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1. 3 6 1
2. RC An 1 7 1 e 2 30 Oe cn ad 3 H s
3. 3 4 CDS 1 1 1
4. x En ae N LY333334 1 7 R 1 7 1 3 TE de TE 2 MEE SU Conta 1 d Na 1 p n cyii WE FIR A AAR BE RH Qo De n Bik
5. WER SDS BED IVS BE IS 11 PER FORTEO rDNA 84 N 34 1 34 rhPTH 1 34 o 4117 8 rDNA
6. 17 1 1 7 1 o ia 600 hg 600 hg 2004 2001 60 mg 5 mg WAT 7 TRAH e uM EHTEL Ser Val Ser Glu Ile Gln Leu Met His A
7. E Un A uen 2 PLE OYSPO CHERV S Bil 2 a 100 3 3 HERE D EE Ze Me L Hcet REI 4 BE OHA BAT C OD Ze AE ROV SPELL AEN
8. 4 8 FORSTE 82 9 84 5 1 FORSTEO 21 10 21 100 lt 1 10 gt 1 1000 lt 1 100 21 10000 lt 1 1000 1 100000
9. 4 1 4 BA LY 333334 EX F3 PARRA Tes 1 6 E
10. E VIRUS Il 4 4 10 40 ug 252 48 GHCS GHDB t 19 0 s
11. FORTEO 5 mg 3 22 89 57 428 19 81 214 FORTEO 214 EKAR 18 1000 mg 800 IU D FORTEO BEC 4 6 FORTEO 3 1 FORTEO 21 18 FORTEO 2 0 FORTEO FET 15
12. HE 2 8C AUC pg hr mL Cs pg mL tinax hr to hr 222 53 0 227 35 7 0 25 0 25 0 75 0 708 0 479 1 21 a CV n 18 b n 18 c n 17 22 11 11 20 pg 1 Thot 2 HLL AUCo KU C 229 pg hr mL 2 7 pg mL
13. x En ae N LY 333334 1 7 R 1 7 1 1 AVE CO PARE Be LRAT A 7705 LEN HIERIE 60 ms 3 E TENE 2 ne AA AST GOT el ALT GPT y GTP vd Br C GREAT MN one TITO des 2 ea e ee IRE 1 3 mi i 7 o AST GOT ALT GPT REM BEDS dh bbs n
14. 5 7 FORTEO 5 aes E 4 5 8
15. E LJE I A S ERRA 1 7K E 0 7
16. 2 3 28 28 WRU 4 1 Es 2 JIS T 3226 2 A A We BD 3 A 4 1 10
17. 1 1 20 pg 1 F 1 1 Wink BA ie AIR FR ALP ERF DERK ST B T gp RYE fi PRESS EF di LJ FEIR p HE AR Ts s EH f AST GOT ALT GPT E y GTP Ex KJR BUR
18. 18 3 ia
19. 7 AN RM E 1 1 20mg R 40 pakg 6 1 T sala 2 BEECH 22 11 11 20 40 18 Rees eae litre 1 5 ug kg H CHER ORT 80 hg 17 54 hg OK BAS 5 Hg kg
20. cf LY 333334 K Tes 13 2 zu 30 HE ugm 6 E 100 300 ug kg F 1 6
21. 8 5 PARE A HIE AT SEE 1637 75 65 23 75 RAE CHK AARI 437 FORTEO 13 75 Cs Ti ARIE CK FEV CLE EFORTEO FORTEO CR LC OIL ZR EGR OEE OPERE FORTEO E 39 65
22. Forsteo Forteo 20034 Forsteo 20044 Forteo 20054 Forteo 20054 Forteo 20044 Forteo 2004 Forteo Forteo Forteo Forsteo Forsteo Forsteo Forteo Forsteo Forsteo Forteo Forteo Forsteo Forteo Forsteo Forsteo Forteo Forteo Forsteo Forteo Forteo Forteo Forsteo Forteo 20054 Forteo 20054 Forteo Forsteo Forteo Forsteo Forteo Forsteo Forsteo Forteo Forteo Forsteo 2004 5 1 Forsteo 2003 6 10 Forsteo f 20044E5 H 11H Forteo 2004 10 7 Forteo LY333334 1 6 R 1 6 1 2010 1 FC Forteo Forsteo 1304 Forteo 7 Forteo
23. 2 2 2 26 5 30 ng 20 ug 3 20 AUC 2 30 ng kg 24 5 30 ng kg 6 6 30 ug kg H 6 20 6 7 v FIC 5uglkg H 6 20
24. 2 2 1 4 6 NN Le RE 1 16 A 16 eb 18 LY333334 1 8 ER GE vo EROS
25. 3 TWH 4 6 7 EE TREES X DHS 2 180 mg CAA H ICI fult A At MILES iat Suu LY333334 1 7 x En af ni 1 7 1
26. 3500 db 25 FB 2 HREJ OTE BO BRS p
27. 1 IL TI i 1 5 2 3 2 1 209 f Aa I M O 00050 nn
28. fi BEY BR An LY333334 12 1 7 1 0 ee uM rE Bs 4 4
29. HE BANE ERARA Hos FRR BSLORBRS RRE ZR REINA FETH ARE E BUF LY333334 1 6 PRE HETH SAVE ZW 2 76 mmol L 3 25 mmol L
30. 62 AS 16 DESC 2 Fill FF B ABO db SRC f Hed ee 3 4 b PARE AN Fr ELA H EF Mee
31. 9 9 2 8C 2 8 CO cus due 3 ous dede Cmax 28 28 AUC qa rd 3 1 28 28 2 JIS T 3226 2 A
32. QOL 2006 Cn EC All AY HLAAIEO AJ JE Z am j dzvCv 2 mU D TREI MELT ORE M EAR dis h SERM BMD PP BI 6 SUED ALFIE OO HIG jz E R Ross et al 1995
33. 2 3 3 S
34. RADA he vb 1 An LY333334 12 1 7 1 a te ek D d pu 3 1 5 1000 FET 2 2 1000 AEC
35. 5 3 lt 18 18 5 2 FN wo J e 0 4 4 4 6 es e
36. iu 1 7 1
37. 4 4 4 6 16 24 ja 16
38. Lal FFF 40 hg x p EWIE 30 mL min AUC ti GHAW
39. 20 5 ug kg C Sugkg KIS OE B 3 6 AU 14 14 1 FARR RHEL AT SEEN ORS FORTEO 1 1 19 1 N 30 18 X in vivo ug 16 160 Bi HU EE ZB 10000 ug
40. on T PRI Bi ete 7 qi Q
41. 8 267 60 meth 6 Db 540 120 GE 4 E A 30 ng kg 30 pg kg 1000 ug kg E pij Hugh 8 16
42. RSET aes o pe AA E C RUTWS AA i87 aa EE 7 5 LOA GEE Ly EI Se Ji Voss ALO E FEE FRM IL FR P
43. Ded 7 5 1 Ob 2388 E 3 mi BH Dt op OY ir mT H
44. 12 ER E CIENS BSAP 1 6 12 45 N NTX KURY 1 PICP 23 E pk amp NTX DPD LY333334 1 6 EORTEO 12 3
45. FORTEO FORTEO rDNA 2002 5 1 13 1 FORTEO 5 1 FORTEO 5 1
46. n E O D Es 6 D D 4 sg cde 5 3
47. 2 Al P gt 9 7 8 PTP PTP 1 PTP PTP PTP PTP 2 8 C i
48. Ei HU EE 2 CEM E BAT ita 1 o me o H ee LATS 53 LY333334 1 6 4 7
49. 3 14 4 1 2 Co 3 1 4 HP 14 20 hg ERT 2 4 48 AUC 1 BERS 18
50. 5 LY333334 R 1 7 1 1 7 x En af ni 6 1 Ries AN REL SM EAS
51. 2 Fill FF B ABO db SRC f Hed ee 3 4 b PARE AN Fr ELA H EF Mee ORME DS Z2 E D
52. 4 E 4 FORSTEO N 544 N 541 9596 CI lala 0 22 055 2 6 0 47 0 25 0 87 1 5 0 38 0 17 0 86 0 09 0 60 N CI X 448 Forsteo f 444 ps0 001 d ps0 025 19 BMD 9 4 p lt 0 001 FORSTEO pivotal study
53. FH 437 58 7 WR T 2 2 2 1 35 39 HARARE MITRE HE HLA TE O 1000 mg 4001IU D 1 6 10 5 2 6 3 9 18 24 BMD 1 4 1 2 FSH LH BMD 3 12 D BMD 1
54. NIH 2000 HED DI BMD oj 1994 BMD BMD 2001 AZ py 2 CH APHEX K Hj a HA stu 7A CA BMD BMD KUF H Hi IUCR 1 Do BMD POH Sb OILS CARE EL 20 44 70 ff
55. 5 es 28 2002 3 18 A E TIER BMD 6 20 hg dg Be EMBL LC S2 EAs ForteoPen 1 1 ForteoPen 1 1 opea mcd n E Et E Adi ao Jp oa 28 H E 60 ng 18 3 O
56. GHAC 1 N H AK ACA HL TAE RB HE Ze EE GHDB 55 A dd M DU Hite LIK 9D AC AA 20 ng H ry 1 A t 1 LEA L2 L4 BMD FE E 20 ug 3 ve bx KER Br 5 in
57. ORME DS Z2 E D MY 4 E H 3 10 HIF 8 3 2 7 2 8 ALP EF 4 ffi
58. 1 12 TUE RE LR LY333334 GR tox22 A Chronic Toxicity Study of LY333334 Administered Subcutaneously to Cynomolgus Monkeys for 1 Year 109795 110895 A Pilot Study in Fischer 344 Rats Given LY 333334 Daily by Subcutaneous Injection for 5 Days p01095 A Dose Ranging Toxicity Study of LY333334 Administered by Subcutaneous Injection to Cynomolgus Monkeys 4 2 3 3 In Vitro tox02 The Effect of LY333334 on the Induction of Reverse Mutations in Salmonella typhimurium and Escherichia coli Using the Ames Test tox01 The Effect of LY333334 on the Induction of Forward Mutation at the Thymidine Kinase Locus of L5178Y Mouse Lymphoma Cells tox06 The Effect of LY333334 on the In Vitro Induction of Chromosome Aberrations in Chinese Hamster Ovary Cells In Vivo
59. GHDB 18 1 5 3 1 Rib E GHCS GHDB GHAC GHAJ 4 GHBJ GHBO GHAD GHAE GHAW GHBA GHBC GHBI GHBR GHCO LY333334 1 5 aema eee Biz nj
60. 203 8 E 20 pg 12 52 9 1 20 ng 10 L2 L4 0 04 9 82 s dg 11 Neer R M et al N Engl J Med 344 1434 2001 P lt 0 001 2 En 52 20 pg ORE L2 L4 ima nes iN and EE 13 18 10 04 18 76 11 93 14 Hock J M J Musculoskel Neuron Interact 2 33 2001 15 Jilka R L Bone 40 1434 2007 2
61. I9 LE 7 tt M MOT KE VACHMTO 3 A 31 75 mL min 12 7 5 40pg C 228 6 pg mL AUC 326 6 pg hymL Ut 1 18 hr 90 mL min 9 fi 5 4 C 222 8 pg mL AUC Eros rae rere hee See 30 mL min 5 3 AX pin 2 40 ug Cu 12277 A Nisi D E N EX fle aka AS TE ae pecu ponis iue M ae in Ple ne Ser Val Ser Glu Ile GIn Leu Met His Asn Leu Gly Lys His Leu Asn Ser GE pr Ei PUR Met Gl
62. 18 10 20 40 60 hg HE F 20 40 60 hg 4 mg 1 AUC Cmax tx to 40 H 1 1 30 I GHCS AR BOT REH BXCG 5R 73 VF
63. 13 07 2009 2 3 07 2009 FORTEO 1 34 rhPTH 1 34 1 1 1 2 1 3 Bi RE 1 1 20 ug Ql 22 2 3 FORTEO 2 4 FORTEO
64. 1 866 382 6813 www forteoregistry rtiore 17 2 FORTEO ee ee E 5 7 BAR p zn 17 3 fat Fit 17 4 HXHEAAEO MORE 22 LY333334 1 6 i
65. FRKE EX BS e A La Hz Eit ZR LY333334 1 8 PTH 20 hg 40 ug 20 hg 40 ug GHAJ TI
66. 71 KRKE 12 3 ZH 6 6 1 LY333334 1 6 FORTEO 28 86 67 1382 21 79 2 11 19 FORTEO 691 691 1000 mg 400 IU D
67. LY333334 1 12 GR 5 3 54 RA SS ap 4 E EUER 5 3 54 B3D MC GHAL IE Ga E CARO ZUSEUE Effects of LY333334 in Postmenopausal Women Who O G H Experience Rapid Bone Loss EE or Multiple Osteoporotic Fractures in Study B3D MC GHAC 3 5 4 2 B3D MC GHAU te GG Effects of LY333334 on Bone Mineral Density in Early 19 Menopausal Women 5 3 5 4 3 B3D MC GHAV NEA EH Effects of Anti Resorptive a Drug on Bone Formation in ofr H Osteoporotic Postmenopausal EN Women Treated with LY333334 5 3 544 B3D IT GHCU Eli Lilly 2004 7 A Pilot Study On The Use Of jand eu Teriparatide In Severe Compan 2003 12 Osteoporotic Women With ly EE Hip Fracture And Submitted To Hip Replacement 5 9 6
68. MEO Ti LIA vent 2006 11 HATRHERAEO TF E c i8 ANN E FC AACA REBRE ICS V LY333334 VV Hee TJERK Flt RR ARE Jun des S Tes FATAR GHAJ GHBZ RL bm
69. AM Zi tt IW x EH mi gt 1 5 2 3 2 5 Il 209 HAs L GHCS 10 ng 40 ng 20 hg 20 ug 12 IHRRKT CHK a I i i i _ OCHRE TOR U oWc Pi _ 7_ ee DS
70. 5 3 24 4 5 15 LOK 4 6 For hOB AER E CN ess
71. II GHDB 1 20 ug 12 1 L2 L4 BMD 20 ug 12 1 8 4 2 2 19 oe ADD 1 20 hg 1
72. 7 4 Szulc and Delmas 2008 I C PICP EFS 1 I N PINP 3 18 BMD Chen et al 2005 BAP 1 PIC 1 22 Dobnig et al 2005 GHMB
73. 20 ug EO 24 48 AUC 21 LY333334 1 9 600 ug 600 hg 1 9 LY333334 1 9 1 9 1 9 AN 1 1 92 INN tette iter e E dert Dore D T RD or erre rhe ttt eda 1 LY333334 1 9 1 9 HHHHHHHHHH 1 9 1 JAN 20 9 0905002 JAN HAA Teriparatide Genetical Recombination 1 34 34 RA T
74. OD 3 WREEETDEE 000 Mu DEREN AREA EE OBSS UH SBR A 31 75 mL min 12 7 5 40pg C 228 6 pg mL AUC 326 6 pg hrmL Ut 1 18 hr 90 mL min EA E 9 5 4 C 222 8 pg mL AUC ox nid pa yin Pup 321 7 pg hr mL t Ll4h RE AN dd ad 30 ml min 5 3 sniparatide Genetical Reconibinanion pa Ps 2 40 pg Come 227 7 LEA 2 Oa Pae OaS N EX He Bl AS TE Affe iB pone ponis iue M oec u
75. 16 2 vw REZ IES REE 1 2 HE FARE EF KILN OER 38 3
76. BMD k IHE Pcr d B PERO 18 BHT Ch SB 1 E 12 L1 L4 BMD EPA 20 hg GHAC 24 HO Gub Fd 24 GHDB AR MEE 00006 RE p Bemis coffe Ps Be ones nH ASF
77. REOR TU VARA STATE RR 2352 L Dep m XF Pie CERE OD do Zo BE Tee Tee 1
78. 20 ng 19 14 3 20 hg 5 0 20 hg 651 0086 x L3 7 1x5 OPI LC MEORE BONARHERUUROUNGEA ree AY NEA RT Him 20 pg L1 L4 0120 360 605 1 13 9 70 ea 8 45 17 30 P lt 0 001 2 US 11 12 20zg
79. 1 5 1 CCC EAT cl HRO Fe EA WMO t EI YE 9T ER ET mt BA PK PK PK PECEEEAT cl ENS Co S BERO WO Y SEI YT LY333334 1 6 600 hg 600 hg 1 6 LY333334 1 6 1 6 Lue eene tenentes 1 1 6 1 ASEESSA S DS LS ee t aiat L ims 1 1 6 2 EU kk 4 LY333334
80. FORTEO FORTEO 5 1 BITERI 6 2 FERRE 13 1 H 1 1 1 FORTEO PARR LE FORTEO KAR 14 1 ZW 1 2 PH OPRED BV RSE CUP REESE A PIC
81. 2 0 D 3 4 5 3 4 2 600 pg 600 pg AE 0 984 mg PIT TER 0 24 mg ID 108 96 mg Im 7 2 mg pH
82. A BD 3 A 41 Ones RIA LTDA iE 2 8 C CHET SLB ID D o o 2 Ed KE eran ICA UR MENT 2 8 CC
83. By VA BUR Fr Hi Ea 1 100 2006 AY PELE TIE 50 AE av TUC SCKBEHE SAPD UT HIE T PER SEDE DT UE 30 4 400 H 12 LLL Hagino et al 2009 80 43 E LC BRUT AF SERM gt BMD
84. NN 34 AME OR 5 1 pal e FV YC Bde SAU AAR A SAB ED E VEER OF PE 1 6 6 asz D ASABE PIE RIL HOA LARTER LY333334 1 6 SENSU SEKI ICR SAE 43
85. OZ MERR iR ED NE a pre Cs f i E da 1 CRUS EUR SORE 14 cee fre DYD EM 3 1 um 14 4 14 10 10
86. 7 18 140 10 40 pg 30 120 mg 2184 252 48 311 19 0 117 37 6 126 8 9 2 9 3 2 7 Pil 9 2 9 2 8 7 5 1 699 1 4 2 8 ALP 4 1 6 Beer mhi 1 6 fW 3 1 6 FRE 4 676 102 1 2 3 1 3 15 1 194 1 2 3 LDH 1 2 160 49 30 6 3 4 CK CPK 10 7 2 6 11
87. x SSS dam MO 2 2 2 1 1 1 4 6 K K 16 J FLME EC RMT SO iB ee E DD
88. 1 34 PTH H CH P E FORSTEO l3 HTRRE amp AE LIBRIS EOD AE RAM CHS 1 1 KATA PE BMI body mass index
89. MY 4 E H 3 10 HIF 8 3 2 7 2 8 ALP EF 4 ffi 10 40 ng 232 48 19 0 1 7 2 8 1 6 ENE 3 1 2 1 296 3 1 296 11 10 5 CBE y 600 u g R
90. ICQ TE Ae 4 WE K N ah TE F fr ik BUN Vw B LY333334 1 7 x En ae n R 1 7 1 2 EED HW iE TRA iif y alt F ff zu LDH CK CPK ER EF ai 1 2
91. 20 ug 40 ug 20 ug 40 ug 13 LY333334 N KE 40 ug 20 hg 1 8 R 20 pg E 1 8 4 2 1 1 2 Leg RET GHCO 50
92. CIILA E UCR FL LCE ZED VRE lt BLT 28 28 i mu JIS T 3226 2 A A HY ax BD A H eens 1 Es hn
93. sc lt LY333334 1 6 8 6 02 3 5A 8 7 BE RE CrC lt 30 mL min AUC Tip BARU 77 IE 12 3 BHR 10 100 ng 60 ng 6 FORTEO 800 pg
94. 95 9s 21 9 Xf SHEA HERE 360 D 251 2 8 40 ng ks 6 Chm 15 20 CLF 3 AUC 7 N 34 1 1 TE 1 1 20 pg
95. 1 D FABRE do HAT 3 REED 2 1 16 AAEE T 2 2 EO AN E Bu 4 6 EEC PRET S uU JE H itti 8 EL A
96. 16 16 1 16 2 17 17 1 17 2 17 3 17 4 17 5 17 6 1 6 FORTEO BAKED WORRIE H E LY333334 1 6 20 ng 3 60
97. 5 3 4 2 600 hg 600 pg AE 0 984 mg PIT TER 0 24 mg ID 108 96 mg Im 7 2 mg pH pH 3 8 4 5 1 OO 0 TEE Mt gt 1 AB SEG BER ORAM TORR ORL EATS 2 1 1
98. 20 40 80 hg 95 20 ng 30 3 62L hr 94 L hr 0 12 LiIKg 25 50 5 1 PTH 1 34 PTH
99. 1 637 20 ng 19 ru LERRA PI ok sys 14 3 20 hg 5 0 20 hg 7651 0086 HAEC LS B7THIZsE 2 Lily Answers 20 pg L1 L4 0120 360 605 1 13 9 70 HS 4
100. 20 hg X WR mc Lee M Ee IRIRE PICAA 8 40 pglkg 6 1 IR sala 2 xm m Pos 22 11 11 20 40 18 p AMRI FRS LEA 1 3 ngkg H CHRR ORI 80 pg 17 54 hg ZOKINS 5 ngkg
101. 53 5 4 5 5 FORTEO 5 5 5 6 5 6 FORTEO 5 7 C10 BERR AOR RED 6 1 1 800 545 5979 FDA 1 800 FDA 1088 X X www fda gov medwatch 8 5 8 7 1 12 3 s
102. FORTEO 1 5 mg LY333334 X 1 6 2 EU 2010 1 1 1E 20 ug 1 1E 2
103. 95 360 251 2 8 40 ng ks 6 CQ S 15 20 7 CLF 3 AUC 7 N 34 1 1 1 1 20 pg
104. 2 4 2 2 5 LY333334 1 6 1 H 20 ug amp 28 3 4 FORTEO 1 8 4 2 5 2
105. 3 2 76 mmol L 11 0 mg dL 3 11 5 91 3 12 mmol L 12 5 mg dL TUER AE RE C IRIBR C do H FORTEO 1000 mg 400 IU D Mum prz v Bg FORTEO 6 14 LY333334 A
106. 03 1 ZR FORTEO es e se LY333334 1 6 FORTEO 1 866 382 6813 www forteoregistry rti org gi 52 2 FORTEO 2
107. Div DPR Faz B 1 5 2 3 1 5 2 3 1 Bs 208 Bs LY333334 rt ees IILTH E tet LAF FDA 2000 11 FILIE T
108. 20 hg bie SURI BE AUC 1 1 BERS 4 E 2 4 48 18 10 20 40 60 hg 0 25 t 20 hg 1 YE 5 1 2 8 1 2 9 1 eae o
109. 17 5 i H E FORTEO 28 28 17 6 TH 2009 7 22 Lilly France
110. 2 18 18 1 8 4 1 8 4 2 1 20 ug GHAC GHAI GHCO GHCS GHAC GHCA 24 GHDB 18 18
111. 5 3 5 4 5 5 FORTEO Wok 5 6 IRMA MILA JV Y ARIE FORTEO
112. BMD REDRE HE 15 2 15 1 1 5 2 1 19 20 PTH PTH
113. Type I 2 4 mL FORSTEO 1 3 1 1 20 hg 80uL 28 11 LY333334 6 6 E A 7 Eli Lilly Nederland B V Grootslag 1 5 NL 3991 RA Houten The Netherlands 8 EU 1 0
114. AAEE T 2 2 EO AN E Bu 4 6 EEC PRET S uU JE H itti 8 EL A 62 AS 16 DESC
115. We A 2009 4 1 9 200 16 ti g TE Su 8 18 ra AUN LY333334 1 8 18424 18 18
116. 20 ug aN AC AS Put PHH 1 8 4 2 1 1 3 H AR PARE LATE EP 10 ug SIFE TOY 40 ug 11 47 BEC 6 40 BO A FEL FATE IL GHCS L2 L4 BMD F 0 66 10 ug z4 SGT PICP BAP CTX
117. 20 hg 18 gt 1 2 18 18 1 D FABRE do HAT 3 REED 2 1 16
