 0774 0649 0922 0669 0556 0805 0791 0632 0989 C 90 0791 0654 0957 0703 0582 0849 0761 0597 0971 9 6 2 29 65 76 05 075 L5 mg 1 6 2 075mg
178. D 2 1 2 1 GLP 1 2 GLP 1 O AMELIA CORRAN e id 10 12H 14 LY2189265 1 8 GE dulaglutide GLP 1 sd 4 KM NE 3 4 IRERE STe ERRE
179. INN INN dulaglutide r INN List 65 WHO Drug Information Vol 25 No 1 2011 LY2189265 19 HHHHHHHHHH dulaglutide WHO Drug Information Vol 25 No 1 2011 Recommended INN List 65 International Nonproprietary Names for Pharmaceutical Substances INN RECOMMENDED International Nonproprietary Names List 65 Notice is hereby given that in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances Off Rec Wid Health Org 1955 60 3 Resolution EB15 R7 1969 173 10 Resolution EB43 R9 Resolution EB115 R4 EB115 2005 REC 1 the following names are selected as Recommended International Nonproprietary Names The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy Lists of Proposed 1 101 and Recommended 1 62 International Nonproprietary Names can be found in Cumulative List No 13 2009 available in CD ROM only D nominations communes internationales des Substances pharmaceutiques DCI D nominations communes internationales RECOMMAND ES Liste 65 Il est notifi que conform ment aux dispositions du paragraphe 7 de la Proc dure suivre en vue du choix de D nominations communes internationales recommand es pour les Substances pharmaceutiques Actes
180. 2 3 ale Y g 37 p hi LY2189265 1 7 dulaglutide R 1 7 3 9 9 1 1 1 1 JIS T 3226 2
181. 2 H Ex I Oc A PESE OB EE c E IS 03 E Zu Bx dE P BIR E TEL ly l 1 n 5 3 TE BY HE OK F E ly 1 0 mg 1 5 mg 1 0 mg 0 75 mg
182. 36 p hi LY2189265 1 7 dulaglutide R 1 7 3 6 6 Re 0 cT m qs 22 pg kg 1 10ug 1 2 ml Be rd LTEM OLTRE REO 229 68 ng kg 1 10 ug 1 2 ITH AO MEH URED 25 E
183. 5341 PD PK PD 5 3 4 1 1 CORP Ela H9X MC 2 y A Placebo Controlled Study of the Electrophysiological Effects on QT Interval of a Single Supratherapeutic Dose of LY2189265 with a Positive Assay Control in Healthy Subjects 19 1 12 FEREN ae e E AR k T SU EH s meh ee LY2189265 dulaglutide Safety Tolerability Pharmacokinetics and Pharmacodynamics of LY2189265 after Single Subcutaneous Dose in Healthy Subjects H9X MC GBCH The Effect of LY2189265 on Gastric Emptying Based on the Pharmacokinetics of Acetaminophen in Healthy H9X MC The Effect of Dulaglutide LY2189265 on Insulin Secretion in Response to Intravenous Glucose Infusion Safety Tolerability Pharmacokinetics and Pharmacodynamics of LY2189265 a
184. Gly Glu Gly Pro Ala Ala 275 2 63 000 0 75 mg 0 5 mL 2 1 7 2 3 7 4 5 6 rasH2 7 2 II GBDP 8 2 1 9
185. 1 3 GLP 1 o UM A m 3 EG Mo RES E TET 4 EETRI UE IRBERGENIMI MERE KAIO 2 E N 3 4 n E o RR 5 ge 1 37 mg
186. 2 1 5 mg 1 E HC 10 2 10 180 AUC 26 HbAlc 1 43 0 05 0 14 0 10 1 57 95 1 79 1 35 HbAlc 0 10 95 0 27 0 07 95 0 4 52 HbAlc 2 1 39 0 06 0 08 0 20 95 0 39 8 280 Bil 2 9 4 137 fil 2 9
187. H9X MC 2010 12 GBCP ae Effect of LY2189265 on the 2011 3 Pharmacokinetics of Atorvastatin in Healthy Subjects 5 3 3 4 4 H9X MC 2011 10 GBCQ Effect of Dulaglutide 2012 2 LY2189265 on Oral Contraceptive Pharmacokinetics in Healthy Female Subjects 18 LY2189265 dulaglutide 5 3 3 5 5 3 3 5 1 5 3 3 5 2 5 3 3 5 3 5 3 4 Regum 4 H9X MC GBCS The Effect of Dulaglutide LY2189265 on the Pharmacokinetics and Pharmacodynamics of Single Dose Warfarin in Healthy H9X MC Study to Evaluate the Effect of Dulaglutide LY2189265 on Sitagliptin Pharmacokinetics in Patients with Type 2 Diabetes Mellitus PK ae BE Population Pharmacokinetic Q and Pharmacodynamic Analyses of Studies in Japanese and Global Patients with T2DM GBCB GBCD GBCL GBCF GBCJ GBCK GBCZ and GBDN Population Pharmacokinetic 2 3 and Pharmacodynamic Analyses of Studies GBCF GBCJ GBCK GBCZ and GBDN Population Pharmacokinetic COM and Pharmacodynamic Analyses of Studies GBCF GBDA and GBDC PD
188. 1 5 ug HERJE SIE AERE Fi 10 ug 3 1 1 la 10 ug 1 2 1 1 1
189. 1 8 2 2 1 II GBCZ GBCZ IT 12 2 12 HbAlc 0 25 0 5 0 75 mg 1 12 HbAlc 0 25 0 5 0 75 mg ps lt 0 001 p lt 0 001 F 0 25 0 5 0 75 mg
190. 1 es 0 07 mg Gace ol MEO MEAE AT HED b HIRED TE HALO BER a 80 19 mg MEDIR GEHA 6 pH 6 0 7 0 MIA 1 nib E 7 E
191. Ga E 3 72 3 1 11 DPP 4 3 72 GLP 1
192. Met 2 1 5 0 75 mg inferentially GBDD f uv in 1 3 II GBDC GBDA GBDB GBDD 2 AEP 7 w o 1 5 3 E A 1 OP H 2013 9
193. 1 2 20 hg 1 TERRE BEBE 12 E ERA OO RR TERRE SLATES HE 172 EERJA OO RS
194. LD dient O L Ze 3 Bl A H eo o E 4 fX CAL CHO A C 4 CHO 1
195. RARAS PA 1 LY2189265 1 7 fi dulaglutide zi M E En un Sat 1 7 1 2 9 s CIA serm zum Be Z gt E
196. System Organ Very common Common Uncommon Rare Class Metabolism and Hypoglycaemia Hypoglycaemia nutrition when used in when used as disorders combination with monotherapy or in prandial insulin combination with metformin or metformin plus metformin plus pioglitazone glimepiride Gastrointestinal Nausea Decreased Acute pancreatitis disorders diarrhoea appetite vomiting dyspepsia abdominal paint constipation flatulence abdominal distention gastroesophageal reflux disease eructation General Fatigue Injection site disorders and reactions administration site conditions Investigations Sinus tachycardia first degree atrioventricular block AVB Documented symptomatic hypoglycaemia and blood glucose lt to 3 9 mmol L Dulaglutide 1 5 mg dose only For dulaglutide 0 75 mg adverse reaction met frequency for next lower incidence grouping Description of selected adverse reactions Hypoglycaemia When dulaglutide 0 75 mg and 1 5 mg were used as monotherapy or in combination with metformin alone or metformin and pioglitazone the incidences of documented symptomatic hypoglycaemia were 5 9 to 10 9 and the rates were 0 14 to 0 62 events patient year and no episodes of severe hypoglycaemia were reported 36 The incidences of documented symptomatic hypoglycaemia when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with a sulphonylurea plus metformin were
197. i j 0 05 8 0 mg 6 3 12 26 IVIII 1 52 104 GBCJ GBCK GBDN 2 1 5 mg 26 24 monitoring ABPM ITI GBCF 2 7 3 2 2 0 75 ambulatory blood pressure y GLP 1 2 5 6 3 1 n 13 2
198. EA E ci 4 2 2 1 5 06 070 OE TD Enzyme Linked Immunosorbent Assay ELISA for the Quantitative Determination of Immunoreactive LY2189265 in Rabbit EDTA Plasma 4 2 2 1 6 06 033 OE HD Enzyme Linked Immunosorbent Assay ELISA for the Quantitative Determination of Immunoreactive LY2189265 in Cynomolgus Monkey EDTA Plasma 4 2 2 1 7 0002299 2008F Eli Lilly and Quantification of LY2189265 Company in Cynomolgus Monkey Plasma by Enzyme Linked Immunosorbent Assay ELISA 4 2 2 1 8 IMJW4 COMA ELISA Method for Analysis of LY2189265 in K3 EDTA Monkey Plasma LY2189265 dulaglutide 4232 d 4 2 3 2 1 8224143 A Repeat Dose Toxicity and Toxicokinetic Study in 001178 W wild type Mice Given LY2189265 Twice Weekly by Subcutaneous Injection for 4 Weeks 4 2 3 2 2 R00359 Repeat Dose Toxicology and Toxicokinetic Studies in Fischer 344 Rats Given LY2189265 Twice Weekly by Subcutaneous Injection for a Total of 10 Doses 4 2 3 2 3 7608 191 A Repeat Dose Tox
199. Q 2 N ne gt E el CAME RA
200. 1 10ug 1 2 FE UTE EE OD MAE PURE COD 143 C 2 C C E 2015 1 7 2015 2 8 XI ROSE 39 LY2189265 18 dulaglutide FJLU Ver 4 BOTE 0 75 mg
201. 2 Be bs 4 4 E 2 B 4 B LIED OE cs
202. 2 0 3 1 0 3 0 6 0 mg 3 2 0 75 mg AH 1 26 7 2 AA 7 in vitro GLP 1 2 3 in vivo
203. Gar RE 5 3 1 4 1 Radioimmunoassay for the OMIT ES E k DAR Quantitative Determination of Concentrations of Immunoreactive LY2189265 in Human EDTA Plasma 53 142 RIA Analysis of LY2189265 in m Es EE K3 EDTA Human Plasma 5 3 1 4 3 Summary Report of Statistical COMER Eli Lilly and Analysis Results for Company Cross Validation of RIA Lilly Corporate Methods for the Determination Center of LY2189265 in Human Plasma between Originating and Destination Laboratories 5 3 1 44 Electrochemiluminescence COM ECL Immunosorbent Assay for Detection of Human Antibodies against LY2189265 15 LY2189265 1 12 dulaglutide Addendum for the Electrochemiluminescence ECL Immunosorbent Assay for Detection of Human Antibodies against LY2189265 Anti LY2189265 Antibodies Confirmatory Validation of an Electrochemiluminescence ECL Immunosorbent Assay for Detection of Human Antibodies against LY2189265 GLP Fc in Human Serum Validation of an Immunoassay for the Detection of Anti GLP 1 Neutralizing Antibodies in Human Serum Validation of an Immunoassay for the Detection of Anti LY2189265 Anti GLP Fc Neutralizing Antibodies in Human Serum LC MS MS Method Validation for the
204. 1 1 2 D DE 3 NOU F ZL ICEL PED 1 namq
205. 43 2 06 37 Bil 47 2 17 36 48 6 18 37 42 9 15 35 Bl 0 25 0 5 0 75 mg 0 25 0 5 0 75 mg 5 4 2 37 Bil 8 3 3 36 Bil 24 3 9 37 14 3 5 35 Bil 0 5 mg p 0 046 0 25 0 75 mg 025 05 0 75 mg 5 05 mg p 0 025
206. i y 1 AME 2 Ir i ES 2 FEE CAPERS 3 TL lies CCDS 24 SOT FB L CWS ARENEO do Z
207. E o ua GI Ex f 2 HbAlc 1 30 50 2008 et al 2012 2014 GLP 1 e 1 et al 2013 Y GLP 1 e 1 1 2 23 e Exendin 4 2 eC 3
208. 2013 9 2014 9 EU 2013 9 2014 11 2013 9 2014 11 2013 9 2014 11 2013 11 2014 11 AA AUR M 2013 12 2014 12 20 200 2090 20 2000 F HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRULICITY safely and effectively See full prescribing information for TRULICITY TRULICITY dulaglutide injection for subcutaneous use Initial U S Approval 2014 WARNING RISK OF THYROID C CELL TUMORS See full prescribing information for complete boxed warning Dulaglutide causes thyroid C cell tumors in rats It is unknown whether TRULICITY causes thyroid C cell tumors including medullary thyroid carcinoma MTC in humans as the human relevance of dulaglutide induced rodent thyroid C cell tumors has not been determined 5 1 13 1 TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 MEN 2 Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors 4 1 5 1 RECENT MAJOR CHANGES
209. 61 1 57 0 1196 3 396 66 1 69 0 13 6 1 71 1 65 0 13 9 9 ED 32 2 32 32 0 10 024 kg a 1 24 0 42 kg 0 87 0 40 kg 1 02 0 35 kg 0 04 0 26 kg 70 mg dL LAF 52 3 2 0 75 mg 1 26 mi AUC 0 3 4 2 1 5 mg 1 4 tp
210. SGLT2 A GHE d z AE HE MR 3E BRT 57g CO ETT GENE 3k Xx i 1 potiri 2 UL SUEDE ITE cu e MAO 3 dud fb a MRE FAB EI 5 ae ae HENS
211. H 2 AR A 1 JIS T 3226 2 A HIME A BD Es ACA JEN EE LO RAID bY y ZOPSE pae H aane
212. LY2189265 dulaglutide 5 9 7 4 5 3 7 4 1 Ears H9X JE G 5 3 1 4 2 d ARR AA ue 0 EKR H9X JE GBCL 5 3 7 4 3 H9X JE GBCZ 5 3 7 4 4 H9X JE GBDP 26 5 3 7 4 4 1 H9X JE GBDP 32 3 7 4 5 H9X JE GBDY 3 7 4 6 H9X JE GBDQ 5 4 Exenatide and rare adverse events A 5 week study of the pharmacokinetics and pharmacodynamics of LY2189265 a novel long acting glucagon like peptide 1 analogue in patients with type 2 diabetes LY2189265 a long acting glucagon like peptide 1 analogue showed a dose dependent effect on insulin secretion in healthy subjects Use of a claims based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide Pancreatic safety of incretin based drugs FDA and EMA assessment Ahmad SR et al Barrington P et al Dore DD et al
213. N 24 e 5 N 24 80 7 60 40 4 207 0 24 48 72 96 120 144 168 hr 2 14 1 1 5 mg 1 2 9 45 3 LS mg AUC 90 0 973 0 941 1 01 0 989 0 956 1 02 Thor 0 75 mg 65 19 gt 80mL mm 16 50 lt lt 80mL min 8
214. 1 4 RAR 1 WIG 3N BA lL DOT MAE 1 ts 4 5 5 TX B INR p hi LY2189265 1 7 dulaglutide R 1 7 1 4
215. 18 GE LY2189265 18 GE dulaglutide EE D Mo S aL 1 1 1 8 2 R 8 1 8 2 1 8 1 8 2 2 8 1 8 2 2 1 IH GBCZ kk 8 1 8 2 2 2 II GBDP GBDY GBDQ 9 1 8 3 GR kk 11 1 8 3 1 NEAR 11 1 8 3 2 A A A 12 1 8 4 R kk 13 LY2189265 dulaglutide 1 8 F 1 8 1 0 75 mg RE 18 R LY2189265 18 dulaglutide OOOO COMO OOMOO 20xx xx 1 87 2499 GLP 1 se isre SE E TRULICITYSATEOS ug BO 2 8eC CRTE BUG EM
216. CON 20 bU 1 12 AE pa tt ES R DIETE p 1 ER E SENE LY2189265 1 12 dulaglutide 4 2 2 4 2 2 1 4 2 2 1 1 09 131 2008 FEA ES E Enzyme Linked Immunosorbent Assay ELISA for the Quantitative Determination of LY2189265 in Mouse EDTA Plasma 4 2 2 1 2 0002294 20M FE Eli Lilly and Quantification of LY2189265 Company in Rat Plasma by Enzyme Linked Immunosorbent Assay ELISA 4 2 2 1 3 06 034 CONF Enzyme Linked Immunosorbent Assay ELISA for the Quantitative Determination of Immunoreactive LY2189265 in Rat EDTA Plasma 4 2 2 1 4 ICD 373 2 ONE TA ELISA Method for Analysis of LY2189265 in K3 EDTA Rat Plasma icd ETE
217. DPP 4 4 GLP 1 4 El SGLT2 TD A MAO I us i ida 5 E B x EO JOE RP wA MAO 1 Ee ARCO tL AE TF TE eic 4 3
218. H 10 cw 12 I 11 13 w 4
219. HRK F INR RAH 4 917 nl gt 2 7 6 2 HE 53 5 8 1 1 Ami SUR E B G 272 29 7 IL 56 6 1
220. HbAlc 0 75 mg 1 44 0 05 0 90 0 05 26 0 75 mg HbAlc 95 0 54 0 67 0 41 95 YO 0 4 F 0 75 mg 0 75 mg p lt 0 001 0 75 mg HERE 75 1 136 81 Fil 61 7 111 180 0 75 mg p 0 007
221. 3 E M GE GLP 1 mino 7 TH w DPP 4
222. 2 HH Ult BA 2 3 4 TE 88 87 84 7 0 75 mg 1 18823 50 2 ts El JAN Dulaglutide Genetical Recombination 1 31 1 485275 IgG4 Fc 2 16 30 37 63 64
223. 3 r 4 38 AL LY2189265 1 7 dulaglutide 1 7 3 10 10 2 250 ug kg 1
224. 8236888 An Investigational Time Course Study of Thyroid C Cell Mass in Rats Treated with LY2189265 Compound 2189265 for up to 12 Months 504758 An Investigative Study of Pancreatic Exocrine Biomarkers Histology and Histomorphometry in Male Zucker Diabetic Fatty ZDF Rats Given LY2189265 by Subcutaneous Injection Twice Weekly for 13 Weeks moe E E diro 20 Aa dip HA HIE 1 12 NET ENER au zu y y LY2189265 dulaglutide REA 4 2 3 7 3 3 8252199 An Investigational Timecourse Study of Calcitonin Responses and Thyroid C Cell Mass and Terminal Evaluation of Pancreatic Structure in Male Cynomolgus Monkeys Treated with LY2189265 Twice Weekly by Subcutaneous Injection for 12 Months
225. 92 1 m L7 V TZD 18 R ER HA ERRE CAR a v Rm vAXVR A Chore 2 SU NN 0 75 mg HbAlc 14 52 HbAlc 1 93 0 09 SU f 52 WARE LOCF 1 69 0 13 TZD f IEE AE EB F 075 ZS E 46 65 il DBE CX 37 394 7 9 31 394 FAD OE A H 85 5 112 131 H 1 5
226. Hypoglycaemia When dulaglutide 0 75 mg and 1 5 mg were used as monotherapy or in combination with metformin alone or metformin and pioglitazone the incidences of documented symptomatic hypoglycaemia were 5 9 to 10 9 and the rates were 0 14 to 0 62 events patient year and no episodes of severe hypoglycaemia were reported The incidences of documented symptomatic hypoglycaemia when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with a sulphonylurea plus metformin were 39 0 and 40 3 and the rates were 1 67 and 1 67 events patient year The severe hypoglycaemia event incidences were 0 and 0 7 and rates were 0 00 and 0 01 events patient year The incidences when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with prandial insulin were 85 3 and 80 0 and rates were 35 66 and 31 06 events patient year The severe hypoglycaemia event incidences were 2 4 and 3 496 and rates were 0 05 and 0 06 events patient year Gastrointestinal adverse reactions Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0 75mg and 1 5 mg respectively included nausea 12 9 and 21 2 96 diarrhoea 10 7 and 13 7 96 and vomiting 6 9 and 11 5 These were typically mild or moderate in severity and were reported to peak during the first 2 weeks of treatment and rapidly declined over the next 4 weeks after which the rate remained relatively constant In clinical pharmacolog
227. 2 14 04 15 DPP 4 GLP 1 15 DDP 4 E 15 LY2189265 18 dulaglutide
228. lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg tt goo goo E E dk once weekly i 279 8 10 1 51 t 78 2 62 7 2 36 1 30 Dulaglutide 0 75 mg hA nd 0 HE HE once weekly n 280 8 05 1 301 65 8 53 2 1 90 0 20 Placebo n 141 8 06 0 46 42 9 24 4 0 26 1 24 Exenatide 10 mcg twice daily 8 07 0 99 523 38 0 1 35 1 07 n 276 52 weeks Dulaglutide 1 5 mg E dh 6 itt onge weekly 2279 8 10 1 36 70 8 57 2 2 04 1 10 Dulaglutide 0 75 mg E once weekly n 280 8 05 1 07 59 1 48 3 1 58 0 44 Exenatide 10 mcg twice daily 8 07 0 80 49 2 34 6 1 03 0 80 n 270 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to exenatide assessed for HbAlc only tt multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to placebo p 0 05 p lt 0 001 dulaglutide treatment group compared to exenatide Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and exenatide twice daily were 0 19 0 14 and 0 75 episodes patient year respectively No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily Combination therapy with prandial
229. tom ETE HERO 3 1 5 X 7 EXP OS HTE SHR viel RS VEA LB n EMA 2006 FDA 2010 EMA 2012 DEA Ki ER c Gs AR AK OWE REMI A O ERE EN E HOA TAPA
230. 43 Exenatide and rare adverse events Changes in arterial blood pressure and heart rate induced by glucagon like peptide 1 7 36 amide in rats Barrag n et al Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies Human antibody effector function and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon producing neuroendocrine tumors EET 2 2 G tT q ait YN 1 12 mass N Engl J Med 2008 358 1969 1972 Am J Physiol 1994 266 E459 466 J Exp Med 19873166 1351 1361 Adv Immunol 1992 51 1 84 Diabetes 2013 62 2595 2604 LY2189265 dulaglutide Occurrence of Spontaneous Pancreatic Lesions in Normal and Diabetic Rats May Confound the Nonclinical Assessment of Glucagon like Peptide GLP 1 Elevating Therapies The effects of feed restriction on reproductive function in Sprague Dawley rats From genome to vaccine in silico predictions ex vivo verification A cohort study of acute pancreatitis in relation to exenatide us
231. If a dose is missed it should be administered as soon as possible if there are at least 3 days 72 hours until the next scheduled dose If less than 3 days 72 hours remain before the next scheduled dose the missed dose should be skipped and the next dose should be administered on the regularly scheduled day In each case patients can then resume their regular once weekly dosing schedule The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days 72 hours before 4 3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6 1 4 4 Special warnings and precautions for use Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis Use of GLP 1 receptor agonists may be associated with gastrointestinal adverse reactions This should be considered when treating patients with impaired renal function since these events i e nausea vomiting and or diarrhoea may cause dehydration which could cause a deterioration of renal function Dulaglutide has not been studied in patients with severe gastrointestinal disease including severe gastroparesis and is therefore not recommended in these patients Acute pancreatitis Use of GLP 1 receptor agonists has been associated with a risk of developing acute pancreatitis In clinical trials acute pancreatitis has been reported in assoc
232. Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes In vitro Activity of LY2119402 Engineering and characterization of the long acting glucagon like peptide 1 analogue LY2189265 an Fc fusion protein The human GLP 1 analogs liraglutide and semaglutide Absence of histopathological effects on the pancreas in nonhuman primates B Gier et al C J Girman et al W Glaesner et al C F Gotfredsen et al 10 1 12 Poster presentation at the NIDDK NCI Workshop on Pancreatitis Diabetes and Pancreatic Cancer June 12 13 2013 Bethesda MD USA Diabetes Care 2010 33 2349 2354 J Clin Endocrinol Metab 2012a 97 121 131 Diabetes 2012b 61 1250 1262 Diabetes Obes Metab 2010 12 766 PEA Internal Report BTDR07 E Diabetes Metab Res Rev 2010 26 287 296 Diabetes 2014 63 2486 2497 LY2189265 of glucagon like peptide 1 GLP 1 immunoreactivity and GLP 1 receptor mRNA in pancreatic islets of rat FDA surveillance of adverse B T Hummer drug effects therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus the FIELD study randomised controlled trial The effects of diet overfeeding K P Keenan and moderate dietary restriction et al on Sprague Dawley rat surviva
233. 1 12 sss zu zy y 1 LY2189265 dulaglutide 42352 HERAS RR Me 4 2 3 5 2 1 353116 An Embryo Fetal Development and Toxicokinetic Study in Sprague Dawley Rats of LY2189265 Administered Via Subcutaneous Injection Every Third Day 4 2 3 5 2 2 353119 Embryo Fetal Development and Toxicokinetic Study in New Zealand White Rabbits of LY2189265 Administered Via Subcutaneous Injection Every Third Day m gE did 27 HAZ 2 42353 4 2 3 5 3 1 4 2 3 5 4 4 2 3 5 4 1 4 2 3 7 3 4 2 3 7 3 1 4 2 3 7 3 2 353253 A Prenatal and Postnatal Development and Toxicokinetic Study Including Maternal Function of LY2189265 Administered via Subcutaneous Injection Every Third Day 353304 A Juvenile Toxicity and Toxicokinetic Study of LY2189265 Administered via Subcutaneous Injection Every Third Day in Sprague Dawley Rats
234. BOXED WARNING RISK OF THYROID C CELL TUMORS 03 2015 INDICATIONS AND USAGE Limitations of Use 1 1 03 2015 WARNINGS AND PRECAUTIONS Risk of Thyroid C cell Tumors 5 1 03 2015 INDICATIONS AND USAGE TRULICITY is a glucagon like peptide GLP 1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Limitations of Use Not recommended as first line therapy for patients inadequately controlled on diet and exercise 1 5 1 Has not been studied in patients with a history of pancreatitis Consider another antidiabetic therapy 1 5 2 Notfor treatment of type 1 diabetes mellitus or diabetic ketoacidosis Notfor patients with pre existing severe gastrointestinal disease Has not been studied in combination with basal insulin DOSAGE AND ADMINISTRATION Administer once weekly at any time of day 2 1 Inject subcutaneously in the abdomen thigh or upper arm 2 1 Initiate at 0 75 mg subcutaneously once weekly Dose can be increased to 1 5 mg once weekly for additional glycemic control 2 1 e Ifa dose is missed administer within 3 days of missed dose 2 1 e Injection 0 75 mg 0 5 mL solution in a single dose pen 3 Injection 1 5 mg 0 5 mL solution in a single dose pen 3 Injection 0 75 mg 0 5 mL solution in a single dose
235. 0 75 mg 66 1 185 280 fil 68 6 94 137 Bil 75 7 53 70 B DAL 56 5 35 62 fh 26 52 SOC 0 75 mg 0 75 mg 1 52 GBDY II 26 F SU 2 SU 0 75 mg 1 1 1 lees of
236. 0 78 61 5 46 0 1 01 2 29 Dulaglutide 0 75 mg once weekly n 270 7 58 0 71 62 6 40 0 1 46 1 36 Metformin 1500 2000 mg day 7 60 0 56 53 6 29 8 1 34 2 22 n 208 S2 Weeks Dulaglutide 1 5 mg 4 HH once weekly n 269 7 63 0 70 60 0 42 3 1 30 1 93 Dulaglutide 0 75 mg once weekly n 270 7 58 0 55 53 2 34 7 1 00 1 09 Metformin 1500 2000 mg day 7 60 0 51 48 3 28 3 1 15 2 20 n 268 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to metformin assessed for HbAlc only p 0 05 p 0 001 dulaglutide treatment group compared to metformin The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and metformin were 0 62 0 15 and 0 09 episodes patient year respectively No cases of severe hypoglycaemia were observed Combination therapy with metformin The safety and efficacy of dulaglutide was investigated in a placebo and active controlled sitagliptin 100 mg daily study of 104 weeks duration all in combination with metformin Treatment with Trulicity 1 5 mg and 0 75 mg resulted in a superior reduction in HbA1c compared to sitagliptin at 24 52 weeks accompanied by a significantly greater proportion of patients achieving HbAlc targets of 7 0 and lt 6 5 These effects were sustained to the end of the study 104 weeks Table 3 Results of a
237. 120 106 135 128 113 144 114 100 129 1 12 0995 126 EE Cy PLE 0 LIB 0963 131 123 105 143 120 102 140 1 11 0950 130 bot D ERA ty 45 A 108 5 AUC ic 1 45 D N AUC ig Cx tax ED tine 2 CL F VF ng hr mL ng mL hr hr L hr L 1 24 5860 46 3 50 33 108 0 0764 11 9 21 22 45 87 94 67 71 3 145 22 24 5 24 8570 3 67 7 48 00 1089 0 0875 F 13 6 gt 21 Q4 22 67 96 48 71 7 167 QD 35 CLF V F FEL Ci 2 3 N 1 FE ng mL dh 2 0 75 mg 1 1 E 23 00 1
238. 318 ILAR News 1990 32 16 19 Endocrinolog y 2013 154 4 8 LY2189265 dulaglutide Liraglutide in type 2 diabetes from pharmacological development to clinical Dractice Extended exenatide treatment causes pancreatic stress and injury in a rodent model of insulin resistance Glucagonlike peptide 1 based S Singh et al therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus a population based matched case control study An industry perspective on the R D Storer et utility of short term al carcinogenicity testing in transgenic mice in pharmaceutical development Thyroid calcitonin cells and parathyroid gland of the Indian rhesus monkey Macaca mulatta in response to experimental hypercalcaemia No evidence of drug induced pancreatitis in rats treated with exenatide for 13 weeks Exenatide does not evoke pancreatitis and attenuates Tatarkiewicz chemically induced pancreatitis Jet al in normal and diabetic rodents The effect of external pH on the J Vereecke et delayed rectifying K current in Jal cardiac ventricular myocytes Pituitary adenylate cyclase P Vertongen activating polypeptide receptors et al of types I and II and glucagon like peptide I receptors are expressed in the rat medullary carcinoma of the thyroid cell line 6 23 The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancr
239. 8H f f f LY2189265 dulaglutide 4 2 3 4 42341 4 2 3 4 1 1 8203405 104 Week Subcutaneous Injection Carcinogenicity and Toxicokinetic Study with LY2189265 Compound 2189265 in Rats 42342 4 2 3 4 2 1 4 2 8 5 4 2 3 5 1 WC ERI 4 2 3 5 1 1 4 2 3 5 1 2 8224144 A Carcinogenicity and Toxicokinetic Study in 001178 T hemizygous Mice Given LY2189265 Twice Weekly by Subcutaneous Injection for 26 Weeks 353113 A Male Fertility Study In Sprague Dawley Rats of LY2189265 Administered Via Subcutaneous Injection Every Third Day 353112 A Female Fertility and Early Embryonic Development Study in Sprague Dawley Rats of LY2189265 Administered Via Subcutaneous Injection Every Third Day 20 db Xp c E E jus c x E ju
240. Egan AG et al 28 EH 1 12 N Engl J Med 2008 358 18 1969 1972 Diabetes Obes Metab 2011a 13 5 426 433 Diabetes Obes Metab 2011b 13 5 1019 1027 N Engl J Med 2014 370 9 794 797 A EIAS APE ESTE PMC ESTE PE LY2189265 dulaglutide Patients with type 2 diabetes mellitus have higher risk for al acute pancreatitis compared with those without diabetes Engineering and characterization of the long acting glucagon like peptide 1 analogue LY2189265 an Fc fusion protein Perceptions about medications diabetes further revision and validation Efficacy and safety profile of Inagaki N et exenatide once weekly al compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug s results from a 26 week randomized open label parallel group multicenter noninferiorit
241. H9X JE GBCB 3 7 1 5 H9X JE GBCL 3 7 1 6 H9X MC GBCM 5 3 7 1 7 H9X MC GBCT 5 3 7 1 8 H9X EW GBDO WES aran FO 20m FRA a ED 20M FA E A 23 1 12 AN re E EBI ERES J ioca BBE th STAT ELE ERNEUT Ad pe xA El BBA LY2189265 1 12 dulaglutide RRR na By Ht ME H9X MC GBCO
242. RAGE MRO Tz TARTA BE H8 Dade uj TA B Rs E i f
243. Tian Y et al Engineering and characterization of the long acting glucagon like peptide 1 analogue LY2189265 an Fc fusion protein Diabetes Metab Res Rev 2010 26 287 296 IDF International Diabetes Federation 2013 IDF Diabetes Atlas sixth edition Introduction Available at http www idf org diabetesatlas introduction Accessed June 27 2014 MERU A LwL7VwvT BHEXERTZT Y ATV Y TAI 2011 21 27 GLP 1 DPP 4 Diabetes Frontier 2013 24 6 695 701 2011 37 50 A ERR KAE V F QDDM 2 QD QDDMT7 2006 49 12 919 927 AE REA E
244. and no episodes of severe hypoglycaemia were reported 21 The incidences of documented symptomatic hypoglycaemia when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with a sulphonylurea plus metformin were 39 0 and 40 3 and the rates were 1 67 and 1 67 events patient year The severe hypoglycaemia event incidences were 0 and 0 7 and rates were 0 00 and 0 01 events patient year The incidences when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with prandial insulin were 85 3 and 80 0 and rates were 35 66 and 31 06 events patient year The severe hypoglycaemia event incidences were 2 4 and 3 496 and rates were 0 05 and 0 06 events patient year Gastrointestinal adverse reactions Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0 75mg and 1 5 mg respectively included nausea 12 9 and 21 2 96 diarrhoea 10 7 and 13 7 96 and vomiting 6 9 and 11 5 These were typically mild or moderate in severity and were reported to peak during the first 2 weeks of treatment and rapidly declined over the next 4 weeks after which the rate remained relatively constant In clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks the majority of gastrointestinal events were reported during the first 2 3 days after the initial dose and declined with subsequent doses Acute pancreatitis The incidence of acute pancreatit
245. ketoacidosis Use of GLP 1 receptor agonists may be associated with gastrointestinal adverse reactions This should be considered when treating patients with impaired renal function since these events i e nausea vomiting and or diarrhoea may cause dehydration which could cause a deterioration of renal function Dulaglutide has not been studied in patients with severe gastrointestinal disease including severe gastroparesis and is therefore not recommended in these patients Acute pancreatitis Use of GLP 1 receptor agonists has been associated with a risk of developing acute pancreatitis In clinical trials acute pancreatitis has been reported in association with dulaglutide see section 4 8 Patients should be informed of the characteristic symptoms of acute pancreatitis If pancreatitis is suspected dulaglutide should be discontinued If pancreatitis is confirmed dulaglutide should not be 48 restarted In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis see section 4 8 Hypoglycaemia Patients receiving dulaglutide in combination with sulphonylurea or insulin may have an increased risk of hypoglycaemia The risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea or insulin see sections 4 2 and 4 8 Populations not studied There is limited experience in patients with congestive heart failure Sodium co
246. trisodium citrate dihydrate 1 37 mg in water for injection 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action TRULICITY contains dulaglutide which is a human GLP 1 receptor agonist with 90 amino acid sequence homology to endogenous human GLP 1 7 37 Dulaglutide activates the GLP 1 receptor a membrane bound cell surface receptor coupled to adenylyl cyclase in pancreatic beta cells Dulaglutide increases intracellular cyclic AMP CAMP in beta cells leading to glucose dependent insulin release Dulaglutide also decreases glucagon secretion and slows gastric emptying 12 2 Pharmacodynamics TRULICITY lowers fasting glucose and reduces postprandial glucose PPG concentrations in patients with type 2 diabetes mellitus The reduction in fasting and postprandial glucose can be observed after a single dose Fasting and Postprandial Glucose In a clinical pharmacology study in adults with type 2 diabetes mellitus treatment with once weekly TRULICITY resulted in a reduction of fasting and 2 hour PPG concentrations and postprandial serum glucose incremental AUC when compared to placebo 25 6 mg dL 59 5 mg dL and 197 mg h dL respectively these effects were sustained after 6 weeks of dosing with the 1 5 mg dose First and Second Phase Insulin Secretion Both first and second phase insulin secretion were increased in patients with type 2 diabetes treated with TRULICITY compared with placebo Insulin and Glucagon Secretion TRULICITY stim