118. E gna E AL i cin Nonclinical Pharmacology Report CG3 02 The Frequency of Daily Injections Determines Induction of an Anabolic Response in Bone by Human Synthetic and Biosynthetic LY333334 Parathyroid Hormone Fragment hPTH 1 34 in Young Rats Pharmacokinetic Profile of Human Parathyorid Hormone 1 34 LY333334 and Serum Chemistry in Rats After Anabolic or Catabolic Injection Protocols Nonclinical Pharmacology Report R00796 R04296 A Study in Intact Male and Ovariectomized Female Fischer 344 Rats Given Recombinant Human Parathyroid Hormone rhPTH 1 34 LY333334 for 1 Year to Assess Effects on Bone Nonclinical Pharmacology Report BN5 01 Recombinant Human Parathyroid Hormone 1 34 Effects on Bone Mass Architecture and Quality in Aged Ovariectomized Rats LY333334 1 12 HR SPS Nonclinical Pharmacology Report X 95 11 A Study in Ovariectomized Adult Cynomolgus Monkeys M fascicularis Giv
119. PTH l LY333334 1 6 FORTEO 20 ug 4 6 12 2 42 mmol L 9 68 mg dL 99 2 76 mmol L 11 0 mg dL FORTEO 11 1 1 EBR 2 64 mmol L 10 6 mg dL 1 5 4 6
120. an AFA PUA HARES AT SPARRO AEDS BEART KIL TOO f TE 2385 lt 72 T 2 Pil 7 5mg 6 LY333334 1 6 EBRD E EHE A HRAJE Pivotal study 1637 CEER 69 5 Chok 90 1 BMD 0 82 g cm T 2 6 1000 mg 400 IU D FORSTEO 24 19 GE 4 1 11 19 FORSTEO
121. ForteoPen 1 E 3 ERAZ 1 E ETE 1 1 5 GO STL TOR 6 20 ug 6 20 ug 18 1 n TER H ForteoPen 1 1 OE 2008 TH dc dg E gt D EE F4 H IC RE RII 2009 MS
122. 203 Bil 67 20 ug 136 203 14 1 ERE 5 20 ug 9 189 2 1 I 1 v PE LE Jn 2388 1 8 R E 55 Fa RL TORRE BASH E 1 8 3 3 EHA RIEZ ET HR
123. BMD 1 4 2000 nmi 1 TE Ay HAE CL BREDTE E YO HOMER EO PET LOT lt BMD E NIH 70 BMD 30 Eu cu dee LOO TEC OG AE OO HEE Hi LAL F NJ DAB Si Wu iE y
124. 24 ORE BOB 18 JA E CX 1 E 18 18 x GHDB 24 GHDB iX pus 18
125. 1 L DE t ok 0 fi j 6 72 EHE RE BEES OD do FEOF 0D d OB B 1 lt 32 054 T QC DRIED th Zo kB E EO 52 d
126. 6 Qai LAX 20 ug 12 52 BMD f f EH IA 1 2 BMD YAM 80 EOD Hv VP FEL RATE RS BMD YAM 70 10 BMD T 2 0 30 85 139 40 ug II z 1 3 f OJE 147 Ss9 E CN USB UE Ld quote qu TON
127. BME HEATED el H N Ix CPMP GHAC AS ES 2009 7 H 22 2008 4 es 24 2009 4 FE9 1 3 2009 2 25 2008 10 3 ar LIK H
128. CAF H 15 7 0 Lad 18 BS Tes Ei HU EE zT A zd8vc MS IU Oa Vd 169 13 FORSTEO 214 16 BC FORSTEO 4 2 vs 1 9 p lt 0 001 3 8 vs 0 9 Pc RA amp EH CC BS Tes VEO BOE GR LY333334 1 6 Kupffer
129. gt 1 2 18 18 17 LY333334 1 8 4 18 5 R b Core Data Sheet CDS 5 ANI _ i a aes 1
130. nig Teriparatide rDNA Origin Forteo Periodic Safety Update Report 26 November 2002 26 November 2003 Teriparatide rDNA Origin Forteo Periodic Safety Update Report 27 November 2003 26 May 2004 Teriparatide rDNA Origin Forteo Periodic Safety Update Report 27 May 2004 through 26 November 2004 29 LY333334 1 12 3 m s S m ay GR WES nce Bene TH GERREA GA TUS 5 3 6 4 Teriparatide rDNA Origin 2005 7 l ENR m Forteo Periodic Safety Update Report 27 November 2004 through 26 May 2005 5 3 6 5 Teriparatide rDNA Origin 2006
131. 1 7 0 9 0 4 9 LY333334 36 X FORSTEO 173 7 7 1595 p 0 84 o cv FORSTEO 3 1 7 p 0 01 214 PIF 18 SUE MUZ LL PHE BMD 5 2 62L hr 1 7L kg CHS BPR ERO EIS 94 L hr 1 A FFE IF Hj ali 5 3 HRZ v RAO 30 1000 ug kg A 2e f 5 UL 7f LPL PTH
132. 20 ug ZE GHAC 20 hg 40 pg E GHAC 1 637 AP AF E 1 1 396 85 3 473 86 9 20 ug 447 82 6 40 ug 476 86 2 40 ng II TB 12 EREET 67 59 Bil 88 1 20 5 R JE ee aC d qd 2
133. A 755 ELE OWN cp 24 OH H 24 2009 2 II GHDB 12 GHDB amp s 6 GHAC 24 GHAC FER CHEE
134. 10 40 ng 232 48 19 0 1 7 2 8 1 6 ENE 3 1 2 1 296 3 1 296 11 10 5 CBE T HE 1 1 600ng R ae y 20 ug Cp 10 2
135. PVAANF AL PREP TLRAIESD FORTEO mg 428 19 BOTRI FORTEO 3d GE A jm 1 5 0 85 0 13 g cm OX B BeAL TV TE KA UE HE o BMD 3 6 3 KABA SA 3 7 C dE 1000 mg F 30 H 3 22 89 OQ 81 FORTEO 214 BMD EHE BMD T 2 5 1 43 8001U 18 H
136. ELA E aps0 001 AROE JS STA JEMEITHIT 7 7 EAE 5 5 FORTEO 2 6 FORTEO FIC EO 3C OENEBE Er TU A 7 BABIC p lt 0 05 2 9 53 Chor FORTEO 0 2 0 7 0 2 0 7 0 4 0 4 0 0 6 0 6 0 9 0 4 1 3 1 1 1 5 V FORTEO 1 o N S Percent of Patients with e L Nonvertebral Osteoporotic Fractures A k eo b 0 2 a 6 8 10 12 14 16 18 20 Months since Randomization 2 Bll HEB BMD FORTEO BMD
137. EA HRS TE PARE deel Ke CHS INZI AHEM AH OBETE23d5 2 FTO fa SALT 2e FER ARREA HARE ZA E amp P3388 LM HVTVWSAS KB ey SAD CLAD SAV TVYZLVY FORTEO FORTEO Z IMI BHARR HORE do BV LA E EUER IE LR E
138. 2002 11 26 1 5 EJ CER lc A 20 Ha we 1998 12 UME dvor 24 200 Ej 1 31 AY RAP 138 21 CPMP 2003 6 10 18 2007 6 J 15 AY 1 5 2 3
139. 800ug UW APL FFD ML FORSTEO 5 51 ATC H05 AA02 84 TD D 725 AAEH LL FORSTEO rhPTH 1 PTH 34
140. ALA FH TES tk F AA A ie Ex GHCS GHCO z II GHAC GHAJ 40 ug SID 50 AKAD BRE 15 BOTS ur zur AUC Cra AME F CL F E BIREN 85 H Oe
141. di GR ZA EIG 3 3 3 1 B3D LC GHAW 19 Pharmacokinetics and Acute my Pharmacodynamics of 209 H LY333334 when Administered Alone and with Furosemide in Stable Chronic Renal Insufficiency 3 3 3 2 B3D LC GHBC3XR 209 FHA Safety Pharmacokinetics and au Acute Pharmacodynamics of 20 LY333334 in Patients with Stable Heart Failure 24 Lilly NUS Centre for Clinical Pharmacolo gy Lilly NUS Centre for Clinical Pharmacolo gy 1 12 eS re Ah ae LY333334 5 3 3 4 PK B3D LC GHAE Safety of LY333334 in Hypertensive Women B3D LC GHBA LY333334 Thiazide Drug Interaction Trial B3D LC GHBR Randomized Single Blind Crossover Interaction Study of LY333334 and Digoxin Pharmacodynamics
142. DD Hon ALP EA 1 JE X ST T Wb SE Bi a he M Fee aR AEG if AST GOT ALT GPT EX y GTP 5 5 ES 6 6
143. H pp 180mL 18 kan 7 i 1 1 AF Ca Mg HRS 1 18 18 1 GY
144. JEDH z A UR X E GHBD 9 EE C BER ER HELA TIE 53 1 8 H WE DIY ODEO Db B EU BMI E V ZKEE E iy H bc
145. 1 14 xx X EDI NDA tT FY ud mA a i NAF ot ae 10 SEN 38 BA TURAE Az 20 ng BO 2 4 48 AUC
146. 600 ng Gg 2010 3 87 2439 600 ug 2 8 18 Forteo BIST 2002 11 ee ime 2 0 D 3 4
147. 0 04 20 ng Bath GE CR ZRVO amp Hr yA K GHDB 20ug 9 82 p lt 0 001 20 ug y yE ANS b Avie PT A KROME Eat LOR DH L2 L4 BMD ru i Bre
148. 600 g 600 g LY333334 1 4 600 ug 600 hg 1 4 LY333334 1 4 A 1 RI 1 1 4 2 ac on es eae ad tas 1 LY333334 1 4 1 A PS A P N LY333334 1 5 600 ug 600 hg 15 LY333334 1 5 1 5 kk 1 1 5 1 db o cR UR 1 1 5 2 Lf ia IT co it
149. OTIZ EHHI E 4 HEMOR RERE D DD 5 can LY333334 1 7 al x En ae N 1 7 1 ue 6 BOT AE UH AA READS amp 6 N 3 CHO Ere BRAN Bist UG
150. LY333334 1 5 2 2 1 19 20 5 I GHCO Cm 1 Ca AUC Lies Ses GHAD 40 ug EH 1 1 14 Cms KU AUC
151. 7 indicis R lt FT SEL BCMA 2 7 8 1 HE 2 9 1 2 8C
152. ES 1 Forsteo ES 1 Forsteo SATOR E6 10 Forsteo E11 16 Forsteo j3H Forsteo LY333334 1 6 2 EU EU 1 6 R 16 2 EU Summary of Product Characteristics R 1 6 2 EU 2010 1 EU k Core Data Sheet CDS Forteo Forsteo 750 ug 3 mL 600 ug 2 4 mL EI Oo fi RE OD m V PH EP HERE FORTEO 750 hg 3 mL 600 hg 2 4 mL
153. Y i patients with primary hyperparathyroidism Intermittent administration of Mitlak bovine PTH 1 34 increases BH serum 1 25 dihydroxyvitamin D concentrations and spinal bone density in senile 23 month rats The anabolic effects of human Mosekild parathyroid hormone hPTH e L on rat vertebral body mass are also reflected in the quality of bone assessed by biomechanical testing A comparison study between hPTH 1 34 and hPTH 1 84 The anabolic effects of parathyroid hormone on cortical bone mass dimensions and strength assessed in a sexually mature ovariectomized rat model Acute hypotensive action of parathyroid hormone 1 34 fragments in hypertensive rats 41253 Failure of parathyroid hormone to cross the nonhuman primate placenta Effect of parathyroid hormone 1 34 on temporal expression of cell growth growth factors and osteoblast phenotype related genes in rat bone cells in vivo Parathyroid hormone 1 34 and 1 84 stimulate cortical bone formation both from periosteum and endosteum Recent advances in the study of the vascular action of parathyroid hormone 18 Arch Intern Med 1992 152 11 2269 2273 J Bone Miner Res 1992 7 5 4 79 484 Endocrinolo gy 1991 129 1 42 1 428 Bone 1993 16 2 2
154. pH 3 8 4 5 1 OO 0 TEE Mt gt 1 AB SEG BER ORAM TORR ORL EATS 2 1 1 20 hg 18 gt 1 2 18 18
155. FORTEO 72 BMD 5 44 10 3 61 mm FORTEO 2 81 mm D F 20 40 ng 12 24 35 ra EO ARR TT RRA Ue 14 2
156. 20 ug HERO 40 ug HE 14 20 ug 40 ug 24 5 80 PINP 20 ug LY333334 20 hg 10 pg BAP CTX 40 hg BMD 1 8
157. GHDB GHDB GHAC X 12 mni Db 20 ug HC 5 GHDB 1 20 ug 1 m i ug HEC 136 116 85 3 Tol FAI GHDB RO HA 15 F na FE 3 Fi
158. 5 1 5 2 5 3 5 4 5 5 5 6 5 7 5 8 6 6 1 6 2 7 7 1 E 72 7 3 8 8 1 8 3 8 4 8 5 8 6 8 7 mss a he 10 11 12 PER HLASIE amp AT RERU FETE X U PEBRBESEU FIC JS BUE O BED LY333334 12 1 12 2 12 3 13 13 1 13 2 14 14 1 PARR TRAE AT SEEN OE 14 2 RITE XC U PERRBEETK Pic k D AHE AT S 143
159. ZefEBI BR 8 7 BH Kupffer PTH 1 34 PTH 1 84 6 Ol ALEC hile bo C 8 Es MLA DHENE SVS FPWR AOR 8 6 SHEN 15 Q
160. PTH 5 1 BAR 31 85 20 30 20 ug 98 5 CrCl 30 72 mL min 11 Dok CrCl lt 30 mL min 5 AUC Tj BARU 77
161. m 1 12 2 XIF HARI AT SER OAR SK FARKUT SLE FU ADF KILLY ARUOY LIGNA U PTH 20ug 1 2 0 4 mg dL i T EAM MLA FAL m 0O HP R 16 L v v L 4 6 jv pss aide UR 6 24
162. 36 um H fe 1 12 Osteoporosi s Jpn 1997 3 2 2 23 226 2005 212 2 139 142
163. 6 8 KORRA 12 3 BHA 7 2 25 mg 40 pg Oft 12 3 A 73 CrCl 13 72 mL min Q0 100 mg 40 pg 24 2 37 RIFE 12 3 ZH 8 8 LY333334
164. GHAL GHAV GHAU GHULE D EB HCREREBUR D ORE BAUR JE C EHTOD E eos PRU B 1 5 3 2 1 5 3 2 JAN 600 ng 600 ug 1 600 ug 1 1 A 20 pg 18
165. 437 FORTEO 1 1 10 FORTEO 20 ng n 151 1000 mg 400 IU D BMD FORTEO BMD 3 FORTEO O uu 20 LY333334 BMD HE 14 B Ls 1 6 E Bi
166. E o o A 1 EN XJ 4 67 ELAR tt TOM LH RE ac DL EE BPE DS ik D Xv 12 x L2 L4 BMD a DY AAR HRE ER MAN II GHAC AE ACCRUE KE 2 20 pg 1 12 ary i uc EC Iu MEZ AA 7H ERX EOI M OW B dd d MC ELS 1 ETL B T3 DIME 8 1
167. EC JER MUL 2006 FY ALAA TE BR IZ 2496 30 gt JAI 3n E 7 PTH T Smt rv VAP AERE OR 2 B LY333334 A E oe E lt
168. V 7 o 18 18 Ap ce E HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FORTEO safely and effectively See full prescribing information for FORTEO FORTEO teriparatide rDNA origin injection for subcutaneous use Initial U S Approval 2002 WARNING POTENTIAL RISK OF OSTEOSARCOMA See full prescribing information for complete boxed warning In rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor 5 1 13 1 Because of the uncertain relevance of the rat osteosarcoma finding to humans prescribe FORTEO only for patients for whom potential benefits outweigh potential risk 5 1 FORTEO s
169. Ei BIS E 14 3 US Eu EU jr E NSHBWE IKEHIT FORTEO D D FORTEO 5 096074 9 3 2 1 65 FORTEO X ds HOR BMD LY333334 1 6 2 FORTEO FORTEO n 444 n 448 96 95 CI 96 9594CD 1 9 3 5 5 13 1 65 45 78
170. nnn Osx A 1 13 gt 1 5 2 3 2 2 GHCO CO E 5 20g ca AD 10 pg 60 ug 10 pg
171. Jiang et al 2003 SERM BMD 2 5 1 2 Riggs and Parfitt 2005
172. 1 1 B PTH PTH PTH N 34 ASAE IRIE c LILO HME ROO AMO XI Eu uu 1 0 1 mg 45 4 mg pH 4 3 3 mL 2 7 mL m 10
173. 37 BMD T 2 53 10mg 9 1 X 57 x HEME BMD T 2 2 10mg 24 1 X 69 18 18 FORSTEO 7 2 3 4 BMD p lt 0 001 FORSTEO 3 6 2 2 BMD p lt 0 01 D BMD FORSTEO 3 7 2 1 p lt 0 05 FORSTEO BMD 18 24
174. Ey HERA MEIC 35v C ASAI 20 ug 40 ug BMD 12 2 6 gt 3 1 65 LY333334 3 GHDB 207 Fr IU BMD YAM 65 AS iit PAE RATE D 400IU 1 tog i
175. ATAR FERIRE LL PIX Be 5 mg 3 N 428 FORSTEO 18 36 Bik RII Tey ba 10 mg 28 1 1000 mg 800 IU D N 277 N 67 N 83 2 7 7 5 mg 34 1 X f 3 61 BMD
176. E RE 3 3 3 HAAS R fee Eme ASANO st E D gt y mes 3 Ca E Mg Rl KEDE z hua 3S
177. 98 2 76 mmol L 11 0 mg dL 1 2 64 mmol L 10 6 mg dL 1 1 FORTEO 1 3 n 2 FORTEO fm 5 5 67 ZR 18 39 n 26 n 33 12 FORTEO 1 6 0 09 0 14 mmol L 0 36 0 56 mg dL Ly
178. FORTEO 3 0 L 0 2 FORTEO LT FORTEO PRE 21 es FAREA d SHE IRL UCHR ABR C GO f bed FORTEO 4 6 12 rS Tes FORTEO 6 0 2 35 mmol L 9 44 mg dL
179. Ka hr 1 17 5 CLIF Lhr 54 3 VIF L 80 1 VIF a CL F VIF a V F 280 1 X 47 47 4 1 62 DOD 600 u g Gg TIREE 20 ug RE 95 14 3 5 0 0 347 65 64 448 22 444 0 218 0 553 A 300 p lt 0 001 a 2 4 9 1 1 0 229 77 250 4 22 448 5 444 0 088 0 600 2X 200 BUE x 9 7 6 3 0 645 35 150 53 544 34 541 0 426 0 976 p 0 036 NES 5 5 2 6 0 469 53 EN 50 4 30 544 14 541 0 252 0 875 IK p 0 015 a X 0 0 0 50 z x 00 1 50 200 b Pearson s chi square test hy c
180. 3 EU AE HA LY333334 1 5 By PTH 1 34 PTH N 34 1 1 BMD BMD
181. BMD BMD T En ER E E 541 PIRU 69 70 BMD 3 E E d 20 ug 40 ug FEIT BV TENEN 3 0 4 4 14 3 p lt 0 001 20 hg 40 ng 40 ng 20hg 40 ug T 4 6
182. fH HERE T5 WEF v PRUSY YZZ NN 2010 3 2009 6 2009 9 LY333334 1 8 600 ug 600 hg 1 8 GE LY 333334 1 8 GS 1 8 1 1 8 2 USAGE GR 600hg SS 1 8 3
183. Teriparatide Following Discontinuation of Alendronate Treatment in Postmenopausal Women With Osteoporosis B3D MC GHCM Effects of Subcutaneous Teriparatide on Serum Calcium in Postmenopausal Women with Osteoporosis Previously Treated with Raloxifene or Alendronate B3D EW GHCX Differential Effects of Teriparatide and Strontium Ranelate on Bone Remodeling and Formation in Postmenopausal Women with Osteoporosis A Histomorphometric Study 5 3 5 2 _ RR B3D MC GHBJ Extended Follow Up of Patients in LY333334 Trials B3D CA GHCP Compliance with and Acceptance of Teriparatide Pen Injection in Severely Osteoporotic Patients CATS 5 3 5 3 5 3 5 3 1 1 5 3 5 3 2 5 3 5 3 1 Statistical results for Bridging 2009 4 Strategy and CTD BUR Statistical results for CTD 2009 8 Integrated Summary of i Li 2000 10 Efficacy 28 1 12
184. kk ForteoPen on 1D Mt AS 7 N 20 hg 36 Harris et al 1999 P S0 7 2 T GROW ON j LY333334 1 5 10 mg RHEL IV
185. Bl m and 208 1 Company 3 2 P 5 Control of Drug Product 20M ERA Eli Lilly and 209 J Company LY333334 1 12 i Reference Standards or Materials Stability 3 2 A Sais yy Raven a TUET ema dian 3 2 A Appendices 2088 80 LH Eli Lilly TAS and Company 3 2 R us GR EH Tetracycline resistance determined by pBR322 is mediated by one polypeptide NMR solution structure of human parathyroid hormone 1 34 Construction and characterization of new cloning vehicles II A multipurpose cloning system Precise location of two promotors for the 2 lactamase gene of pBR322 The effect of parathyroid hormone on the concentration of ad
186. FORTEO 12 LY 333334 O 3 mL 2 4 mL 1 mL 230 hg 0 41 ms 3mg i ens E 1 6 10 20pug 28 3 12 12 1 84 TEA Bl MN A Es i Ns alli 6 E
187. tox03 The Effect of LY333334 Given Subcutaneously for 2 Consecutive Days on the Induction of Micronuclei in Bone Marrow of ICR Mice 11 1 12 RE LY333334 4 2 3 4 4 2 3 4 1 GR AGE H tox36 An Oncogenic Study in Fischer 344 Rats Given LY333334 by Subcutaneous Injection for 2 Years tox43 A Special Chronic Study in Female Fischer 344 Rats Given LY333334 Teriparatide by Subcutaneous Injection for up to 2 Years 1691 003 Long Term Study in Ovariectomized Female Cynomolgus Monkeys Treated Subcutaneously with LY333334 for 18 Months Followed by a 3 Year Observation Period 4 2 3 5 BUR tox20 A Segment I Reproduction Study of LY333334 Administered Subc
188. 1262 FORSTEO DE EH m 7 E mi FORSTEO 18 1 41 p 0 004 3 503 83 FORSTEO 24 24 BMD 8 LY333334 1 6 BEDRE
189. 2003 11 2 2003 6 10 2004 1 2005 3 24 Forteo Forteo 2009 10 1 Forteo TA Rey 2004 1 Forsteo 20044F8 A 27 A Forteo 2003 5 1 Forteo 2003 6 10 Forsteo 2005 9 28 2003 6 10 20054 FILA Forteo Forteo Forsteo LY333334 1 6 1 2010 1 IL
190. 25s 7 7 pee Pu lt 8 8 1 20 LY333334 1 8 ER CDS CDS
191. 5 4 PARRA OO ATARI BE TOE AREER wm 5 3 3 ud sux A D HUA cul 2 BUE Dum DD 1 D pa DER ERA
192. VIF L 80 1 VIF a CL F VIF 1 62 a V F 280 1 X 47 4 47 4 600 ug Gg TIREE 20 ug RE 95 14 3 5 0 0 347 65 64 448 22 444 0 218 0 553 A soo p 0 001 a 2 4 9 1 1 0 229 77 250 4 22 448 5 444 0 088 0 600 E J p 0 001 x z 9 7 6 3 0 645 35 150 4 53 544 34 541 0 426 0 976 p 0 036 9 NES 5 5 2 6 0 469 53 EN 50 4 30 544 14 541 0 252 0 875 p 0 015 Ot 4 a X 0 0 050 z x 00 1 50 200 b Pearson s chi square test hr c 20 hg
193. 1 20 ng 10 L2 L4 0 04 9 82 oe en 11 Neer R M et al N Engl J Med 344 1434 2001 x Yds BL Bly gt drip 3 a 10 P lt 0 001 2 t P 12 Sato M et al Endocrinology 138 4330 1997 12 5238 20 pg L2 L4 13 5 eh HENE 34 4 18 10 04 18 76 11 93 MER RRT 14 Hock J M J Musculoskel Neuron Interact 2 33 2001 15 Jilka R L Bone 40 1434 2007 NYHA New York Heart Association 1 3 Bi 2 1 637
194. EV 0s c0c0 EEEEEEEEEEEEEEEEEEN MM OWS eB F113 LY333334 1 5 2 3 2 BOREN GHAC 6 JERY EAE A gt RF 2 BEB or GHDB EOD iB v VEAP AE RAE EE 20 ug 12 nul j 1 III BMD Zi EN OR 5 Ne 2007 2 2009 9
195. 479 pg mL 438 pgmL 2 5 AUG 802 pg hr mL 767 pg hr mL TEU EB EISE 5122 E 10 20 40 hg 94 NRE 20 ng AUC C 373 7 pg hr mL 229 5 pg mL Crx payee mee iagadad 1 5 1 na
196. cu EN x s Y im T dd x a H i x En ae att LY333334 1 7 1 7 1 x 1 2 8 GKE E UL IA 14
197. 1 5 4 Cauley JA Thompson DE Ensrud KC Scott JC Black D Risk of mortality following clinical fractures Osteoporos Int 2000 11 556 61 Chen P Satterwhite JH Licata AA Lewiecki EM Sipos AA Misurski DM et al Early changes in biochemical markers of bone formation predict BMD response to Teriparatide in postmenopausal women with osteoporosis J Bone Miner Res 2005 20 6 962 70 Dobnig H Sipos A Jiang Y Fahrleitner Pammer A Ste Marie L Gallagher JC et al Early changes in biochemical markers of bone formation correlate with improvements in bone structure during Teriparatide therapy J Clin Endocrinol Metab 2005 90 7 3970 7 Fujiwara S Kasagi F Masunari N Naito K Suzuki G Fukunaga M Fracture prediction from bone mineral density in Japanese men and women J Bone Miner Res 2003 18 8 1547 53 Hagino H Furukawa K Fujiwara S Okano T Katagiri H Yamamoto K et al Recent trends in the incidence and lifetime risk of hip fracture in Tottori Japan Osteoporos Int 2009 20 4 543 8 Harris ST Watts NB Genant HK McKeever CD Hangartner T Keller M et al Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis JAMA 1999 Oct 13 282 14 1344 52 Jiang Y Zhao JJ Mitlak BH Wang O Genant HK Eriksen EF Recombinant human parathyroid hormone 1 34 Teriparatide improves both cortical and cancellous bone structure J Bone Miner Res 2003
198. 10 20 40 60 hg 0 25 t 1 20 ng FF OSEE S72 5 AUC pg hr mL Cmax pg mL tinax hr to hr 222 53 0 227 35 7 0 25 0 25 0 75 0 708 0 479 121 a CV n 18 b n 18 c n 17 22 11 11 20 ng AUC KO C 229 pg hymL 112 7 pg mL 281 pg hymL KU 125 7 pg mL Tot 2 24 40 pg 14 1 1 1 18 14 16 C
199. Fe Ee v b 600 hg 1 EX F 600ug 1 fai 20 ug 1 1 18 600 ug 600 ug ug kg ug kg H ug kg H 0 10 30 100 300 e 10 10 EE F BST ERT VV 2 Aba bh ER AOD GR MERI AP RU TERRA OO py HE SD JR Pos nm ETE fth CRUEL IKR BRE do BV LAE HEA EEO a PRUE 1 10 LY333334 0 10 30 210
200. ina 1 KADHAL eo Clk RARE EFRI Dis KIERR RIOZE 2 1 8 3 4 12 LY333334 1 8 ER 1 8 4 GE 1 8 4 1 R 1 1 20 ug 2 gt 1
201. EE MEN 8 4 mois TX LOY QT d 3 i uk i 5 Stevens Johnson ROS te Lyell mor Ime Stevens Veitch Johnson Lyell HE 6 SBIR irn fale zi x 5 U amp 4m HE Wd REX n LI IB yy
202. ed Ales 1 8 4 2 1 1 1 8 4 2 1 1 1 GHAC 20 ug 40ug 1 1 19 20 ug 40 ng 65 69 20 hg 40 hg 35 40 ee ee c te E 2 GHAC GHAJ 20 ug FER 40 ug L1 L4 BMD GHAC GHAI
203. FORSTEO 2 8 LDL 2 8 12 BMD 4 9 JERK OTEK 100 ng 60 ng 6 LY333334 1 6 A A RECESS ud EE ORR
204. GHBM 20 ng 10 mg 18 BMD 18 BMD 10 922 5 51 6 BMD de 3 GHAC porosity
205. LI L4 8 26 18 10 31 7 1 LY333334 1 8 8 R 1 8 3 1 1 8 VEHJE 1 2 1 8 3 2 1 8 3 2 1 GHAC 20 ug 40 ug 1 Su Bx dE EH ij II
206. 3 2 7 2 8 7 2 8 ALP 4 1 6 fiti 3 Bi 12 3 1 2 3 1 2 105 HIF 11 10 5 2338 1 A eee ie b 1 5 1 uec 19 LY333334 1 8 EHE HG THE Wink Ht Hi8
207. Development of a simple precise nonradioactive in vitro cellular bioassay for hPTH 1 34 and comparison to the chick hypercalcemic bioassay Structure of human parathyroid hormone 1 34 in d LA the presence of solvents and micelles Complete nucleotide sequence Sutcliffe of the Escherichia coli plasmid JG Automated MAD and MIR structure solution Bovine Parathyroid Hormone Minimum chain length of synthetic peptide required for biological activity A new revision of the sequence of plasmid pBR322 Conformation of parathyroid hormone time resolved fluorescence studies rea HB ges SEED E E 1 12 Pharm Forum 1996 22 6 3293 3304 Biochemistr y 1993 32 605 0 6057 Cold Spring Harbor Symposium Quantitative Biology 1979 43 77 90 Endocrinolo gy 1973 93 134 9 1353 Gene 1988 70 399 403 Biochemistr y 1992 31 37 78924 8931 Acta Crystallogr 1999 D55 849 861 LY333334 1 12 4 4 4 1 4 4 BUR MR en ER ts m ea 2 g 4 2 1 1
208. FORTEO FORTEO BRUTE EV YE TE 17 5 H 25 2 FORTEO 2 3 H 20 ug 28 4 FORTEO HIHA 62 ZH 5 5 1
209. 1 5 2 3 2 3 L COM E EA E e II USURDUANUICHUSU MEN EE nn OCH LZ 6 LY333334 1 5 SSS 1 9 1 13 1 5 2 3 2 4 Il GHCS 2005 4 H 2006 3 10 ug 20 ug 40 ug 6 II L2 L4 BMD 10 ug BF 20 ug HERU 40 ug NS 20 ng 40 h
210. 8 1 8 3 es FORTEO 51 84 17 LY 333334 1 1 1 2 1 3 1 2 2 1 2 2 2 3 Er dr o fa BRPED TV EME SL PERR BERE LK RICE A HIE AT ABO 2 4 2 5 3 4 5
211. LZE Ay E In 4 8 mmol 190 mg H 0 76 mmol FORTEO AN DEY 210 mg H A gt 7 5 mmol Ca JI rH FORTEO RIE x ify lae ICa E HH gi S CA BMA 20 oO REE BRT FORTEO P 1 25 OHD2D 25 OH D 3 12 4 2 mmol 30 mg H gt 7 5 mmol Ca H 1000 mg 400 IU 1 5 6mmol A 2 LRL 6 0 2 mmol H 300 mg H 8 0 mg y vie Bl amp XEF B5 L 7 RETKRRABR IIS V C FH Hr LJE HA PICL OAH RIEL AT SF FY
212. Dj Gm T mo A AN x S zl 25 5 1 2 el OOS ER Cu yes Ty ROH Pe 6 1 120 mg
213. D 20 ug 40 ug 1H 1 BMD TIE BLY Bk HER 1 zh 151 20 ug MILA 437 3 59 BMD 0 87 gem 11 BMD 0 34 Xil 20 ug 40 ug 3 73 8 752 EE p lt 0 001 HATE 5l uU ER Ou B SOLER ST PERCH eT oO 1 8 3 2 GHDB ERI 2 28 2
214. 3 FORTEO FORE A HIE Se AT hn LY333334 1 6 BMD 3 3 FORTEO BMD BMD ERSE BMD BMD BMD i zT E T 5 BMD Ward BMD 4 2 0 8 TEI 13BMD 2 1 1 3 BMD 0 1 1 6 intent to treat LOCF 5 p lt 0 001 e p lt 0 05 FORTEO 96 BMD
215. FEX LY333334 20 ng 18 Shireen ake s EJ 2 1 GHDB BRI L OK LICR OE 1 8 4 2 20 ng 18 S E PRENDE 1 8 E 90 4 F 123 136 p 0 834 18 A 3 0 3
216. FORTEO 1 FORTEO 16 19 FORTEO 7 6 2 sen FORTEO 2 1 1 2 FORTEO 2 FORTEO f
217. LY333334 1 12 1 12 3 3 3 1 3 3 SURNAM ak B MEL RY 3 2 3 2 5 AX 8 General Information Manufacture Characterisation Control of Drug Substance Reference Standards or Materials Container Closure System Stability 3 2 P y ee pe m Em s Hates Pn 3 2 P 1 Description and Composition 208 07 Eli Lilly ENER SEA EAS of the Drug Product d and i Ga 1 Company 3 2 P 2 Pharmaceutical Development 209 7H Eli Lilly m e and 20 ll Company 3 2 P 3 Manufacture 20 Eli Lilly lig D and 209 1 Company 3 2 P 4 Control of Excipients 209 UH Eli Lilly
218. R kk 1 8 3 1 Jl 1 8 3 2 Ape L SE SCIAS ILU NER ERE E OE 1 8 3 2 1 Eupeare d RN REOR 9 1 8 3 2 2 ki2 i 10 1 8 3 3 kk 1 8 3 4 EON TR NORUNT 184 JAY FE kk kkk 1 8 4 1 21 inquo ent i dn c e MD D o eT Ee E EE ol TREE 1 8 42 1 kk 1 8 4 2 1 1 kk 1 8 4 2 1 1 1 E ka 13 1 8 4 2 1 1 2 Lk 1 8 4 2 1 1 3 1 8 4 2 2 EISE pot vu ta Sedge artes ws M UR E RE DS E UE 1 8 4 2 3 AM CI nC T En D renee ar dert 1 8 4 2 4 oro S 17 18 5 Oe sechs PME e Wiad a anl 1 8 LY333334 1 8 1 8 GE 1 8 1 600ug
219. n 691 n 691 PEI 21 3 20 5 LY333334 1 6 FORTEO 3 15 541 12 BMD FORTEO 4 6 16 FORTEO 4 6 1 2 1 FORTEO 11 6
220. C BACT 0BES FORTEO Od 580 1 Fy ROWED HAE NR RIC 48v Cie CTS H g m 1000 ug kg H 2 8 3 723 BOR 8 4 PL VE XC CER Pia 5 1 ZH Mi FORTEO DORA ET lee AR AI H BT 3 E FORTEO 60 1 6 120
221. BMD BMD OH BMD HI O 2 4 nz Lt WEIL X mo k T A REZ AE EX BMD h BMD BMD Kanis et al 2005 Fujiwara et al 2003 2004b
222. CAF Zhe eR ARK OD AREY LATE Ic E LY333334 1 5 BMD 20 ug M GHDB 20 ng 12 20 hg GHAC
223. FORTEO BSAP 17807 19 C S 12 FH 10 1 z ONDE V PICP EFORTEO 12 RETOR FA VER J Les act 41 BSAP BSAP 3 DPD BSAP
224. J Clin Endocrinol Metab 2002 87 8 3609 3617 J Clin Endocrinol Metab 2005 90 7 3970 3977 Osteoporos Int 1999 10 1 59 65 J Bone Miner Res 2003 18 8 1547 1553 Osteoporos Int 2009 20 4 543 548 Endocrine Reviews 2005 26 5 688 703 J Bone Miner Res 2003 18 11 1932 1941 J Bone Miner Res 2004a Jun 19 6 893 899 J Bone Miner Res 2007 22 2 334 JAMA 1999 Oct 13 282 14 1344 52 LY333334 Excess mortality after hospitalisation for vertebral fracture Assessment of fracture risk A reference standard for the description of osteoporosis Effects of Teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis Efficacy and tolerability of once weekly administration of 17 5 mg risedronate in Japanese patients Atypical fractures of the femoral diaphysis in postmenopausal women taking Alendronate Metabolic stability of human parathyroid hormone peptide hPTH 1 34 in rat tissue homogenates kinetics and products of proteolytic degradation Effect of risedronate on the risk of hip fracture in elderly women Parathyroid hormone
225. 20 ug 1 PINP I N FF NTX 2 7 3 3 2 2 3 2 modelimg based formation mi LY333334 1 5 anabolic window 5 GHAC 123 Pil 22 6 20pug 91 16 8 40ug 87
226. 24 18 Al EU SRST aE B HHEN REER 24 750ug 3mL E 600 hg 2 4mL Forteo Forsteo CH 1 6 1 1 6 1 2010 1 Forsteo 2003 5 28 Forsteo Forteo 2004 4 20 Forsteo Forteo 2006 10 11 Forsteo 2003 6 10 Forsteo 19 2008 10 20
227. USE DH 100 TLE Fr Bae YET WAY s v m DYLIR P HENE SD EDR EREE KRR OF i O RINE JUVE MIT 277 TAIT 0 05 2 SATCU ifr H 10 WERE C 10 40 ng 252 48 19 096 i 48 252 5 19 096 E FEME BR RAA LY333334 112 600 ug 600 hg 1 12
228. 10 5 5 LHD 3 yes 1 1 1 1 R X 1 1 20 ng 1 096 AA O GE 3 W eae 1 NM SOC FEDRI als 0 4 imu IER uino 7
229. 13 LY333334 1 12 4 3 3 PEN I uH 4 af EK Calcium balance in laboratory Buss SL Miner rabbits Electrolyte Metab 1984 10 2 127 132 Sex steroids and bone Physiol Reviews 2001 81 419 447 Characteristics of bovine Am J parathyroid hormone Physiol 1981 241 3 E208 E214 Am J the hepatic extraction of Physiol bioactive human PTH 1 34 1989 256 1 in rats Pt 1 E87 E92 Metabolism of N terminal and Daugaar Endocrinolo C terminal parathyroid gy hormone fragments by isolated 1994 134 3 perfused rat kidney and liver 1373 1381 BA P m BA Ro Anabolic actions of Endocr Rev parathyroid hormone on bone 1993 14 6 690 709 Evidence that intermittent 1 Endocrinolo treatment with parathyroid gy hormone increases bone 1995 136 8 formation in adult rats by 13632 3638 activation of bone lining cells Cancellous bone remodeling Eriksen J Bone in type I postmenopausal EF Miner Res osteoporosis quantitative 1990 5 4 3 assessment of rates of 11 319 formation resorption and bone loss at tissue and cellular levels Anabolic and catabolic bone IFrolik Bone effects of human parathyroid CA 2003 33 3 hormone 1 34 are predicted 372 379 by duration of hormone exposure Distribution and
230. 2 37 RRR AIC BE Ze 6 O CER D7 T 3E EH ATEA 7 3 AH 13 JERR FEE 13 1 Fischer 344 2 1 5 30 Rik 75 ngykg 2 24 20 hg 3 20 60 AUC 40 50
231. 20 ug 2 2 1 1 20 ug LY333334 1 6 2 3 1 1 20 ug 2 4 FORTEO FORTEO FORTEO MED LAL SER P CREST SIL FEROE EOW 5 7 SH FORTEO
232. 281 pg hymL KU 125 7 pg mL 24 40 ng 14 1 1 1 18 14 16 C 479 pg mL 438 pgmL 2 5 AUE 802 pg hr mL 767 pg hr mL TL 10 20 40 hg 94 FRES 20 ng AUC C 373 7 pg jn 229 5 pg mL Cra HAE ICIS STU ATF ROR Ka hr 17 5 CLIF Lhhr 54 3
233. Miner Res 2005 20 6 962 970 J Bone Miner Res 2006 21 11 1785 1790 J Bone Miner Res 2007 22 8 1173 1180 JAMA 1998 280 24 2077 82 ZB Z JAMA 2002 288 15 1889 97 Danish Medical Bulletin 1996 43 3 203 215 LY333334 Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis four year results from a randomized clinical trial Early changes in biochemical markers of bone formation correlate with improvements in bone structure during Teriparatide therapy Total body and regional bone mineral density in men effect of age Fracture prediction from bone mineral density in Japanese men and women Recent trends in the incidence and lifetime risk of hip fracture in Tottori Japan Osteosarcoma and Teriparatide Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis Parathyroid hormone and Teriparatide for the treatment of osteoporosis a review of the evidence and suggested guidelines for its use Recombinant human parathyroid hormone 1 34 Teriparatide improves both cortical and cancellous bone structure A meta analysis of prior corticosteroid use and fracture risk Delmas PD ftti Dobnig H ff 32 1 12
234. 1 1 RE 2 o5 7 amp s 2
235. 15 8 3 p 0 008 GHBM 38 6 20 pg 25 5 p 0 05 5 2670 Meta analysis 0 66 0 60 0 44 2 7 4 2 1 1 13 1 9 Nevitt et al 2006 1 5 3 2 GHDB 12 GHAC
236. Do not freeze Do not use FORTEO if it has been frozen 17 PATIENT COUNSELING INFORMATION See Medication Guide 17 1 Potential Risk of Osteosarcoma and Voluntary FORTEO Patient Registry Patients should be made aware that in rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor that was dependent on dose and treatment duration Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO Enrollment information can be obtained by calling 1 866 382 6813 or by visiting www forteoregistry rti org 17 2 Orthostatic Hypotension FORTEO should be administered initially under circumstances where the patient can immediately sit or lie down if symptoms occur Patients should be instructed that if they feel lightheaded or have palpitations after the injection they should sit or lie down until the symptoms resolve If symptoms persist or worsen patients should be instructed to consult a physician before continuing treatment see Warnings and Precautions 5 7 17 3 Hypercalcemia Although symptomatic hypercalcemia was not observed in clinical trials physicians should instruct patients taking FORTEO to contact a health care provider if they develop persistent symptoms of hypercalcemia e g nausea vomiting constipation lethargy muscle weakness 17 4 Other Osteoporosis