247. 16 and 19 organogenesis fetal skeletal malformations of the vertebrae and or ribs were observed in conjunction with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0 41 mg kg a systemic exposure 13 fold the MRHD based on AUC No developmental adverse effects were observed at 4 fold the MRHD based on AUC 8 In a prenatal postnatal study in F maternal rats given subcutaneous doses of 0 2 0 49 or 1 63 mg kg every third day from implantation through lactation F1 pups from Fo maternal rats given 1 63 mg kg dulaglutide had statistically significantly lower mean body weight from birth through post natal day 63 for males and post natal day 84 for females F4 offspring from Fo maternal rats receiving 1 63 mg kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano preputial separation Females had decreased startle response These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment F female offspring of the Fo maternal rats given 1 63 mg kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze These findings occurred in conjunction with decreased Fo maternal food intake and decreased weight gain attrib
248. 20 H MN LT IRRE Do 3 Eo CHEER EP AR 7 o TK 2 amp SUE SE 25 1 Tq 12 48 EDAD DIL ULE EE FAY 8 A TER ZR a TON Jc lia
249. 33 and 21 for mild moderate and severe hepatic impairment groups respectively compared to subjects with normal hepatic function and Cmax was decreased by a similar magnitude Figure 1 see Use in Specific Population 8 6 Drug Interactions The potential effect of co administered medications on the PK of dulaglutide and vice versa was studied in several single and multiple dose studies in healthy subjects patients with type 2 diabetes mellitus and patients with hypertension Potential for Dulaglutide to Influence the Pharmacokinetics of Other Drugs Dulaglutide slows gastric emptying and as a result may reduce the extent and rate of absorption of orally co administered medications In clinical pharmacology studies dulaglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree Pharmacokinetic PK measures indicating the magnitude of these interactions are presented in Figure 2 No dose adjustment is recommended for any of the evaluated co administered medications 11 Coadministered Drug PK Ratio and 90 Cl Recommendation Lisinopril AUC B No dose adjustment Cmax Ee Metoprolol AUC oe No dose adjustment Cmax Digoxin AUC or No dose adjustment Cmax EE Norelgestromin AUC ce No dose adjustment Cmax Ethinylestradiol AUC No dose adjustment Cmax Atorvastatin AUC No dose adjustment Cmax Metformin AUC m am No dose adjustment
250. 39 0 and 40 3 and the rates were 1 67 and 1 67 events patient year The severe hypoglycaemia event incidences were 0 and 0 7 and rates were 0 00 and 0 01 events patient year The incidences when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with prandial insulin were 85 3 and 80 0 and rates were 35 66 and 31 06 events patient year The severe hypoglycaemia event incidences were 2 4 and 3 496 and rates were 0 05 and 0 06 events patient year Gastrointestinal adverse reactions Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0 75mg and 1 5 mg respectively included nausea 12 9 and 21 2 96 diarrhoea 10 7 and 13 7 96 and vomiting 6 9 and 11 5 These were typically mild or moderate in severity and were reported to peak during the first 2 weeks of treatment and rapidly declined over the next 4 weeks after which the rate remained relatively constant In clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks the majority of gastrointestinal events were reported during the first 2 3 days after the initial dose and declined with subsequent doses Acute pancreatitis The incidence of acute pancreatitis in Phase II and III clinical studies was 0 07 for dulaglutide compared to 0 14 for placebo and 0 19 for comparators with or without additional background antidiabetic therapy Pancreatic enzymes Dulaglutide is associated with mean
251. 48 3 1 58 0 44 Exenatide 10 mcg twice daily 8 07 0 80 49 2 34 6 1 03 0 80 n 270 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to exenatide assessed for HbAlc only tt multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to placebo p 0 05 p lt 0 001 dulaglutide treatment group compared to exenatide Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and exenatide twice daily were 0 19 0 14 and 0 75 episodes patient year respectively No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily Combination therapy with prandial insulin with or without metformin In this study patients on 1 or 2 insulin injections per day prior to study entry discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily both in combination with prandial insulin lispro three times daily with or without metformin At 26 weeks both Trulicity 1 5 mg and 0 75mg were superior to insulin glargine in lowering of HbAlc and this effect was sustained at 52 weeks A greater percentage of patients ach
252. 63 0 70 60 0 42 3 1 30 1 93 Dulaglutide 0 75 mg once weekly n 270 7 58 0 55 53 2 34 7 1 00 1 09 Metformin 1500 2000 mg day 7 60 0 51 48 3 28 3 1 15 2 20 n 268 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to metformin assessed for HbAlc only p 0 05 p 0 001 dulaglutide treatment group compared to metformin The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and metformin were 0 62 0 15 and 0 09 episodes patient year respectively No cases of severe hypoglycaemia were observed Combination therapy with metformin The safety and efficacy of dulaglutide was investigated in a placebo and active controlled sitagliptin 100 mg daily study of 104 weeks duration all in combination with metformin Treatment with Trulicity 1 5 mg and 0 75 mg resulted in a superior reduction in HbA1c compared to sitagliptin at 39 52 weeks accompanied by a significantly greater proportion of patients achieving HbAlc targets of 7 0 and lt 6 5 These effects were sustained to the end of the study 104 weeks Table 3 Results of a 104 week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc we
253. 7 See 17 for PATIENT COUNSELING INFORMATION and FDA approved Medication Guide Revised 03 2015 5 WARNINGS AND PRECAUTIONS 5 1 Risk of Thyroid C cell Tumors 5 2 Pancreatitis 5 3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin 5 4 Hypersensitivity Reactions 5 5 Renal Impairment 5 6 Severe Gastrointestinal Disease 5 7 Macrovascular Outcomes 6 ADVERSE REACTIONS 6 1 Clinical Studies Experience 7 DRUG INTERACTIONS 7 1 Oral Medications 10 11 12 13 14 16 17 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy 8 3 Nursing Mothers 8 4 Pediatric Use 8 5 Geriatric Use 8 6 Hepatic Impairment 8 7 Renal Impairment 8 8 Gastroparesis OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12 1 Mechanism of Action 12 2 Pharmacodynamics 12 3 Pharmacokinetics NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis and Impairment of Fertility 13 2 Animal Toxicology and or Pharmacology CLINICAL STUDIES 14 1 Monotherapy 14 2 Combination Therapy HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied 16 2 Storage and Handling PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION WARNING RISK OF THYROID C CELL TUMORS In male and female rats dulaglutide causes a dose related and treatment duration dependent increase in the incidence of thyroid C cell tumors adenomas and carcinomas after lifetime expos
254. 75 mg and 1 5 mg respectively and glargine in this trial excluded the pre specified non inferiority margin of 0 4 17 Table 6 Results at Week 52 of TRULICITY Compared to Insulin Glargine Both as Add on to Metformin and Sulfonylurea 52 Week Primary Time Point TRULICITY TRULICITY Insulin Glargine 0 75 mg 1 5 mg Intent to Treat ITT Population N 272 273 262 HbA1c Mean Baseline 8 1 8 2 8 1 Change from baseline adjusted mean 0 8 1 1 0 6 Fasting Serum Glucose mg dL Mean Baseline 161 165 163 Change from baseline adjusted mean 16 27 32 Neel insulin glargine Adjusted 16 9 23 5 2 12 _ Body Weight kg Mean Baseline mean 86 4 85 2 87 6 Change from baseline adjusted mean 1 3 1 9 1 4 Dilicrence from insulin Adjusted mean 2 8 34 2 2 3 3 3 9 2 7 9596 CI Abbreviations HbA1c hemoglobin A1c ntent to treat population Last observation carried forward LOCF was used to impute missing data Data post onset of rescue therapy are treated as missing At Week 52 primary efficacy was missing for 17 13 and 12 of individuals randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and glargine respectively Least squares LS mean adjusted for baseline value and other stratification factors Subjects included in the analysis are a subset of the ITT population that had at least one post baseline assessment The primary analysis included 267 263 and 25
255. ADA 1 4 13 910 D12 CR AS 1 LF RH 1 lies 2 H 3 zu 2 El EZK II LS amp ay E LE LY2189265 1 9 dulaglutide FJLU Ver 4 BOTE 0 75 mg 19 LY2189265 dulaglutide 1 9 AN 1 9 1 1 9 2 INN 1 9 LY2189265 1 9 dulaglutide 19 19 1 JAN 0917 2 26 9 17 Dulaglutide Genetical Recombination 1 9 2
256. BEE ik 1 BRE 2 REPRIME BUE RARAS o RE 3 3 4 LY2189265 1 7 dulaglutide AT R 1 7 2 2 2 1 1
257. Cmax re Acetaminophen AUC No dose adjustment Cmax ET al S Warfarin AUC No dose adjustment Cmax oo R warfarin AUC No dose adjustment Cmax Sitagliptin AUC A No dose adjustment Cmax E T T 1 0 0 0 5 1 0 1 5 2 0 Ratio Relative to Reference Abbreviations AUC area under the time concentration curve Cl confidence interval Cnax maximum concentration PK pharmacokinetics Note Reference group is co administered medication given alone Figure 2 Impact of dulaglutide on the pharmacokinetics of co administered medications Potential for Co administered Drugs to Influence the Pharmacokinetics of Dulaglutide In a clinical pharmacology study the coadministration of a single dose of dulaglutide 1 5 mg with steady state sitagliptin 100 mg caused an increase in dulaglutide AUC and Cmax of approximately 38 and 27 which is not considered clinically relevant 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis and Impairment of Fertility A 2 year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0 05 0 5 1 5 and 5 0 mg kg 0 5 7 20 and 58 fold the MRHD of 1 5 mg once weekly based on AUC administered by subcutaneous injection twice weekly In rats dulaglutide caused a dose related and treatment duration dependent increase in the incidence of thyroid C cell tumors adenomas and or carcinomas compared to controls at 27 fold the MRHD based on AUC A st
258. Determination of Acetaminophen Hydrocodone and Hydromorphone in Human Plasma TAH HA Method Validation for the Quantitation of Atorvastatin o Hydroxyatorvastatin and p Hydroxyatorvastatin in Human Plasma by Turbo Ion Spray LC MS MS Method Validation for the Quantitation of Digoxin in Human Serum by Turbo Ion Spray LC MS MS Validation of a Method for the Determination of Ethinyl Estradiol and Norelgestromin in Human Plasma by HPLC with MS MS Detection Bioanalytical Method Validation Report Quantification of Lisinopril in Sodium Heparinized Human Plasma by LC MS MS Quantitation of Metformin in Human Plasma via HPLC with MS MS Detection 1T T et FY 16 LY2189265 dulaglutide Validation of a Method for the Determination of Metoprolol and Omeprazole in Human Plasma by HPLC with MS MS Detection Partial Method Validation for the Quantitation of Total R and S Warfarin in Human Plasma by Turbo Ion Spray LC MS MS Method Validation for the Quantitation of Moxifloxacin in Human Plasma by Turbo Ion Spray LC MS MS Validation of a Method for the Determination of Sitagliptin in Human Plasma by HPLC with MS MS Detection ab pared i 1 12 TED PIE Bii d Pl
259. Diabetes Obes Metab Pharmacokin et 2010 49 10 Diabetes Care 2009 Electrocardiol 1998 31 3 157 187 Curr Med Res Opin 2010 26 5 1013 1022 Diabetes Obes Metab 2012 14 10 910 917 LY2189265 dulaglutide Possible interethnic differences Shin JG et al in quinidine induced QT prolongation between healthy Caucasian and Korean subjects Increased risk of acute pancreatitis in patients with type 2 diabetes an observational study using a Japanese hospital database GLP 1 DPP 4 HE RIP TE ARO FE 2 D JDDM7 JA E Urushihara H et al Wap
260. Ecl FLA HIE su 5l 6 1 21 1 0 mg kg 1 7 fi ONES 0 05 mg kg 4 cec AED
261. GSFFLYSRLT VDKSRWQEGN 250 VFSCSVMHEA LHNHYTOKSL SLSLG 275 Disulfide bridges location Position des ponts disulfure Posiciones de los puentes disulfuro 55 55 58 58 90 150 90 150 196 254 196 254 N 1R 2R 1 2 3 dihydro 1 4 benzodioxin 6 yl 1 hydroxy 3 pyrrolidin 1 yl propan 2 yl octanamide N 1R 2R 1 2 3 dihydro 1 4 benzodioxin 6 yl 1 hydroxy 3 pyrrolidin 1 yl propan 2 yl octanamide N 1R 2R 1 2 3 dihidro 1 4 benzodioxin 6 il 1 hidroxi 3 pirrolidin 1 il propan 2 iljoctanamida Ca H 36N 204 L arginyl L phenylalanyl L valyl L prolyl L a aspartylglycyl L asparaginyl L arginyl L isoleucine human soluble Vascular Endothelial Growth Factor Receptor VEGFR2 169 177 peptide L arginyl L ph nylalanyl L valyl L prolyl L a aspartylglycyl L asparaginyl L arginyl L isoleucine R cepteur du Facteur de Croissance de l Endoth lium Vasculaire RFCEV2 soluble humain 169 177 peptide L arginil L fenilalanil L valil L prolil L a aspartilglicil L asparaginil L arginil L isoleucina receptor del factor de crecimiento endotelial vascular RFCEV2 soluble humano 169 177 p ptido Ca Hz N 16013 H Arg Phe Val Pro Asp Gly Asn Arg lle OH 9 57 LY2189265 1 10 EXE MSR OIE E AREE RD E Ld dulaglutide FJLU Ver 4 RhiEO0 75 mg 1 10 LY218
262. TRULICITY Compared to Sitagliptin used as Add On to Metformin 52 Week Primary Time Point TRULICITY TRULICITY Sitagliptin 0 75 mg 1 5 mg 100 mg Intent to Treat ITT Population N 281 279 273 HbA1c Mean Baseline 8 2 8 1 8 0 Change from baseline adjusted mean 0 9 1 1 0 4 Difference from sitagliptin 95 Cl 0 5 0 7 0 3 0 7 0 9 0 5 Percentage of patients HbA1c lt 7 0 49 59 33 Fasting Plasma Glucose mg dL Mean Baseline 174 173 171 Change from baseline adjusted mean 30 41 14 Difference from sitagliptin 9596 CI 15 22 9 27 33 20 Body Weight kg Mean Baseline mean 85 5 86 5 85 8 Change from baseline adjusted mean 2 7 3 1 1 5 Difference from sitagliptin 95 Cl 1 2 1 8 0 6 1 5 2 1 0 9 Abbreviations HbA1c hemoglobin A1c AINITT patients randomized after the dose finding portion of the study Last observation carried forward LOCF was used to impute missing data At Week 52 primary efficacy was missing for 15 19 and 20 of individuals randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and sitagliptin respectively b Least squares LS mean adjusted for baseline value and other stratification factors i Subjects included in the analysis are a subset of the ITT population that had at least one post baseline assessment The primary analysis included 276 277 and 270 individuals randomized to TRUL
263. an increased risk of hypoglycaemia The risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea or insulin see sections 4 2 and 4 8 Populations not studied There is limited experience in patients with congestive heart failure Sodium content This medicinal product contains less than 1 mmol sodium 23 mg per 1 5 mg dose i e essentially sodium free 4 5 Interaction with other medicinal products and other forms of interaction Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products Dulaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption For some prolonged release formulations an increased release due to an extended gastric residence time may slightly increase drug exposure Paracetamol Following a first dose of 1 and 3 mg dulaglutide paracetamol Cmax was reduced by 36 and 50 96 respectively and the median tmax occurred later 3 and 4 hours respectively After coadministration with up to 3 mg of dulaglutide at steady state there were no statistically significant differences on AUCo Cmax OT tmax Of paracetamol No dose adjustment of paracetamol is necessary when administered with dulaglutide Atorvastatin Coadministration of dulaglutide with atorvastatin decreased Cmax and AUC 0 up to 70 and 21 96 respectively for atorvasta
264. and 1 417 were treated with Trulicity 0 75 mg weekly In all studies dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin Alc HbAIc Monotherapy Dulaglutide was studied in a 52 week active controlled monotherapy study in comparison to metformin Trulicity 1 5 mg and 0 75 mg were superior to metformin 1500 2000 mg day in the reduction in HbAlc and a significantly greater proportion of patients reached an HbA Ic target of lt 7 0 and lt 6 5 with Trulicity 1 5 mg and Trulicity 0 75 mg compared to metformin at 26 weeks Table 2 Results of a 52 week active controlled monotherapy study with two doses of dulaglutide in comparison to metformin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 4 Hi once weekly n 269 7 63 0 78 61 5 46 0 1 01 2 29 Dulaglutide 0 75 mg once weekly n 270 7 58 0 71 62 6 40 0 1 46 1 36 Metformin 1500 2000 mg day 7 60 0 56 53 6 29 8 1 34 2 22 n 208 S2 Weeks Dulaglutide 1 5 mg 4 HH once weekly n 269 7 63 0 70 60 0 42 3 1 30 1 93 Dulaglutide 0 75 mg once weekly n 270 7 58 0 55 53 2 34 7 1 00 1 09 Metformin 1500 2000 mg day 7 60 0 51 48 3 28 3 1 15 2 20 n 268 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority
265. both in combination with prandial insulin lispro three times daily with or without metformin At 26 weeks both Trulicity 1 5 mg and 0 75mg were superior to insulin glargine in lowering of HbAlc and this effect was sustained at 52 weeks A greater percentage of patients achieved HbAlc targets of 7 0 96 or 6 5 96 at 26 weeks and 7 0 96 at 52 weeks than with insulin glargine 42 Table 7 Results of a 92 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 7o mmol L kg 26 weeks Dulaglutide 1 5 mg HE 4 once weekly n 295 8 46 1 64 67 6 48 0 0 27 0 87 Dulaglutide 0 75 mg tt He at once weekly n 293 8 40 1 59 69 0 43 0 0 22 0 18 Insulin glargine once daily n 296 8 53 1 41 56 8 37 5 1 58 2 33 52 weeks Dulaglutide 1 5 mg tt Ht onee weekly n 295 8 46 1 48 58 5 36 7 0 08 0 35 Dulaglutide 0 75 mg HB aH once weekly 1293 8 40 1 42 56 3 34 7 0 41 0 86 Insulin glargine ghee daily n 296 8 53 23 49 3 30 4 1 01 2 89 Tt multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilizing an algo
266. deficits in female offspring at exposures that were 16 fold higher than those proposed clinically 6 PHARMACEUTICAL PARTICULARS 6 1 List of excipients Sodium citrate Citric acid anhydrous Mannitol Polysorbate 80 Water for injections 6 2 Incompatibilities In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products 45 6 3 Shelf life 2 years 6 4 Special precautions for storage Store in a refrigerator 2 C 8 C Do not freeze Store in original package in order to protect from light In use Trulicity may be stored unrefrigerated for up to 14 days at a temperature not above 30 C 6 5 Nature and contents of container Glass syringe type I Each pre filled syringe contains 0 5 ml of solution Packs of 4 pre filled syringes and multipack of 12 3 packs of 4 pre filled syringes Not all pack sizes may be marketed 6 6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements Instructions for use The pre filled syringe is for single use only The instructions for using the syringe included with the package leaflet must be followed carefully Trulicity should not be used if particles appear or if the solution is cloudy and or coloured Trulicity that has been frozen must not be used 7 MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B V Gr
267. dulaglutide were observed The safety and efficacy of dulaglutide was also investigated in an active controlled study liraglutide 1 8 mg daily of 26 weeks duration both in combination with metformin Treatment with Trulicity 1 5 mg resulted in similar lowering of HbAlc and patients achieving HbAlc targets of lt 7 0 and lt 6 5 compared to liraglutide 40 Table 4 Results of a 26 week active controlled study of one dose of dulaglutide in comparison to liraglutide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 1 42 once weekly n 299 8 06 68 3 54 6 1 93 2 90 Liraglutide 1 8 mg 1 36 daily n 300 8 05 67 9 50 9 1 90 3 61 E for HbAlc p lt 0 05 dulaglutide treatment group compared to liraglutide were up titrated to 1 2 mg day and then at Week 2 to 1 8 mg day The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg was 0 12 episodes patient year and with liraglutide was 0 29 episodes patient year No cases of severe hypoglycaemia were observed Combination therapy with metformin and sulphonylurea In an active controlled study of 78 weeks duration dulaglutide was compared to insulin glargine both on a background of metformin and a sulphonylurea At 52 weeks Trulicity 1 5 mg demonstrated superior lowering in HbAlc to insulin gla
268. existing therapy of a sulphonylurea or prandial insulin a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia see sections 4 4 and 4 8 The use of Trulicity does not require blood glucose self monitoring Self monitoring may be necessary to adjust the dose of sulphonylurea or prandial insulin Elderly patients gt 65 years old No dose adjustment is required based on age see section 5 2 However the therapeutic experience in patients gt 75 years is very limited see section 5 1 and in these patients 0 75 mg once weekly can be considered as a starting dose Patients with renal impairment No dosage adjustment is required in patients with mild or moderate renal impairment There is very limited experience in patients with severe renal impairment eGFR by CKD EPI lt 30 ml min 1 73 m or end stage renal disease therefore Trulicity is not recommended in this population see section 5 2 Patients with hepatic impairment No dosage adjustment is required in patients with hepatic impairment Paediatric population The safety and efficacy of dulaglutide in children aged less than 18 years have not yet been established No data are available Method of administration Trulicity is to be injected subcutaneously in the abdomen thigh or upper arm It should not be administered intravenously or intramuscularly The dose can be administered at any time of day with or without meals
269. hypoglycemia occurred in 0 and 0 7 of patients when TRULICITY 0 75 mg and 1 5 mg respectively was co administered with a sulfonylurea Documented symptomatic hypoglycemia occurred in 85 and 80 of patients when TRULICITY 0 75 mg and 1 5 mg respectively was co administered with prandial insulin Severe hypoglycemia occurred in 2 4 and 3 4 of patients when TRULICITY 0 75 mg and 1 5 mg respectively was co administered with prandial insulin Heart Rate Increase and Tachycardia Related Adverse Reactions TRULICITY 0 75 mg and 1 5 mg resulted in a mean increase in heart rate HR of 2 4 beats per minute bpm The long term clinical effects of the increase in HR have not been established see Warnings and Precautions 5 7 Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY Sinus tachycardia was reported in 3 0 2 8 and 5 6 of patient treated with placebo TRULICITY 0 75 mg and TRULICITY 1 5 mg respectively Persistence of sinus tachycardia reported at more than 2 visits was reported in 0 296 0 496 and 1 6 of patients treated with placebo TRULICITY 0 75 mg and TRULICITY 1 5 mg respectively Episodes of sinus tachycardia associated with a concomitant increase from baseline in heart rate of 215 beats per minute were reported in 0 7 1 3 and 2 2 of patient treated with placebo TRULICITY 0 75 mg and TRULICITY 1 5 mg respectively Immunogenicity Across four Phase 2 and five Phase 3
270. insulin glargine assessed for HbAlc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 1 67 1 67 and 3 02 episodes patient year respectively Two cases of severe hypoglycaemia were observed with Trulicity 1 5mg and two cases of severe hypoglycaemia were observed with insulin glargine 41 Combination therapy with metformin and pioglitazone In a placebo and active exenatide twice daily controlled study both in combination with metformin and pioglitazone Trulicity 1 5 mg and 0 75 mg demonstrated superiority for HbAlc reduction in comparison to placebo and exenatide accompanied by a significantly a greater percentage of patients achieving HbAlc targets of lt 7 0 or lt 6 5 Table 6 Results of a 52 week active controlled study with two doses of dulagltuide in comparison to exenatide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg tt goo goo E E dk once weekly i 279 8 10 1 51 t 78 2 62 7 2 36 1 30 Dulaglutide 0 75 mg hA nd 0 HE HE once weekly n 280 8 05 1 301 65 8 53 2 1 90 0 20 Placeb
271. insulin with or without metformin In this study patients on 1 or 2 insulin injections per day prior to study entry discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily both in combination with prandial insulin lispro three times daily with or without metformin At 26 weeks both Trulicity 1 5 mg and 0 75mg were superior to insulin glargine in lowering of HbAlc and this effect was sustained at 52 weeks A greater percentage of patients achieved HbAlc targets of 7 0 96 or 6 5 96 at 26 weeks and 7 0 96 at 52 weeks than with insulin glargine 27 Table 7 Results of a 92 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 7o mmol L kg 26 weeks Dulaglutide 1 5 mg HE 4 once weekly n 295 8 46 1 64 67 6 48 0 0 27 0 87 Dulaglutide 0 75 mg tt He at once weekly n 293 8 40 1 59 69 0 43 0 0 22 0 18 Insulin glargine once daily n 296 8 53 1 41 56 8 37 5 1 58 2 33 52 weeks Dulaglutide 1 5 mg tt Ht onee weekly n 295 8 46 1 48 58 5 36 7 0 08 0 35 Dulaglutide 0 75 mg HB aH once weekly 1293 8 40 1 42 56 3 34 7 0 41 0 86 Insulin glargine ghee daily n 296 8 53 23 49 3 30 4 1 01 2 89 Tt multiplicity adjusted 1 sid
272. medicinal products including insulin when these together with diet and exercise do not provide adequate glycaemic control see section 5 1 for data with respect to different combinations 4 2 Posology and method of administration Posology Monotherapy The recommended dose is 0 75 mg once weekly Add on therapy The recommended dose is 1 5 mg once weekly For potentially vulnerable populations such as patients gt 75 years 0 75 mg once weekly can be considered as a starting dose When Trulicity is added to existing metformin and or pioglitazone therapy the current dose of metformin and or pioglitazone can be continued When it is added to existing therapy of a sulphonylurea or prandial insulin a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia see sections 4 4 and 4 8 47 The use of Trulicity does not require blood glucose self monitoring Self monitoring may be necessary to adjust the dose of sulphonylurea or prandial insulin Elderly patients gt 65 years old No dose adjustment is required based on age see section 5 2 However the therapeutic experience in patients gt 75 years is very limited see section 5 1 and in these patients 0 75 mg once weekly can be considered as a starting dose Patients with renal impairment No dosage adjustment is required in patients with mild or moderate renal impairment There is very limited experience in patients with seve
273. multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to metformin assessed for HbAlc only p 0 05 p 0 001 dulaglutide treatment group compared to metformin The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and metformin were 0 62 0 15 and 0 09 episodes patient year respectively No cases of severe hypoglycaemia were observed Combination therapy with metformin The safety and efficacy of dulaglutide was investigated in a placebo and active controlled sitagliptin 100 mg daily study of 104 weeks duration all in combination with metformin Treatment with Trulicity 1 5 mg and 0 75 mg resulted in a superior reduction in HbA1c compared to sitagliptin at 54 52 weeks accompanied by a significantly greater proportion of patients achieving HbAlc targets of 7 0 and lt 6 5 These effects were sustained to the end of the study 104 weeks Table 3 Results of a 104 week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 S mmol L kg 26 weeks e 8 12 122 69 9 geget 53gee9 3 get once weekly n 304 i e a Lol 55 2 apost popat 63e once weekly n 302 i i 3 Placebo n 177 8 10 0 03 21 0 12 5 0 49 1 47 Sitagliptin 100 m
274. number of patients developing dulaglutide anti drug antibodies was low examination of the phase III data revealed no clear impact of dulaglutide anti drug antibodies on changes in HbAlc Hypersensitivity In the phase II and phase III clinical studies systemic hypersensitivity events e g urticaria edema were reported in 0 5 of patients receiving dulaglutide None of the patients with systemic hypersensitivity developed dulaglutide anti drug antibodies 22 Injection site reactions Injection site adverse events were reported in 1 9 of patients receiving dulaglutide Potentially immune mediated injection site adverse events e g rash erythema were reported in 0 7 of patients and were usually mild Discontinuation due to an adverse event In studies of 26 weeks duration the incidence of discontinuation due to adverse events was 2 6 0 75 mg and 6 1 1 5 mg for dulaglutide versus 3 7 for placebo Through the full study duration up to 104 weeks the incidence of discontinuation due to adverse events was 5 1 0 73 mg and 8 4 1 5 mg for dulaglutide The most frequent adverse reactions leading to discontinuation for 0 75 mg and 1 5 mg dulaglutide respectively were nausea 1 0 1 9 96 diarrhoea 0 5 0 6 and vomiting 0 4 0 6 96 and were generally reported within the first 4 6 weeks Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product i
275. or elsewhere in the prescribing information Risk of Thyroid C cell Tumors see Warnings and Precautions 5 1 Pancreatitis see Warnings and Precautions 5 2 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin see Warnings and Precautions 5 3 Hypersensitivity reactions see Warnings and Precautions 5 4 Renal impairment see Warnings and Precautions 5 5 Severe Gastrointestinal Disease see Warnings and Precautions 5 6 6 1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice Pool of Placebo controlled Trials The data in Table 1 are derived from the placebo controlled trials see Clinical Studies 14 These data reflect exposure of 1670 patients to TRULICITY and a mean duration of exposure to TRULICITY of 23 8 weeks Across the treatment arms the mean age of patients was 56 years 1 were 75 years or older and 53 were male The population in these studies was 6996 White 796 Black or African American 1396 Asian 3096 were of Hispanic or Latino ethnicity At baseline the population had diabetes for an average of 8 0 years and had a mean HbA1c of 8 0 At baseline 2 596 of the population reported retinopathy Baseline estimated renal function was normal or mildly im
276. regularly scheduled day In each case patients can then resume their regular once weekly dosing schedule The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days 72 hours before 4 3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6 1 4 4 Special warnings and precautions for use Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis Use of GLP 1 receptor agonists may be associated with gastrointestinal adverse reactions This should be considered when treating patients with impaired renal function since these events i e nausea vomiting and or diarrhoea may cause dehydration which could cause a deterioration of renal function Dulaglutide has not been studied in patients with severe gastrointestinal disease including severe gastroparesis and is therefore not recommended in these patients Acute pancreatitis Use of GLP 1 receptor agonists has been associated with a risk of developing acute pancreatitis In clinical trials acute pancreatitis has been reported in association with dulaglutide see section 4 8 Patients should be informed of the characteristic symptoms of acute pancreatitis If pancreatitis is suspected dulaglutide should be discontinued If pancreatitis is confirmed dulaglutide should not be 18 restarted In the absence of other
277. see section 6 1 3 PHARMACEUTICAL FORM Solution for injection Injection Clear colourless solution 4 CLINICAL PARTICULARS 4 1 Therapeutic indications Trulicity is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications Add on therapy In combination with other glucose lowering medicinal products including insulin when these together with diet and exercise do not provide adequate glycaemic control see section 5 1 for data with respect to different combinations 4 2 Posology and method of administration Posology Monotherapy The recommended dose is 0 75 mg once weekly Add on therapy The recommended dose is 1 5 mg once weekly For potentially vulnerable populations such as patients 7 75 years 0 75 mg once weekly can be considered as a starting dose When Trulicity is added to existing metformin and or pioglitazone therapy the current dose of metformin and or pioglitazone can be continued When it is added to existing therapy of a sulphonylurea or prandial insulin a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia see sections 4 4 and 4 8 17 The use of Trulicity does not require blood glucose self monitoring Self monitoring may be necess
278. severe renal impairment or end stage renal disease Patients with hepatic impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study where subjects with hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30 to 33 for mean Cmax and AUC respectively compared to healthy controls There was a general increase in tmax of dulaglutide with increased hepatic impairment However no trend in dulaglutide exposure was observed relative to the degree of hepatic impairment These effects were not considered to be clinically relevant Paediatric population Studies characterising the pharmacokinetics of dulaglutide in paediatric patients have not been performed 5 3 Preclinical safety data Non clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat dose toxicity In a 6 month carcinogenicity study in transgenic mice there was no tumorigenic response In a 2 year carcinogenicity study in rats at 7 7 times the human clinical exposure following 1 5 mg dulaglutide per week dulaglutide caused statistically significant dose related increases in the incidence of thyroid C cell tumours adenomas and carcinomas combined The clinical relevance of these findings is currently unknown During the fertility studies a reduction in the number of corpora lutea and prolonged oestrous cycle were observed at dose levels that wer
279. the duration of studies from baseline to final time point 0 35 kg to 2 90 kg Changes in body weight with Trulicity 0 75 mg ranged from 0 86 kg to 2 63 kg Reduction in body weight was observed in patients treated with dulaglutide irrespective of nausea though the reduction was numerically larger in the group with nausea Patient reported outcomes Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily In addition there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily 28 Blood pressure The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes Treatment with dulglutide provided reductions in systolic blood pressure SBP 2 8 mmHg difference compared to placebo at 16 weeks There was no difference in diastolic blood pressure DBP Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study Cardiovascular Evaluation In a meta analysis of phase II and III studies a total of 51 patients dulaglutide 26 N 3 885 all comparators 25 N 2 125 experienced at least one cardiovascular CV event death due to CV causes nonfatal MI nonfatal stroke or hospitalisation for unstable angina The results showed that there was no increase in CV risk with dulaglutide compared with control therap
280. twice daily were 0 19 0 14 and 0 75 episodes patient year respectively No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily Combination therapy with prandial insulin with or without metformin In this study patients on 1 or 2 insulin injections per day prior to study entry discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily both in combination with prandial insulin lispro three times daily with or without metformin At 26 weeks both Trulicity 1 5 mg and 0 75mg were superior to insulin glargine in lowering of HbAlc and this effect was sustained at 52 weeks A greater percentage of patients achieved HbAlc targets of 7 0 96 or 6 5 96 at 26 weeks and 7 0 96 at 52 weeks than with insulin glargine 12 Table 7 Results of a 92 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 7o mmol L kg 26 weeks Dulaglutide 1 5 mg HE 4 once weekly n 295 8 46 1 64 67 6 48 0 0 27 0 87 Dulaglutide 0 75 mg tt He at once weekly n 293 8 40 1 59 69 0 43 0 0 22 0 18 Insulin glargine once daily n 296 8 53 1 41 56 8 37 5 1 58 2 33 52 weeks Dulaglutide 1 5 mg tt Ht one
281. was observed relative to the degree of hepatic impairment These effects were not considered to be clinically relevant Paediatric population Studies characterising the pharmacokinetics of dulaglutide in paediatric patients have not been performed 5 3 Preclinical safety data Non clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat dose toxicity In a 6 month carcinogenicity study in transgenic mice there was no tumorigenic response In a 2 year carcinogenicity study in rats at 7 7 times the human clinical exposure following 1 5 mg dulaglutide per week dulaglutide caused statistically significant dose related increases in the incidence of thyroid C cell tumours adenomas and carcinomas combined The clinical relevance of these findings is currently unknown During the fertility studies a reduction in the number of corpora lutea and prolonged oestrous cycle were observed at dose levels that were associated with decreased food intake and body weight gain in maternal animals however no effects on indices of fertility and conception or embryonic development were observed In reproductive toxicology studies skeletal effects and a reduction in foetal growth were observed in the rat and rabbit at exposures of dulaglutide 11 to 44 fold higher than those proposed clinically but no foetal malformations were observed Treatment of rats throughout pregnancy and lactation produced memory
282. were achieved between 2 and 4 weeks following once weekly administration Site of subcutaneous administration abdomen upper arm and thigh had no statistically significant effect on the exposure to dulaglutide Absorption The mean absolute bioavailability of dulaglutide following subcutaneous administration of single 0 75 mg and 1 5 mg doses was 65 and 47 respectively Distribution The mean volumes of distribution after subcutaneous administration of TRULICITY 0 75 mg and 1 5 mg to steady state were approximately 19 2 L range 14 3 to 26 4 L and 17 4 L range 9 3 to 33 L respectively Metabolism Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways Elimination The mean apparent clearance at steady state of dulaglutide is approximately 0 111 L h for the 0 75 mg dose and 0 107 L h for the 1 5 mg dose The elimination half life of dulaglutide for both doses is approximately 5 days Specific Populations No dose adjustment of dulaglutide is needed based on age gender race ethnicity body weight or renal or hepatic impairment The effects of intrinsic factors on the PK of dulaglutide are shown in Figure 1 Intrinsic Factor Weight 70 kg Weight 120 kg Age gt 65 years old Age gt 75 years old PK Ratio and 90 CI Recommendation No dose adjustment No dose adjustment No dose adjustment No dose adjustment Female No dose adjustment Hispanic No
283. 0 LA LY2189265 1 7 dulaglutide p hi R 17 1 2 d HERS nee
284. 1 57 0 11 SU 85 5 112 131 Bl 83 6 51 61 fil a GI 70 8 46 65 ill TZD 80 3 53 66 an 73 2 52 71 Bil SOC 1 5 2 6 1 4 1 13 20 m1 GTA RR ie N 000 EE 0077 e NN GEN TM NES Y IANS 2 gt 5 ce o ctio AM CN loa n
285. 104 week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 S mmol L kg 26 weeks e 8 12 122 69 9 geget 53gee9 3 get once weekly n 304 i e a Lol 55 2 apost popat 63e once weekly n 302 i i 3 Placebo n 177 8 10 0 03 21 0 12 5 0 49 1 47 Sitagliptin 100 mg once daily 8 09 0 61 37 8 21 8 0 97 1 46 n 315 52 weeks Dulaglutide 1 5 mg HH HH j iH E at ones weekly 1304 8 12 1 10 57 6 41 7 2 38 3 03 Dulaglutide 0 75 mg HH Hi T iH k se obte wecllyi a 302 8 19 0 87 48 8 29 0 1 63 2 60 Sitagliptin 100 mg E E oce duly GES 8 09 0 39 33 0 19 2 0 90 1 53 104 weeks Dulaglutide 1 5 mg m Hi HE 4 once weekly n 304 8 12 0 99 54 3 39 1 1 99 2 88 Dulaglutide 0 75 mg E aH He Hi once weekly n 302 8 19 0 71 44 8 242 1 39 2 39 Sitagliptin 100 mg price dal i 8 09 0 32 31 1 14 1 0 47 1 75 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide compared to sitagliptin assessed only for HbAlc at 52 and 104 weeks multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 001 dulaglutide treatment group compared to placebo p lt 0 001 dulaglutide tr
286. 125 experienced at least one cardiovascular CV event death due to CV causes nonfatal MI nonfatal stroke or hospitalisation for unstable angina The results showed that there was no increase in CV risk with dulaglutide compared with control therapies HR 0 57 CI 0 30 1 10 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with dulaglutide in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus see section 4 2 for information on paediatric use 5 2 Pharmacokinetic properties Absorption Following subcutaneous administration to patients with type 2 diabetes dulaglutide reaches peak plasma concentrations in 48 hours The mean peak Cmax and total AUC exposures were approximately 114 ng ml and 14 000 ngh ml respectively after multiple subcutaneous 1 5 mg doses of dulaglutide in patients with type 2 diabetes Steady state plasma concentrations were achieved between 2 to 4 weeks of once weekly administration of dulaglutide 1 5 mg Exposures after subcutaneous administration of single dulaglutide 1 5 mg doses in the abdomen thigh or upper arm were comparable The mean absolute bioavailability of dulaglutide following single dose subcutaneous administration of single 1 5 mg and 0 75 mg doses was 47 96 and 65 respectively Distribution The mean volume of distribution after subcutaneous administration of dulaglutide 0 75 mg
287. 2 1 12 0 88 0 02 1 02 1 22 0 80 0 98 0 05 1 03 4 12 11 1 15 0 99 0 02 1 05 1 26 0 89 1 10 1 03 1 02 1 2121 0 96 0 78 0 50 ee 0 88 1 03 _ 0 67 0 92 0 00 1 50 0 25 mg 2 21 20 0 96 0 83 0 50 0 89 1 04 0 71 0 98 0 00 0 50 27 27 0 79 0 30 40 mg 0 75 0 82 0 25 0 36 T om 200 0 65 0 85 0 00 2 00 li 087 RIA 030 0 90 1 09 0 79 0 97 0 00 2 00 1 28 29 1 01 0 89 0 50 Jd losa 0 86 1 17 _ 0 73 1 08 0 00 1 02 100 mg 2 2827 0 93 0 79 1 09 0 63 0 94 0 00 1 00 1 2 48 max 1 1 LY2189265 dulaglutide N AUC AUC 0 24hr AUC oo tmax 1 2 pol NE 0 25 mg 3
288. 22 AUCIR increased by 2 which is unlikely to be clinically significant and there was no effect on maximum international normalised ratio response INR max The time of international normalised ratio response tINR max was delayed by 6 hours 34 consistent with delays in tmax of approximately 4 and 6 hours for S and R warfarin respectively These changes are not clinically relevant No dose adjustment for warfarin is necessary when given together with dulaglutide Oral contraceptives Coadministration of dulaglutide with an oral contraceptive norgestimate 0 18 mg ethinyl estradiol 0 025 mg did not affect the overall exposure to norelgestromin and ethinyl estradiol Statistically significant reductions in Cmax of 26 and 13 and delays in tmax of 2 and 0 30 hours were observed for norelgestromin and ethinyl estradiol respectively These observations are not clinically relevant No dose adjustment for oral contraceptives is required when given together with dulaglutide Metformin Following coadministration of multiple dose dulaglutide with steady state metformin immediate release formula IR metformin AUC increased up to 15 and Cmax decreased up to 12 96 respectively with no changes in tmax These changes are consistent with the gastric emptying delay of dulaglutide and within the pharmacokinetic variability of metformin and thus are not clinically relevant No dose adjustment for metformin IR is recommended when given with
289. 3E SE 26 0 75 mg 56 1 157 280 Bil 33 7 39 70 55 5 76 137 Bil THV Fa 0 75 mg 0 75 mg 0 75 mg 20 4 57 280 8 6 6 70 Bil 27 7 38 137 Bil 0 75 mg 0 75 mg EHC 5 0 75 mg
290. 4 Insulin glargine once daily 1 262 8 10 0 59 30 5 16 6 1 58 1 28 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAlc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 1 67 1 67 and 3 02 episodes patient year respectively Two cases of severe hypoglycaemia were observed with Trulicity 1 5mg and two cases of severe hypoglycaemia were observed with insulin glargine 26 Combination therapy with metformin and pioglitazone In a placebo and active exenatide twice daily controlled study both in combination with metformin and pioglitazone Trulicity 1 5 mg and 0 75 mg demonstrated superiority for HbAlc reduction in comparison to placebo and exenatide accompanied by a significantly a greater percentage of patients achieving HbAlc targets of lt 7 0 or lt 6 5 Table 6 Results of a 52 week active controlled study with two doses of dulagltuide in comparison to exenatide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0
291. 4 3 56 4 3 57 4 3 58 4 3 59 4 3 60 4 3 61 Functional importance of GLP 1 receptor species and expression levels in cell lines Neonatal Fc receptor and IgG based therapeutics Systemic administration of the long acting GLP 1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats Antibody pharmacokinetics and pharmacodynamics Correlation between gender and spontaneous C cell tumors in the thyroid gland of the Wistar rat de HA EH L1 MIN MIN Ll M Zander et al NI oM NR E L Knudsen et al M RN RE P J Larsen et al m A E E MO Lacave et al 14 1 12 Cell Immunol 2000 200 16 26 Diabetes Res Clin Pract 2006 73 107 110 Diabetes 1999 48 2270 2276 Pancreas 2012 41 1235 1240 Poster presentation at the 52nd Annual Meeting of the Society of Toxicology March 10 14 2013 San Antonio TX USA Physiol Rev 2007 87 1409 1439 Regul Pept 2012 175 21 29 MAbs 2011 3 422 430 Diabetes 2001 50 2530 2539 J Pharm Sci 2004 93 2645 2668 Cell Tissue Res 1999 297 451 457 LY2189265 1 12 dulaglutide 5 5 5 2 _
292. 5 mg 41 0 More patients receiving TRULICITY 0 75 mg 1 3 and TRULICITY 1 5 mg 3 5 discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo 0 2 Investigators graded the severity of gastrointestinal adverse reactions occurring on 0 75 mg and 1 5 mg of TRULICITY as mild in 58 and 48 of cases respectively moderate in 35 and 42 of cases respectively or severe in 7 and 11 of cases respectively In addition to the reactions in Table 1 the following adverse reactions were reported more frequently in TRULICITY treated patients than placebo frequencies listed respectively as placebo 0 75 mg 1 5 mg constipation 0 7 3 9 3 7 flatulence 1 4 1 4 3 4 abdominal distension 0 7 2 9 2 3 gastroesophageal reflux disease 0 5 1 7 2 0 and eructation 0 2 0 6 1 6 Pool of Placebo and Active Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo and active controlled trials evaluating the use of TRULICITY as monotherapy and add on therapy to oral medications or insulin see Clinical Studies 14 In this pool a total of 3342 patients with type 2 diabetes were treated with TRULICITY for a mean duration of 52 weeks The mean age of patients was 56 years 2 were 75 years or older and 51 were male The population in these studies was 71 White 7 Black or Africa
293. 7 1 33 Insulin glargine once daily n 262 8 10 0 63 30 9 13 5 1 76 1 44 78 weeks Dulaglutide 1 5 mg aH once weekly n 273 8 18 0 90 49 0 28 1 1 10 1 96 Dulaglutide 0 75 mg HH se once weekly n 272 8 13 0 62 34 1 22 1 0 58 1 54 Insulin glargine once daily 1 262 8 10 0 59 30 5 16 6 1 58 1 28 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAlc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 1 67 1 67 and 3 02 episodes patient year respectively Two cases of severe hypoglycaemia were observed with Trulicity 1 5mg and two cases of severe hypoglycaemia were observed with insulin glargine 11 Combination therapy with metformin and pioglitazone In a placebo and active exenatide twice daily controlled study both in combination with metformin and pioglitazone Trulicity 1 5 mg and 0 75 mg demonstrated superiority for HbAlc reduction in comparison to placebo and exenatide accompanied by a significantly a greater percentage of patients achieving HbAlc targets of lt 7 0 or lt 6 5 Ta
294. 75 mg and 1 5 mg once weekly resulted in a reduction in HbA1c from baseline The difference in observed effect size between TRULICITY 0 75 mg and 1 5 mg respectively and glargine in this trial excluded the pre specified non inferiority margin of 0 496 Table 7 Results at Week 26 of TRULICITY Compared to Insulin Glargine Both in Combination with Insulin Lispro 26 Week Primary Time Point TRULICITY TRULICITY 0 75 mg 1 5 mg Insulin Glargine Intent to Treat ITT Population N 293 295 296 HbA1c Mean Baseline 8 4 8 5 8 5 Change from baseline adjusted mean 1 6 1 6 1 4 18 Fasting Serum Glucose mg dL Mean Baseline 150 157 154 Change from baseline adjusted mean 4 5 28 Difference from insulin glargine Adjusted mean 95 ch 3 AA 2h 19 92 Body Weight kg Mean Baseline mean 91 7 91 0 90 8 Change from baseline adjusted mean 0 2 0 9 2 3 Difference from insulin glargine 2 2 2 8 1 5 3 2 3 8 2 6 Adjusted mean 95 CI Intent to treat population Last observation carried forward LOCF was used to impute missing data Data post onset of rescue therapy are treated as missing At Week 26 primary efficacy was missing for 14 15 and 14 of individuals randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and glargine respectively Least squares LS mean adjusted for baseline value and other stratification factors Subjects included
295. 8 0 11 ff 1 57 0 11 ee nes iX HE 26 LOCF SU o GI TZD 83 6 51 61 70 8 80 3 53 66 73 2 52 71 23 0 14 61 22 8 90 394 v Lb LORBEK 3X8 SOC E Fed HbAlc fi 23 Ta E M OE F p ms HF DX amp DE Nr FA x 1 8 3 1 8 3 1 1 LEA ar R E 32 3 2
296. 9 individuals randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and glargine respectively 0 Add on to Prandial Insulin with or without Metformin In this 52 week 26 week primary endpoint open label comparator study double blind with respect to TRULICITY dose assignment 884 patients on 1 or 2 insulin injections per day were enrolled Randomization occurred after a 9 week lead in period during the initial 2 weeks of the lead in period patients continued their pre study insulin regimen but could be initiated and or up titrated on metformin based on investigator discretion this was followed by a 7 week glycemic stabilization period prior to randomization At randomization patients discontinued their pre study insulin regimen and were randomized to TRULICITY 0 75 mg once weekly TRULICITY 1 5 mg once weekly or insulin glargine once daily all in combination with prandial insulin lispro 3 times daily with or without metformin Insulin lispro was titrated in each arm based on preprandial and bedtime glucose and insulin glargine was titrated to a fasting plasma glucose goal of 100 mg dL Only 3696 of patients randomized to glargine were titrated to the fasting glucose goal at the 26 week primary timepoint Patients had a mean age of 59 years mean duration of type 2 diabetes of 13 years 5496 were male race White Black and Asian were 79 10 and 4 respectively and 33 of the study population were in the US Treatment with TRULICITY 0
297. 9265 110 dulaglutide 1 10 ER D OD E RIO Lesser ttes 1 LY2189265 110 dulaglutide 140 R 1 10 1 A DE 2 amp GEGTFTSDV SSYLEEQAAK EFIAWLVKGG GGGGGSGGGG SGGGGSAESK YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MTSRTPEVTC VVVDVSQEDP EVOFNWYVDG VEVHNAKTKP REEOFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG OPREPOVYTL PPSQEEMTKN QVSLTCLVKG dem FYPSDIAVEW ESNGOPENNY KTTPPVLDSD GSFFLYSRLT VDKSRWOEGN VFSCSVMHEA LHNHYTOKSL SLSLG N126 C55 C55 C58 C58 Z ETIR 1 SB 0 75 mg 1 y BLU gt 0 75 mg 1 0 75 mg
298. COLOGICAL PROPERTIES 5 1 Pharmacodynamic properties Pharmacotherapeutic group not yet assigned ATC code not yet assigned Mechanism of action Dulaglutide is a long acting glucagon like peptide 1 GLP 1 receptor agonist The molecule consists of 2 identical disulfide linked chains each containing a modified human GLP 1 analogue sequence covalently linked to a modified human immunoglobulin G4 IgG4 heavy chain fragment Fc by a small peptide linker The GLP 1 analog portion of dulaglutide is approximately 90 homologous to native human GLP 1 7 37 Native GLP 1 has a half life of 1 5 2 minutes due to degradation by DPP 4 and renal clearance In contrast to native GLP 1 dulaglutide is resistant to degradation by DPP 4 and has a large size that slows absorption and reduces renal clearance These engineering features result in a soluble formulation and a prolonged half life of 4 7 days which makes it suitable for once weekly subcutaneous administration In addition the dulaglutide molecule was engineered to prevent the Fcy receptor dependent immune response and to reduce its immunogenic potential Dulaglutide exhibits several antihyperglycaemic actions of GLP 1 In the presence of elevated glucose concentrations dulaglutide increases intracellular cyclic AMP cAMP in pancreatic beta cells leading to insulin release Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes Lowe
299. E EMTKNQVSLT CLVKGFYPSD TAVEWESNGO PENNYKTTPP 400 VLDSDGSFFL YSKLTVDKSR WQOGNVFSCS VMHEALHNHY TOKSLSLSPG 450 K 451 Light chain Chaine l g re Cadena ligera SELTODPAVS VALGOTVRIT CSGDSLRSYY ASWYOOKPGO APVLVIYGAN 50 NRPSGIPDRF SGSSSGNTAS LTITGAQAED EADYYCNSAD SSGNHVVFGG 100 GTKLTVLGQP KAAPSVTLFP PSSEELOANK ATLVCLISDF YPGAVTVAWK 150 ADSSPVKAGV ETTTPSKOSN NKYAASSYLS LTPEOWKSHK SYSCOVTHEG 200 STVEKTVAPT ECS 213 Disulfide bridges location Position des ponts disulfure Posiciones de los puentes disulfuro Intra H 22 96 148 204 265 325 371 429 22 96 148 204 265 325 371 429 Intra L 21 86 135 194 21 86 135 194 Inter H L 224 212 224 212 Inter H H 230 230 233 233 N glycosylation sites Sites de N glycosylation Posiciones de N glicosilacion 301 301 dulaglutidum dulaglutide glucagon like peptide 1 immunoglobulin G4 fusion protein 2 glycyl 16 L glutamyl 30 glycyl human glucagon like peptide 1 7 37 peptide 8 A gt G 22 G gt E 36 R gt G GLP 1 7 37 fusion protein with tris tetraglycyl L seryl L alanine linker fusion protein with des 276 lysine 57 L proline 63 L alanine 64 L alanine human immunoglobulin G4 Fc region 10 S gt P H 4 F gt A 5 L gt A CH2 107 K gt CH3 of IGHG4 01 dimer 55 55 58 58 bisdisulfide dulaglutide prot ine de fusion entre le peptide 1 semblable au glucagon et l i mmunoglobuline G4 2 glycyl 16 L glutamyl 30 glycyl peptide 1 semblable au glucagon humain 7 37 pep
300. Federation IDF 2013 24 950 1100 2013 21 1 90 2 2011 2 B 2
301. GBCK T HSA 9X MC GBDN T EOS AUR ES 9X MC GBCF T ERRA 9X MC GBDA T ERASE ERRA EY 9X MC GBDB T 9X MC GBDC T I FS nA EERE SLE Bh ERRA 9X MC GBDD T EAS TUB SES H9X JE GBDQ 27 1 12 E 2 HAR d SSE 2 HAR SSE HAR d HAR SSE 4 HAR BSE HAR 2 HAR 21
302. HOU 0 3m90 000 HHHHHHHHHHHH LY2189265 1 5 dulaglutide FJLU Ver 4 BOTE 0 75 mg 15 LY2189265 1 5 dulaglutide 1 5 kk 1 1 51 A 1 1 5 2 rU ol TEL 1 1 5 2 1 A AN E ere nT AN 1 1 5 2 2 OO 0 2 1 5 2 3 a S put MN A SR 3 1 5 2 4 IO A E aa 5 1 5 2 5 JERR TS es 5 1 5 2 5 1 E R A AA 5 1 5 2 5 2 E AS AS 6 1 5 2 5 3 O A 6 1 5 2 6 E A 7 1 5 2 6 1 8 1 5 2 6 1 1 IL GBCB GBCL kk 8 1 5 2 6 1 2 I GBCZ da ia 9 1 5 2 6 1 3 GBDP GBDY GBDQ ak 9 Pl IA 11 psorqbhy Jaw VEL aliit A114 12 1 5 2 62 kk 13 E OAO EDE A 13 1 5 4 i 14 LS AS A atadas 14
303. ICITY 0 75 mg TRULICITY 1 5 mg and sitagliptin respectively Ti Multiplicity adjusted 1 sided p value 0 001 for superiority of TRULICITY compared to sitagliptin assessed only for HbA1c P5 p 0 001 TRULICITY compared to sitagliptin assessed only for HbA1c 7 096 14 8 4 Ji TRULICITY 1 5 mg 82 TRULICITY 0 75 mg i Sitagliptin 100 mg Placebo 8 0 lt 7 8 2 amp 76 c 74 a 7 7 0 i 6 8 0 4 8 13 26 39 Bar et Weeks Post Randomization Number of subjects with observed data Placebo 139 108 TRULICITY 0 75 mg 281 258 238 TRULICITY 1 5 mg 279 249 225 Sitagliptin 273 241 219 Mean change from baseline adjusted for baseline HbA1c and country Figure 3 Adjusted Mean HbA1c Change at each Time Point ITT MMRM and at Week 52 ITT LOCF Add on to Metformin and Thiazolidinedione In this 52 week placebo controlled study 26 week primary endpoint 976 patients were randomized to placebo TRULICITY 0 75 mg once weekly TRULICITY 1 5 mg once weekly or exenatide 10 mcg BID all as add on to maximally tolerated doses of metformin 21500 mg per day and pioglitazone up to 45 mg per day Exenatide treatment group assignment was open label while the treatment assignments to placebo TRULICITY 0 75 mg and TRULICITY 1 5 mg were blinded After 26 weeks patients in the placebo treatment group were randomized to either TRULICITY 0 75 mg once weekly or TRULICITY 1 5 mg once weekly to main
304. In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products 60 6 3 Shelf life 2 years 6 4 Special precautions for storage Store in a refrigerator 2 C 8 C Do not freeze Store in original package in order to protect from light In use Trulicity may be stored unrefrigerated for up to 14 days at a temperature not above 30 C 6 5 Nature and contents of container Glass syringe type I Each pre filled syringe contains 0 5 ml of solution Packs of 4 pre filled syringes and multipack of 12 3 packs of 4 pre filled syringes Not all pack sizes may be marketed 6 6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements Instructions for use The pre filled syringe is for single use only The instructions for using the syringe included with the package leaflet must be followed carefully Trulicity should not be used if particles appear or if the solution is cloudy and or coloured Trulicity that has been frozen must not be used 7 MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B V Grootslag 1 5 NL 3991 RA Houten The Netherlands 8 MARKETING AUTHORISATION NUMBER EU 1 14 956 009 EU 1 14 956 010 9 DATE OF FIRST AUTHORISATION RENEWAL OF THE AUTHORISATION Date of first authorisation 10 DATE OF REVISION OF THE TEXT Detailed information on
305. ME OF THE MEDICINAL PRODUCT Trulicity 0 75 mg solution for injection in pre filled pen 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre filled pen contains 0 75 mg of dulaglutide in 0 5 ml solution Produced in CHO cells by recombinant DNA technology For the full list of excipients see section 6 1 3 PHARMACEUTICAL FORM Solution for injection injection Clear colourless solution 4 CLINICAL PARTICULARS 4 1 Therapeutic indications Trulicity is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications Add on therapy In combination with other glucose lowering medicinal products including insulin when these together with diet and exercise do not provide adequate glycaemic control see section 5 1 for data with respect to different combinations 4 2 Posology and method of administration Posology Monotherapy The recommended dose is 0 75 mg once weekly Add on therapy The recommended dose is 1 5 mg once weekly For potentially vulnerable populations such as patients 7 75 years 0 75 mg once weekly can be considered as a starting dose When Trulicity is added to existing metformin and or pioglitazone therapy the current dose of metformin and or pioglitazone can be continued When it is added to
306. Overdose Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders and hypoglycaemia In the event of overdose appropriate supportive treatment should be initiated according to the patient s clinical signs and symptoms 5 PHARMACOLOGICAL PROPERTIES 5 1 Pharmacodynamic properties Pharmacotherapeutic group not yet assigned ATC code not yet assigned Mechanism of action Dulaglutide is a long acting glucagon like peptide 1 GLP 1 receptor agonist The molecule consists of 2 identical disulfide linked chains each containing a modified human GLP 1 analogue sequence covalently linked to a modified human immunoglobulin G4 IgG4 heavy chain fragment Fc by a small peptide linker The GLP 1 analog portion of dulaglutide is approximately 90 homologous to native human GLP 1 7 37 Native GLP 1 has a half life of 1 5 2 minutes due to degradation by DPP 4 and renal clearance In contrast to native GLP 1 dulaglutide is resistant to degradation by DPP 4 and has a large size that slows absorption and reduces renal clearance These engineering features result in a soluble formulation and a prolonged half life of 4 7 days which makes it suitable for once weekly subcutaneous administration In addition the dulaglutide molecule was engineered to prevent the Fcy receptor dependent immune response and to reduce its immunogenic potential Dulaglutide exhibits several antihyperglycaemic actions of GLP 1 In the p
307. P 4 2 9 1 EE 2 fm LY2 189265 dulaglutide 3 x 1 14
308. Q 25 Glaesner W et al Diabetes Metab Res Rev 26 287 2010 26 in vitro 12451 5 LY2189265 27 2 28 29 SG 30 SQI 31 1 2 32 2 II E T651 0086 7 1 Lilly Answers 0120 360 605 8 45 17 30 www lillyanswers jp LY2189265 18 dulaglutide
309. The mean apparent clearance of dulaglutide 0 75 mg and 1 5 mg at steady state was 0 073 L h and 0 107 L h with an elimination half life of 4 5 and 4 7 days respectively Special populations Elderly patients gt 65 years old Age had no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide Gender and race Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide Body weight or body mass index Pharmacokinetic analyses have demonstrated a statistically significant inverse relationship between body weight or body mass index BMD and dulaglutide exposure although there was no clinically relevant impact of weight or BMI on glycaemic control 29 Patients with renal impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment CrCl lt 30 ml min including end stage renal disease requiring dialysis In clinical studies the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall T2DM population These studies did not include patients with severe renal impairment or end stage renal disease Patients with hepatic impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study where subjects with hepatic impairment had statistically significant decreases