237. HBR MEAT REI LER TC do 1 1 2 om 2 1 0 DL FORA C o 0 FARR 5 30 85 T OH TES 1637 85 1 0 82 g cm2 4 19 544 20 us A 40 ug F 552
238. a B weer 5 3 7 5 z 30 LY333334 5 4 5 Adverse effects of bisphosphonates A comparative review Suppressed bone turnover during alendronate therapy for high turnover osteoporosis Peripheral metabolism of PTH fate of biologically active amino terminus in vivo Risk of mortality following clinical fractures Early changes in biochemical markers of bone formation predict BMD response to Teriparatide in postmenopausal women with osteoporosis Change in lumber spine BMD and vertebral fracture risk reduction in Teriparatide treated postmenopausal women with osteoporosis Increase in BMD correlate with improvements in bone microarchitecture with Teriparatide treatment in postmenopausal women with osteoporosis Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures Clinical use of bone densitometry Peripheral metabolism of parathyroid hormone D o e 31 1 12 Drug Saf 1996 14 3 158 170 N Engl J Med 2006 335 19 2048 2050 Am J Physiol 1988 255 88 6 93 Osteoporos Int 2000 11 7 556 561 J Bone
239. 1 Forteo Periodic Safety Update Report 27 May 2005 through 31 October 2005 5 3 6 6 Teriparatide rDNA Origin 2006 7 Forteo Periodic Safety Update Report 01 November 2005 through 26 May 2006 5 3 6 7 Teriparatide rDNA Origin 2007 1 Forteo Periodic Safety Update Report 27 May 2006 through 26 November 2006 5 3 6 8 Teriparatide rDNA Origin 2007 7 Forteo Periodic Safety Update Report 27 November 2006 through 26 May 2007 5 3 6 9 Teriparatide rDNA Origin 2008 1 Forteo Periodic Safety Update Report 27 May 2007 through 26 November 2007 5 3 6 10 Teriparatide rDNA Origin 2008 7 x x Forteo Periodic Safety Update Report 27 November 2007 through 26 May 2008 5 3 6 11 Teriparatide rDNA Origin gt 2009 1 Forteo Periodic Safety Update Report 27 May 2008 through 26 November 2008 5 3 7 gt Fi NE E H ET AS S ag xA en A TO Dore PPE 5 3 7 1 P LAR emer 5 3 7 2 3 ge 5 3 7 3 PHE 5 3 7 4 UK AE
240. 1 1 ForteoPen 1 1 14 oo i ForteoPen 1 1 Ki 28 coti H 14 600 pg 14 er 1 5 3 1 5 3 1 1 Me EX v E Lee ie 600 ug 28 f EO mv VAP LAE R tt
241. 10 BMD FORTEO 10 5 4 FORTEO 10 94 FORTEO 53 BMD 4 BMD BMD FORTEO N 151 N 147 BMD 5 9 0 5 KiB SAH BMD 1 5 0 3 BMD 1 2 0 5 BMD 1 3 1 1 KF iT BMD 1 2 0 6 Ward BMD 2 8 1 1 BMD 0 4 0 4 13BMD 0 5 0 2 BMD 0 5 0 3 intent to treat LOCF 5 p lt 0 001 p 0 05 14 3
242. 7 FEI 40 JE 19 x 1 5 2 EED RIH DREW LE OI BMD aD 2 E BMD 1 AZ 14 mu 2 ft8 EE 5 OR Fo e xc B LC E 14 ae
243. BMD p lt 0 001 FORTEO 21 7 5 mg E E35 57 18 SD E BMD BMD FORTEO Cia F 7 2 D BMD D Like LC FORTEO LY333334 1 6 Body Mass Imdex PARFUM AL oM CE IE OR 16 16
244. BO H 18 uu Tex ue 20 hg DE Nd E 3 7 5 136 EE CHO E 20 hg BMD n a 5 2 4 LY333334 12 HR ABLES n 12 MEO Br LO ARARAT 1 1 n E 2002 4 G 200 Sa UR
245. F 67640 Fegersheim France PA 9401 FSAMP 2002 2009 Eli Lilly and Company Eli Lilly and Company Indianapolis IN 46285 USA www forteo com 23 FORTEO ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT FORSTEO 20 micrograms 80 microliters solution for injection in pre filled pen 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each dose contains 20 micrograms of teriparatide One pre filled pen of 2 4 ml contains 600 micrograms of teriparatide corresponding to 250 micrograms per ml Teriparatide rhPTH 1 34 produced in E coli using recombinant DNA technology is identical to the 34 N terminal amino acid sequence of endogenous human parathyroid hormone For a full list of excipients see section 6 1 3 PHARMACEUTICAL FORM Solution for injection in a pre filled pen Colourless clear solution 4 CLINICAL PARTICULARS 4 4 Therapeutic indications Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture see section 5 1 In postmenopausal women a significant reduction in the incidence of vertebral and non vertebral fractures but not hip fractures has been demonstrated Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture
246. PTH PTH 1 84 6 6 1 m T e pH 6 2 6 3 2 2 8 C 28 2 8 C 28 6 4 2 8 C 6 5
247. 16 LY333334 1 6 595 xmECfRTLE SEETHATEH 7 1 BIR RERA 20 yg 40 ng ie Gas ae 24 15 Ct TN i E HHEH 7 2 BHR 9 CrCl 13 72 mL min 17 20 100 mg 40 ug 24
248. 180 mL NL M 30 4 1 ES L 1 1 TEJE M FER LEE AE HS CAREER E E ELTH JE cel eh i uL
249. 30 40 C AUC 2 7 2 2 2 1 EK 2 7 4 2 1 1 11 1 GHCS 1 E GHAC GHAJ
250. B3D AA GHCF Eli Lilly Comparison of Teriparatide jand and Calcitonin in the Compan Treatment of Postmenopausal y Women with Osteoporosis B3D MC GHCD Combined Use of Teriparatide and Raloxifene in Postmenopausal Women With Osteoporosis BUR 199 8 A 19 19A 19 2002 12 2008 1 2001 11 2005 7 NNI 2002 12 2004 6 2003 8 2004 11 2003 6 2004 8 2002 7 2004 6 27 1 12 2H PE DH 2H 1 1 1 LAR LAR LAR LAK TE B S LY333334 RR H r ae LG
251. Common Hypercholesterolaemia Uncommon Hypercalcemia greater than 2 76 mmol L Hyperuricemia Rare Hypercalcemia greater than 3 25 mmol L Vascular disorders Common Hypotension General disorders and administration site conditions Common Fatigue Chest pain Asthenia Mild and transient injection site events including pain swelling erythema localised bruising pruritis and minor bleeding at injection site Uncommon Injection site erythema Injection site reaction Rare Possible allergic events soon after injection acute dyspnoea oro facial oedema generalised urticaria chest pain oedema mainly peripheral Psychiatric disorders Common Depression Serious cases of back cramp or pain have been reported within minutes of the injection In clinical trials the following reactions were reported at a gt 1 difference in frequency from placebo vertigo nausea pain in limb dizziness depression dyspnoea FORSTEO increases serum uric acid concentrations In clinical trials 2 8 of FORSTEO patients had serum uric acid concentrations above the upper limit of normal compared with 0 7 of placebo patients However the hyperuricemia did not result in an increase in gout arthralgia or urolithiasis In a large clinical trial antibodies that cross reacted with teriparatide were detected in 2 8 of women receiving FORSTEO Generally antibodies were first detected following 12 months of treatment and diminished aft
252. LY333334 Company Administered Subcutaneously in Pregnant CD Rats 4 2 3 5 2 5 b00297 20 Eli Lilly A Dose Ranging Study of and PTH LY333334 Company Administered Subcutaneously in New Zealand White Rabbits 4 2 3 5 2 6 tox37 I Z2 m Eli Lilly A Pilot Developmental nz and Toxicity Study of LY333334 2085 Company Administered by Subcutaneous Injection to Pregnant New Zealand White Rabbits 4 2 3 5 3 em RR Study of the Effects of LY333334 on Embryo Fetal and Postnatal Development Including Maternal Function 4 2 3 7 4 2 3 7 7 GR A Special Study to Assess Renal Function in Cynomolgus Monkeys Given LY333334 rhPTH 1 34 by Subcutaneous Injection for Approximately 4 Months With a 3 Month Reversibility Period tox26 Histopathologic Evaluation of Kidneys From Ovariectomized Female Cynomolgus Monkeys Given LY333334 Daily by Subcutaneous Injection for up to 18 Months
253. effects on bone quality in gy aged ovariectomized rats 1997 138 10 4330 4337 SERM SERM ey HACE PB EONAR SERM 2003 16 42 Intermittent parathyroid i Endocrinolo hormone treatment increases gy osteoblast number steady state 1995 136 11 messenger ribonucleic acid 5127 levels for osteocalcin and 5134 bone formation in tibial metaphysis of hypophysectomized female rats Metabolism of parathyroid J Clin hormone by isolated rat Invest Kupffer cells and hepatocytes 1981 67 449 457 19 LY333334 GR Effects of combined and separate intermittent administration of low dose human parathyroid hormone fragment 1 34 and 17 beta estradiol on bone histomorphometry in ovariectomized rats with established osteopenia Loss of cancellous bone mass and connectivity in ovariectomized rats can be restored by combined treatment with parathyroid hormone and estradiol Effects of reciprocal treatment with estrogen and estrogen plus parathyroid hormone on bone structure and strength in ovariectomized rats Parathyroid hormone 1 34 increased total body bone mass in aged female rats Transcriptiona
254. i AC TER ZR D AJA H D HF 20 mg H 12 19 BAY 2 RATE La VF AL FESSEREE EUER H 25 OH D 170 mg 300 mg Leyes FORTEO H 0 3 mmol H 6 1 0 5 mmol H 12 mg 5 3 mmol H 20 mg JE FORTEO lt 0 74 mmol L 2 4 mg dL FORTEO CN Jes H L25 OH D La j Eo Y v E E 14
255. in women and 14 in men compared with baseline In the placebo group this concentration decreased by 2 in women and increased by 5 in men The median serum 25 hydroxyvitamin D concentration at 12 months was decreased by 19 in women and 10 in men compared with baseline In the placebo group this concentration was unchanged in women and increased by 1 in men In the study of patients with glucocorticoid induced osteoporosis the effects of FORTEO on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids Effects on Markers of Bone Turnover Daily administration of FORTEO to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation as shown by increases in the formation markers serum bone specific alkaline phosphatase BSAP and procollagen I carboxy terminal propeptide PICP Data on biochemical markers of bone turnover were available for the first 12 months of treatment Peak concentrations of PICP at 1 month of treatment were approximately 4196 above baseline followed by a decline to near baseline values by 12 months BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months The maximum increases of BSAP were 4596 above baseline in women and 23 in men After discontinuation of therapy BSAP concentrations returned toward baseline The increases in formation markers were accompanied by secondary
256. reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure e Osteosarcoma Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period The causality to FORTEO use is unclear Long term osteosarcoma surveillance studies are ongoing see Warnings and Precautions 5 1 Hypercalcemia Hypercalcemia greater than 13 0 mg dL has been reported with FORTEO use Adverse events reported since market introduction that were temporally but not necessarily causally related to FORTEO therapy include the following Allergic Reactions Anaphylactic reactions drug hypersensitivity angioedema urticaria Investigations Hyperuricemia e Respiratory System Acute dyspnea chest pain Musculoskeletal Muscle spasms of the leg or back Other Injection site reactions including injection site pain swelling and bruising oro facial edema 7 DRUG INTERACTIONS 7 1 Digoxin A single FORTEO dose did not alter the effect of digoxin on the systolic time interval from electrocardiographic Q wave onset to aortic valve closure a measure of digoxin s calcium mediated cardiac effect However because FORTEO may transiently increase serum calcium FORTEO should be used with caution in patients taking digoxin see Warnings and Precaution 5 8 and Clinical Pharmacology 12 3 7 2 Hydrochlorothiazide The c
257. 1 3 RE Hj E 31 85 LO zl EE Er DA 3 100 ug kg H 1 E INRA HE Lifo E PEI Il B
258. 18 11 1932 41 LY333334 1 5 Kanis JA Oden A Johnell O De Laet C Jonsson B Excess mortality after hospitalisation for vertebral fracture Osteoporos Int 2004b 15 2 108 12 Kanis JA Borgstrom F De Laet C Johansson H Johnell O Jonsson B et al Assessment of fracture risk Osteoporos Int 2005 16 581 9 Nevitt MC Chen P Dore RK Reginster J Kiel DP Zanchetta JR et al Reduced risk of back pain following Teriparatide treatment a meta analysis Osteoporos Int 2006 17 273 80 NIH Osteoporosis Prevention Diagnosis and Therapy NIH Consensus Statement 2000 17 1 1 45 Riggs BL Parfitt AM Drugs used to treat osteoporosis the critical need for a uniform nomenclature based on their action on bone remodeling J Bone Miner Res 2005 20 2 177 84 Ross PD Fujiwara S Huang C Davis JW Epstein RS Wasnich RD et al Vertebral fracture prevalence in women in Hiroshima compared to Caucasians or Japanese in the US Int J Epidemiol 1995 24 6 1171 7 Szulc P Delmas PD Biochemical markers of bone turnover potential use in the investigation and management of postmenopausal osteoporosis Osteoporos Int 2008 19 1683 704 PRE
259. 2 Aag Lm 1 GHCO IL 20 GHCO 10 pg 60 pg Ff LE HH DS 2007 2 8 dO FARA 2 EO ARAL L EZS wo E SUB ae Bg ER Chit LT PARR A ALE GHAC
260. 8 45 17 30 P lt 0 001 2 11 12 20zg LI LA 8 26 18 10 31 7 1 LY333334 1 8 ER 1 8 2 600ug 600 u g Gg 2010 3 LETRA 87 2439 600 ug 2 8 18 Forteo BIST 2002 11 ee ime
261. TAAERZ IST AETERNI E E 2000 Hp 2001 18 3 76 82 19 2008 editor 2006 2006 EEA 08 38 0D Rf Osteoporosis Jpn 1997 5 2 223 6 ERF ARE CPST RE AERA 2005 94 4 13 19 SI y FRR a m m 3 HE RDR RA ae BUR lt E
262. agents restore vertebral bone mass and strength in aged ovariectomized rats Immunohistochemical localization of selected early response genes expressed in trabecular bone of young rats given hPTH1 34 Preexisting bone loss associated with ovariectomy in rats is reversed by parathyroid hormone The renal handling of parathyroid hormone role of peritubular uptake and glomerular filtration Selective uptake of the synthetic amino terminal fragment of bovine parathyroid hormone by isolated perfused bone Introduction PTH differentially regulates McClella MMP 9 creatine kinase and collagen I in rat bone in vivo Intermittent administration of McClella parathyroid hormone 1 34 nd P stimulates matrix metalloproteinase 9 MMP 9 expression in long bone 17 1 2 Amino Acids 2009 In progress Cells and Materials 1991 Suppl 1 23 33 Bone 1995 16 6 629 635 Calc Tissue Int 1999 65 5 369 373 J Bone Miner Res 1991 6 10 1071 1080 J Clin Invest 1977 60 808 814 J Clin Invest 1978 62 2 256 261 New actions of parathyroid hormone 1989 xiii xv J Bone Miner Res 1997 12 Suppl 1 S169 J Cell Biochem 1998 70 3 391 401 LY333334 1 12
263. ba Ge LY 333334 Ki a A HAART DBI OO FW A 4 60 30 7 JERV piy H RORI gm 2p In DES 70 3799 80 ruido FIED TE Lia 50 42 1 5 GB 2007 oe e lcs 1997 I REOR S HEURE OH C5 10 1 CHBEOTE LIBR AT 1 1 700 2005 70 25
264. in Healthy Volunteers G B3D JE GHCS_PPK Population Pharmacokinetic Analysis of Study B3D JE GHCS Assessment of Dose Response of LY333334 in Japanese Postmenopausal Women with Osteoporosis B3D MC GHAJ PPK Population Pharmacokinetic Analyses of GHAJ Effects of LY333334 in the Treatment of Men with Osteoporosis 5 3 4 PD 5 3 4 1 PD PK PD pele GR 8 B3D MC GHAM Assessment of Renal Effects of LY333334 Alone or in Combination with Raloxifene HCI or Continuous Combined Hormone Replacement Therapy 25 1 12 RE LY333334 1 12 5 3 4 2 PD PK PD Fe AES de
265. indicated for use in pediatric or young adult patients with open epiphyses see Warnings and Precautions 5 1 8 5 Geriatric Use Of the patients receiving FORTEO in the osteoporosis trial of 1637 postmenopausal women 75 were 65 years of age and over and 23 were 75 years of age and over Of the patients receiving FORTEO in the osteoporosis trial of 437 men 39 were 65 years of age and over and 1396 were 75 years of age and over No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients but greater sensitivity of some older individuals cannot be ruled out 8 6 Hepatic Impairment No studies have been performed in patients with hepatic impairment see Clinical Pharmacology 12 3 8 7 Renal Impairment In 5 patients with severe renal impairment CrCI 30 mL min the AUC and Ti of teriparatide were increased by 73 and 77 respectively Maximum serum concentration of teriparatide was not increased see Clinical Pharmacology 12 3 10 OVERDOSAGE Incidents of overdose in humans have not been reported in clinical trials Teriparatide has been administered in single doses of up to 100 mcg and in repeated doses of up to 60 mcg day for 6 weeks The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension Nausea vo
266. kg ngm 2700 20 ug 1637 FORTEO 20 ug n 541 D 1000 mg X K 90 1484 EO XK 400 IU H F ff JT DA pun ee c p 0 001 Ts
267. mg day for at least 6 months high underlying disease activity low sex steroid levels Postmenopausal osteoporosis The pivotal study included 1637 postmenopausal women mean age 69 5 years At baseline ninety percent of the patients had one or more vertebral fractures and on average vertebral BMD was 0 82 g cm equivalent to a T score 2 6 All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day Results from up to 24 months median 19 months treatment with FORSTEO demonstrate statistically significant fracture reduction Table 4 To prevent one or more new vertebral fractures 11 women had to be treated for a median of 19 months Table 4 MENEE Placebo FORSTEO Relative risk N 544 96 N 541 96 95 CT vs placebo fracture 21 0 22 0 55 9 1 Non vertebral 5 5 2 6 0 47 fragility fractures 0 25 0 87 Major non vertebral 3 9 1 5 0 38 fragility fractures 0 17 0 86 Abbreviations N number of patients randomly assigned to each treatment group CI Confidence Interval 0 Multiple vertebral 4 Lr 0 23 fractures 22 0 09 0 60 d d The incidence of vertebral fractures was assessed in 448 placebo and 444 Forsteo patients who had baseline and follow up spine radiographs px0 001 compared with placebo A significant reduction in the incidence of hip fractures has not been demonstrated d px0 025 compared with placebo After 19 months m
268. of teriparatide was not increased No studies have been performed in patients undergoing dialysis for chronic renal failure see Use in Specific Populations 8 7 Hepatic Impairment No studies have been performed in patients with hepatic impairment Non specific proteolytic enzymes in the liver possibly Kupffer cells cleave PTH 1 34 and PTH 1 84 into fragments that are cleared from the circulation mainly by the kidney see Use in Specific Populations 8 6 Drug Interactions Digoxin In a study of 15 healthy people administered digoxin daily to steady state a single FORTEO dose did not alter the effect of digoxin on the systolic time interval from electrocardiographic Q wave onset to aortic valve closure a measure of digoxin s calcium mediated cardiac effect However sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity Because FORTEO may transiently increase serum calcium FORTEO should be used with caution in patients taking digoxin see Drug Interactions 7 1 Hydrochlorothiazide In a study of 20 healthy people the coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg The 24 hour urine excretion of calcium was reduced by a clinically unimportant amount 15 The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied see Drug Inte
269. of first authorisation 10 June 2003 Date of last renewal 10 June 2008 10 DATE OF REVISION OF THE TEXT LY333334 1 6 183m S on te ES LY333334 1 FORSTEO 20 ug 2 1 20 hg BS E 1 600 ug 250 ng mL 2 4 mL rhPTH 1 34 J 80 uL i 4 3 Az 4 41 6 1 4 2 FORSTEO 20 ug 1 AO gt AB UM p DNA dE EM Er 24 4 4 24 ER OF EDF HLF E
270. on fracture rates was demonstrated 5 2 Pharmacokinetic properties FORSTEO is eliminated through hepatic and extra hepatic clearance approximately 62 l hr in women and 94 1 hr in men The volume of distribution is approximately 1 7 l kg The half life of FORSTEO is approximately 1 hour when administered subcutaneously which reflects the time required for absorption from the injection site No metabolism or excretion studies have been performed with FORSTEO but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney Patient characteristics Geriatrics No differences in FORSTEO pharmacokinetics were detected with regard to age range 31 to 85 years Dosage adjustment based on age is not required 5 3 Preclinical safety data Teriparatide was not genotoxic in a standard battery of tests It produced no teratogenic effects in rats mice or rabbits There were no important effects observed in pregnant rats or mice administered teriparatide at daily doses of 30 to 1000 ug kg However fetal resorption and reduced litter size occurred in pregnant rabbits administered daily doses of 3 to 100 ug kg The embryotoxicity observed in rabbits may be related to their much greater sensitivity to the effects of PTH on blood ionised calcium compared with rodents Rats treated with near life time daily injections had dose dependent exaggerated bone formation and increased incidence of osteosarcoma most proba
271. secretion and action evidence for discrete receptors for the carboxyl terminal region and related biological actions of carboxyl terminal ligands Effect of Alendronate on limited activity days and bed disability days caused by back pain in postmenopausal women with existing vertebral fractures 5 4 21 5 4 22 5 4 23 5 4 24 5 4 25 5 4 26 5 4 27 5 4 28 5 4 29 5 4 30 33 1 12 Osteoporos Int 2004b 15 2 7108 112 Osteoporos Int 2003 16 6 581 589 Bone 2008 42 467 475 J Bone Miner Res 2007 22 1 149 157 J Bone Miner Metab 2006 24 5 405 413 N Engl J Med 2008 358 12 1304 1306 Amino Acids In press N Engl J Med 2001 344 5 333 340 Endocrine Reviews 2003 26 1 78 113 Arch Intem Med 2000 160 77 85 LY333334 1 12 aie zh Reduced risk of back pain i Osteoporos following Teriparatide Int treatment a meta analysis 2006 17 273 280 Osteoporosis Prevention NIH Diagnosis and Therapy Consensus Statement 2000 17 1 1 45 Clinician s guide to prevention National and treatment of osteoporosis Os
272. see section 5 1 4 2 Posology and method of administration The recommended dose of FORSTEO is 20 micrograms administered once daily by subcutaneous injection in the thigh or abdomen Patients must be trained to use the proper injection techniques see section 6 6 A User Manual is also available to instruct patients on the correct use of the pen The maximum total duration of treatment with FORSTEO should be 24 months see section 4 4 The 24 month course of FORSTEO should not be repeated over a patient s lifetime Patients should receive supplemental Calcium and vitamin D supplements if dietary intake 1s inadequate Following cessation of FORSTEO therapy patients may be continued on other osteoporosis therapies Use in renal impairment FORSTEO should not be used in patients with severe renal impairment see 4 3 In patients with moderate renal impairment FORSTEO should be used with caution Use in hepatic impairment no data are available in patients with impaired hepatic function see section 5 3 Paediatric population and young adults with open epiphyses There is no experience in paediatric patients less than 18 years FORSTEO should not be used in paediatric patients less than 18 years or young adults with open epiphyses Elderly patients Dosage adjustment based on age is not required see section 5 2 4 3 Contraindications Hypersensitivity to the active substance or to any of the excipients Pregnancy and
273. teriparatide 20 mcg was 2 42 mmol L 9 68 mg dL at 12 months The peak serum calcium remained below 2 76 mmol L 11 0 mg dL in gt 99 of women at each visit Sustained hypercalcemia was not observed In this study 11 1 of women treated with FORTEO had at least 1 serum calcium value above the upper limit of normal 2 64 mmol L 10 6 mg dL compared with 1 5 of women treated with placebo The percentage of women treated with FORTEO whose serum calcium was above the upper limit of normal on consecutive 4 to 6 hour post dose measurements was 3 0 compared with 0 2 of women treated with placebo In these women calcium supplements and or FORTEO doses were reduced The timing of these dose reductions was at the discretion of the investigator FORTEO dose adjustments were made at varying intervals after the first observation of increased serum calcium median 21 weeks During these intervals there was no evidence of progressive increases in serum calcium In a clinical study of men with either primary or hypogonadal osteoporosis the effects on serum calcium were similar to those observed in postmenopausal women The median peak serum calcium concentration measured 4 to 6 hours after dosing with FORTEO was 2 35 mmol L 9 44 mg dL at 12 months The peak serum calcium remained below 2 76 mmol L 11 0 mg dL in 98 of men at each visit Sustained hypercalcemia was not observed In this study 6 0 of men treated with FORTEO daily had at least 1 serum calci
274. terminal human Chem parathyroid hormone 1998 273 8 fragments 4308 43 16 Biochemistr y possible relation to biological 1992 31 205 activities 6 2063 Solution structure and Biochemistr adenylyl cyclase stimulating y activities of C terminal 1995 34 27 truncated human parathyroid 18835 8842 hormone analogues Processing of X ray diffraction Otwinow Methods data collected in oscillation i Enzymol mode 1997 276 30 7 326 Revised sequence of the Peden Gene tetracycline resistance gene of K WC 1983 22 277 pBR322 280 Addressing the tertiary Pellegrin J Biol structure of human parathyroid i M Chem hormone 1 34 1998 273 17 10420 10427 A constrained regularization Provench Comp Phys method for inverting data er SW Commun represented by linear algebraic 1982a 27 21 or integral equations 3 227 A general purpose constrained Provench Comp Phys regularization program for er SW Commun inverting noisy linear 1982b 27 22 algebraic and integral 9 242 equations Estimation of globular protein Provench Biochemistr secondary structure from y circular dichroism 1981 20 1 33 37 SHELXL high resolution i Methods refinement Enzymol 1997 277 31 9 343 3 3 18 3 3 19 3 3 20 3 3 21 3 3 22 3 3 23 3 3 24 3 3 25 3 3 26 3 3 27 3 3 28 3 3 29 LY333334
275. the ap TR EACUS sigs di PER Er bud 3 mknan BRE 5 3 4 2 1 B3D MC GHAC PPK PD 1996 12 ES ENR men ES Population ad Pharmacokinetic Pharmacody 1999 4 namic Analyses of GHAC Effects of LY333334 in the Treatment of Postmenopausal Women with Osteoporosis 5 3 5 5 3 5 1 RIS ges B3D JE GHCS Assessment of Dose Response of LY333334 in Japanese Postmenopausal Women with Osteoporosis B3D JE GHDB Efficacy and Safety of LY333334 in Japanese Patients with Osteoporosis B3D JE GHDB 18 1 Efficacy and Safety of LY333334 in Japanese Patients with Osteoporosis B3D MC GHAC3XR Effects of LY333334 in the Treatment of Postmenopausal Women with Osteoporosis B3D MC GHAJ Clinical Study Report Effects of LY333334 in the Treatment of Men with Osteoporosis B3D MC GHBM Teriparatide Compared With Alendronate on Spine Bone
276. 0 a px0 001 compared with placebo 11 New Nonvertebral Osteoporotic Fractures FORTEO significantly reduced the risk of any nonvertebral fracture from 5 5 in the placebo group to 2 6 in the FORTEO group p lt 0 05 The absolute reduction in risk was 2 9 and the relative reduction was 53 The incidence of new nonvertebral fractures in the FORTEO group compared with the placebo group was ankle foot 0 2 0 7 hip 0 2 0 7 humerus 0 4 0 4 pelvis 0 0 6 ribs 0 6 0 9 wrist 0 4 1 3 and other sites 1 1 1 5 respectively The cumulative percentage of postmenopausal women with osteoporosis who sustained new nonvertebral fractures was lower in women treated with FORTEO than in women treated with placebo see Figure 1 Figure 1 Cumulative Percentage of Postmenopausal Women with Osteoporosis Sustaining New Nonvertebral Osteoporotic Fractures 70 o GS FORTEO Placebo Percent of Patients with Nonvertebral Osteoporotic Fractures A 0 2 4 6 8 10 12 14 16 18 20 Months since Randomization Effect on Bone Mineral Density BMD FORTEO increased lumbar spine BMD in postmenopausal women with osteoporosis Statistically significant increases were seen at 3 months and continued throughout the treatment period Postmenopausal women with osteoporosis who were treated with FORTEO had statistically significant increases in BMD from baseline t
277. 0 ug 1 1E 20 ug 1 6 H 20 pg 24 FID 24 D FEET AG SRR
278. 1 FORTEO 3 mL NDC 0002 8971 01 MS8971 2 4 mL NDC 0002 8400 01 MS8400 16 2 FORTEO 2 8 C 36 46 F oy 17 17 1 FORTEO EE FORTEO
279. 12 FORTEO 2 14 7 BH 7 3 6 3 6 3 5 1 4 1 FIRB 3 1 LY333334 1 6 6 2 FORTEO FORTBO 5 1 BA 13 0 mg dL FORTEO
280. 16 1 6 1 LY333334 GE 83 2000 11 29 2002 4 1 6 2010 4 E ff E 11 26 i 1 4 iH a att A gt E BR Bs n Bb ER RY BE dp om lt EU 2003 6 10 EU