310. ad no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide Gender and race Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide Body weight or body mass index Pharmacokinetic analyses have demonstrated a statistically significant inverse relationship between body weight or body mass index BMD and dulaglutide exposure although there was no clinically relevant impact of weight or BMI on glycaemic control 44 Patients with renal impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment CrCl lt 30 ml min including end stage renal disease requiring dialysis In clinical studies the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall T2DM population These studies did not include patients with severe renal impairment or end stage renal disease Patients with hepatic impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study where subjects with hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30 to 33 for mean Cmax and AUC respectively compared to healthy controls There was a general increase in tmax of dulaglutide with increased hepatic impairment However no trend in dulaglutide exposure
311. aemic control as Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications Add on therapy In combination with other glucose lowering medicinal products including insulin when these together with diet and exercise do not provide adequate glycaemic control see section 5 1 for data with respect to different combinations 4 2 Posology and method of administration Posology Monotherapy The recommended dose is 0 75 mg once weekly Add on therapy The recommended dose is 1 5 mg once weekly For potentially vulnerable populations such as patients gt 75 years 0 75 mg once weekly can be considered as a starting dose When Trulicity is added to existing metformin and or pioglitazone therapy the current dose of metformin and or pioglitazone can be continued When it is added to existing therapy of a sulphonylurea or prandial insulin a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia see sections 4 4 and 4 8 32 The use of Trulicity does not require blood glucose self monitoring Self monitoring may be necessary to adjust the dose of sulphonylurea or prandial insulin Elderly patients gt 65 years old No dose adjustment is required based on age see section 5 2 However the therapeutic experience in patients gt 75 years is very limite
312. agliptin tnax increased approximately 0 5 hours following coadministration with dulaglutide compared to sitagliptin alone Sitagliptin can produce up to 80 inhibition of DPP 4 over a 24 hour period Dulaglutide coadministration with sitagliptin increased dulaglutide exposure and Cmax by approximately 38 and 27 96 respectively and median tax increased approximately 24 hours Therefore dulaglutide does have a high degree of protection against DPP 4 inactivation see section 5 1 The increased exposure may enhance the effects of dulaglutide on blood glucose levels 4 6 Fertility pregnancy and lactation Pregnancy There are no or limited amount of data from the use of dulaglutide in pregnant women Studies in animals have shown reproductive toxicity see section 5 3 Therefore the use of dulaglutide is not recommended during pregnancy Breast feeding It is unknown whether dulaglutide is excreted in human milk A risk to newborns infants cannot be excluded Dulaglutide should not be used during breast feeding Fertility The effect of dulaglutide on fertility in humans is unknown In the rat there was no direct effect on mating or fertility following treatment with dulaglutide see section 5 3 4 7 Effects on ability to drive and use machines Trulicity has no or negligible influence on the ability to drive or use machines When it is used in combination with a sulphonylurea or prandial insulin patients should be advised to take pre
313. aglutide paracetamol Cmax was reduced by 36 and 50 96 respectively and the median tmax occurred later 3 and 4 hours respectively After coadministration with up to 3 mg of dulaglutide at steady state there were no statistically significant differences on AUCo Cmax OT tmax Of paracetamol No dose adjustment of paracetamol is necessary when administered with dulaglutide Atorvastatin Coadministration of dulaglutide with atorvastatin decreased Cmax and AUC 0 up to 70 and 21 96 respectively for atorvastatin and its major metabolite o hydroxyatorvastatin The mean t of atorvastatin and o hydroxyatorvastatin were increased by 17 and 41 46 respectively following dulaglutide administration These observations are not clinically relevant No dose adjustment of atorvastatin is necessary when administered with dulaglutide Digoxin After coadministration of steady state digoxin with 2 consecutive doses of dulaglutide overall exposure AUC and tnax of digoxin were unchanged and Cmax decreased by up to 22 This change is not expected to have clinical consequences No dose adjustment is required for digoxin when administered with dulaglutide Anti hypertensives Coadministration of multiple dulaglutide doses with steady state lisinopril caused no clinically relevant changes in the AUC or Cmax of lisinopril Statistically significant delays in lisinopril tax of approximately 1 hour were observed on Days 3 and 24 of the study When a s
314. ancia respectiva en medicina o en farmacia Las listas de Denominaciones Comunes Internacionales Propuestas 1 101 y Recomendadas 1 62 se encuentran reunidas en Cumulative List No 13 2009 disponible s lo en CD ROM 49 LY2189265 19 HHHHHHHHHH dulaglutide Recommended INN List 65 WHO Drug Information Vol 25 No 1 2011 drozitumab inmunoglobulina G1 lambda anti Homo sapiens TNFRSF10B miembro 10B de la superfamilia de receptores del factor de necrosis tumoral DR5 receptor de muerte 5 TRAIL R2 receptor 2 del ligando inductor de la apoptosis de la familia TNF TR 2 CD262 anticuerpo monoclonal de Homo sapiens cadena pesada gamma1 1 451 Homo sapiens VH IGHV3 20 01 91 8096 IGHD IGHJ2 01 R120 gt K L123 gt T 8 8 14 1 121 IGHG1 03 CH1 R120 gt K 122 451 224 212 disulfuro con la cadena ligera lambda 1 213 Homo sapiens V LAMBDA IGLV3 19 01 96 8096 IGLJ3 01 6 3 11 1 107 IGLC3 03 108 213 d mero 230 230 233 233 bisdisulfuro Heavy chain Chaine lourde Cadena pesada EVOLVOSGGG VERPGGSLRL SCAASGFTFD DYAMSWVRQA PGKGLEWVSG 50 INWOGGSTGY ADSVKGRVTI SRDNAKNSLY LOMNSLRAED TAVYYCAKIL 100 GAGRGWYFDY WGKGTTVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLOS SGLYSLSSVV TVPSSSLGTO 200 TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250 PKDTLMISRT PEVTCVVVDV SHEDPEVKEN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHODWLNG KEYKCKVSNK ALPAPIEKTI SKAKGOPREP 350 OVYTLPPSR
315. and 1 5 mg at steady state in patients with type 2 diabetes mellitus were approximately 19 2 L and 17 4 L Biotransformation Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways Elimination The mean apparent clearance of dulaglutide 0 75 mg and 1 5 mg at steady state was 0 073 L h and 0 107 L h with an elimination half life of 4 5 and 4 7 days respectively Special populations Elderly patients gt 65 years old Age had no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide Gender and race Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide Body weight or body mass index Pharmacokinetic analyses have demonstrated a statistically significant inverse relationship between body weight or body mass index BMD and dulaglutide exposure although there was no clinically relevant impact of weight or BMI on glycaemic control 14 Patients with renal impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment CrCl lt 30 ml min including end stage renal disease requiring dialysis In clinical studies the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall T2DM population These studies did not include patients with
316. ary to adjust the dose of sulphonylurea or prandial insulin Elderly patients gt 65 years old No dose adjustment is required based on age see section 5 2 However the therapeutic experience in patients gt 75 years is very limited see section 5 1 and in these patients 0 75 mg once weekly can be considered as a starting dose Patients with renal impairment No dosage adjustment is required in patients with mild or moderate renal impairment There is very limited experience in patients with severe renal impairment eGFR by CKD EPI lt 30 ml min 1 73 m or end stage renal disease therefore Trulicity is not recommended in this population see section 5 2 Patients with hepatic impairment No dosage adjustment is required in patients with hepatic impairment Paediatric population The safety and efficacy of dulaglutide in children aged less than 18 years have not yet been established No data are available Method of administration Trulicity is to be injected subcutaneously in the abdomen thigh or upper arm It should not be administered intravenously or intramuscularly The dose can be administered at any time of day with or without meals If a dose is missed it should be administered as soon as possible if there are at least 3 days 72 hours until the next scheduled dose If less than 3 days 72 hours remain before the next scheduled dose the missed dose should be skipped and the next dose should be administered on the
317. ase from baseline in PR interval of 2 3 milliseconds was observed in TRULICITY treated patients in contrast to a mean decrease of 0 9 millisecond in placebo treated patients The adverse reaction of first degree AV block occurred more frequently in patients treated with TRULICITY than placebo 0 9 1 7 and 2 3 for placebo TRULICITY 0 75 mg and TRULICITY 1 5 mg respectively On electrocardiograms a PR interval increase to at least 220 milliseconds was observed in 0 796 2 596 and 3 296 of patients treated with placebo TRULICITY 0 75 mg and TRULICITY 1 5 mg respectively Amylase and Lipase Increase Patients exposed to TRULICITY had mean increases from baseline in lipase and or pancreatic amylase of 1496 to 2096 while placebo treated patients had mean increases of up to 396 7 DRUG INTERACTIONS 7 1 Oral Medications TRULICITY slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications Caution should be exercised when oral medications are concomitantly administered with TRULICITY Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with TRULICITY In clinical pharmacology studies TRULICITY did not affect the absorption of the tested orally administered medications to a clinically relevant degree see Clinical Pharmacology 12 3 8 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy Pregnancy Category C T
318. atistically significant increase in C cell adenomas was observed in rats receiving dulaglutide at 20 5 mg kg Numerical increases in thyroid C cell carcinomas occurred at 5 mg kg 58 times the MRHD based on AUC and were considered to be treatment related despite the absence of statistical significance A 6 month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0 3 1 0 and 3 0 mg kg administered by subcutaneous injection twice weekly Dulaglutide did not produce increased incidences of thyroid C cell hyperplasia or neoplasia at any dose Dulaglutide is a recombinant protein no genotoxicity studies have been conducted Human relevance of thyroid C cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies see Boxed Warning and Warnings and Precautions 5 1 In fertility and early embryonic development studies in male and female rats no adverse effects of dulaglutide on sperm morphology mating fertility conception and embryonic survival were observed at up to 16 3 mg kg 130 fold the MRHD based on AUC In female rats an increase in the number of females with prolonged diestrus and a dose related decrease in the mean number of corpora lutea implantation sites and viable embryos were observed at 24 9 mg kg 232 fold the MRHD based on AUC which occurred in the presence of decreased maternal food consumption and body weight gain 12 13 2 Animal Toxicology an
319. be OC HERE UT C 6 GLP 1 GLP 1 SABES PIER 1 5 2 6 GBCB o Eg 4 D E Biel HH 1 E C
320. ble 6 Results of a 52 week active controlled study with two doses of dulagltuide in comparison to exenatide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg tt goo goo E E dk once weekly i 279 8 10 1 51 t 78 2 62 7 2 36 1 30 Dulaglutide 0 75 mg hA nd 0 HE HE once weekly n 280 8 05 1 301 65 8 53 2 1 90 0 20 Placebo n 141 8 06 0 46 42 9 24 4 0 26 1 24 Exenatide 10 mcg twice daily 8 07 0 99 523 38 0 1 35 1 07 n 276 52 weeks Dulaglutide 1 5 mg E dh 6 itt onge weekly 2279 8 10 1 36 70 8 57 2 2 04 1 10 Dulaglutide 0 75 mg E once weekly n 280 8 05 1 07 59 1 48 3 1 58 0 44 Exenatide 10 mcg twice daily 8 07 0 80 49 2 34 6 1 03 0 80 n 270 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to exenatide assessed for HbAlc only tt multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to placebo p 0 05 p lt 0 001 dulaglutide treatment group compared to exenatide Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and exenatide
321. cautions to avoid hypoglycaemia while driving and using machines see section 4 4 50 4 8 Undesirable effects Summary of safety profile In the phase II and phase III studies conducted 4 006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products The most frequently reported adverse reactions in clinical trials were gastrointestinal including nausea vomiting and diarrhoea In general these reactions were mild or moderate in severity and transient in nature Tabulated list of adverse reactions The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence very common gt 1 10 common gt 1 100 to lt 1 10 uncommon gt 1 1 000 to lt 1 100 rare gt 1 10 000 to lt 1 1 000 very rare lt 1 10 000 and not known cannot be estimated from available data Within each incidence grouping adverse reactions are presented in order of decreasing frequency Table 1 The frequency of adverse reactions of dulaglutide System Organ Very common Common Uncommon Rare Class Metabolism and Hypoglycaemia Hypoglycaemia nutrition when used in when used as disorders combination with monotherapy or in prandial insulin combination with metformin or metformin plus metfor
322. clinical studies 64 1 6 TRULICITY treated patients developed anti drug antibodies ADAs to the active ingredient in TRULICITY i e dulaglutide Of the 64 dulaglutide treated patients that developed dulaglutide ADAs 34 patients 0 996 of the overall population had dulaglutide neutralizing antibodies and 36 patients 0 996 of the overall population developed antibodies against native GLP 1 The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay Additionally the observed incidence of antibody including neutralizing antibody positivity in an assay may be influenced by several factors including assay methodology sample handling timing of sample collection concomitant medications and underlying disease For these reasons the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products Hypersensitivity Systemic hypersensitivity adverse reactions sometimes severe e g severe urticaria systemic rash facial edema lip swelling occurred in 0 596 of patients on TRULICITY in the four Phase 2 and five Phase 3 studies Injection site Reactions In the placebo controlled studies injection site reactions e g injection site rash erythema were reported in 0 596 of TRULICITY treated patients and in 0 096 of placebo treated patients PR Interval Prolongation and Adverse Reactions of First Degree Atrioventricular AV Block A mean incre
323. cluding medullary thyroid carcinoma MTC in humans as the human relevance of dulaglutide induced rodent thyroid C cell tumors has not been determined One case of MTC was reported in a patient treated with TRULICITY This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal ULN Cases of MTC in patients treated with liraglutide another GLP 1 receptor agonist have been reported in the postmarketing period the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP 1 receptor agonist use in humans TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2 Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors e g a mass in the neck dysphagia dyspnea persistent hoarseness Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY Such monitoring may increase the risk of unnecessary procedures due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values gt 50 ng L If serum calcitonin is measured and found to be elevated the patient should be further evaluated Patients with thyroid nodules n
324. d see section 5 1 and in these patients 0 75 mg once weekly can be considered as a starting dose Patients with renal impairment No dosage adjustment is required in patients with mild or moderate renal impairment There is very limited experience in patients with severe renal impairment eGFR by CKD EPI lt 30 ml min 1 73 m or end stage renal disease therefore Trulicity is not recommended in this population see section 5 2 Patients with hepatic impairment No dosage adjustment is required in patients with hepatic impairment Paediatric population The safety and efficacy of dulaglutide in children aged less than 18 years have not yet been established No data are available Method of administration Trulicity is to be injected subcutaneously in the abdomen thigh or upper arm It should not be administered intravenously or intramuscularly The dose can be administered at any time of day with or without meals If a dose is missed it should be administered as soon as possible if there are at least 3 days 72 hours until the next scheduled dose If less than 3 days 72 hours remain before the next scheduled dose the missed dose should be skipped and the next dose should be administered on the regularly scheduled day In each case patients can then resume their regular once weekly dosing schedule The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days 72 hours b
325. d or Pharmacology Zucker diabetic fatty ZDF rats were given 0 5 1 5 or 5 0 mg kg twice weekly of dulaglutide 3 8 and 30 fold the MRHD based on AUC for 3 months Increases of 12 to 33 in total and pancreatic amylase but not lipase were observed at all doses without microscopic pancreatic inflammatory correlates in individual animals Other changes in the dulaglutide treated animals included increased interlobular ductal epithelium without active ductal cell proliferation 20 5 mg kg increased acinar atrophy with without inflammation 21 5 mg kg and increased neutrophilic inflammation of the acinar pancreas 5 mg kg Treatment of monkeys for 12 months with 8 15 mg kg twice weekly of dulaglutide nearly 500 fold the MRHD based on AUC demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia In 4 of 19 monkeys on dulaglutide treatment there was an increase in goblet cells within the pancreatic ducts but no differences from the control group in total amylase or lipase at study termination There were no proliferative changes in the thyroid C cells 14 CLINICAL STUDIES TRULICITY has been studied as monotherapy and in combination with metformin metformin and sulfonylurea metformin and thiazolidinedione and prandial insulin with or without metformin The studies evaluated the use of TRULICITY 0 75 mg and 1 5 mg Uptitration was not performed in any of the trials patients were initiated and maintained o
326. dose adjustment Asian No dose adjustment Black No dose adjustment Renal Impairment mild No dose adjustment moderate No dose adjustment severe No dose adjustment ESRD No dose adjustment Hepatic Impairment mild moderate severe No dose adjustment No dose adjustment No dose adjustment 0 0 0 5 1 0 1 5 2 0 Ratio Relative to Reference Abbreviations AUC area under the time concentration curve Cl confidence interval Cnax maximum concentration ESRD end stage renal disease PK pharmacokinetics Note Reference values for weight age gender and race comparisons are 93 kg 56 years old male and white respectively reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function from the respective clinical pharmacology studies The weight values shown in the plot 70 and 120 kg are the 10 and 90 percentiles of weight in the Phase 3 PK population Figure 1 Impact of intrinsic factors on dulaglutide pharmacokinetics Renal Dulaglutide systemic exposure was increased by 20 28 14 and 12 for mild moderate severe and ESRD renal impairment sub groups respectively compared to subjects with normal renal function The corresponding values for increase in Cmax were 13 23 20 and 11 respectively Figure 1 see Dosage and Administration 2 3 Warning and Precautions 5 5 Use in Specific Population 8 7 Hepatic Dulaglutide systemic exposure decreased by 23
327. dulaglutide Sitagliptin Sitagliptin exposure was unaffected when coadministered with a single dose of dulaglutide Following coadministration with 2 consecutive doses of dulaglutide sitagliptin AUC and Cmax decreased by approximately 7 4 and 23 1 96 respectively Sitagliptin tnax increased approximately 0 5 hours following coadministration with dulaglutide compared to sitagliptin alone Sitagliptin can produce up to 80 inhibition of DPP 4 over a 24 hour period Dulaglutide coadministration with sitagliptin increased dulaglutide exposure and Cmax by approximately 38 and 27 96 respectively and median tax increased approximately 24 hours Therefore dulaglutide does have a high degree of protection against DPP 4 inactivation see section 5 1 The increased exposure may enhance the effects of dulaglutide on blood glucose levels 4 6 Fertility pregnancy and lactation Pregnancy There are no or limited amount of data from the use of dulaglutide in pregnant women Studies in animals have shown reproductive toxicity see section 5 3 Therefore the use of dulaglutide is not recommended during pregnancy Breast feeding It is unknown whether dulaglutide is excreted in human milk A risk to newborns infants cannot be excluded Dulaglutide should not be used during breast feeding Fertility The effect of dulaglutide on fertility in humans is unknown In the rat there was no direct effect on mating or fertility following treatment with
328. dulaglutide see section 5 3 4 7 Effects on ability to drive and use machines Trulicity has no or negligible influence on the ability to drive or use machines When it is used in combination with a sulphonylurea or prandial insulin patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines see section 4 4 35 4 8 Undesirable effects Summary of safety profile In the phase II and phase III studies conducted 4 006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products The most frequently reported adverse reactions in clinical trials were gastrointestinal including nausea vomiting and diarrhoea In general these reactions were mild or moderate in severity and transient in nature Tabulated list of adverse reactions The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence very common gt 1 10 common gt 1 100 to lt 1 10 uncommon gt 1 1 000 to lt 1 100 rare gt 1 10 000 to lt 1 1 000 very rare lt 1 10 000 and not known cannot be estimated from available data Within each incidence grouping adverse reactions are presented in order of decreasing frequency Table 1 The frequency of adverse reactions of dulaglutide
329. e 2 2 Concomitant Use with an Insulin Secretagogue e g Sulfonylurea or with Insulin When initiating TRULICITY consider reducing the dosage of concomitantly administered insulin secretagogues e g sulfonylureas or insulin to reduce the risk of hypoglycemia see Warnings and Precautions 5 3 2 3 Dosage in Patients with Renal Impairment No dose adjustment is recommended in patients with renal impairment including end stage renal disease ESRD Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions see Warning and Precautions 5 5 Use in Specific Populations 8 7 Clinical Pharmacology 12 3 2 4 Important Administration Instructions Prior to initiation of TRULICITY patients should be trained by their healthcare professional on proper injection technique Training reduces the risk of administration errors such as improper injection site needle sticks and incomplete dosing Refer to the accompanying Instructions for Use for complete administration instructions with illustrations The instructions can also be found at www trulicity com When using TRULICITY with insulin instruct patients to administer as separate injections and to never mix the products It is acceptable to inject TRULICITY and insulin in the same body region but the injections should not be adjacent to each other 4 When injecting in the same body region advise patients to use a different injection site each
330. e Glucagon like peptides D J Drucker The biology of incretin D J Drucker hormones Pancreatic safety of incretin based drugs FDA and EMA assessment Pancreatitis pancreatic and M Elashoff et thyroid cancer with glucagon Jal like peptide 1 based therapies 1 12 Poster presentation at the NIDDK NCI Workshop on Pancreatitis Diabetes and Pancreatic Cancer June 12 13 2013 Bethesda MD USA Fundam Appl Toxicol 1993 20 23 29 Vaccine 2001 19 4385 4395 Diabetes Obes Metab 2011 13 559 566 Diabetes 1998 47 159 169 Cell Metab 2006 3 153 165 Gastroenterol ogy 20113141 150 156 LY2189265 dulaglutide 4 3 14 Characterizationofthe T Forest etal Potr Exocrine Pancreas in the Zucker Diabetic Fatty Rat Model of Type 2 Diabetes Treated with Sitagliptin a Dipeptidyl Peptidase 4 Inhibitor Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin a retrospective observational pharmacy claims analysis Glucagon like peptide 1 receptor expression in the human thyroid gland Chronic GLP 1 receptor activation by exendin 4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the GI2D Kras mouse model
331. e e g a sulfonylurea or insulin consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia 5 3 Hypersensitivity Reactions Discontinue TRULICITY if suspected Monitor and treat promptly per standard of care until signs and symptoms resolve 5 4 Renal Impairment Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions 5 5 Macrovascular outcomes There have been no studies establishing conclusive evidence of macrovascular risk reduction with TRULICITY or any other antidiabetic drug 5 7 The most common adverse reactions reported in 2596 of patients treated with TRULICITY are nausea diarrhea vomiting abdominal pain and decreased appetite 6 1 To report SUSPECTED ADVERSE REACTIONS contact Eli Lilly and Company at 1 800 LillyRx 1 800 545 5979 or FDA at 1 800 FDA 1088 or www fda gov medwatch Xxx nde t D IE DRUG INTERACTIONS Dulaglutide slows gastric emptying and may impact absorption of concomitantly administered oral medications 7 1 12 3 Pregnancy TRULICITY may cause fetal harm only use if potential benefit justifies potential risk to fetus 8 1 Nursing Mothers Discontinue nursing or discontinue TRULICITY 8 3 Renal Impairment No dosage adjustment recommended Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions 5 5 8
332. e adverse events were reported in 1 9 of patients receiving dulaglutide Potentially immune mediated injection site adverse events e g rash erythema were reported in 0 7 of patients and were usually mild Discontinuation due to an adverse event In studies of 26 weeks duration the incidence of discontinuation due to adverse events was 2 6 0 75 mg and 6 1 1 5 mg for dulaglutide versus 3 7 for placebo Through the full study duration up to 104 weeks the incidence of discontinuation due to adverse events was 5 1 0 73 mg and 8 4 1 5 mg for dulaglutide The most frequent adverse reactions leading to discontinuation for 0 75 mg and 1 5 mg dulaglutide respectively were nausea 1 0 1 9 96 diarrhoea 0 5 0 6 and vomiting 0 4 0 6 96 and were generally reported within the first 4 6 weeks Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important It allows continued monitoring of the benefit risk balance of the medicinal product Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4 9 Overdose Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders and hypoglycaemia In the event of overdose appropriate supportive treatment should be initiated according to the patient s clinical signs and symptoms 5 PHARMA
333. e associated with decreased food intake and body weight gain in maternal animals however no effects on indices of fertility and conception or embryonic development were observed In reproductive toxicology studies skeletal effects and a reduction in foetal growth were observed in the rat and rabbit at exposures of dulaglutide 11 to 44 fold higher than those proposed clinically but no foetal malformations were observed Treatment of rats throughout pregnancy and lactation produced memory deficits in female offspring at exposures that were 16 fold higher than those proposed clinically 6 PHARMACEUTICAL PARTICULARS 6 1 List of excipients Sodium citrate Citric acid anhydrous Mannitol Polysorbate 80 Water for injections 6 2 Incompatibilities In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products 15 6 3 Shelf life 2 years 6 4 Special precautions for storage Store in a refrigerator 2 C 8 C Do not freeze Store in original package in order to protect from light In use Trulicity may be stored unrefrigerated for up to 14 days at a temperature not above 30 C 6 5 Nature and contents of container Glass syringe type I encased in a disposable pen Each pre filled pen contains 0 5 ml of solution Packs of 2 and 4 pre filled pens and multipack of 12 3 packs of 4 pre filled pens Not all pack sizes may be marketed 6 6 Special precautions for disposal and
334. e demonstrated a statistically significant inverse relationship between body weight or body mass index BMD and dulaglutide exposure although there was no clinically relevant impact of weight or BMI on glycaemic control 59 Patients with renal impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment CrCl lt 30 ml min including end stage renal disease requiring dialysis In clinical studies the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall T2DM population These studies did not include patients with severe renal impairment or end stage renal disease Patients with hepatic impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study where subjects with hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30 to 33 for mean Cmax and AUC respectively compared to healthy controls There was a general increase in tmax of dulaglutide with increased hepatic impairment However no trend in dulaglutide exposure was observed relative to the degree of hepatic impairment These effects were not considered to be clinically relevant Paediatric population Studies characterising the pharmacokinetics of dulaglutide in paediatric patients have not been performed 5 3 Preclinical safe