281. 23 230 Proc Soc Exp Biol Med 1981 168 2 168 171 Am J Obstet Gynecol 1977 129 4 449 453 J Bone Miner Res 1995 10 Suppl 1 S487 Calcif Tissue Int 1993 53 6 394 399 New actions of parathyroid hormone 1989 127 135 LY333334 1 12 UAT ERE EA ang i pw 3 E In vivo demonstration that Pollock J Bone 2 parathyroid hormone and JH Miner Res parathyroid hormone related 1996 11 6 protein stimulate expression 754 759 by osteoblasts of interleukin 6 and leukemia inhibitory factor Keynote address First Potts JT New actions international conference on Jr of new actions of parathyroid parathyroid hormone hormone 1989 1 7 Parathyroid hormone Potts JT Endocrinolo physiology chemistry Jr gy 3rd ed biosynthesis secretion Vol 2 metabolism and mode of 1995 920 action 966 A comparison of the anabolic Qi H th J Bone effects of parathyroid hormone Miner Res at skeletal sites with moderate 1995 10 948 and severe osteopenia in aged 55 ovariectomized rats Static and tetracycline based Recker J Bone bone histomorphometric data RR Miner Res from 34 normal 1988 3 2 1 postmenopausal females 33 144 Biosynthetic human PTH 1 Sato M Endocrinolo 34
282. 3 247 001 002 9 2003 6 10 10 2008 6 10 H el CAST OE Teriparatide Core Data Sheet ay I mn BEES EE a gt S SAAAA A A Us I LY333334 1 7 600 ug 600 hg ct x M On 1 7 UN 1 7 2 LY333334 1 7 LY333334 1 7 1 7 2010 1 LY333334 All
283. 3334 5 5 5 1 5 CR im m M 5 2 ARE sue 93S 5 5 3 5 3 1 5 3 1 1 BA KREA B3D LC GHBI Absolute Bioavailability of LY333334 Administered via Subcutaneous Injection 5 3 1 2 BA BE PRI de p AV Ties 5 3 1 2 1 IB3D EW GHAK 70 ETAR Bee LY333334 Relative me Bioavailability Administered O ga i by Inhalation and Subcutaneous Injection with Scintigraphic Evaluation of Lung Deposition 5 3 1 2 2 B3D EW GHAN IE 53 E LY333334 A Relative Bioavailability Study of the O g E Buccal Route of Administration Compared to Subcutaneous Delive
284. 989a 125 4 PTHrP 1 34 and PTH 1 34 2022 on bone in rats 2027 Resorption is not essential for Hock JM J Bone the stimulation of bone growth Miner Res by hPTH 1 34 in rats in 1989b 4 3 vivo 449 458 Anabolic effect of human Hock JM Endocrinolo synthetic parathyroid hormone gy 1 34 depends on growth 1990 127 4 hormone 71804 1810 Effects of continuous and Hock JM J Bone intermittent administration and Miner Res inhibition of resorption on the 1992 7 1 6 anabolic response of bone to 5 72 Z gt Z gt Z gt parathyroid hormone E a a al 15 LY333334 Growth hormone does not human parathyroid hormone 1 34 on bone in aging multiparous and virgin rats Anabolic actions of PTH in the skeletons of animals Effect of human parathyroid hormone PTH 1 34 on experimental osteopenia of Recombinant human parathyroid hormone 1 34 pharmacokinetics tissue distribution and excretion in rats Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone Molecular and cellular mechanisms of the anabolic effect of intermittent PTH Modulation of ovariectomy related bone loss by parathyroid hormone in rats A comparison of iliac bone histomorphometric data in and normal subjects The effect of recombinant human 1 84 or synthetic human 1 34 parathyroid hormone
285. AR ie MRED E AIR PEME ALP E f p F DEC ST X T RNN HE RYE fi RSS ER FAYE EJ FEIR p HE AR fs A H i AST GOT ALT GPT y GTP KJR BUR 5 Sty 6 1 A ASA
286. D 1 3 1 1 Intertrochanter BMD 1 2 0 6 Ward s triangle BMD 2 8 1 1 Total body BMD 0 4 0 4 Distal 1 3 radius BMD 0 5 0 2 Ultradistal radius BMD 0 5 0 3 a b Intent to treat analysis last observation carried forward p 0 001 compared with placebo p lt 0 05 compared with placebo C 14 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis The efficacy of FORTEO for treating glucocorticoid induced osteoporosis was assessed in a randomized double blind active controlled trial of 428 patients 19 men 81 women aged 22 to 89 years mean 57 years treated with gt 5 mg day prednisone or equivalent for a minimum of 3 months The duration of the trial was 18 months with 214 patients exposed to FORTEO In the FORTEO group the baseline median glucocorticoid dose was 7 5 mg day and the median duration of glucocorticoid use was 1 5 years The mean SD baseline lumbar spine BMD was 0 85 0 13 g cm and lumbar spine BMD T score was 2 5 1 number of 13 standard deviations below the mean BMD value for healthy adults A total of 30 of patients had prevalent vertebral fracture s and 43 had prior non vertebral fracture s The patients had chronic rheumatologic respiratory or other diseases that required sustained glucocorticoid therapy All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day Because of differences in mechanism of action anabolic vs anti resorptive
287. E Cauley et al 2000 QOL 1 2006 2008 LEA SA TRO P Cn QOL gt f ly S BERO HA clas fav APRA LT TTL ie B A Th QOL BK OO HAHAERAEO BPE C do OA HLAAIE C 1 2006 A Kanis et al TE a
288. EO are nausea pain in limb headache and dizziness The undesirable reactions associated with the use of teriparatide in osteoporosis clinical trials and post marketing exposure are summarised in the table below The following convention has been used for the classification of the adverse reactions very common 1 10 common gt 1 100 to lt 1 10 uncommon gt 1 1 000 to lt 1 100 rare 1 10 000 to lt 1 1 000 very rare lt 1 10 000 not known cannot be estimated from the available data Investigations Uncommon Weight increased Cardiac murmur alkaline phosphatase increase Cardiac disorders Common Palpitations Uncommon Tachycardia Blood and lymphatic system disorders Common Anaemia Nervous system disorders Common Dizziness Headache Sciatica Ear and labyrinth disorders Common Vertigo Respiratory thoracic and mediastinal disorders Common Dyspnoea Uncommon Emphysema Gastrointestinal disorders Common Nausea Vomiting Hiatus hernia Gastroesophageal reflux disease Uncommon Haemorrhoids Renal and urinary disorders Uncommon Urinary incontinence Polyuria Micturition urgency Not known Renal failure impairment Skin and subcutaneous tissue disorders Common Sweating increased Musculoskeletal and connective tissue disorders Very common Pain in limb Common Muscle cramps Uncommon Myalgia Arthralgia Not known Back cramp pain Metabolism and nutrition disorders
289. 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 Treatment of Osteoporosis in Men and Postmenopausal Women The safety of FORTEO in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized double blind placebo controlled trials of 1382 patients 21 men 79 women aged 28 to 86 years mean 67 years The median durations of the trials were 11 months for men and 19 months for women with 691 patients exposed to FORTEO and 691 patients to placebo All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day The incidence of all cause mortality was 1 in the FORTEO group and 1 in the placebo group The incidence of serious adverse events was 16 in FORTEO patients and 19 in placebo patients Early discontinuation due to adverse events occurred in 7 of FORTEO patients and 6 of placebo patients Table 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in gt 2 of FORTEO treated and more frequently than placebo treated patients Table 1 Percentage of Patients with Adverse Events Reported by at Least 2 of FORTEO Treated Patients and in More FORTEO Treated Patients than Placebo Treated Patient
290. FORTEO 3 1 FORTEO FORTEO BERIE 12 2 BHR FORTEO 1 FORTEO 3 BUN pH
291. FORTEO transiently increased serum calcium with the maximal effect observed at approximately 4 to 6 hours post dose Serum calcium measured at least 16 hours post dose was not different from pretreatment levels In clinical trials the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 2 of women and none of the men treated with placebo to 11 of women and 6 of men treated with FORTEO The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3 of women and 1 of men Urinary Calcium FORTEO increased urinary calcium excretion but the frequency of hypercalciuria in clinical trials was similar for patients treated with FORTEO and placebo see Clinical Pharmacology 12 2 Serum Uric Acid FORTEO increased serum uric acid concentrations In clinical trials 3 of FORTEO patients had serum uric acid concentrations above the upper limit of normal compared with 1 of placebo patients However the hyperuricemia did not result in an increase in gout arthralgia or urolithiasis Renal Function No clinically important adverse renal effects were observed in clinical studies Assessments included creatinine clearance measurements of blood urea nitrogen BUN creatinine and electrolytes in serum urine specific gravity and pH and examination of urine sediment Studies in Men and Women with Glucocorticoid Induced
292. HO 14 99 BAK B ee MZ 337 HL ako ME LT ERO AA Be BBE IL ELT Pria 1 1 HH 1 4 XR 1 2 d EE E LY333334 1 5 UX 08 i 2 29950 MEER nn ao 14 14 14 a on
293. Inactivation Garel JM Horm Metab of Labeled Parathyroid Res 1972 Indomethacin does not inhibit Gera I Calcif the anabolic effect of Tissue Int parathyroid hormone on the 1987 40 4 long bones of rats 206 211 14 A B R nt LY333334 1 12 TREE oe RRND 5 lt Intrauterine growth retardation Graham J Reprod Z in a woman with primary EM Med hyperparathyroidism A case 1998 43 5 report 451 454 Increased trabecular bone Metab Bone mass in rats treated with Dis amp Rel human synthetic parathyroid Res hormone 1984 5 4 1 77 181 1 25 Dihydroxyvitamin D Calcif alone or in combination with Tissue Int parathyroid hormone does not 1988 43 5 increase bone mass in young 284 288 rats Loss of the anabolic effect of Bone parathyroid hormone on bone 1989 10 6 after discontinuation of 447 452 hormone in rats Increase of whole body i Clin Sci calcium and skeletal mass in 1982 62 4 normal and osteoporotic adult 389 396 rats treated with parathyroid hormone Human parathyroid hormone Endocrinolo 1 34 increases bone mass in gy ovariectomized and 1988 122 6 orchidectomized rats 2899 2904 Comparison of the anabolic Hock JM Endocrinolo effects of synthetic parathyroid gy hormone related protein 1
294. L D RAREZA T REOR E FORTEO BRER 14 2 ZH i8 FORTEO 1 BED Smg ELE Bk 143 2H 2 2 1 1 1
295. Mineral Density in Postmenopausal Women With Osteoporosis B3D EW GHCA Comparison of a 2 Year Therapy of Teriparatide Alone 20054F and its Sequential Use for 1 Year with or without Raloxifene HCl in the Treatment of Severe Postmenopausal Osteoporosis 26 LY333334 51 7 5 3 5 1 8 5 3 5 1 9 5 3 5 1 10 5 3 5 1 11 5 3 5 1 12 5 3 5 1 13 5 3 5 1 14 5 3 5 1 15 B3D MC GHAA Safety and Pharmacological Effects of LY333334 on Biochemical Markers of Bone Metabolism in Healthy Postmenopausal Women B3D MC GHAF Effects of LY333334 in Postmenopausal Women on Estrogen and Progestin Therapy B3D MC GHAH LY333334 Compared with Alendronate in Postmenopausal Women with Osteoporosis B3D US GHBZ Comparison of the Effects of Teriparatide With Those of Alendronate Sodium on Lumbar Spine Bone Mineral Density in Glucocorticoid Induced Osteoporosis B3D MC GHBQ Sequential Use of Teriparatide and Raloxifene HCl in the Treatment of Postmenopausal Women with Osteoporosis B3D TW GHCB Comparison of Teriparatide and Calcitonin in the Treatment of Postmenopausal Women with Osteoporosis B3D KL GHCC Comparison of Teriparatide and Calcitonin in the Treatment of Postmenopausal Women with Osteoporosis
296. Osteoporosis The safety of FORTEO in the treatment of men and women with glucocorticoid induced osteoporosis was assessed in a randomized double blind active controlled trial of 428 patients 19 men 81 women aged 22 to 89 years mean 57 years treated with gt 5mg per day prednisone or equivalent for a minimum of 3 months The duration of the trial was 18 months with 214 patients exposed to FORTEO and 214 patients exposed to oral daily bisphosphonate active control All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day The incidence of all cause mortality was 4 in the FORTEO group and 6 in the active control group The incidence of serious adverse events was 21 in FORTEO patients and 18 in active control patients and included pneumonia 3 FORTEO 1 active control Early discontinuation because of adverse events occurred in 15 of FORTEO patients and 12 of active control patients and included dizziness 2 FORTEO 0 active control Adverse events reported at a higher incidence in the FORTEO group and with at least a 2 difference in FORTEO treated patients compared with active control treated patients were nausea 14 7 gastritis 7 3 pneumonia 6 3 dyspnea 6 3 insomnia 5 1 anxiety 4 1 and herpes zoster 3 1 respectively 6 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of FORTEO Because these reactions are
297. Serum Pharmacokinetics of LY333334 in Male and Female Cynomolgus Monkeys Following a Single Intravenous or Subcutaneous Dose of 10 ug kg LY333334 1 12 Marb ADME Report 27 A Serum Pharmacokinetic Study in Rhesus Monkeys Given a Single Intravenous or Subcutaneous Dose of LY333334 ADME Report 4 Serum Pharmacokinetics of LY333334 in Male and Female F344 Rats Following Daily Subcutaneous Doses of 10 30 100 or 300 mg kg for 43 days Study R12995 ADME Report 7 Serum Pharmacokinetics of LY333334 in Male and Female F344 Rats Following Daily Subcutaneous Doses of 0 10 30 or 100 mg kg of LY333334 for Approximately 140 Days Studies R04396 and R01196 ADME Report 9 Serum Concentrations of Immunoreactive LY333334 in Male and Female Cynomolgus Monkeys Following Daily Subcutaneous Administrations of 0 2 10 20 or 40 pg kg for Approximately 3 Months Study B96 020 ADME Report 14 J Eli Lilly Serum Pharmacokinetics of and LY333334 in Cynomolgus Company Monkeys Following a Daily Subcutaneous Dose of 0 5 2 or 10 pg kg LY333334 for 1 Year ADME Report 30 Serum Toxicokinetics of Immunoreactive LY333334 in Female Cynomolgus Monkeys Following Da
298. Treatment Modalities Patients should be informed regarding the roles of supplemental calcium and or vitamin D weight bearing exercise and modification of certain behavioral factors such as cigarette smoking and or alcohol consumption 17 5 Useof Delivery Device Pen Patients and caregivers who administer FORTEO should be instructed on how to properly use the delivery device refer to User Manual properly dispose of needles and be advised not to share their delivery device with other patients The contents of the delivery device should NOT be transferred to a syringe Each FORTEO delivery device can be used for up to 28 days including the first injection from the delivery device After the 28 day use period discard the FORTEO delivery device even if it still contains some unused solution 17 6 Availability of Medication Guide and User Manual Patients should read the Medication Guide and delivery device pen User Manual before starting therapy with FORTEO and re read them each time the prescription is renewed Patients need to understand and follow the instructions in the FORTEO delivery device User Manual Failure to do so may result in inaccurate dosing Literature revised July 22 2009 PA 9401 FSAMP Manufactured by Lilly France F 67640 Fegersheim France for Eli Lilly and Company Indianapolis IN 46285 USA www forteo com Copyright 2002 2009 Eli Lilly and Company All rights reserved 14 LY333334 1 6
299. aaa k tame ie 3 1 5 2 1 Screen 3 1 5 2 2 4 1 5 2 3 IAS INGER ABE UES oso esee eine hog pte tet aad tte fete tet an es le eos 4 1 5 2 3 1 SECRI Ps 215 Me 4 1 5 2 3 2 kk 5 1 5 2 3 2 1 20 go eee 6 1 5 2 3 2 2 1 GHCO Co e 20 PI 6 1 5 2 3 2 3 TI COM ERA ESO on 6 1 5 2 3 2 4 T GHCS 2005 4 2006 3 NR E E E AA 7 1 5 2 3 2 5 COMES Loo 7 1 5 2 3 2 6 IL GHDB 2007 2 2009 9 8 1 5 2 4 DU cA o Er 9 1 53 kk 10 1 5 3 1 kk 10 1 5 3 2 12 DSA Zea pud CONUS cee tien triacetate ETE 13 LY333334 1 5 15 1
300. and lack of clarity regarding differences in BMD as an adequate predictor of fracture efficacy data on the active comparator are not presented Effect on Bone Mineral Density BMD In patients with glucocorticoid induced osteoporosis FORTEO increased lumbar spine BMD compared with baseline at 3 months through 18 months of treatment In patients treated with FORTEO the mean percent change in BMD from baseline to endpoint was 7 2 at the lumbar spine 3 6 at the total hip and 3 7 at the femoral neck p lt 0 001 all sites The relative treatment effects of FORTEO were consistent in subgroups defined by gender age geographic region body mass index underlying disease prevalent vertebral fracture baseline glucocorticoid dose prior bisphosphonate use and glucocorticoid discontinuation during trial 16 HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied The FORTEO delivery device pen is available in the following package sizes 3 mL prefilled delivery device NDC 0002 8971 01 MS8971 2 4 mL prefilled delivery device NDC 0002 8400 01 MS8400 16 2 Storage and Handling The FORTEO delivery device should be stored under refrigeration at 2 to 8 C 36 to 46 F at all times Recap the delivery device when not in use to protect the cartridge from physical damage and light During the use period time out of the refrigerator should be minimized the dose may be delivered immediately following removal from the refrigerator
301. bly due to an epigenetic mechanism Teriparatide did not increase the incidence of any other type of neoplasia in rats Due to the differences in bone physiology in rats and humans the clinical relevance of these findings is probably minor No bone tumours were observed in ovariectomised monkeys treated for 18 months or during a 3 year follow up period after treatment cessation In addition no osteosarcomas have been observed in clinical trials or during the post treatment follow up study Animal studies have shown that severely reduced hepatic blood flow decreases exposure of PTH to the principal cleavage system Kupffer cells and consequently clearance of PTH 1 84 6 PHARMACEUTICAL PARTICULARS 6 1 List of excipients Glacial acetic acid Sodium acetate anhydrous Mannitol Metacresol Hydrochloric acid Sodium hydroxide Water for injections Hydrochloric acid and or sodium hydroxide solution may be added to adjust pH 6 2 Incompatibilities In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products 6 3 Shelf life 2 years Chemical physical and microbiological in use stability has been demonstrated for 28 days at 2 8 C Once opened the product may be stored for a maximum of 28 days at 2 C to 8 C Other in use storage times and conditions are the responsibility of the user 6 4 Special precautions for storage Store in a refrigerator 2 C 8 C at all times The pe
302. density mean T scores were 2 2 and 2 1 respectively At baseline 35 of patients had a vertebral fracture and 59 had a non vertebral fracture All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day Lumbar spine BMD significantly increased by 3 months After 12 months BMD had increased in the lumbar spine and total hip by 5 and 1 respectively compared with placebo However no significant effect on fracture rates was demonstrated Glucocorticoid induced osteoporosis The efficacy of Forsteo in men and women N 428 receiving sustained systemic glucocorticoid therapy equivalent to 5 mg or greater of prednisone for at least 3 months was demonstrated in the 18 month primary phase of a 36 month randomised double blind comparator controlled study alendronate 10 mg day Twenty eight percent of patients had one or more radiographic vertebral fractures at baseline All patients were offered 1000 mg calcium per day and 800 IU vitamin D per day This study included postmenopausal women N 277 premenopausal women N 67 and men N 83 At baseline the postmenopausal women had a mean age of 61 years mean lumbar spine BMD T score of 2 7 median prednisone equivalent dose of 7 5 mg day and 34 had one or more radiographic vertebral fractures premenopausal women had a mean age of 37 years mean lumbar spine BMD T score of 2 5 median prednisone equivalent dose of 10 mg day and 9 had one or more radi
303. e in ord RIEN Ser Val Ser Glu Ile GIn Leu Met His Asn Leu Gly Lys His Leu Asn Ser cS b ic ei puli Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe 1 1 20ng R 4 2 4mL 1 13 Bl 8 20 ug C 118 9 pg mL AUC 9 135 9 pg hr mL Cd or 1 Arthritis Rheum 60 3346 2009 i NYHA New York Heart Association 2 deb ce ONS et SN 2 MEN HAYS 27 1 7 EY 7 q ORIEL SHEBO 4 CTD 5 6 NON Lad nunt 7
304. ed by the absence of woven bone and marrow fibrosis 14 2 Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis The safety and efficacy of once daily FORTEO median exposure of 10 months were examined in a double blind multicenter placebo controlled clinical study of 437 men with either primary idiopathic or hypogonadal osteoporosis FORTEO 20 mcg n 151 All men received 1000 mg of calcium and at least 400 IU of vitamin D per day The primary efficacy endpoint was change in lumbar spine BMD FORTEO increased lumbar spine BMD in men with primary or hypogonadal osteoporosis Statistically significant increases were seen at 3 months and continued throughout the treatment period FORTEO was effective in increasing lumbar spine BMD regardless of age baseline rate of bone turnover and baseline BMD The effects of FORTEO at additional skeletal sites are shown in Table 4 FORTEO treatment for a median of 10 months increased lumbar spine BMD from baseline in 94 of men treated Fifty three percent of patients treated with FORTEO achieved at least a 596 increase in spine BMD and 1496 gained 1096 or more Table 4 Mean Percent Change in BMD from Baseline to Endpoint in Men with Primary or Hypogonadal Osteoporosis Treated with FORTEO or Placebo for a Median of 10 Months FORTEO Placebo N 151 N 147 Lumbar spine BMD 5 9 0 5 Femoral neck BMD 1 5 0 3 Total hip BMD 1 2 0 5 Trochanter BM
305. edian treatment bone mineral density BMD had increased in the lumbar spine and total hip respectively by 9 and 4 compared with placebo p 0 001 Post treatment management Following treatment with FORSTEO 1262 postmenopausal women from the pivotal trial enrolled in a post treatment follow up study The primary objective of the study was to collect safety data of FORSTEO During this observational period other osteoporosis treatments were allowed and additional assessment of vertebral fractures was performed During a median of 18 months following discontinuation of FORSTEO there was a 41 reduction p 0 004 compared with placebo in the number of patients with a minimum of one new vertebral fracture In an open label study 503 postmenopausal women with severe osteoporosis and a fragility fracture within the previous 3 years 83 had received previous osteoporosis therapy were treated with FORSTEO for up to 24 months At 24 months the mean increase from baseline in lumbar spine total hip and femoral neck BMD was 10 5 2 6 and 3 9 respectively The mean increase in BMD from 18 to 24 months was 1 4 1 2 and 1 6 at the lumbar spine total hip and femoral neck respectively Male osteoporosis 437 patients mean age 58 7 years were enrolled in a clinical trial for men with hypogonadal defined as low morning free testosterone or an elevated FSH or LH or idiopathic osteoporosis Baseline spinal and femoral neck bone mineral
306. efined as a history of osteoporotic fracture multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy see Clinical Studies 14 2 1 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture FORTEO is indicated for the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy daily dosage equivalent to 5 mg or greater of prednisone at high risk for fracture defined as a history of osteoporotic fracture multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy see Clinical Studies 14 3 2 DOSAGE AND ADMINISTRATION 2 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture The recommended dose is 20 mcg subcutaneously once a day 2 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture The recommended dose is 20 mcg subcutaneously once a day 2 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture The recommended dose is 20 mcg subcutaneously once a day 2 4 Administration FORTEO should be administered as a subcutaneous injection into the thigh or abdominal wall There are no data available on the safety or efficacy of intravenous or intramuscular injection of FORTEO FORTEO should be administered initially under ci
307. en LY333334 Once Daily by Subcutaneous Injections for 18 Months or for 12 Months Followed by 6 Months of Observation to Assess Effects on Bone Covance 1691 003 J Covance Long Term Study in Laboratorie Ovariectomized Female 1 s GmbH Cynomolgus Monkeys Treated Subcutaneously with LY333334 for 18 Months Followed by a 3 Year Observation Period Nonclinical Pharmacology Report W53 23 Sequential Studies With Human Parathyroid Hormone 1 34 and Raloxifene or Ethynyl Estradiol in Ovariectomized Rats With Established Osteopenia 4 2 1 8 genpharm01 The Acute Cardiovascular Effects of LY333334 PTH 1 34 Administered Subcutaneously to Conscious genpharm02 An Acute Cardiovascular Toxicity Study With LY333334 Administered Subcutaneously in Conscious Instrumented Female Beagle Dogs tox11 A Toxicity Study of LY333334 Administered Subcutaneously to Cynomolgus Monkeys for 3 Months LY333334 1 12 5 HF 4 m
308. enosine 3 5 monophosphate in skeletal tissue in vitro The bioactive conformation of human parathyroid hormone Structural evidence for the extended helix postulate Gene 1983 26 197 203 Biochemistr y 1993 32 712 6 7132 Gene 1977 J Biol Chem 1982 257 92 05 9210 J Biol Chem 1970 245 7 21520 1526 J Am Chem Soc 2000 122 30 07 3014 LY333334 Differential effects of parathyroid hormone and its analogues on cytosolic calcium ion and cAMP levels in cultured rat osteoblast like cells Calculation of protein a oo extinction coefficients from amino acid sequence data Analysis of the requirements for parathyroid hormone action in renal membranes with the use of inhibiting analogues New method for generating deletions and gene replacements in Escherichia coli Action of bPTH and bPTH fragments on embryonic bone in vitro dissociation of the cyclic AMP and bone resorbing response Restriction site bank vectors II DNA sequence analysis of plasmid pJRD158 Collapse of parallel folding channels in dihydrofolate reductase from Escherichia coli by site directed mutagenesis Crystal structure of human parathyroid hormone 1 34 at 0 9 A resolution Secondary structure of proteins through circular dichroism spectroscopy Further definition of the Prote
309. er 3 3 mL to deliver 3 mL or 2 7 mL to deliver 2 4 mL Each mL contains 250 mcg teriparatide corrected for acetate chloride and water content 0 41 mg glacial acetic acid 0 1 mg sodium acetate anhydrous 45 4 mg mannitol 3 mg Metacresol and Water for Injection In addition hydrochloric acid solution 10 and or sodium hydroxide solution 10 may have been added to adjust the product to pH 4 Each cartridge pre assembled into a delivery device delivers 20 mcg of teriparatide per dose each day for up to 28 days 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action Endogenous 84 amino acid parathyroid hormone PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney Physiological actions of PTH include regulation of bone metabolism renal tubular reabsorption of calcium and phosphate and intestinal calcium absorption The biological actions of PTH and teriparatide are mediated through binding to specific high affinity cell surface receptors Teriparatide and the 34 N terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney Teriparatide is not expected to accumulate in bone or other tissues The skeletal effects of teriparatide depend upon the pattern of systemic exposure Once daily administration of teriparatide stimulates new bone formation on trabecular and cortical periosteal and or endosteal bone surfaces by preferential stimulation of o
310. er withdrawal of therapy There was no evidence of hypersensitivity reactions allergic reactions effects on serum calcium or effects on BMD response 4 9 Overdose Signs and symptoms No cases of overdose were reported during clinical trials FORSTEO has been administered in single doses of up to 100 micrograms and in repeated doses of up to 60 micrograms day for 6 weeks The effects of overdose that might be expected include delayed hypercalcaemia and risk of orthostatic hypotension Nausea vomiting dizziness and headache can also occur Overdose experience based on post marketing spontaneous reports In post marketing spontaneous reports there have been cases of medication error where the entire contents up to 800 ug of the teriparatide pen have been administered as a single dose Transient events reported have included nausea weakness lethargy and hypotension In some cases no adverse events occurred as a result of the overdose No fatalities associated with overdose have been reported Overdose management There is no specific antidote for FORSTEO Treatment of suspected overdose should include transitory discontinuation of FORSTEO monitoring of serum calcium and implementation of appropriate supportive measures such as hydration 5 PHARMACOLOGICAL PROPERTIES 5 1 Pharmacodynamic properties Pharmaco therapeutic group parathyroid hormones and analogues ATC code H05 AA02 Mechanism of action Endogenous 84 amino acid para