335. e gastrointestinal events e g nausea vomiting and non severe hypoglycemia In the event of overdose appropriate supportive care including frequent plasma glucose monitoring should be initiated according to the patient s clinical signs and symptoms 11 DESCRIPTION TRULICITY contains dulaglutide a human GLP 1 receptor agonist The molecule is a fusion protein that consists of 2 identical disulfide linked chains each containing an N terminal GLP 1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 IgG4 heavy chain by a small peptide linker and is produced using mammalian cell culture The GLP 1 analog portion of dulaglutide is 90 homologous to native human GLP 1 7 37 Structural modifications were introduced in the GLP 1 part of the molecule responsible for interaction with the enzyme dipeptidyl peptidase IV DPP 4 Additional modifications were made in an area with a potential T cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high affinity Fc receptors and half antibody formation The overall molecular weight of dulaglutide is approximately 63 kilodaltons 9 TRULICITY is a clear colorless sterile solution Each 0 5 mL of TRULICITY solution contains 0 75 mg or 1 5 mg of dulaglutide Each single dose pen or prefilled syringe contains 0 5 mL of solution and the following excipients citric acid anhydrous 0 07 mg mannitol 23 2 mg polysorbate 80 0 10 mg
336. e weekly n 295 8 46 1 48 58 5 36 7 0 08 0 35 Dulaglutide 0 75 mg HB aH once weekly 1293 8 40 1 42 56 3 34 7 0 41 0 86 Insulin glargine ghee daily n 296 8 53 23 49 3 30 4 1 01 2 89 Tt multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 31 06 35 66 and 40 95 episodes patient year respectively Ten patients reported severe hypoglycaemia with Trulicity 1 5 mg seven with Trulicity 0 75 mg and fifteen with insulin glargine Fasting blood glucose Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks The improvement in fasting glucose was sustained through the longest study duration of 104 weeks Postprandial glucose Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline changes from baseline to primary time point 1 95 mmol L to 4 23 mmol L Beta cell function Clinical studies with dulaglutide have indicated enhanced beta cell functi
337. eas in male and female ZDF rats a quantitative and 13 N Vrang et i i al qualitative analysis revealing no evidence of drug induced pancreatitis 1 12 Acta Biomed 2009 80 93 101 The Toxicologist 2013 132 156 Abstract 725 JAMA Intern Med 2013 173 534 539 Toxicol Pathol 2010 38 51 61 Ann Endocrinol Paris 1979 40 403 412 Diabetes Obes Metab 2013 15 417 426 Am J Physiol Endocrinol Metab 2010 299 E1076 1086 Endocrinolog y 1994 135 1537 1542 Am J Physiol Endocrinol Metab 2012 303 E253 264 LY2189265 dulaglutide 4 3 50 In vitro characterization of five humanized OKT3 effector function variant antibodies GLP 1 exendin 4 facilitates B cell neogenesis in rat and human pancreatic ducts 4 3 51 4 3 52 Exendin 4 stimulates both B cell replication and neogenesis resulting in increased B cell mass and improved glucose tolerance in diabetic rats Exenatide induced chronic damage of pancreatic tissue in rats 4 3 53 4 3 54 4 3 55 Effect of 6 week course of glucagon like peptide 1 on glycaemic control insulin sensitivity and B cell function in type 2 diabetes a parallel group study Extended exenatide treatment causes pancreatic stress and injury in a rodent model of insulin resistance The physiology of glucagon like peptide 1
338. eatment group compared to sitagliptin The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and sitagliptin were 0 19 0 18 and 0 17 episodes patient year respectively No cases of severe hypoglycaemia with dulaglutide were observed The safety and efficacy of dulaglutide was also investigated in an active controlled study liraglutide 1 8 mg daily of 26 weeks duration both in combination with metformin Treatment with Trulicity 1 5 mg resulted in similar lowering of HbAlc and patients achieving HbAlc targets of lt 7 0 and lt 6 5 compared to liraglutide 25 Table 4 Results of a 26 week active controlled study of one dose of dulaglutide in comparison to liraglutide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 1 42 once weekly n 299 8 06 68 3 54 6 1 93 2 90 Liraglutide 1 8 mg 1 36 daily n 300 8 05 67 9 50 9 1 90 3 61 E for HbAlc p lt 0 05 dulaglutide treatment group compared to liraglutide were up titrated to 1 2 mg day and then at Week 2 to 1 8 mg day The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg was 0 12 episodes patient year and with liraglutide was 0 29 episodes patient year No cases of severe hypoglycaemia were observed Combination therapy with metformin and sulphonylu
339. ed p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 31 06 35 66 and 40 95 episodes patient year respectively Ten patients reported severe hypoglycaemia with Trulicity 1 5 mg seven with Trulicity 0 75 mg and fifteen with insulin glargine Fasting blood glucose Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks The improvement in fasting glucose was sustained through the longest study duration of 104 weeks Postprandial glucose Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline changes from baseline to primary time point 1 95 mmol L to 4 23 mmol L Beta cell function Clinical studies with dulaglutide have indicated enhanced beta cell function as measured by homeostasis model assessment HOMA2 B The durability of effect on beta cell function was maintained through the longest study duration of 104 weeks Body weight Trulicity 1 5 mg was associated with sustained weight reduction over
340. efore 4 3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6 1 4 4 Special warnings and precautions for use Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis Use of GLP 1 receptor agonists may be associated with gastrointestinal adverse reactions This should be considered when treating patients with impaired renal function since these events i e nausea vomiting and or diarrhoea may cause dehydration which could cause a deterioration of renal function Dulaglutide has not been studied in patients with severe gastrointestinal disease including severe gastroparesis and is therefore not recommended in these patients Acute pancreatitis Use of GLP 1 receptor agonists has been associated with a risk of developing acute pancreatitis In clinical trials acute pancreatitis has been reported in association with dulaglutide see section 4 8 Patients should be informed of the characteristic symptoms of acute pancreatitis If pancreatitis is suspected dulaglutide should be discontinued If pancreatitis is confirmed dulaglutide should not be 33 restarted In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis see section 4 8 Hypoglycaemia Patients receiving dulaglutide in combination with sulphonylurea or insulin may have
341. ency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily 58 Blood pressure The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes Treatment with dulglutide provided reductions in systolic blood pressure SBP 2 8 mmHg difference compared to placebo at 16 weeks There was no difference in diastolic blood pressure DBP Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study Cardiovascular Evaluation In a meta analysis of phase II and III studies a total of 51 patients dulaglutide 26 N 3 885 all comparators 25 N 2 125 experienced at least one cardiovascular CV event death due to CV causes nonfatal MI nonfatal stroke or hospitalisation for unstable angina The results showed that there was no increase in CV risk with dulaglutide compared with control therapies HR 0 57 CI 0 30 1 10 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with dulaglutide in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus see section 4 2 for information on paediatric use 5 2 Pharmacokinetic properties Absorption Following subcutaneous administration to patients with type 2 diabetes dulaglutide reaches peak plasma concentrations in 48 hours The mean peak Cma
342. ented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 1 67 1 67 and 3 02 episodes patient year respectively Two cases of severe hypoglycaemia were observed with Trulicity 1 5mg and two cases of severe hypoglycaemia were observed with insulin glargine 56 Combination therapy with metformin and pioglitazone In a placebo and active exenatide twice daily controlled study both in combination with metformin and pioglitazone Trulicity 1 5 mg and 0 75 mg demonstrated superiority for HbAlc reduction in comparison to placebo and exenatide accompanied by a significantly a greater percentage of patients achieving HbAlc targets of lt 7 0 or lt 6 5 Table 6 Results of a 52 week active controlled study with two doses of dulagltuide in comparison to exenatide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg tt goo goo E E dk once weekly i 279 8 10 1 51 t 78 2 62 7 2 36 1 30 Dulaglutide 0 75 mg hA nd 0 HE HE once weekly n 280 8 05 1 301 65 8 53 2 1 90 0 20 Placebo n 141 8 06 0 46 42 9 24 4 0 26 1 24 Exenatide 10 mcg twice daily 8 07 0 99 523 38 0 1 35 1 07 n 276 52 weeks Dulaglutide 1 5 mg E dh 6 itt onge weekly 2279 8 10 1 36 70 8 57 2 2 04 1 10 Dulaglutide 0 75 mg E once weekly n 280 8 05 1 07 59 1
343. form patients that serious hypersensitivity reactions have been reported during postmarketing use of GLP 1 receptor agonists If symptoms of hypersensitivity reactions occur patients must stop taking TRULICITY and seek medical advice promptly Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant Prior to initiation of TRULICITY train patients on proper injection technique to ensure a full dose is delivered Refer to the accompanying Instructions for Use for complete administration instructions with illustrations Inform patients of the potential risks and benefits of TRULICITY and of alternative modes of therapy Inform patients about the importance of adherence to dietary instructions regular physical activity periodic blood glucose monitoring and HbA1c testing recognition and management of hypoglycemia and hyperglycemia and assessment for diabetes complications During periods of stress such as fever trauma infection or surgery medication requirements may change and advise patients to seek medical advice promptly Each weekly dose of TRULICITY can be administered at any time of day with or without food The day of once weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before If a dose is missed and there are at least 3 days 72 hours until the next scheduled dose it should be administered as soon as possible Thereafter patient
344. fter Multiple Subcutaneous Doses in Patients with Type 2 Diabetes Mellitus H9X EW GBDM A Study to Evaluate the Effect of Dulaglutide on Gastric Emptying Using Scintigraphy in Patients with Type 2 Diabetes Mellitus 20 1 12 LY2189265 dulaglutide 5 3 5 5 3 5 1 5 3 5 1 1 5 3 5 1 2 5 3 5 1 2 1 5 3 5 1 3 5 3 5 1 4 5 3 5 1 5 5 3 5 1 6 H9X JE GBCZ Assessment of Dose Dependent Effects of LY2189265 on Glycemic Control in Japanese Patients with Type 2 Diabetes 26 H9X JE GBDP A Phase 3 Study of LY2189265 Monotherapy Compared to Placebo and Liraglutide in Patients with Type 2 Diabetes Mellitus 5248 H9X JE GBDP A Phase 3 Study of LY2189265 Monotherapy Compared to Placebo and Liraglutide in Patients with Type 2 Diabetes Mellitus H9X JE GBDY A Phase 3 Study of LY2189265 Compared to Insulin Glargine in Patients with Type 2 Diabetes Mellitus on a Sulfonylurea and or Biguanide
345. g once daily 8 09 0 61 37 8 21 8 0 97 1 46 n 315 52 weeks Dulaglutide 1 5 mg HH HH j iH E at ones weekly 1304 8 12 1 10 57 6 41 7 2 38 3 03 Dulaglutide 0 75 mg HH Hi T iH k se obte wecllyi a 302 8 19 0 87 48 8 29 0 1 63 2 60 Sitagliptin 100 mg E E oce duly GES 8 09 0 39 33 0 19 2 0 90 1 53 104 weeks Dulaglutide 1 5 mg m Hi HE 4 once weekly n 304 8 12 0 99 54 3 39 1 1 99 2 88 Dulaglutide 0 75 mg E aH He Hi once weekly n 302 8 19 0 71 44 8 242 1 39 2 39 Sitagliptin 100 mg price dal i 8 09 0 32 31 1 14 1 0 47 1 75 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide compared to sitagliptin assessed only for HbAlc at 52 and 104 weeks multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 001 dulaglutide treatment group compared to placebo p lt 0 001 dulaglutide treatment group compared to sitagliptin The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and sitagliptin were 0 19 0 18 and 0 17 episodes patient year respectively No cases of severe hypoglycaemia with dulaglutide were observed The safety and efficacy of dulaglutide was also investigated in an active controlled study liraglutide 1 8 mg daily of 26 weeks duration both in combination with metformin Treatment with Trulicity 1 5 mg resulted in similar lowering of HbAlc a
346. gG4 Fc Fc IgG4 Fc Glaesner et al 2010 1 1 5 2 152 4 ED 2013 3 8200 2033 5 9200 1 7500 International Diabetes
347. ge leaflet must be followed carefully Trulicity should not be used if particles appear or if the solution is cloudy and or coloured Trulicity that has been frozen must not be used 7 MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B V Grootslag 1 5 NL 3991 RA Houten The Netherlands 8 MARKETING AUTHORISATION NUMBER EU 1 14 956 006 EU 1 14 956 007 EU 1 14 956 008 9 DATE OF FIRST AUTHORISATION RENEWAL OF THE AUTHORISATION Date of first authorisation 10 DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http www ema europa eu 31 y This medicinal product is subject to additional monitoring This will allow quick identification of new safety information Healthcare professionals are asked to report any suspected adverse reactions See section 4 8 for how to report adverse reactions 1 NAME OF THE MEDICINAL PRODUCT Trulicity 0 75 mg solution for injection in pre filled syringe 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre filled syringe contains 0 73 mg of dulaglutide in 0 5 ml solution Produced in CHO cells by recombinant DNA technology For the full list of excipients see section 6 1 3 PHARMACEUTICAL FORM Solution for injection Injection Clear colourless solution 4 CLINICAL PARTICULARS 4 1 Therapeutic indications Trulicity is indicated in adults with type 2 diabetes mellitus to improve glyc
348. glimepiride Randomization occurred after a 10 week lead in period during the initial 2 weeks of the lead in period patients were titrated to maximally tolerated doses of metformin and glimepiride This was followed by a 6 to 8 week glycemic stabilization period prior to randomization Patients randomized to insulin glargine were started on a dose of 10 U once daily Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self measured fasting plasma glucose FPG followed by once weekly titration through Week 8 of study treatment utilizing an algorithm that targeted a fasting plasma glucose of 100 mg dL Only 24 of patients were titrated to goal at the 52 week primary endpoint The dose of glimepiride could be reduced or discontinued after randomization at the discretion of the investigator in the event of persistent hypoglycemia The dose of glimepiride was reduced or discontinued in 28 3296 and 29 of patients randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and glargine Patients had a mean age of 57 years mean duration of type 2 diabetes of 9 years 5196 were male race White Black and Asian were 71 196 and 17 respectively and 0 of the study population were in the US Treatment with TRULICITY once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea Table 6 The difference in observed effect size between TRULICITY 0
349. h prandial insulin were 85 3 and 80 0 and rates were 35 66 and 31 06 events patient year The severe hypoglycaemia event incidences were 2 4 and 3 496 and rates were 0 05 and 0 06 events patient year Gastrointestinal adverse reactions Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0 75mg and 1 5 mg respectively included nausea 12 9 and 21 2 96 diarrhoea 10 7 and 13 7 96 and vomiting 6 9 and 11 5 These were typically mild or moderate in severity and were reported to peak during the first 2 weeks of treatment and rapidly declined over the next 4 weeks after which the rate remained relatively constant In clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks the majority of gastrointestinal events were reported during the first 2 3 days after the initial dose and declined with subsequent doses Acute pancreatitis The incidence of acute pancreatitis in Phase II and III clinical studies was 0 07 for dulaglutide compared to 0 14 for placebo and 0 19 for comparators with or without additional background antidiabetic therapy Pancreatic enzymes Dulaglutide is associated with mean increases from baseline in pancreatic enzymes lipase and or pancreatic amylase of 11 to 21 see section 4 4 In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis Heart rate i
350. he GLP 1 and modified IgG4 parts of the dulaglutide molecule together with high homology with native GLP 1 and native IgG4 minimise the risk of immune response against dulaglutide Patients with dulaglutide anti drug antibodies generally had low titres and although the number of patients developing dulaglutide anti drug antibodies was low examination of the phase III data revealed no clear impact of dulaglutide anti drug antibodies on changes in HbAlc Hypersensitivity In the phase II and phase III clinical studies systemic hypersensitivity events e g urticaria edema were reported in 0 5 of patients receiving dulaglutide None of the patients with systemic hypersensitivity developed dulaglutide anti drug antibodies Injection site reactions Injection site adverse events were reported in 1 9 of patients receiving dulaglutide Potentially immune mediated injection site adverse events e g rash erythema were reported in 0 7 of patients and were usually mild Discontinuation due to an adverse event In studies of 26 weeks duration the incidence of discontinuation due to adverse events was 2 6 0 75 mg and 6 1 1 5 mg for dulaglutide versus 3 7 for placebo Through the full study duration up to 104 weeks the incidence of discontinuation due to adverse events was 5 1 0 73 mg and 8 4 1 5 mg for dulaglutide The most frequent adverse reactions leading to discontinuation for 0 75 mg and 1 5 mg dulaglutide respectively
351. he rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg was 0 12 episodes patient year and with liraglutide was 0 29 episodes patient year No cases of severe hypoglycaemia were observed Combination therapy with metformin and sulphonylurea In an active controlled study of 78 weeks duration dulaglutide was compared to insulin glargine both on a background of metformin and a sulphonylurea At 52 weeks Trulicity 1 5 mg demonstrated superior lowering in HbAlc to insulin glargine which was maintained at 78 weeks whereas lowering in HbAlc with Trulicity 0 75 mg was non inferior to insulin glargine With Trulicity 1 5 mg a significantly higher percentage of patients reached a target HbA 1c of lt 7 0 or lt 6 5 at 52 and 78 weeks compared to insulin glargine 1 sided p value p lt 0 001 for noninferiority of dulaglutide compared to liraglutide assessed only Patients randomised to liraglutide were initiated at a dose of 0 6 mg day After Week 1 patients Table 5 Results of a 78 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 52 weeks Dulaglutide 1 5 mg i dh dH once weekly n 273 8 18 1 08 53 2 27 0 1 50 1 87 Dulaglutide 0 75 mg at once weekly n 272 8 13 0 76 37 1 22 5 0 8
352. here are no adequate and well controlled studies of TRULICITY in pregnant women The risk of birth defects loss or other adverse outcomes is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control It is essential for patients with diabetes to maintain good metabolic control before conception and throughout pregnancy TRULICITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus In rats and rabbits dulaglutide administered during the major period of organogenesis produced fetal growth reductions and or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide In pregnant rats given subcutaneous doses of 0 49 1 63 or 4 89 mg kg dulaglutide on Gestation Days 6 9 12 and 15 organogenesis reduced fetal weights associated with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at 21 63 mg kg a systemic exposure 214 fold the MRHD based on AUC Irregular skeletal ossifications and increases in post implantation loss also were observed at 4 89 mg kg a systemic exposure 44 fold the MRHD based on AUC No developmental adverse effects were observed at 4 fold the MRHD based on AUC In pregnant rabbits given subcutaneous doses of 0 04 0 12 or 0 41 mg kg dulaglutide on Gestation Days 7 10 13
353. iation with dulaglutide see section 4 8 Patients should be informed of the characteristic symptoms of acute pancreatitis If pancreatitis is suspected dulaglutide should be discontinued If pancreatitis is confirmed dulaglutide should not be restarted In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis see section 4 8 Hypoglycaemia Patients receiving dulaglutide in combination with sulphonylurea or insulin may have an increased risk of hypoglycaemia The risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea or insulin see sections 4 2 and 4 8 Populations not studied There is limited experience in patients with congestive heart failure Sodium content This medicinal product contains less than 1 mmol sodium 23 mg per 1 5 mg dose i e essentially sodium free 4 5 Interaction with other medicinal products and other forms of interaction Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products Dulaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption For some prolonged release formulations an increased release due to an extended gastric residence time may slightly increase drug exposure Paracetamol Following a first dose of 1 and 3 mg dul
354. icology and Toxicokinetic Study in Sprague Dawley Rats Given LY2189265 Twice Weekly by Subcutaneous Injection for a Total of 27 Doses 4 2 3 2 4 7608 236 A Repeat Dose Toxicity and Toxicokinetic Study in Rats Given LY2189265 Twice Weekly by Subcutaneous Injection for 6 Months with a 1 Month Recovery 4 2 3 2 5 P00054 A Repeat Dose Toxicology Study in Cynomolgus Monkeys Given LY2189265 Twice Weekly by Subcutaneous Injection for a Total of 9 Doses 4 2 3 2 6 7608 192 A Repeat Dose Toxicology Study in Cynomolgus Monkeys Given LY2189265 Twice Weekly by Subcutaneous Injection for a Total of 27 Doses 4 2 3 2 7 7608 235 A Repeat Dose Toxicity Toxicokinetic and Immunotoxicology Study in Cynomolgus Monkeys Given LY2189265 Twice Weekly by Subcutaneous Injection for 9 Months with a 2 Month Recovery Em GE NE 20 7 0 7 Eee m C Ee me i ME S Eli Lilly and Company Eli Lilly and Company 1 12 su au xp E j zu EHI
355. ies HR 0 57 CI 0 30 1 10 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with dulaglutide in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus see section 4 2 for information on paediatric use 5 2 Pharmacokinetic properties Absorption Following subcutaneous administration to patients with type 2 diabetes dulaglutide reaches peak plasma concentrations in 48 hours The mean peak Cmax and total AUC exposures were approximately 114 ng ml and 14 000 ngh ml respectively after multiple subcutaneous 1 5 mg doses of dulaglutide in patients with type 2 diabetes Steady state plasma concentrations were achieved between 2 to 4 weeks of once weekly administration of dulaglutide 1 5 mg Exposures after subcutaneous administration of single dulaglutide 1 5 mg doses in the abdomen thigh or upper arm were comparable The mean absolute bioavailability of dulaglutide following single dose subcutaneous administration of single 1 5 mg and 0 75 mg doses was 47 96 and 65 respectively Distribution The mean volume of distribution after subcutaneous administration of dulaglutide 0 75 mg and 1 5 mg at steady state in patients with type 2 diabetes mellitus were approximately 19 2 L and 17 4 L Biotransformation Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways Elimination
356. ieved HbAlc targets of 7 0 96 or 6 5 96 at 26 weeks and 7 0 96 at 52 weeks than with insulin glargine 57 Table 7 Results of a 92 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 7o mmol L kg 26 weeks Dulaglutide 1 5 mg HE 4 once weekly n 295 8 46 1 64 67 6 48 0 0 27 0 87 Dulaglutide 0 75 mg tt He at once weekly n 293 8 40 1 59 69 0 43 0 0 22 0 18 Insulin glargine once daily n 296 8 53 1 41 56 8 37 5 1 58 2 33 52 weeks Dulaglutide 1 5 mg tt Ht onee weekly n 295 8 46 1 48 58 5 36 7 0 08 0 35 Dulaglutide 0 75 mg HB aH once weekly 1293 8 40 1 42 56 3 34 7 0 41 0 86 Insulin glargine ghee daily n 296 8 53 23 49 3 30 4 1 01 2 89 Tt multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 31 06 35 66 and 40 95 episodes patient year respectively Ten patients reported severe hypogl
357. ight 7 0 lt 6 S mmol L kg 26 weeks e 8 12 122 69 9 geget 53gee9 3 get once weekly n 304 i e a Lol 55 2 apost popat 63e once weekly n 302 i i 3 Placebo n 177 8 10 0 03 21 0 12 5 0 49 1 47 Sitagliptin 100 mg once daily 8 09 0 61 37 8 21 8 0 97 1 46 n 315 52 weeks Dulaglutide 1 5 mg HH HH j iH E at ones weekly 1304 8 12 1 10 57 6 41 7 2 38 3 03 Dulaglutide 0 75 mg HH Hi T iH k se obte wecllyi a 302 8 19 0 87 48 8 29 0 1 63 2 60 Sitagliptin 100 mg E E oce duly GES 8 09 0 39 33 0 19 2 0 90 1 53 104 weeks Dulaglutide 1 5 mg m Hi HE 4 once weekly n 304 8 12 0 99 54 3 39 1 1 99 2 88 Dulaglutide 0 75 mg E aH He Hi once weekly n 302 8 19 0 71 44 8 242 1 39 2 39 Sitagliptin 100 mg price dal i 8 09 0 32 31 1 14 1 0 47 1 75 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide compared to sitagliptin assessed only for HbAlc at 52 and 104 weeks multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 001 dulaglutide treatment group compared to placebo p lt 0 001 dulaglutide treatment group compared to sitagliptin The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and sitagliptin were 0 19 0 18 and 0 17 episodes patient year respectively No cases of severe hypoglycaemia with
358. in dulaglutide exposure of up to 30 to 33 for mean Cmax and AUC respectively compared to healthy controls There was a general increase in tmax of dulaglutide with increased hepatic impairment However no trend in dulaglutide exposure was observed relative to the degree of hepatic impairment These effects were not considered to be clinically relevant Paediatric population Studies characterising the pharmacokinetics of dulaglutide in paediatric patients have not been performed 5 3 Preclinical safety data Non clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat dose toxicity In a 6 month carcinogenicity study in transgenic mice there was no tumorigenic response In a 2 year carcinogenicity study in rats at 7 7 times the human clinical exposure following 1 5 mg dulaglutide per week dulaglutide caused statistically significant dose related increases in the incidence of thyroid C cell tumours adenomas and carcinomas combined The clinical relevance of these findings is currently unknown During the fertility studies a reduction in the number of corpora lutea and prolonged oestrous cycle were observed at dose levels that were associated with decreased food intake and body weight gain in maternal animals however no effects on indices of fertility and conception or embryonic development were observed In reproductive toxicology studies skeletal effects and a reduction in f
359. in the analysis are a subset of the ITT population that had at least one post baseline assessment The primary analysis included 275 273 and 276 individuals randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and glargine respectively 16 HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied Each TRULICITY single dose pen or prefilled syringe is packaged in a cardboard outer carton Carton of 4 Single Dose Pens 0 75 mg 0 5 mL solution in a single dose pen NDC 0002 1433 80 1 5 mg 0 5 mL solution in a single dose pen NDC 0002 1434 80 Carton of 4 Prefilled Syringes 0 75 mg 0 5 mL solution in a single dose prefilled syringe NDC 0002 1431 80 1 5 mg 0 5 mL solution in a single dose prefilled syringe NDC 0002 1432 80 16 2 Storage and Handling Store TRULICITY in the refrigerator at 36 F to 46 F 2 C to 8 C Do not use TRULICITY beyond the expiration date If needed each single dose pen or prefilled syringe can be kept at room temperature not to exceed 86 F 30 C for a total of 14 days Do not freeze TRULICITY Do not use TRULICITY if it has been frozen TRULICITY must be protected from light Storage of TRULICITY in the original carton is recommended until time of administration Discard the TRULICITY single dose pen or prefilled syringe after use in a puncture resistant container 17 PATIENT COUNSELING INFORMATION See FDA approved Medication Guide Inform patients that TRULICITY causes benign a
360. increases from baseline in pancreatic enzymes lipase and or pancreatic amylase of 11 to 21 see section 4 4 In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis Heart rate increase Small mean increases in heart rate of 2 to 4 beats per minute bpm and a 1 3 and 1 4 incidence of sinus tachycardia with a concomitant increase from baseline 7 15 bpm were observed with dulaglutide 0 75mg and 1 5 mg respectively First degree AV block PR interval prolongation Small mean increases from baseline in PR interval of 2 to 3 msec and a 1 596 and 2 4 96 incidence of first degree AV block were observed with dulaglutide 0 75 mg and 1 5 mg respectively Immunogenicity In clinical studies treatment with dulaglutide was associated with a 1 6 incidence of treatment emergent dulaglutide anti drug antibodies indicating that the structural modifications in the GLP 1 and modified IgG4 parts of the dulaglutide molecule together with high homology with native GLP 1 and native IgG4 minimise the risk of immune response against dulaglutide Patients with dulaglutide anti drug antibodies generally had low titres and although the number of patients developing dulaglutide anti drug antibodies was low examination of the phase III data revealed no clear impact of dulaglutide anti drug antibodies on changes in HbAlc Hypersensitivity In the phase II and phase III c
361. ingle dose of dulaglutide and metoprolol were coadministered the AUC and Cmax of metoprolol increased by19 and 32 respectively While metoprolol tmax was delayed by 1 hour this change was not statistically significant These changes were not clinically relevant therefore no dose adjustment of lisinopril or metoprolol is necessary when administered with dulaglutide Warfarin Following dulaglutide coadministration S and R warfarin exposure and R warfarin Cmax Were unaffected and S warfarin Cmax decreased by 22 AUCIR increased by 2 which is unlikely to be clinically significant and there was no effect on maximum international normalised ratio response INR max The time of international normalised ratio response tINR max was delayed by 6 hours 4 consistent with delays in tmax of approximately 4 and 6 hours for S and R warfarin respectively These changes are not clinically relevant No dose adjustment for warfarin is necessary when given together with dulaglutide Oral contraceptives Coadministration of dulaglutide with an oral contraceptive norgestimate 0 18 mg ethinyl estradiol 0 025 mg did not affect the overall exposure to norelgestromin and ethinyl estradiol Statistically significant reductions in Cmax of 26 and 13 and delays in tmax of 2 and 0 30 hours were observed for norelgestromin and ethinyl estradiol respectively These observations are not clinically relevant No dose adjustment for oral contraceptives is
362. intravenous bolus of glucose In the same study a single 1 5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the B cells and to enhance B cell function in subjects with type 2 diabetes mellitus as compared with placebo Consistent with the pharmacokinetic profile dulaglutide has a pharmacodynamic profile suitable for once weekly administration see section 5 2 Clinical efficacy and safety Glycaemic control The safety and efficacy of dulaglutide was evaluated in six randomised controlled phase III trials involving 5 171 patients with type 2 diabetes Of these 958 were gt 65 years of which 93 were 7 75 years These studies included 3 136 dulaglutide treated patients of whom 1 719 were treated with Trulicity 1 5 mg weekly and 1 417 were treated with Trulicity 0 75 mg weekly In all studies dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin Alc HbAIc Monotherapy Dulaglutide was studied in a 52 week active controlled monotherapy study in comparison to metformin Trulicity 1 5 mg and 0 75 mg were superior to metformin 1500 2000 mg day in the reduction in HbAlc and a significantly greater proportion of patients reached an HbA Ic target of lt 7 0 and lt 6 5 with Trulicity 1 5 mg and Trulicity 0 75 mg compared to metformin at 26 weeks Table 2 Results of a 52 week active controlled monotherapy study with two doses of dulaglutide in co
363. is in Phase II and III clinical studies was 0 07 for dulaglutide compared to 0 14 for placebo and 0 19 for comparators with or without additional background antidiabetic therapy Pancreatic enzymes Dulaglutide is associated with mean increases from baseline in pancreatic enzymes lipase and or pancreatic amylase of 11 to 21 see section 4 4 In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis Heart rate increase Small mean increases in heart rate of 2 to 4 beats per minute bpm and a 1 3 and 1 4 incidence of sinus tachycardia with a concomitant increase from baseline 7 15 bpm were observed with dulaglutide 0 75mg and 1 5 mg respectively First degree AV block PR interval prolongation Small mean increases from baseline in PR interval of 2 to 3 msec and a 1 596 and 2 4 96 incidence of first degree AV block were observed with dulaglutide 0 75 mg and 1 5 mg respectively Immunogenicity In clinical studies treatment with dulaglutide was associated with a 1 6 incidence of treatment emergent dulaglutide anti drug antibodies indicating that the structural modifications in the GLP 1 and modified IgG4 parts of the dulaglutide molecule together with high homology with native GLP 1 and native IgG4 minimise the risk of immune response against dulaglutide Patients with dulaglutide anti drug antibodies generally had low titres and although the
364. is necessary when administered with dulaglutide Digoxin After coadministration of steady state digoxin with 2 consecutive doses of dulaglutide overall exposure AUC and tnax of digoxin were unchanged and Cmax decreased by up to 22 This change is not expected to have clinical consequences No dose adjustment is required for digoxin when administered with dulaglutide Anti hypertensives Coadministration of multiple dulaglutide doses with steady state lisinopril caused no clinically relevant changes in the AUC or Cmax of lisinopril Statistically significant delays in lisinopril tax of approximately 1 hour were observed on Days 3 and 24 of the study When a single dose of dulaglutide and metoprolol were coadministered the AUC and Cmax of metoprolol increased by19 and 32 respectively While metoprolol tmax was delayed by 1 hour this change was not statistically significant These changes were not clinically relevant therefore no dose adjustment of lisinopril or metoprolol is necessary when administered with dulaglutide Warfarin Following dulaglutide coadministration S and R warfarin exposure and R warfarin Cmax Were unaffected and S warfarin Cmax decreased by 22 AUCIR increased by 2 which is unlikely to be clinically significant and there was no effect on maximum international normalised ratio response INR max The time of international normalised ratio response tINR max was delayed by 6 hours 49 consistent with de
365. l disease and toxicology Glucagon like Peptide 1 L B Knudsen receptor agonists activate rodent thyroid C cells causing calcitonin release and C cell proliferation Glucagon like peptide 1 receptor activation modulates pancreatitis associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice J A Koehler GLP 1 receptor expression in M K rner et human tumors and human al normal tissues potential for in vivo targeting Glucagon like peptide 1 GLP J J Meier et 1 in biology and pathology al 11 1 12 Pancreas 1997 14 290 Platform presentation at the NIDDK NCI Workshop on Pancreatitis Diabetes and Pancreatic Cancer June 12 13 2013 Bethesda MD USA Lancet 2005 366 1849 1861 J Nutr 1997 127 5 Suppl 851S 856S Endocrinolog y 2010 151 1473 1486 Diabetes 2009 58 2148 2161 J Nucl Med 2007 48 736 743 Diabetes Metab Res Rev 2005 21 91 117 LY2189265 dulaglutide Stereologic Methods to Estimate Cell Number and al Compartment Volume of Acini Ducts and Islets in Pancreas of Cynomolgus Monkey Given Albiglutide a Glucagon like Peptide 1 Receptor Agonist Biochemical and histological J S Nachnani effects of exendin 4 exenatide et al on the rat pancreas Increased risk
366. lays in tmax of approximately 4 and 6 hours for S and R warfarin respectively These changes are not clinically relevant No dose adjustment for warfarin is necessary when given together with dulaglutide Oral contraceptives Coadministration of dulaglutide with an oral contraceptive norgestimate 0 18 mg ethinyl estradiol 0 025 mg did not affect the overall exposure to norelgestromin and ethinyl estradiol Statistically significant reductions in Cmax of 26 and 13 and delays in tmax of 2 and 0 30 hours were observed for norelgestromin and ethinyl estradiol respectively These observations are not clinically relevant No dose adjustment for oral contraceptives is required when given together with dulaglutide Metformin Following coadministration of multiple dose dulaglutide with steady state metformin immediate release formula IR metformin AUC increased up to 15 and Cmax decreased up to 12 96 respectively with no changes in tmax These changes are consistent with the gastric emptying delay of dulaglutide and within the pharmacokinetic variability of metformin and thus are not clinically relevant No dose adjustment for metformin IR is recommended when given with dulaglutide Sitagliptin Sitagliptin exposure was unaffected when coadministered with a single dose of dulaglutide Following coadministration with 2 consecutive doses of dulaglutide sitagliptin AUC and Cmax decreased by approximately 7 4 and 23 1 96 respectively Sit
367. lico Evaluation of T cell Epitopes for Dulaglutide LY2189265 4 2 1 1 6 bTDRO2 Assessment of the Time Action of Insulinotropic Activity of LY2189265 in an Intravenous Glucose Tolerance Test IVGTT in Sprague Dawley Rats 20M FRA Um 5 2 V as BED Eli Lilly and Company Lilly Kinsale Ireland Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Lilly Biotechnology Center Eli Lilly and Company 1 12 x ES ENER EY E EA E Ey Ey Y I EN c y ot aul zu y 2 zu 8H EHI
368. linical studies systemic hypersensitivity events e g urticaria edema were reported in 0 5 of patients receiving dulaglutide None of the patients with systemic hypersensitivity developed dulaglutide anti drug antibodies 37 Injection site reactions Injection site adverse events were reported in 1 9 of patients receiving dulaglutide Potentially immune mediated injection site adverse events e g rash erythema were reported in 0 7 of patients and were usually mild Discontinuation due to an adverse event In studies of 26 weeks duration the incidence of discontinuation due to adverse events was 2 6 0 75 mg and 6 1 1 5 mg for dulaglutide versus 3 7 for placebo Through the full study duration up to 104 weeks the incidence of discontinuation due to adverse events was 5 1 0 73 mg and 8 4 1 5 mg for dulaglutide The most frequent adverse reactions leading to discontinuation for 0 75 mg and 1 5 mg dulaglutide respectively were nausea 1 0 1 9 96 diarrhoea 0 5 0 6 and vomiting 0 4 0 6 96 and were generally reported within the first 4 6 weeks Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important It allows continued monitoring of the benefit risk balance of the medicinal product Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4 9
369. ls see Adverse Reactions 6 1 If a hypersensitivity reaction occurs the patient should discontinue TRULICITY and promptly seek medical advice 5 5 Renal Impairment In patients treated with GLP 1 receptor agonists there have been postmarketing reports of acute renal failure and worsening of chronic renal failure which may sometimes require hemodialysis Some of these events were reported in 5 patients without known underlying renal disease A majority of reported events occurred in patients who had experienced nausea vomiting diarrhea or dehydration Because these reactions may worsen renal function use caution when initiating or escalating doses of TRULICITY in patients with renal impairment Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions see Dosage and Administration 2 3 Use in Specific Populations 8 7 5 6 Severe Gastrointestinal Disease Use of TRULICITY may be associated with gastrointestinal adverse reactions sometimes severe see Adverse Reactions 6 1 TRULICITY has not been studied in patients with severe gastrointestinal disease including severe gastroparesis and is therefore not recommended in these patients 5 7 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRULICITY or any other antidiabetic drug 6 ADVERSE REACTIONS The following serious reactions are described below
370. lt 1 10 000 and not known cannot be estimated from available data Within each incidence grouping adverse reactions are presented in order of decreasing frequency Table 1 The frequency of adverse reactions of dulaglutide System Organ Very common Common Uncommon Rare Class Metabolism and Hypoglycaemia Hypoglycaemia nutrition when used in when used as disorders combination with monotherapy or in prandial insulin combination with metformin or metformin plus metformin plus pioglitazone glimepiride Gastrointestinal Nausea Decreased Acute pancreatitis disorders diarrhoea appetite vomiting dyspepsia abdominal paint constipation flatulence abdominal distention gastroesophageal reflux disease eructation General Fatigue Injection site disorders and reactions administration site conditions Investigations Sinus tachycardia first degree atrioventricular block AVB Documented symptomatic hypoglycaemia and blood glucose lt to 3 9 mmol L Dulaglutide 1 5 mg dose only For dulaglutide 0 75 mg adverse reaction met frequency for next lower incidence grouping Description of selected adverse reactions Hypoglycaemia When dulaglutide 0 75 mg and 1 5 mg were used as monotherapy or in combination with metformin alone or metformin and pioglitazone the incidences of documented symptomatic hypoglycaemia were 5 9 to 10 9 and the rates were 0 14 to 0 62 events patient year
371. lutide is resistant to degradation by DPP 4 and has a large size that slows absorption and reduces renal clearance These engineering features result in a soluble formulation and a prolonged half life of 4 7 days which makes it suitable for once weekly subcutaneous administration In addition the dulaglutide molecule was engineered to prevent the Fcy receptor dependent immune response and to reduce its immunogenic potential Dulaglutide exhibits several antihyperglycaemic actions of GLP 1 In the presence of elevated glucose concentrations dulaglutide increases intracellular cyclic AMP cAMP in pancreatic beta cells leading to insulin release Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes Lower glucagon concentrations lead to decreased hepatic glucose output Dulaglutide also slows gastric emptying Pharmacodynamic effects Dulaglutide improves glycaemic control through the sustained effects of lowering fasting pre meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval A pharmacodynamic study with dulaglutide demonstrated in patients with type 2 diabetes a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects on placebo and improved second phase insulin secretion in response to an
372. ly relevant change in dulaglutide pharmacokinetics PK was observed see Clinical Pharmacology 12 3 8 7 Renallmpairment In the four Phase 2 and five Phase 3 randomized clinical studies at baseline 50 1 296 TRULICITY treated patients had mild renal impairment eGFR 260 but 90 mL min 1 73 m 171 4 396 TRULICITY treated patients had moderate renal impairment eGFR 230 but 60 mL min 1 73 m and no TRULICITY treated patients had severe renal impairment eGFR 30 mL min 1 73 m No overall differences in safety or effectiveness were observed relative to patients with normal renal function though conclusions are limited due to small numbers In a clinical pharmacology study in subjects with renal impairment including end stage renal disease ESRD no clinically relevant change in dulaglutide PK was observed see Clinical Pharmacology 12 3 There is limited clinical experience in patients with severe renal impairment or ESRD TRULICITY should be used with caution and if these patients experience adverse gastrointestinal side effects renal function should be closely monitored see Dosage and Administration 2 3 Warning and Precautions 5 5 Clinical Pharmacology 12 3 8 8 Gastroparesis Dulaglutide slows gastric emptying TRULICITY has not been studied in patients with preexisting gastroparesis 10 OVERDOSAGE Overdoses have been reported in clinical studies Effects associated with these overdoses were primarily mild or moderat
373. max These changes are consistent with the gastric emptying delay of dulaglutide and within the pharmacokinetic variability of metformin and thus are not clinically relevant No dose adjustment for metformin IR is recommended when given with dulaglutide Sitagliptin Sitagliptin exposure was unaffected when coadministered with a single dose of dulaglutide Following coadministration with 2 consecutive doses of dulaglutide sitagliptin AUC and Cmax decreased by approximately 7 4 and 23 1 96 respectively Sitagliptin tnax increased approximately 0 5 hours following coadministration with dulaglutide compared to sitagliptin alone Sitagliptin can produce up to 80 inhibition of DPP 4 over a 24 hour period Dulaglutide coadministration with sitagliptin increased dulaglutide exposure and Cmax by approximately 38 and 27 96 respectively and median tax increased approximately 24 hours Therefore dulaglutide does have a high degree of protection against DPP 4 inactivation see section 5 1 The increased exposure may enhance the effects of dulaglutide on blood glucose levels 4 6 Fertility pregnancy and lactation Pregnancy There are no or limited amount of data from the use of dulaglutide in pregnant women Studies in animals have shown reproductive toxicity see section 5 3 Therefore the use of dulaglutide is not recommended during pregnancy Breast feeding It is unknown whether dulaglutide is excreted in human milk A risk to newborns infa
374. mg 1 0 9mg 1 1 1 1 0 3 mg 1 0 3 mg 1 0 9 mg LY2189265 1 7 dulaglutide AT R 1 7 1 1 1 1 13 2 0 9 mg 0 6 mg
375. min plus pioglitazone glimepiride Gastrointestinal Nausea Decreased Acute pancreatitis disorders diarrhoea appetite vomiting dyspepsia abdominal paint constipation flatulence abdominal distention gastroesophageal reflux disease eructation General Fatigue Injection site disorders and reactions administration site conditions Investigations Sinus tachycardia first degree atrioventricular block AVB Documented symptomatic hypoglycaemia and blood glucose lt to 3 9 mmol L Dulaglutide 1 5 mg dose only For dulaglutide 0 75 mg adverse reaction met frequency for next lower incidence grouping Description of selected adverse reactions Hypoglycaemia When dulaglutide 0 75 mg and 1 5 mg were used as monotherapy or in combination with metformin alone or metformin and pioglitazone the incidences of documented symptomatic hypoglycaemia were 5 9 to 10 9 and the rates were 0 14 to 0 62 events patient year and no episodes of severe hypoglycaemia were reported 51 The incidences of documented symptomatic hypoglycaemia when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination with a sulphonylurea plus metformin were 39 0 and 40 3 and the rates were 1 67 and 1 67 events patient year The severe hypoglycaemia event incidences were 0 and 0 7 and rates were 0 00 and 0 01 events patient year The incidences when dulaglutide 0 75 mg and 1 5 mg respectively were used in combination wit
376. mparison to metformin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 4 Hi once weekly n 269 7 63 0 78 61 5 46 0 1 01 2 29 Dulaglutide 0 75 mg once weekly n 270 7 58 0 71 62 6 40 0 1 46 1 36 Metformin 1500 2000 mg day 7 60 0 56 53 6 29 8 1 34 2 22 n 208 S2 Weeks Dulaglutide 1 5 mg 4 HH once weekly n 269 7 63 0 70 60 0 42 3 1 30 1 93 Dulaglutide 0 75 mg once weekly n 270 7 58 0 55 53 2 34 7 1 00 1 09 Metformin 1500 2000 mg day 7 60 0 51 48 3 28 3 1 15 2 20 n 268 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to metformin assessed for HbAlc only p 0 05 p 0 001 dulaglutide treatment group compared to metformin The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and metformin were 0 62 0 15 and 0 09 episodes patient year respectively No cases of severe hypoglycaemia were observed Combination therapy with metformin The safety and efficacy of dulaglutide was investigated in a placebo and active controlled sitagliptin 100 mg daily study of 104 weeks duration all in combination with metformin Treatment with Trulicity 1 5 mg and 0 75 mg resulted in a superior reduction i
377. n American 11 Asian 32 were of Hispanic or Latino ethnicity At baseline the population had diabetes for an average of 8 2 years and had a mean HbA1c of 7 6 8 5 At baseline 5 2 of the population reported retinopathy Baseline estimated renal function was normal or mildly impaired eGFR 260 ml min 1 73 m in 95 7 of the TRULICITY population In the pool of placebo and active controlled trials the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1 Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of documented symptomatic 70 mg dL glucose threshold and severe hypoglycemia in the placebo controlled clinical studies Table 2 Incidence of Documented Symptomatic and Severe Hypoglycemia Adverse Reactions in Placebo Controlled Trials Placebo TRULICITY 0 75 mg TRULICITY 1 5 mg Add on to Metformin 26 weeks N 177 N 302 N 304 Documented symptomatic 1 1 2 6 5 6 Severe 0 0 0 Add on to Metformin Pioglitazone 26 weeks N 141 N 280 N 279 Documented symptomatic 1 4 4 6 5 0 Severe 0 0 0 Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin see Warnings and Precautions 5 3 Documented symptomatic hypoglycemia occurred in 39 and 40 of patients when TRULICITY 0 75 mg and 1 5 mg respectively was co administered with a sulfonylurea Severe
378. n HbA1c compared to sitagliptin at 52 weeks accompanied by a significantly greater proportion of patients achieving HbAlc targets of 7 0 and lt 6 5 These effects were sustained to the end of the study 104 weeks Table 3 Results of a 104 week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 S mmol L kg 26 weeks e 8 12 122 69 9 geget 53gee9 3 get once weekly n 304 i e a Lol 55 2 apost popat 63e once weekly n 302 i i 3 Placebo n 177 8 10 0 03 21 0 12 5 0 49 1 47 Sitagliptin 100 mg once daily 8 09 0 61 37 8 21 8 0 97 1 46 n 315 52 weeks Dulaglutide 1 5 mg HH HH j iH E at ones weekly 1304 8 12 1 10 57 6 41 7 2 38 3 03 Dulaglutide 0 75 mg HH Hi T iH k se obte wecllyi a 302 8 19 0 87 48 8 29 0 1 63 2 60 Sitagliptin 100 mg E E oce duly GES 8 09 0 39 33 0 19 2 0 90 1 53 104 weeks Dulaglutide 1 5 mg m Hi HE 4 once weekly n 304 8 12 0 99 54 3 39 1 1 99 2 88 Dulaglutide 0 75 mg E aH He Hi once weekly n 302 8 19 0 71 44 8 242 1 39 2 39 Sitagliptin 100 mg price dal i 8 09 0 32 31 1 14 1 0 47 1 75 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide compared to sitagliptin assessed only f
379. n either 0 75 mg or 1 5 mg for the duration of the trials In patients with type 2 diabetes mellitus TRULICITY produced reductions from baseline in HbA1c compared to placebo No overall differences in glycemic effectiveness were observed across demographic subgroups age gender race ethnicity duration of diabetes 14 4 Monotherapy In a 52 week double blind study 26 week primary endpoint 807 patients inadequately treated with diet and exercise or with diet and exercise and one anti diabetic agent used at submaximal dose were randomized to TRULICITY 0 75 mg once weekly TRULICITY 1 5 mg once weekly or metformin 1500 to 2000 mg day following a two week washout Seventy five percent 7596 of the randomized population were treated with one antidiabetic agent at the screening visit Most patients previously treated with an antidiabetic agent were receiving metformin 90 at a median dose of 1000 mg daily and approximately 1096 were receiving a sulfonylurea Patients had a mean age of 56 years and a mean duration of type 2 diabetes of 3 years Forty four percent were male The White Black and Asian race accounted for 7496 796 and 896 of the population respectively Twenty nine percent of the study population were from the US Treatment with TRULICITY 0 75 mg and 1 5 mg once weekly resulted in reduction in HbA1c from baseline at the 26 week primary timepoint Table 3 The difference in observed effect size between TRULICITY 0 75 mg and 1 5 mg
380. n release and C cell proliferation Effect of exenatide on the steady state pharmacokinetics of digoxin Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women an open label randomised crossover trial Dipeptidyl peptidase 4 inhibitors and pancreatitis risk a meta analysis of randomized clinical trials Development of a population pharmacokinetic model for atorvastatin acid and its fee metabolite Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes a retrospective cohort study The Novacode criteria for classification of ECG abnormalities and their clinically significant progression and regression Efficacy and safety of the once daily human GLP 1 analogue liraglutide vs glibenclamide monotherapy in Japanese patients with type 2 diabetes Randomized double blind placebo controlled trial of the once daily GLP 1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea GetGoal L Asia Knudsen LB Kothare PA et al Kothare PA et al Monami M et al MINS DEN 30 1 12 2005 366 950 0 1849 1861 Endocrinolog y 2010 151 4 1473 1486 J Clin Pharmacol 2005 45 9 1032 1037 BMC Clin Pharmacol 2012 12 8 1 9
381. ncrease Small mean increases in heart rate of 2 to 4 beats per minute bpm and a 1 3 and 1 4 incidence of sinus tachycardia with a concomitant increase from baseline 7 15 bpm were observed with dulaglutide 0 75mg and 1 5 mg respectively First degree AV block PR interval prolongation Small mean increases from baseline in PR interval of 2 to 3 msec and a 1 596 and 2 4 96 incidence of first degree AV block were observed with dulaglutide 0 75 mg and 1 5 mg respectively Immunogenicity In clinical studies treatment with dulaglutide was associated with a 1 6 incidence of treatment emergent dulaglutide anti drug antibodies indicating that the structural modifications in the GLP 1 and modified IgG4 parts of the dulaglutide molecule together with high homology with native GLP 1 and native IgG4 minimise the risk of immune response against dulaglutide Patients with dulaglutide anti drug antibodies generally had low titres and although the number of patients developing dulaglutide anti drug antibodies was low examination of the phase III data revealed no clear impact of dulaglutide anti drug antibodies on changes in HbAlc Hypersensitivity In the phase II and phase III clinical studies systemic hypersensitivity events e g urticaria edema were reported in 0 5 of patients receiving dulaglutide None of the patients with systemic hypersensitivity developed dulaglutide anti drug antibodies 52 Injection site reactions Injection sit
382. nd malignant thyroid C cell tumors in rats and that the human relevance of this finding has not been determined Counsel patients to report symptoms of thyroid tumors e g a lump in the neck persistent hoarseness dysphagia or dyspnea to their physician see Boxed Warning and Warnings and Precautions 5 1 Inform patients that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting is the hallmark symptom of acute pancreatitis Instruct patients to discontinue TRULICITY promptly and to contact their physician if persistent severe abdominal pain occurs see Warnings and Precautions 5 2 The risk of hypoglycemia may be increased when TRULICITY is used in combination with a medicine that can cause hypoglycemia such as a sulfonylurea or insulin Review and reinforce instructions for hypoglycemia management when initiating TRULICITY therapy particularly when concomitantly administered with a sulfonylurea or insulin see Warnings and Precautions 5 3 Patients treated with TRULICITY should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion Inform patients treated with TRULICITY of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment as well as the possibility of dialysis as a medical intervention if renal failure occurs 19 In
383. nd patients achieving HbAlc targets of lt 7 0 and lt 6 5 compared to liraglutide 55 Table 4 Results of a 26 week active controlled study of one dose of dulaglutide in comparison to liraglutide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 1 42 once weekly n 299 8 06 68 3 54 6 1 93 2 90 Liraglutide 1 8 mg 1 36 daily n 300 8 05 67 9 50 9 1 90 3 61 E for HbAlc p lt 0 05 dulaglutide treatment group compared to liraglutide were up titrated to 1 2 mg day and then at Week 2 to 1 8 mg day The rate of documented symptomatic hypoglycaemia with Trulicity 1 5 mg was 0 12 episodes patient year and with liraglutide was 0 29 episodes patient year No cases of severe hypoglycaemia were observed Combination therapy with metformin and sulphonylurea In an active controlled study of 78 weeks duration dulaglutide was compared to insulin glargine both on a background of metformin and a sulphonylurea At 52 weeks Trulicity 1 5 mg demonstrated superior lowering in HbAlc to insulin glargine which was maintained at 78 weeks whereas lowering in HbAlc with Trulicity 0 75 mg was non inferior to insulin glargine With Trulicity 1 5 mg a significantly higher percentage of patients reached a target HbA 1c of lt 7 0 or lt 6 5 at 52 and 78 weeks compared t
384. nt with the pharmacokinetic profile dulaglutide has a pharmacodynamic profile suitable for once weekly administration see section 5 2 Clinical efficacy and safety Glycaemic control The safety and efficacy of dulaglutide was evaluated in six randomised controlled phase III trials involving 5 171 patients with type 2 diabetes Of these 958 were gt 65 years of which 93 were 7 75 years These studies included 3 136 dulaglutide treated patients of whom 1 719 were treated with Trulicity 1 5 mg weekly and 1 417 were treated with Trulicity 0 75 mg weekly In all studies dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin Alc HbAIc Monotherapy Dulaglutide was studied in a 52 week active controlled monotherapy study in comparison to metformin Trulicity 1 5 mg and 0 75 mg were superior to metformin 1500 2000 mg day in the reduction in HbAlc and a significantly greater proportion of patients reached an HbA Ic target of lt 7 0 and lt 6 5 with Trulicity 1 5 mg and Trulicity 0 75 mg compared to metformin at 26 weeks Table 2 Results of a 52 week active controlled monotherapy study with two doses of dulaglutide in comparison to metformin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 4 Hi once weekly n 269 7 63
385. ntent This medicinal product contains less than 1 mmol sodium 23 mg per 1 5 mg dose i e essentially sodium free 4 5 Interaction with other medicinal products and other forms of interaction Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products Dulaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption For some prolonged release formulations an increased release due to an extended gastric residence time may slightly increase drug exposure Paracetamol Following a first dose of 1 and 3 mg dulaglutide paracetamol Cmax was reduced by 36 and 50 96 respectively and the median tmax occurred later 3 and 4 hours respectively After coadministration with up to 3 mg of dulaglutide at steady state there were no statistically significant differences on AUCo Cmax OT tmax Of paracetamol No dose adjustment of paracetamol is necessary when administered with dulaglutide Atorvastatin Coadministration of dulaglutide with atorvastatin decreased Cmax and AUC 0 up to 70 and 21 96 respectively for atorvastatin and its major metabolite o hydroxyatorvastatin The mean t of atorvastatin and o hydroxyatorvastatin were increased by 17 and 41 46 respectively following dulaglutide administration These observations are not clinically relevant No dose adjustment of atorvastatin
386. nts cannot be excluded Dulaglutide should not be used during breast feeding Fertility The effect of dulaglutide on fertility in humans is unknown In the rat there was no direct effect on mating or fertility following treatment with dulaglutide see section 5 3 4 7 Effects on ability to drive and use machines Trulicity has no or negligible influence on the ability to drive or use machines When it is used in combination with a sulphonylurea or prandial insulin patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines see section 4 4 20 4 8 Undesirable effects Summary of safety profile In the phase II and phase III studies conducted 4 006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products The most frequently reported adverse reactions in clinical trials were gastrointestinal including nausea vomiting and diarrhoea In general these reactions were mild or moderate in severity and transient in nature Tabulated list of adverse reactions The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence very common gt 1 10 common gt 1 100 to lt 1 10 uncommon gt 1 1 000 to lt 1 100 rare gt 1 10 000 to lt 1 1 000 very rare
387. o n 141 8 06 0 46 42 9 24 4 0 26 1 24 Exenatide 10 mcg twice daily 8 07 0 99 523 38 0 1 35 1 07 n 276 52 weeks Dulaglutide 1 5 mg E dh 6 itt onge weekly 2279 8 10 1 36 70 8 57 2 2 04 1 10 Dulaglutide 0 75 mg E once weekly n 280 8 05 1 07 59 1 48 3 1 58 0 44 Exenatide 10 mcg twice daily 8 07 0 80 49 2 34 6 1 03 0 80 n 270 ft multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to exenatide assessed for HbAlc only tt multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to placebo p 0 05 p lt 0 001 dulaglutide treatment group compared to exenatide Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and exenatide twice daily were 0 19 0 14 and 0 75 episodes patient year respectively No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily Combination therapy with prandial insulin with or without metformin In this study patients on 1 or 2 insulin injections per day prior to study entry discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily
388. o fi AZ ORAS 3 Wo 1 17 LY2189265 dulaglutide 1 8 R T m Q 5510 75 mg 21 LIH SERE Eh 34 BRO EROS REED RED DALI f R 1 E LIGA MAE HORE HE H amp 1 A RARE ILP ooi AA Dot E 0 75 mg 27 0 75 mg D149 2O71 DOr for
389. o insulin glargine 1 sided p value p lt 0 001 for noninferiority of dulaglutide compared to liraglutide assessed only Patients randomised to liraglutide were initiated at a dose of 0 6 mg day After Week 1 patients Table 5 Results of a 78 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 52 weeks Dulaglutide 1 5 mg i dh dH once weekly n 273 8 18 1 08 53 2 27 0 1 50 1 87 Dulaglutide 0 75 mg at once weekly n 272 8 13 0 76 37 1 22 5 0 87 1 33 Insulin glargine once daily n 262 8 10 0 63 30 9 13 5 1 76 1 44 78 weeks Dulaglutide 1 5 mg aH once weekly n 273 8 18 0 90 49 0 28 1 1 10 1 96 Dulaglutide 0 75 mg HH se once weekly n 272 8 13 0 62 34 1 22 1 0 58 1 54 Insulin glargine once daily 1 262 8 10 0 59 30 5 16 6 1 58 1 28 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to insulin glargine assessed for HbAlc only p lt 0 05 p lt 0 001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of docum
390. oetal growth were observed in the rat and rabbit at exposures of dulaglutide 11 to 44 fold higher than those proposed clinically but no foetal malformations were observed Treatment of rats throughout pregnancy and lactation produced memory deficits in female offspring at exposures that were 16 fold higher than those proposed clinically 6 PHARMACEUTICAL PARTICULARS 6 1 List of excipients Sodium citrate Citric acid anhydrous Mannitol Polysorbate 80 Water for injections 6 2 Incompatibilities In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products 30 6 3 Shelf life 2 years 6 4 Special precautions for storage Store in a refrigerator 2 C 8 C Do not freeze Store in original package in order to protect from light In use Trulicity may be stored unrefrigerated for up to 14 days at a temperature not above 30 C 6 5 Nature and contents of container Glass syringe type I encased in a disposable pen Each pre filled pen contains 0 5 ml of solution Packs of 2 and 4 pre filled pens and multipack of 12 3 packs of 4 pre filled pens Not all pack sizes may be marketed 6 6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements Instructions for use The pre filled pen is for single use only The instructions for using the pen included with the packa
391. of acute R A Noel et pancreatitis and biliary disease fal observed in patients with type 2 diabetes a retrospective cohort study The human GLP 1 analog liraglutide and the pancreas evidence for the absence of structural pancreatic changes in three species Nyborg et al Evaluation of a Tier 1 screening J C O battery for detecting endocrine Connor et al active compounds EACs using the positive controls testosterone coumestrol progesterone and RU486 GLP 1 receptor activation N Panjwani indirectly reduces hepatic lipid et al accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE mice Development and validation of B S Parekh an antibody dependent cell et al mediated cytotoxicity reporter gene assay Weighing risks and benefits of liraglutide the FDA s review of a new antidiabetic therapy Zucker diabetic fatty rat as a model for non insulin dependent diabetes mellitus The glucagon like peptide 1 receptor or not 12 1 12 Poster presentation at the NIDDK NCI Workshop on Pancreatitis Diabetes and Pancreatic Cancer June 12 13 2013 Bethesda MD USA Diabetologia 2010 53 153 159 Diabetes Care 2009 32 834 838 Diabetes 2012 61 1243 1249 Toxicol Sci 2000 54 338 354 Endocrinolog y 2013 154 127 139 mAbs 2012 4 310
392. off Org mond Sant 1955 60 3 r solution EB15 R7 1969 173 10 r solution EB43 R9 r solution EB115 R4 EB115 2005 REC 1 les d nominations ci dessous sont choisies par l Organisation mondiale de la Sant en tant que d nominations communes internationales recommand es L inclusion d une d nomination dans les listes de DCI recommand es n implique aucune recommandation en vue de l utilisation de la substance correspondante en m decine ou en pharmacie On trouvera d autres listes de D nominations communes internationales propos es 1 101 et recommand es 1 62 dans la Liste r capitulative No 13 2009 disponible sur CD ROM seulement Denominaciones Comunes Internacionales para las Sustancias Farmac uticas DCI Denominaciones Comunes Internacionales RECOMENDADAS Lista 65 De conformidad con lo que dispone el p rrafo 7 del Procedimiento de Selecci n de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmac uticas Act Of Mund Salud 1955 60 3 Resoluci n EB15 R7 1969 173 10 Resoluci n EB43 R9 R solution EB115 R4 EB115 2005 REC 1 EB115 R4 EB115 2005 REC 1 se comunica por el presente anuncio que las denominaciones que a continuaci n se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas La inclusi n de una denominaci n en las listas de las Denominaciones Comunes Recomendadas no supone recomendaci n alguna en favor del empleo de la sust
393. on as measured by homeostasis model assessment HOMA2 B The durability of effect on beta cell function was maintained through the longest study duration of 104 weeks Body weight Trulicity 1 5 mg was associated with sustained weight reduction over the duration of studies from baseline to final time point 0 35 kg to 2 90 kg Changes in body weight with Trulicity 0 75 mg ranged from 0 86 kg to 2 63 kg Reduction in body weight was observed in patients treated with dulaglutide irrespective of nausea though the reduction was numerically larger in the group with nausea Patient reported outcomes Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily In addition there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily 13 Blood pressure The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes Treatment with dulglutide provided reductions in systolic blood pressure SBP 2 8 mmHg difference compared to placebo at 16 weeks There was no difference in diastolic blood pressure DBP Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study Cardiovascular Evaluation In a meta analysis of phase II and III studies a total of 51 patients dulaglutide 26 N 3 885 all comparators 25 N 2
394. ons 5 2 Consider other antidiabetic therapies in patients with a history of pancreatitis TRULICITY should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis TRULICITY is not a substitute for insulin TRULICITY has not been studied in patients with severe gastrointestinal disease including severe gastroparesis The use of TRULICITY is not recommended in patients with pre existing severe gastrointestinal disease see Warnings and Precautions 5 6 The concurrent use of TRULICITY and basal insulin has not been studied 2 DOSAGE AND ADMINISTRATION 2 4 Dosage The recommended initiating dose of TRULICITY is 0 75 mg once weekly The dose may be increased to 1 5 mg once weekly for additional glycemic control The maximum recommended dose is 1 5 mg once weekly Administer TRULICITY once weekly any time of day with or without food TRULICITY should be injected subcutaneously in the abdomen thigh or upper arm If a dose is missed instruct patients to administer as soon as possible if there are at least 3 days 72 hours until the next scheduled dose If less than 3 days remain before the next scheduled dose skip the missed dose and administer the next dose on the regularly scheduled day In each case patients can then resume their regular once weekly dosing schedule The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days befor
395. ootslag 1 5 NL 3991 RA Houten The Netherlands 8 MARKETING AUTHORISATION NUMBER EU 1 14 956 004 EU 1 14 956 005 9 DATE OF FIRST AUTHORISATION RENEWAL OF THE AUTHORISATION Date of first authorisation 10 DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http www ema europa eu 46 y This medicinal product is subject to additional monitoring This will allow quick identification of new safety information Healthcare professionals are asked to report any suspected adverse reactions See section 4 8 for how to report adverse reactions 1 NAME OF THE MEDICINAL PRODUCT Trulicity 1 5 mg solution for injection in pre filled syringe 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre filled syringe contains 1 5 mg of dulaglutide in 0 5 ml solution Produced in CHO cells by recombinant DNA technology For the full list of excipients see section 6 1 3 PHARMACEUTICAL FORM Solution for injection Injection Clear colourless solution 4 CLINICAL PARTICULARS 4 1 Therapeutic indications Trulicity is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications Add on therapy In combination with other glucose lowering
396. opulation N 141 280 279 276 HbA1c Mean Baseline 8 1 8 1 8 1 8 1 Change from baseline adjusted mean 0 5 1 3 1 5 1 0 Difference from placebo 95 CI 0 8 1 0 0 7 1 1 1 2 0 9 Difference from exenatide 9596 CI 0 3 0 4 0 2 t 0 5 0 7 0 4 it Percentage of patients HbA1c 7 096 43 opo Bro 52 Fasting Serum Glucose mg dL Mean Baseline 166 159 162 164 Change from baseline adjusted mean 5 34 42 24 Difference from placebo 95 Cl 30 36 23 38 45 31 Difference from exenatide 95 Cl 10 15 5 18 24 13 Body Weight kg Mean Baseline mean 94 1 95 5 96 2 97 4 Change from baseline adjusted mean 1 2 0 2 1 3 1 1 Difference from placebo 95 CI 1 0 1 8 0 3 2 5 3 3 1 8 Difference from exenatide 95 CI 1 3 0 6 1 9 0 2 0 9 0 4 Abbreviations BID twice daily HbA1c hemoglobin A1c a Intent to treat population Last observation carried forward LOCF was used to impute missing data Data post onset of rescue therapy are treated as missing At Week 26 primary efficacy was missing for 23 10 7 and 12 of individuals randomized to placebo TRULICITY 0 75 mg TRULICITY 1 5 mg and exenatide respectively b Least squares LS mean adjusted for baseline value and other stratification factors i Subjects included in the analysis are a subset of the ITT population that had at least one post baseline assessment i Multiplicit
397. or HbAlc at 52 and 104 weeks multiplicity adjusted 1 sided p value lt 0 001 for superiority of dulaglutide compared to placebo assessed for HbAIc only p lt 0 001 dulaglutide treatment group compared to placebo p lt 0 001 dulaglutide treatment group compared to sitagliptin The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and sitagliptin were 0 19 0 18 and 0 17 episodes patient year respectively No cases of severe hypoglycaemia with dulaglutide were observed The safety and efficacy of dulaglutide was also investigated in an active controlled study liraglutide 1 8 mg daily of 26 weeks duration both in combination with metformin Treatment with Trulicity 1 5 mg resulted in similar lowering of HbAlc and patients achieving HbAlc targets of lt 7 0 and lt 6 5 compared to liraglutide 10 Table 4 Results of a 26 week active controlled study of one dose of dulaglutide in comparison to liraglutide Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 1 42 once weekly n 299 8 06 68 3 54 6 1 93 2 90 Liraglutide 1 8 mg 1 36 daily n 300 8 05 67 9 50 9 1 90 3 61 E for HbAlc p lt 0 05 dulaglutide treatment group compared to liraglutide were up titrated to 1 2 mg day and then at Week 2 to 1 8 mg day T
398. oted on physical examination or neck imaging should also be further evaluated 5 2 Pancreatitis In Phase 2 and Phase 3 clinical studies 12 3 4 cases per 1000 patient years pancreatitis related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non incretin comparators 2 7 cases per 1000 patient years An analyses of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY 1 4 cases per 1000 patient years versus 1 case in non incretin comparators 0 88 cases per 1000 patient years After initiation of TRULICITY observe patients carefully for signs and symptoms of pancreatitis including persistent severe abdominal pain If pancreatitis is suspected promptly discontinue TRULICITY If pancreatitis is confirmed TRULICITY should not be restarted TRULICITY has not been evaluated in patients with a prior history of pancreatitis Consider other antidiabetic therapies in patients with a history of pancreatitis 5 3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin The risk of hypoglycemia is increased when TRULICITY is used in combination with insulin secretagogues e g sulfonylureas or insulin Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting see Adverse Reactions 6 1 5 4 Hypersensitivity Reactions Systemic hypersensitivity reactions were observed in patients receiving TRULICITY in clinical tria
399. other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements Instructions for use The pre filled pen is for single use only The instructions for using the pen included with the package leaflet must be followed carefully Trulicity should not be used if particles appear or if the solution is cloudy and or coloured Trulicity that has been frozen must not be used 7 MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B V Grootslag 1 5 NL 3991 RA Houten The Netherlands 8 MARKETING AUTHORISATION NUMBER EU 1 14 956 001 EU 1 14 956 002 EU 1 14 956 003 9 DATE OF FIRST AUTHORISATION RENEWAL OF THE AUTHORISATION Date of first authorisation 10 DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http www ema europa eu 16 y This medicinal product is subject to additional monitoring This will allow quick identification of new safety information Healthcare professionals are asked to report any suspected adverse reactions See section 4 8 for how to report adverse reactions 1 NAME OF THE MEDICINAL PRODUCT Trulicity 1 5 mg solution for injection in pre filled pen 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre filled pen contains 1 5 mg of dulaglutide in 0 5 ml solution Produced in CHO cells by recombinant DNA technology For the full list of excipients
400. paired eGFR 260mL min 1 73 m in 96 0 of the pooled study populations Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of TRULICITY in the pool of placebo controlled trials These adverse reactions were not present at baseline occurred more commonly on TRULICITY than on placebo and occurred in at least 596 of patients treated with TRULICITY Table 1 Adverse Reactions in Placebo Controlled Trials Reported in 25 of TRULICITY Treated Patients Adverse Reaction Placebo Trulicity 0 75 mg Trulicity 1 5 mg N 568 N 836 N 834 Nausea 5 3 12 4 21 1 Diarrhea 6 7 8 9 12 6 Vomiting 2 3 6 0 12 7 Abdominal Pain 4 9 6 5 9 4 Decreased Appetite 1 6 4 9 8 6 Dyspepsia 2 3 4 1 5 8 Fatigue 2 6 4 2 5 6 Includes diarrhea fecal volume increased frequent bowel movements Includes retching vomiting vomiting projectile Includes abdominal discomfort abdominal pain abdominal pain lower abdominal pain upper abdominal tenderness gastrointestinal pain Includes fatigue asthenia malaise Note Percentages reflect the number of patients that reported at least 1 treatment emergent occurrence of the adverse reaction o o a Gastrointestinal Adverse Reactions In the pool of placebo controlled trials gastrointestinal adverse reactions occurred more frequently among patients receiving TRULICITY than placebo placebo 21 3 0 75 mg 31 6 1
401. paracetamol No dose adjustment of paracetamol is necessary when administered with dulaglutide Atorvastatin Coadministration of dulaglutide with atorvastatin decreased Cmax and AUC 0 up to 70 and 21 96 respectively for atorvastatin and its major metabolite o hydroxyatorvastatin The mean t of atorvastatin and o hydroxyatorvastatin were increased by 17 and 41 46 respectively following dulaglutide administration These observations are not clinically relevant No dose adjustment of atorvastatin is necessary when administered with dulaglutide Digoxin After coadministration of steady state digoxin with 2 consecutive doses of dulaglutide overall exposure AUC and tnax of digoxin were unchanged and Cmax decreased by up to 22 This change is not expected to have clinical consequences No dose adjustment is required for digoxin when administered with dulaglutide Anti hypertensives Coadministration of multiple dulaglutide doses with steady state lisinopril caused no clinically relevant changes in the AUC or Cmax of lisinopril Statistically significant delays in lisinopril tax of approximately 1 hour were observed on Days 3 and 24 of the study When a single dose of dulaglutide and metoprolol were coadministered the AUC and Cmax of metoprolol increased by19 and 32 respectively While metoprolol tmax was delayed by 1 hour this change was not statistically significant These changes were not clinically relevant therefore no do
402. prefilled syringe 3 Injection 1 5 mg 0 5 mL solution in a single dose prefilled syringe 3 FULL PRESCRIBING INFORMATION CONTENTS WARNING RISK OF THYROID C CELL TUMORS 1 INDICATIONS AND USAGE 1 1 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2 1 Dosage 2 2 Concomitant Use with an Insulin Secretagogue e g Sulfonylurea or with Insulin 2 3 Dosage in Patients with Renal Impairment 2 4 Important Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4 1 Medullary Thyroid Carcinoma 4 2 Hypersensitivity CONTRAINDICATIONS TRULICITY is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 4 1 5 1 13 1 TRULICITY is contraindicated in patients with a prior serious hypersensitivity reaction to TRULICITY or any of the product components 4 2 5 4 WARNINGS AND PRECAUTIONS Thyroid C cell Tumors See Boxed Warning 5 1 Pancreatitis Has been reported in clinical trials Discontinue promptly if pancreatitis is suspected Do not restart if pancreatitis is confirmed Consider other antidiabetic therapies in patients with history of pancreatitis 5 2 Hypoglycemia When TRULICITY is used with an insulin secretagogu
403. r glucagon concentrations lead to decreased hepatic glucose output Dulaglutide also slows gastric emptying Pharmacodynamic effects Dulaglutide improves glycaemic control through the sustained effects of lowering fasting pre meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval A pharmacodynamic study with dulaglutide demonstrated in patients with type 2 diabetes a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects 53 on placebo and improved second phase insulin secretion in response to an intravenous bolus of glucose In the same study a single 1 5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the B cells and to enhance B cell function in subjects with type 2 diabetes mellitus as compared with placebo Consistent with the pharmacokinetic profile dulaglutide has a pharmacodynamic profile suitable for once weekly administration see section 5 2 Clinical efficacy and safety Glycaemic control The safety and efficacy of dulaglutide was evaluated in six randomised controlled phase III trials involving 5 171 patients with type 2 diabetes Of these 958 were gt 65 years of which 93 were 7 75 years These studies included 3 136 dulaglutide treated patients of whom 1 719 were treated with Trulicity 1 5 mg weekly
404. re renal impairment eGFR by CKD EPI lt 30 ml min 1 73 m or end stage renal disease therefore Trulicity is not recommended in this population see section 5 2 Patients with hepatic impairment No dosage adjustment is required in patients with hepatic impairment Paediatric population The safety and efficacy of dulaglutide in children aged less than 18 years have not yet been established No data are available Method of administration Trulicity is to be injected subcutaneously in the abdomen thigh or upper arm It should not be administered intravenously or intramuscularly The dose can be administered at any time of day with or without meals If a dose is missed it should be administered as soon as possible if there are at least 3 days 72 hours until the next scheduled dose If less than 3 days 72 hours remain before the next scheduled dose the missed dose should be skipped and the next dose should be administered on the regularly scheduled day In each case patients can then resume their regular once weekly dosing schedule The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days 72 hours before 4 3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6 1 4 4 Special warnings and precautions for use Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic
405. rea In an active controlled study of 78 weeks duration dulaglutide was compared to insulin glargine both on a background of metformin and a sulphonylurea At 52 weeks Trulicity 1 5 mg demonstrated superior lowering in HbAlc to insulin glargine which was maintained at 78 weeks whereas lowering in HbAlc with Trulicity 0 75 mg was non inferior to insulin glargine With Trulicity 1 5 mg a significantly higher percentage of patients reached a target HbA 1c of lt 7 0 or lt 6 5 at 52 and 78 weeks compared to insulin glargine 1 sided p value p lt 0 001 for noninferiority of dulaglutide compared to liraglutide assessed only Patients randomised to liraglutide were initiated at a dose of 0 6 mg day After Week 1 patients Table 5 Results of a 78 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 52 weeks Dulaglutide 1 5 mg i dh dH once weekly n 273 8 18 1 08 53 2 27 0 1 50 1 87 Dulaglutide 0 75 mg at once weekly n 272 8 13 0 76 37 1 22 5 0 87 1 33 Insulin glargine once daily n 262 8 10 0 63 30 9 13 5 1 76 1 44 78 weeks Dulaglutide 1 5 mg aH once weekly n 273 8 18 0 90 49 0 28 1 1 10 1 96 Dulaglutide 0 75 mg HH se once weekly n 272 8 13 0 62 34 1 22 1 0 58 1 5
406. required when given together with dulaglutide Metformin Following coadministration of multiple dose dulaglutide with steady state metformin immediate release formula IR metformin AUC increased up to 15 and Cmax decreased up to 12 96 respectively with no changes in tmax These changes are consistent with the gastric emptying delay of dulaglutide and within the pharmacokinetic variability of metformin and thus are not clinically relevant No dose adjustment for metformin IR is recommended when given with dulaglutide Sitagliptin Sitagliptin exposure was unaffected when coadministered with a single dose of dulaglutide Following coadministration with 2 consecutive doses of dulaglutide sitagliptin AUC and Cmax decreased by approximately 7 4 and 23 1 96 respectively Sitagliptin tnax increased approximately 0 5 hours following coadministration with dulaglutide compared to sitagliptin alone Sitagliptin can produce up to 80 inhibition of DPP 4 over a 24 hour period Dulaglutide coadministration with sitagliptin increased dulaglutide exposure and Cmax by approximately 38 and 27 96 respectively and median tax increased approximately 24 hours Therefore dulaglutide does have a high degree of protection against DPP 4 inactivation see section 5 1 The increased exposure may enhance the effects of dulaglutide on blood glucose levels 4 6 Fertility pregnancy and lactation Pregnancy There are no or limited amount of data from the
407. resence of elevated glucose concentrations dulaglutide increases intracellular cyclic AMP cAMP in pancreatic beta cells leading to insulin release Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes Lower glucagon concentrations lead to decreased hepatic glucose output Dulaglutide also slows gastric emptying Pharmacodynamic effects Dulaglutide improves glycaemic control through the sustained effects of lowering fasting pre meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval A pharmacodynamic study with dulaglutide demonstrated in patients with type 2 diabetes a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects 38 on placebo and improved second phase insulin secretion in response to an intravenous bolus of glucose In the same study a single 1 5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the B cells and to enhance B cell function in subjects with type 2 diabetes mellitus as compared with placebo Consistent with the pharmacokinetic profile dulaglutide has a pharmacodynamic profile suitable for once weekly administration see section 5 2 Clinical efficacy and safety Glycaemic control The safety and efficacy of dulaglutide was eval
408. respectively and metformin excluded the pre specified non inferiority margin of 0 496 Table 3 Results at Week 26 in a Trial of TRULICITY as Monotherapy 26 Week Primary Time Point TRULICITY TRULICITY Metformin 0 75 mg 1 5 mg 1500 2000 mg Intent to Treat ITT Population N 270 269 268 HbAtc Mean Baseline HbA1c 7 6 7 6 7 6 Change from baseline adjusted mean 0 7 0 8 0 6 Fasting Serum Glucose mg dL Mean Baseline 161 164 161 Change from baseline adjusted mean 26 29 24 Body Weight kg Mean Baseline mean 91 8 92 7 92 4 Change from baseline adjusted mean 1 4 2 3 2 2 Abbreviation HbA1c hemoglobin A1c i Subjects included in the analysis are a subset of the ITT population that had at least one post baseline assessment The primary analysis included 265 individuals in each of the treatment arms ntent to treat population Last observation carried forward LOCF was used to impute missing data Data post onset of rescue therapy are treated as missing At Week 26 primary efficacy was missing for 10 12 and 14 of individuals randomized to TRULICITY 0 75 mg TRULICITY 1 5 mg and metformin respectively 13 14 2 Combination Therapy Add on to Metformin In this 104 week placebo controlled double blind study 52 week primary endpoint 972 patients were randomized to placebo TRULICITY 0 75 mg once weekly TRULICITY 1 5 mg once weekly or sitagliptin 100 mg day af
409. rgine which was maintained at 78 weeks whereas lowering in HbAlc with Trulicity 0 75 mg was non inferior to insulin glargine With Trulicity 1 5 mg a significantly higher percentage of patients reached a target HbA 1c of lt 7 0 or lt 6 5 at 52 and 78 weeks compared to insulin glargine 1 sided p value p lt 0 001 for noninferiority of dulaglutide compared to liraglutide assessed only Patients randomised to liraglutide were initiated at a dose of 0 6 mg day After Week 1 patients Table 5 Results of a 78 week active controlled study with two doses of dulaglutide in comparison to insulin glargine Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 52 weeks Dulaglutide 1 5 mg i dh dH once weekly n 273 8 18 1 08 53 2 27 0 1 50 1 87 Dulaglutide 0 75 mg at once weekly n 272 8 13 0 76 37 1 22 5 0 87 1 33 Insulin glargine once daily n 262 8 10 0 63 30 9 13 5 1 76 1 44 78 weeks Dulaglutide 1 5 mg aH once weekly n 273 8 18 0 90 49 0 28 1 1 10 1 96 Dulaglutide 0 75 mg HH se once weekly n 272 8 13 0 62 34 1 22 1 0 58 1 54 Insulin glargine once daily 1 262 8 10 0 59 30 5 16 6 1 58 1 28 f multiplicity adjusted 1 sided p value lt 0 025 for noninferiority multiplicity adjusted 1 sided p value lt 0 025 for superiority of dulaglutide to
410. rithm with a fasting plasma glucose target of lt 5 6 mmol L The rates of documented symptomatic hypoglycaemia with Trulicity 1 5 mg and 0 75 mg and insulin glargine were 31 06 35 66 and 40 95 episodes patient year respectively Ten patients reported severe hypoglycaemia with Trulicity 1 5 mg seven with Trulicity 0 75 mg and fifteen with insulin glargine Fasting blood glucose Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks The improvement in fasting glucose was sustained through the longest study duration of 104 weeks Postprandial glucose Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline changes from baseline to primary time point 1 95 mmol L to 4 23 mmol L Beta cell function Clinical studies with dulaglutide have indicated enhanced beta cell function as measured by homeostasis model assessment HOMA2 B The durability of effect on beta cell function was maintained through the longest study duration of 104 weeks Body weight Trulicity 1 5 mg was associated with sustained weight reduction over the duration of studies from baseline to final time point 0 35 kg to 2 90 kg Changes in body weight with Trulicity 0 75 mg ranged from 0 86 kg to 2 63 kg Reduction in body weight was observed in patients treated with dulaglutide irre
411. s administration In addition the dulaglutide molecule was engineered to prevent the Fcy receptor dependent immune response and to reduce its immunogenic potential Dulaglutide exhibits several antihyperglycaemic actions of GLP 1 In the presence of elevated glucose concentrations dulaglutide increases intracellular cyclic AMP cAMP in pancreatic beta cells leading to insulin release Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes Lower glucagon concentrations lead to decreased hepatic glucose output Dulaglutide also slows gastric emptying Pharmacodynamic effects Dulaglutide improves glycaemic control through the sustained effects of lowering fasting pre meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval A pharmacodynamic study with dulaglutide demonstrated in patients with type 2 diabetes a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects 23 on placebo and improved second phase insulin secretion in response to an intravenous bolus of glucose In the same study a single 1 5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the B cells and to enhance B cell function in subjects with type 2 diabetes mellitus as compared with placebo Consiste
412. s can resume their usual once weekly dosing schedule If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days the patient should not administer the missed dose and instead resume TRULICITY with the next regularly scheduled dose see Dosage and Administration 2 Advise patients treated with TRULICITY of the potential risk of gastrointestinal side effects see Adverse Reactions 6 1 Instruct patients to read the Medication Guide and the Instructions for Use before starting TRULICITY therapy and review them each time the prescription is refilled Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom or if any known symptom persists or worsens Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels with a goal of decreasing these levels towards the normal range HbA1c is especially useful for evaluating long term glycemic control Eli Lilly and Company Indianapolis IN 46285 USA US License Number 1891 Copyright O 2014 2015 Eli Lilly and Company All rights reserved TRU 0003 USPI 20150309 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS y This medicinal product is subject to additional monitoring This will allow quick identification of new safety information Healthcare professionals are asked to report any suspected adverse reactions See section 4 8 for how to report adverse reactions 1 NA
413. s important It allows continued monitoring of the benefit risk balance of the medicinal product Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4 9 Overdose Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders and hypoglycaemia In the event of overdose appropriate supportive treatment should be initiated according to the patient s clinical signs and symptoms 5 PHARMACOLOGICAL PROPERTIES 5 1 Pharmacodynamic properties Pharmacotherapeutic group not yet assigned ATC code not yet assigned Mechanism of action Dulaglutide is a long acting glucagon like peptide 1 GLP 1 receptor agonist The molecule consists of 2 identical disulfide linked chains each containing a modified human GLP 1 analogue sequence covalently linked to a modified human immunoglobulin G4 IgG4 heavy chain fragment Fc by a small peptide linker The GLP 1 analog portion of dulaglutide is approximately 90 homologous to native human GLP 1 7 37 Native GLP 1 has a half life of 1 5 2 minutes due to degradation by DPP 4 and renal clearance In contrast to native GLP 1 dulaglutide is resistant to degradation by DPP 4 and has a large size that slows absorption and reduces renal clearance These engineering features result in a soluble formulation and a prolonged half life of 4 7 days which makes it suitable for once weekly subcutaneou
414. se III clinical studies and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence very common gt 1 10 common gt 1 100 to lt 1 10 uncommon gt 1 1 000 to lt 1 100 rare gt 1 10 000 to lt 1 1 000 very rare lt 1 10 000 and not known cannot be estimated from available data Within each incidence grouping adverse reactions are presented in order of decreasing frequency Table 1 The frequency of adverse reactions of dulaglutide System Organ Very common Common Uncommon Rare Class Metabolism and Hypoglycaemia Hypoglycaemia nutrition when used in when used as disorders combination with monotherapy or in prandial insulin combination with metformin or metformin plus metformin plus pioglitazone glimepiride Gastrointestinal Nausea Decreased Acute pancreatitis disorders diarrhoea appetite vomiting dyspepsia abdominal paint constipation flatulence abdominal distention gastroesophageal reflux disease eructation General Fatigue Injection site disorders and reactions administration site conditions Investigations Sinus tachycardia first degree atrioventricular block AVB Documented symptomatic hypoglycaemia and blood glucose lt to 3 9 mmol L Dulaglutide 1 5 mg dose only For dulaglutide 0 75 mg adverse reaction met frequency for next lower incidence grouping Description of selected adverse reactions
415. se adjustment of lisinopril or metoprolol is necessary when administered with dulaglutide Warfarin Following dulaglutide coadministration S and R warfarin exposure and R warfarin Cmax Were unaffected and S warfarin Cmax decreased by 22 AUCIR increased by 2 which is unlikely to be clinically significant and there was no effect on maximum international normalised ratio response INR max The time of international normalised ratio response tINR max was delayed by 6 hours 19 consistent with delays in tmax of approximately 4 and 6 hours for S and R warfarin respectively These changes are not clinically relevant No dose adjustment for warfarin is necessary when given together with dulaglutide Oral contraceptives Coadministration of dulaglutide with an oral contraceptive norgestimate 0 18 mg ethinyl estradiol 0 025 mg did not affect the overall exposure to norelgestromin and ethinyl estradiol Statistically significant reductions in Cmax of 26 and 13 and delays in tmax of 2 and 0 30 hours were observed for norelgestromin and ethinyl estradiol respectively These observations are not clinically relevant No dose adjustment for oral contraceptives is required when given together with dulaglutide Metformin Following coadministration of multiple dose dulaglutide with steady state metformin immediate release formula IR metformin AUC increased up to 15 and Cmax decreased up to 12 96 respectively with no changes in t
416. signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis see section 4 8 Hypoglycaemia Patients receiving dulaglutide in combination with sulphonylurea or insulin may have an increased risk of hypoglycaemia The risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea or insulin see sections 4 2 and 4 8 Populations not studied There is limited experience in patients with congestive heart failure Sodium content This medicinal product contains less than 1 mmol sodium 23 mg per 1 5 mg dose i e essentially sodium free 4 5 Interaction with other medicinal products and other forms of interaction Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products Dulaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption For some prolonged release formulations an increased release due to an extended gastric residence time may slightly increase drug exposure Paracetamol Following a first dose of 1 and 3 mg dulaglutide paracetamol Cmax was reduced by 36 and 50 96 respectively and the median tmax occurred later 3 and 4 hours respectively After coadministration with up to 3 mg of dulaglutide at steady state there were no statistically significant differences on AUCo Cmax OT tmax Of
417. spective of nausea though the reduction was numerically larger in the group with nausea Patient reported outcomes Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily In addition there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily 43 Blood pressure The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes Treatment with dulglutide provided reductions in systolic blood pressure SBP 2 8 mmHg difference compared to placebo at 16 weeks There was no difference in diastolic blood pressure DBP Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study Cardiovascular Evaluation In a meta analysis of phase II and III studies a total of 51 patients dulaglutide 26 N 3 885 all comparators 25 N 2 125 experienced at least one cardiovascular CV event death due to CV causes nonfatal MI nonfatal stroke or hospitalisation for unstable angina The results showed that there was no increase in CV risk with dulaglutide compared with control therapies HR 0 57 CI 0 30 1 10 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with dulaglutide in one or more subsets of the paediatric population in the treatment of t
418. tain study blind Randomization occurred after a 12 week lead in period during the initial 4 weeks of the lead in period patients were titrated to maximally tolerated doses of metformin and pioglitazone this was followed by an 8 week glycemic stabilization period prior to randomization Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID Patients had a mean age of 56 years mean duration of type 2 diabetes of 9 years 58 were male race White Black and Asian were 74 8 and 396 respectively and 8196 of the study population were in the US Treatment with TRULICITY 0 75 mg and 1 5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo at 26 weeks and compared to exenatide at 26 weeks Table 5 and Figure 4 Over the 52 week study period the percentage of patients who required glycemic rescue was 8 996 in the TRULICITY 0 75 mg once weekly metformin and pioglitazone treatment group 3 296 in the TRULICITY 1 5 mg once weekly metformin and pioglitazone treatment group and 8 796 in the exenatide BID metformin and pioglitazone treatment group 15 Table 5 Results at Week 26 of TRULICITY Compared to Placebo and Exenatide All as Add On to Metformin and Thiazolidinedione 26 Week Primary Time Point Placebo TRULICITY TRULICITY Exenatide 0 75 mg 1 5 mg 10 mcg BID Intent to Treat ITT P
419. ter 26 weeks patients in the placebo treatment group received blinded sitagliptin 100 mg day for the remainder of the study all as add on to metformin Randomization occurred after an 11 week lead in period to allow for a metformin titration period followed by a 6 week glycemic stabilization period Patients had a mean age of 54 years mean duration of type 2 diabetes of 7 years 48 were male race White Black and Asian were 53 4 and 27 respectively and 24 of the study population were in the US At the 26 week placebo controlled time point the HbA1c change was 0 1 1 0 1 2 and 0 6 for placebo TRULICITY 0 75 mg TRULICITY 1 5 mg and sitagliptin respectively The percentage of patients who achieved HbA1c lt 7 0 was 22 56 62 39 for placebo TRULICITY 0 75 mg TRULICITY 1 5 mg and sitagliptin respectively At 26 weeks there was a mean weight reduction of 1 4 kg 2 7 kg 3 0 kg and 1 4 kg for placebo TRULICITY 0 75 mg TRULICITY 1 5 mg and sitagliptin respectively There was a mean reduction of fasting glucose of 9 mg dL 35 mg dL 41 mg dL and 18 mg dL for placebo TRULICITY 0 75 mg TRULICITY 1 5 mg and sitagliptin respectively Treatment with TRULICITY 0 75 mg and 1 5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo at 26 weeks and compared to sitagliptin at 26 and 52 all in combination with metformin Table 4 and Figure 4 Table 4 Results at Week 52 of
420. this medicinal product is available on the website of the European Medicines Agency http www ema europa eu 61 DULAGLUTIDE Dulaglutide Core Data Sheet WT Jl Company Confidential Eli Lilly and Company LY2189265 1 7 dulaglutide FJLU TF 4 BOTE 0 75 mg 1 u i vat 1 7 LY2189265 dulaglutide 1 7 UUUUUUUUUO0ODODDOD LY2189265 1 7 dulaglutide 1 7 AT 1 7 1 KHNL 0 75 mg 18 mg 2010 1 20 S ESTO DIES ae 1 31
421. tide 8 A gt G 22 G gt E 36 R gt G GLP 1 7 37 prot ine de fusion avec le tris t traglycyl L s ryl L alanine lien prot ine de fusion avec la d s 276 lysine 57 L proline 63 L alanine 64 L alanine r gion Fc de l immunoglobuline G4 humaine 10 S gt P H 4 F gt A 5 L gt A CH2 107 K gt CH3 du IGHG4 01 55 55 58 58 bisdisulfure du dimere 56 LY2189265 dulaglutide WHO Drug Information Vol 25 No 1 2011 dulaglutida eliglustatum eliglustat liglustat eliglustat elpamotidum elpamotide elpamotide elpamotida 19 HHHHHHHHHH Recommended INN List 65 prote na de fusi n entre el p ptido similar al glucag n 1 y la inmunoglobulina G4 2 glicil 16 L glutamil 30 glicil p ptido similar al glucag n humano 1 7 37 p ptido 8 A gt G 22 G gt E 36 R gt G GLP 1 7 37 prote na de fusi n con el tris tetraglicil L seril L alanina v nculo prote na de fusi n con la des 276 lisina 57 L prolina 63 L alanina 64 L alanina regi n Fc de la inmunoglobulina G4 humana 10 S gt P H 4 F gt A 5 L gt A CH2 107 K gt CH3 del IGHG4 01 55 55 58 58 bisdisulfuro del dimero Cze4eH4o44 Nzo4OsseS 18 Monomer Monomere Monomero HGEGTFTSDV SSYLEEQAAK EFIAWLVKGG GGGGGSGGGG SGGGGSAESK 50 YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP 100 EVOENWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC 150 KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG 200 FYPSDIAVEW ESNGOPENNY KTTPPVLDSD
422. tin and its major metabolite o hydroxyatorvastatin The mean t of atorvastatin and o hydroxyatorvastatin were increased by 17 and 41 46 respectively following dulaglutide administration These observations are not clinically relevant No dose adjustment of atorvastatin is necessary when administered with dulaglutide Digoxin After coadministration of steady state digoxin with 2 consecutive doses of dulaglutide overall exposure AUC and tnax of digoxin were unchanged and Cmax decreased by up to 22 This change is not expected to have clinical consequences No dose adjustment is required for digoxin when administered with dulaglutide Anti hypertensives Coadministration of multiple dulaglutide doses with steady state lisinopril caused no clinically relevant changes in the AUC or Cmax of lisinopril Statistically significant delays in lisinopril tax of approximately 1 hour were observed on Days 3 and 24 of the study When a single dose of dulaglutide and metoprolol were coadministered the AUC and Cmax of metoprolol increased by19 and 32 respectively While metoprolol tmax was delayed by 1 hour this change was not statistically significant These changes were not clinically relevant therefore no dose adjustment of lisinopril or metoprolol is necessary when administered with dulaglutide Warfarin Following dulaglutide coadministration S and R warfarin exposure and R warfarin Cmax Were unaffected and S warfarin Cmax decreased by
423. ty data Non clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat dose toxicity In a 6 month carcinogenicity study in transgenic mice there was no tumorigenic response In a 2 year carcinogenicity study in rats at 7 7 times the human clinical exposure following 1 5 mg dulaglutide per week dulaglutide caused statistically significant dose related increases in the incidence of thyroid C cell tumours adenomas and carcinomas combined The clinical relevance of these findings is currently unknown During the fertility studies a reduction in the number of corpora lutea and prolonged oestrous cycle were observed at dose levels that were associated with decreased food intake and body weight gain in maternal animals however no effects on indices of fertility and conception or embryonic development were observed In reproductive toxicology studies skeletal effects and a reduction in foetal growth were observed in the rat and rabbit at exposures of dulaglutide 11 to 44 fold higher than those proposed clinically but no foetal malformations were observed Treatment of rats throughout pregnancy and lactation produced memory deficits in female offspring at exposures that were 16 fold higher than those proposed clinically 6 PHARMACEUTICAL PARTICULARS 6 1 List of excipients Sodium citrate Citric acid anhydrous Mannitol Polysorbate 80 Water for injections 6 2 Incompatibilities
424. uated in six randomised controlled phase III trials involving 5 171 patients with type 2 diabetes Of these 958 were gt 65 years of which 93 were 7 75 years These studies included 3 136 dulaglutide treated patients of whom 1 719 were treated with Trulicity 1 5 mg weekly and 1 417 were treated with Trulicity 0 75 mg weekly In all studies dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin Alc HbAIc Monotherapy Dulaglutide was studied in a 52 week active controlled monotherapy study in comparison to metformin Trulicity 1 5 mg and 0 75 mg were superior to metformin 1500 2000 mg day in the reduction in HbAlc and a significantly greater proportion of patients reached an HbA Ic target of lt 7 0 and lt 6 5 with Trulicity 1 5 mg and Trulicity 0 75 mg compared to metformin at 26 weeks Table 2 Results of a 52 week active controlled monotherapy study with two doses of dulaglutide in comparison to metformin Baseline Mean Patients at target Change in Change in HbAlc change in HbAlc FBG body HbAlc weight lt 7 0 lt 6 5 mmol L kg 26 weeks Dulaglutide 1 5 mg 4 Hi once weekly n 269 7 63 0 78 61 5 46 0 1 01 2 29 Dulaglutide 0 75 mg once weekly n 270 7 58 0 71 62 6 40 0 1 46 1 36 Metformin 1500 2000 mg day 7 60 0 56 53 6 29 8 1 34 2 22 n 208 S2 Weeks Dulaglutide 1 5 mg 4 HH once weekly n 269 7
425. ulates glucose dependent insulin secretion and reduces glucagon secretion Treatment with TRULICITY 0 75 mg and 1 5 mg once weekly increased fasting insulin from baseline at Week 26 by 35 38 and 17 50 pmol L respectively and C peptide concentration by 0 09 and 0 07 nmol L respectively in a Phase 3 monotherapy study In the same study fasting glucagon concentration was reduced by 1 71 and 2 05 pmol L from baseline with TRULICITY 0 75 mg and 1 5 mg respectively Gastric Motility Dulaglutide causes a delay of gastric emptying The delay is largest after the first dose and diminishes with subsequent doses Cardiac Electrophysiology QTc The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study Dulaglutide did not produce QTc prolongation at supratherapeutic doses of 4 and 7 mg 12 3 Pharmacokinetics The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus Following subcutaneous administration the time to maximum plasma concentration of dulaglutide at steady state ranges from 24 to 72 hours with a median of 48 hours After multiple dose administration of 1 5 mg to steady state the mean peak plasma concentration Cmax and total systemic exposure AUC of dulaglutide were 114 ng mL range 56 to 231 ng mL and 14 000 ng h mL range 6940 to 26 000 ng h mL respectively accumulation ratio was approximately 1 56 Steady state plasma dulaglutide concentrations
426. ure It is unknown whether TRULICITY causes thyroid C cell tumors including medullary thyroid carcinoma MTC in humans as human relevance of dulaglutide induced rodent thyroid C cell tumors has not been determined see Warnings and Precautions 5 1 and Nonclinical Toxicology 13 1 TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 MEN 2 Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors e g mass in the neck dysphagia dyspnea persistent hoarseness Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY see Contraindications 4 1 and Warnings and Precautions 5 1 1 INDICATIONS AND USAGE TRULICITY is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 1 1 Limitations of Use TRULICITY is not recommended as a first line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C cell tumor findings to humans Prescribe TRULICITY only to patients for whom the potential benefits outweigh the potential risk see Warnings and Precautions 5 1 TRULICITY has not been studied in patients with a history of pancreatitis see Warnings and Precauti
427. us AWARD 4 Assessment of Weekly Administration of LY2189265 in Diabetes 4 22 1 12 LY2189265 dulaglutide 5 3 5 2 5 3 52 1 H9X JE GBDQ A 52 Week Open Label Long Term Safety Study of LY2189265 in Combination with Monotherapy of Oral Antihyperglycemic Medications in Patients with Type 2 Diabetes Mellitus CRUE RERBA K LET 2011 12 2013 12 5353 5 3 5 3 1 1 Patient Narrative Report for GBDQ 5 3 5 3 1 2 Patient Narrative Report for GBDY 5 3 5 3 1 3 Patient Narrative Report for interim GBDP 5 3 5 3 1 3 1 Patient Narrative Report for final GBDP 5 3 5 3 2 Integrated Summary of Safety Information 5 3 5 3 3 Dulaglutide Cardiovascular Event Risk Assessment Cardiovascular Meta Analysis 5 3 7 5 3 7 1 5 3 7 1 1 H9X MC GBCN 3 7 1 2 H9X MC GBDR 5 3 7 1 3 H9X MC GBDT 5 3 7 1 4
428. use of dulaglutide in pregnant women Studies in animals have shown reproductive toxicity see section 5 3 Therefore the use of dulaglutide is not recommended during pregnancy Breast feeding It is unknown whether dulaglutide is excreted in human milk A risk to newborns infants cannot be excluded Dulaglutide should not be used during breast feeding Fertility The effect of dulaglutide on fertility in humans is unknown In the rat there was no direct effect on mating or fertility following treatment with dulaglutide see section 5 3 4 7 Effects on ability to drive and use machines Trulicity has no or negligible influence on the ability to drive or use machines When it is used in combination with a sulphonylurea or prandial insulin patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines see section 4 4 4 8 Undesirable effects Summary of safety profile In the phase II and phase III studies conducted 4 006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products The most frequently reported adverse reactions in clinical trials were gastrointestinal including nausea vomiting and diarrhoea In general these reactions were mild or moderate in severity and transient in nature Tabulated list of adverse reactions The following adverse reactions have been identified based on evaluation of the full duration of the phase II and pha
429. uted to the pharmacologic activity at 1 63 mg kg a systemic exposure 16 fold the MRHD based on AUC The human relevance of these memory deficits in the F4 female rats is not known 8 3 Nursing Mothers It is not known whether TRULICITY is excreted in human milk Because many drugs are excreted in human milk and because of the potential for clinical adverse reactions from TRULICITY in nursing infants a decision should be made whether to discontinue nursing or to discontinue TRULICITY taking into account the importance of the drug to the mother 8 4 Pediatric Use Safety and effectiveness of TRULICITY have not been established in pediatric patients TRULICITY is not recommended for use in pediatric patients younger than 18 years 8 5 Geriatric Use In the pool of placebo and active controlled trials see Adverse Reactions 6 1 620 18 696 TRULICITY treated patients were 65 years of age and over and 65 TRULICITY treated patients 1 996 patients were 75 years of age and over No overall differences in safety or efficacy were detected between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out 8 6 Hepatic Impairment There is limited clinical experience in patients with mild moderate or severe hepatic impairment Therefore TRULICITY should be used with caution in these patient populations In a clinical pharmacology study in subjects with varying degrees of hepatic impairment no clinical
430. utide 1 7 1 1 7 p hi 1 0 75 mg KF LEGAO mye PUREE ED 71 21 ed i 1 0 75 mg O 2745 m 1 0 75 mg O 149 Teer sl RELA OR A AZ ed S
431. utide 2 4 MuLV MMV PRV 3 Reo 3 A EM ME y 374 A rv MuLV LY2189265 110 dulaglutide 2 II GEM 2 4 E PABLO AY
432. week TRULICITY must not be administered intravenously or intramuscularly TRULICITY solution should be visually inspected for particulate matter and discoloration prior to administration 3 DOSAGE FORMS AND STRENGTHS Injection 0 75 mg 0 5 mL or solution in a single dose pen Injection 1 5 mg 0 5 mL solution in a single dose pen Injection 0 75 mg 0 5 mL solution in a single dose prefilled syringe Injection 1 5 mg 0 5 mL solution in a single dose prefilled syringe 4 CONTRAINDICATIONS 4 14 Medullary Thyroid Carcinoma TRULICITY is contraindicated in patients with a personal or family history of medullary thyroid carcinoma MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 MEN 2 see Warnings and Precautions 5 1 4 2 Hypersensitivity TRULICITY is contraindicated in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components see Warnings and Precautions 5 4 5 WARNINGS AND PRECAUTIONS 5 1 Risk of Thyroid C cell Tumors In male and female rats dulaglutide causes a dose related and treatment duration dependent increase in the incidence of thyroid C cell tumors adenomas and carcinomas after lifetime exposure see Nonclinical Toxicology 13 1 Glucagon like peptide GLP 1 receptor agonists have induced thyroid C cell adenomas and carcinomas in mice and rats at clinically relevant exposures It is unknown whether TRULICITY will cause thyroid C cell tumors in
433. were nausea 1 0 1 9 96 diarrhoea 0 5 0 6 and vomiting 0 4 0 6 96 and were generally reported within the first 4 6 weeks Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important It allows continued monitoring of the benefit risk balance of the medicinal product Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V 4 9 Overdose Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders and hypoglycaemia In the event of overdose appropriate supportive treatment should be initiated according to the patient s clinical signs and symptoms 5 PHARMACOLOGICAL PROPERTIES 5 1 Pharmacodynamic properties Pharmacotherapeutic group not yet assigned ATC code not yet assigned Mechanism of action Dulaglutide is a long acting glucagon like peptide 1 GLP 1 receptor agonist The molecule consists of 2 identical disulfide linked chains each containing a modified human GLP 1 analogue sequence covalently linked to a modified human immunoglobulin G4 IgG4 heavy chain fragment Fc by a small peptide linker The GLP 1 analog portion of dulaglutide is approximately 90 homologous to native human GLP 1 7 37 Native GLP 1 has a half life of 1 5 2 minutes due to degradation by DPP 4 and renal clearance In contrast to native GLP 1 dulag
434. x and total AUC exposures were approximately 114 ng ml and 14 000 ngh ml respectively after multiple subcutaneous 1 5 mg doses of dulaglutide in patients with type 2 diabetes Steady state plasma concentrations were achieved between 2 to 4 weeks of once weekly administration of dulaglutide 1 5 mg Exposures after subcutaneous administration of single dulaglutide 1 5 mg doses in the abdomen thigh or upper arm were comparable The mean absolute bioavailability of dulaglutide following single dose subcutaneous administration of single 1 5 mg and 0 75 mg doses was 47 96 and 65 respectively Distribution The mean volume of distribution after subcutaneous administration of dulaglutide 0 75 mg and 1 5 mg at steady state in patients with type 2 diabetes mellitus were approximately 19 2 L and 17 4 L Biotransformation Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways Elimination The mean apparent clearance of dulaglutide 0 75 mg and 1 5 mg at steady state was 0 073 L h and 0 107 L h with an elimination half life of 4 5 and 4 7 days respectively Special populations Elderly patients gt 65 years old Age had no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide Gender and race Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide Body weight or body mass index Pharmacokinetic analyses hav
435. y study Development and psychometric Ishii H et al validation of the Diabetes Therapy Related QOL DTR QOL questionnaire Efficacy and safety of exenatide Ji L et al once weekly vs exenatide twice daily in Asian patients with type 2 diabetes mellitus Improved glycemic control and Kadowaki T reduced bodyweight with exenatide a double blind randomized phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks Kaku K et al with minimal hypoglycaemia and no weight change with the once daily human glucagon like peptide 1 analogue liraglutide as add on to sulphonylurea in Japanese patients with type 2 diabetes Improved glycaemic control 29 1 12 Obes Metab 2010 12 9 766 771 Diabetes Metab Res Rev 2010 26 4 287 296 International Society for Quality of Life Research 2009 A 83 Abstract 104 1252 Clin Ther 2012 34 9 1892 1908 J Med Econ 2012 15 3 556 563 J Diabetes J Diabetes Investig 2011 2 3 210 217 Diabetes Obes Metab 2010 12 4 341 347 LY2189265 dulaglutide o ee Dome EN Effects of long term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus the FIELD study randomised controlled trial Glucagon like peptide 1 receptor agonists activate rodent thyroid C cells causing calcitoni
436. y adjusted 1 sided p value 0 001 for superiority of TRULICITY compared to placebo assessed only for HbA1c B Multiplicity adjusted 1 sided p value 0 001 for superiority of TRULICITY compared to exenatide assessed only for HbA1c Subjects included in the analysis are a subset of the ITT population that had at least one post baseline assessment The primary analysis included 119 269 271 and 266 individuals randomized to placebo TRULICITY 0 75 mg TRULICITY 1 5 mg and exenatide respectively p 0 001 TRULICITY compared to placebo assessed only for HbA1c 7 096 p lt 0 001 TRULICITY compared to exenatide assessed only for HbA1c 7 096 16 8 5 TRULICITY 1 5 mg TRULICITY 0 75 mg Exenatide 8 0 Placebo LS Mean HbAtc 0 13 26 Whee mE LOCF Weeks Post Randomization Number of subjects with observed data Placebo 141 108 TRULICITY 0 75 mg 280 251 TRULICITY 1 5 mg 279 259 Exenatide 276 242 Mean change from baseline adjusted for baseline HbA1c and country Figure 4 Adjusted Mean HbA1c Change at Each Time Point ITT and at Week 26 ITT LOCF Add on to Metformin and Sulfonylurea In this 78 week 52 week primary endpoint open label comparator study double blind with respect to TRULICITY dose assignment 807 patients were randomized to TRULICITY 0 75 mg once weekly TRULICITY 1 5 mg once weekly or insulin glargine once daily all as add on to maximally tolerated doses of metformin and
437. y studies conducted in patients with type 2 diabetes mellitus up to 6 weeks the majority of gastrointestinal events were reported during the first 2 3 days after the initial dose and declined with subsequent doses Acute pancreatitis The incidence of acute pancreatitis in Phase II and III clinical studies was 0 07 for dulaglutide compared to 0 14 for placebo and 0 19 for comparators with or without additional background antidiabetic therapy Pancreatic enzymes Dulaglutide is associated with mean increases from baseline in pancreatic enzymes lipase and or pancreatic amylase of 11 to 21 see section 4 4 In the absence of other signs and symptoms of acute pancreatitis elevations in pancreatic enzymes alone are not predictive of acute pancreatitis Heart rate increase Small mean increases in heart rate of 2 to 4 beats per minute bpm and a 1 3 and 1 4 incidence of sinus tachycardia with a concomitant increase from baseline 7 15 bpm were observed with dulaglutide 0 75mg and 1 5 mg respectively First degree AV block PR interval prolongation Small mean increases from baseline in PR interval of 2 to 3 msec and a 1 596 and 2 4 96 incidence of first degree AV block were observed with dulaglutide 0 75 mg and 1 5 mg respectively Immunogenicity In clinical studies treatment with dulaglutide was associated with a 1 6 incidence of treatment emergent dulaglutide anti drug antibodies indicating that the structural modifications in t
438. ycaemia with Trulicity 1 5 mg seven with Trulicity 0 75 mg and fifteen with insulin glargine Fasting blood glucose Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks The improvement in fasting glucose was sustained through the longest study duration of 104 weeks Postprandial glucose Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline changes from baseline to primary time point 1 95 mmol L to 4 23 mmol L Beta cell function Clinical studies with dulaglutide have indicated enhanced beta cell function as measured by homeostasis model assessment HOMA2 B The durability of effect on beta cell function was maintained through the longest study duration of 104 weeks Body weight Trulicity 1 5 mg was associated with sustained weight reduction over the duration of studies from baseline to final time point 0 35 kg to 2 90 kg Changes in body weight with Trulicity 0 75 mg ranged from 0 86 kg to 2 63 kg Reduction in body weight was observed in patients treated with dulaglutide irrespective of nausea though the reduction was numerically larger in the group with nausea Patient reported outcomes Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily In addition there was significantly lower perceived frequ
439. ype 2 diabetes mellitus see section 4 2 for information on paediatric use 5 2 Pharmacokinetic properties Absorption Following subcutaneous administration to patients with type 2 diabetes dulaglutide reaches peak plasma concentrations in 48 hours The mean peak Cmax and total AUC exposures were approximately 114 ng ml and 14 000 ngh ml respectively after multiple subcutaneous 1 5 mg doses of dulaglutide in patients with type 2 diabetes Steady state plasma concentrations were achieved between 2 to 4 weeks of once weekly administration of dulaglutide 1 5 mg Exposures after subcutaneous administration of single dulaglutide 1 5 mg doses in the abdomen thigh or upper arm were comparable The mean absolute bioavailability of dulaglutide following single dose subcutaneous administration of single 1 5 mg and 0 75 mg doses was 47 96 and 65 respectively Distribution The mean volume of distribution after subcutaneous administration of dulaglutide 0 75 mg and 1 5 mg at steady state in patients with type 2 diabetes mellitus were approximately 19 2 L and 17 4 L Biotransformation Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways Elimination The mean apparent clearance of dulaglutide 0 75 mg and 1 5 mg at steady state was 0 073 L h and 0 107 L h with an elimination half life of 4 5 and 4 7 days respectively Special populations Elderly patients gt 65 years old Age h

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