311. eriparatide is a recombinant peptide corresponding to human parathyroid hormone at positions 1 34 Teriparatide consists of 34 amino acid residues 1 9 2 INN INN teriparatide r INN List 24 Supplement to WHO Chronicle 1984 Vol 38 6 LY 333334 1 10 600 hg 600 hg 1 10 LY333334 110 EX P Bz 1 10 ER BIR OFF EEA ED FSW ace ed ei ted 1 LY333334 1 10 1 10 1 10 1 1 i m OOWOOOOCOOQS 20 15 Gy STISSSS OOSEOHOEO Fe
312. f supplemental calcium and at least 400 IU of vitamin D daily FORTEO increased urinary calcium excretion The median urinary excretion of calctum was 4 8 mmol day 190 mg day at 6 months and 4 2 mmol day 170 mg day at 12 months These levels were 0 76 mmol day 30 mg day and 0 3 mmol day 12 mg day higher respectively than in women treated with placebo The incidence of hypercalciuria gt 7 5 mmol Ca day or 300 mg day was similar in the women treated with FORTEO or placebo In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D daily FORTEO had inconsistent effects on urinary calcium excretion The median urinary excretion of calcium was 5 6 mmol day 220 mg day at 1 month and 5 3 mmol day 210 mg day at 6 months These levels were 0 5 mmol day 20 mg day higher and 0 2 mmol day 8 0 mg day lower respectively than in men treated with placebo The incidence of hypercalciuria 77 5 mmol Ca day or 300 mg day was similar in the men treated with FORTEO or placebo Phosphorus and Vitamin D In single dose studies teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration However hypophosphatemia 0 74 mmol L or 2 4 mg dL was not observed in clinical trials with FORTEO In clinical trials of daily FORTEO the median serum concentration of 1 25 dihydroxyvitamin D was increased at 12 months by 19
313. g 10 hg UF BAP I C 40 ug 10 ug 20 ug BMD 10 hg 40 hg 20 hg
314. hould not be prescribed for patients at increased baseline risk for osteosarcoma e g those with Paget s disease of bone or unexplained elevations of alkaline phosphatase pediatric and young adult patients with open epiphyses or prior external beam or implant radiation therapy involving the skeleton 5 1 RECENT MAJOR CHANGES Indications and Usage Treatment of Men and Women 07 2009 with Glucocorticoid Induced Osteoporosis 1 3 Dosage and Administration Treatment of Men and Women 07 2009 with Glucocorticoid Induced Osteoporosis 2 3 FORTEO is recombinant human parathyroid hormone analog 1 34 rhPTH 1 34 indicated for e Treatment of postmenopausal women with osteoporosis at high risk for fracture 1 1 e Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture 1 2 e Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture 1 3 DOSAGE AND ADMINISTRATION e Recommended dose is 20 mcg subcutaneously once a day 2 1 2 2 2 3 e Administer as a subcutaneous injection into the thigh or abdominal wall 2 4 e Administer initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic
315. hypotension occur 2 4 e Use of the drug for more than 2 years during a patient s lifetime is not recommended 2 5 meg 3 e Patients with Paget s disease of bone pediatric and young adult patients with open epiphyses and patients with prior external beam or implant radiation involving the skeleton Should not be treated with FORTEO 5 1 8 4 e Treatment duration Use of FORTEO for more than 2 years during a patient s lifetime is not recommended 5 2 e Patients with bone metastases history of skeletal malignancies metabolic bone diseases other than osteoporosis or hypercalcemic disorders Should not be treated with FORTEO 5 3 5 4 5 5 e Laboratory alterations FORTEO may increase serum calcium urinary calcium and serum uric acid 5 5 5 6 e Urolithiasis Use with caution in patients with active or recent urolithiasis because of risk of exacerbation 5 6 e Orthostatic hypotension Transient orthostatic hypotension may occur with initial doses of FORTEO 5 7 Most common adverse reactions gt 10 include arthralgia pain and nausea 6 1 To report SUSPECTED ADVERSE REACTIONS contact Eli Lilly and Company at 1 800 545 5979 or FDA at 1 800 FDA 1088 or www fda gov medwatch Digoxin Use FORTEO with caution in patients receiving digoxin Transient hypercalcemia may predispose patients to digitalis toxicity 5 8 7 1 12 3 e Pregnancy Based on animal studies may cause fetal harm 8 1 e Nursing Mothers Disco
316. iations interrupted rib extra vertebra or rib When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose the fetuses showed no abnormal findings In a perinatal postnatal study pregnant rats received subcutaneous teriparatide from organogenesis through lactation Mild growth retardation in female offspring at doses 2120 times the human dose based on surface area mcg m Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose respectively Exposure multiples were normalized based on body surface area mcg m Actual animal doses mice 30 to 1000 mcg kg day rats 30 to 1000 mcg kg day 8 3 Nursing Mothers It is not known whether teriparatide is excreted in human milk Because of the potential for tumorigenicity shown for teriparatide in animal studies a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother 8 4 Pediatric Use The safety and efficacy of FORTEO have not been established in any pediatric population FORTEO should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses Therefore FORTEO is not
317. ily Subcutaneous Administration of 5 g kg LY333334 for up to 18 Months LY333334 4 2 2 4 ME GR ADME Report 6 Effects on Hepatic Microsomal Drug Metabolizing Enzymes in Cynomolgus Monkeys Given LY333334 Daily by Subcutaneous Administration for 3 Months Toxicology Study B96 020 4 2 3 4 23 1 HE GR The Acute Toxicity of Biosynthetic Human Parathyroid Hormone 1 34 LY333334 Administered Subcutaneously to Fischer 344 Rats tox05 The Acute Toxicity of Biosynthetic Human Parathyroid Hormone 1 34 LY333334 Administered Intravenously to Fischer 344 I GE A Subchronic Toxicity and Companion Blood Level Study in Fischer 344 Rats Given LY333334 by Subcutaneous Injection for 6 Weeks tox12 A Chronic Toxicity and Comparison Blood Level Study in Fischer 344 Rats Given LY333334 by Subcutaneous Injection for 6 Months tox11 A Toxicity Study of LY333334 Administered Subcutaneously to Cynomolgus Monkeys for 3 Months 10
318. in Kinase C activation domain of the parathyroid hormone Investigation of the solution structure of the human parathyroid hormone fragment 1 34 by IH NMR spectroscopy distance geometry and molecular dynamics calculations 3 3 10 3 3 11 3 3 12 3 3 13 3 3 14 3 3 15 3 3 16 3 3 17 0 HEEN E ee 7A GOA 1 12 J Biol Chem 1988 263 27 13522 13527 Analytical Biochem 1989 182 31 9 326 J Biol Chem 1975 250 8 73199 3203 J Bacteriol 1989 171 4617 4622 Calcif Tissue Int 1983 35 70 77 Biochemistr Z y 1993332 13566 13574 Ann Rev Biophys Biophys Chem 1988 17 145 166 JBoneand Mineral Res 1994 9 6 9 Biochemistr y 1991 30 28 16936 6942 DNA 1984 3 259 268 J Biol Chem 2000 275 35 27238 27244 LY333334 1 12 NL Nuclear magnetic resonance Lee MS Protein Z chemical shift comparison of Engng estimated secondary structures 1996 9 1 1 in peptides by nuclear 5 25 magnetic resonance and circular dichroism Structure of human J Biol parathyroid hormone 1 37 in Chem solution 1995 270 25 15194 15202 Structure activity relation of J Biol NH2
319. increase in bone mass and focal osteoblast hyperplasia The second 2 year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg kg equivalent to 3 and 20 times the human exposure at the 20 mcg dose based on AUC comparison The study showed that the occurrence of osteosarcoma osteoblastoma and osteoma was dependent upon dose and duration of exposure Bone tumors were observed when immature 2 month old rats were treated with 30 mcg kg day for 24 months or with 5 or 30 mcg kg day for 6 months Bone tumors were also observed when mature 6 month old rats were treated with 30 mcg kg day for 6 or 20 months Tumors were not detected when mature 6 month old rats were treated with 5 mcg kg day for 6 or 20 months The results did not demonstrate a difference in susceptibility to bone tumor formation associated with teriparatide treatment between mature and immature rats The relevance of these animal findings to humans is uncertain Mutagenesis Teriparatide was not genotoxic in any of the following test systems the Ames test for bacterial mutagenesis the mouse lymphoma assay for mammalian cell mutation the chromosomal aberration assay in Chinese hamster ovary cells with and without metabolic activation and the in vivo micronucleus test in mice Impairment of Fertilit
320. increases in the markers of bone resorption urinary N telopeptide NTX and urinary deoxypyridinoline DPD consistent with the physiological coupling of bone formation and resorption in skeletal remodeling Changes in BSAP NTX and DPD were lower in men than in women possibly because of lower systemic exposure to teriparatide in men In the study of patients with glucocorticoid induced osteoporosis the effects of FORTEO on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids 12 3 Pharmacokinetics Absorption Teriparatide is absorbed after subcutaneous injection the absolute bioavailability is approximately 95 based on pooled data from 20 40 and 80 mcg doses The rates of absorption and elimination are rapid The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20 mcg dose and declines to non quantifiable concentrations within 3 hours Distribution Systemic clearance of teriparatide approximately 62 L hr in women and 94 L hr in men exceeds the rate of normal liver plasma flow consistent with both hepatic and extra hepatic clearance Volume of distribution following intravenous injection is approximately 0 12 L kg Intersubject variability in systemic clearance and volume of distribution is 25 to 50 The half life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximatel
321. l control of osteoblast growth and differentiation Maintaining bone mass by bisphosphonate incadronate disodium YM175 sequential treatment after discontinuation of intermittent human parathyroid hormone 1 34 administration in ovariectomized rats Expression of the c fos gene induced by parathyroid hormone in the bones of SAMP6 mice a murine model for senile osteoporosis Comparison of the effects of intermittent and continuous administration of human parathyroid hormone 1 34 on rat bone 20 1 12 Calcif Tissue Int 1992 50 3 214 220 J Clin Invest 1993 91 6 2479 2487 J Clin Invest 1995 96 11 12331 2338 J Pharmacol Exp Ther 1998 286 1 1341 344 Physiol Rev 1996 76 2 593 629 J Bone Miner Res 1996 11 2 169 177 Mechanisms of Ageing amp Developmen t 1999 108 1 187 97 LY333334 Discrepancy of response of hPTH administration and its withdrawal between trabecular and cortical bone sites in ovx rats PTH EBM NR HEA E ERKA 21 1 12 Bone 1995 17 Suppl 279 S 283S CLINICAL CALCIUM 2003 13 1 46 53 1 12 LY33
322. lactation see section 4 4 and 4 6 Pre existing hypercalcemia Severe renal impairment Metabolic bone diseases including hyperparathyroidism and Paget s disease of the bone other than primary osteoporosis or glucorticoid induced osteoporosis Unexplained elevations of alkaline phosphatase Prior external beam or implant radiation therapy to the skeleton Patients with skeletal malignancies or bone metastases should be excluded from treatment with teriparatide 4 4 Special warnings and precautions for use In normocalcemic patients slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide Routine calcium monitoring during therapy is not required Therefore if any blood samples are taken from a patient this should be done at least 16 hours after the most recent FORSTEO injection FORSTEO may cause small increases in urinary calcium excretion but the incidence of hypercalciuria did not differ from that in the placebo treated patients in clinical trials FORSTEO has not been studied in patients with active urolithiasis FORSTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition In short term clinical studies with FORSTEO isolated episodes of transient orthos
323. ld not be treated with FORTEO 5 6 Urolithiasis or Pre existing Hypercalciuria In clinical trials the frequency of urolithiasis was similar in patients treated with FORTEO and placebo However FORTEO has not been studied in patients with active urolithiasis If active urolithiasis or pre existing hypercalciuria are suspected measurement of urinary calcium excretion should be considered FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition 5 7 Orthostatic Hypotension FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur In short term clinical pharmacology studies with teriparatide transient episodes of symptomatic orthostatic hypotension were observed in 596 of patients Typically an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours When transient orthostatic hypotension occurred it happened within the first several doses it was relieved by placing the person in a reclining position and it did not preclude continued treatment 5 8 Drug Interactions Hypercalcemia may predispose patients to digitalis toxicity Because FORTEO transiently increases serum calcium patients receiving digoxin should use FORTEO with caution see Drug Interactions 7 1 and Clinical Pharmacology 12 3 6 ADVERSE REACTIONS 6 1 Clinical Trials
324. miting dizziness and headache might also occur In postmarketing spontaneous reports there have been cases of medication errors in which the entire contents up to 800 mcg of the FORTEO delivery device pen have been administered as a single dose Transient events reported have included nausea weakness lethargy and hypotension In some cases no adverse events occurred as a result of the overdose No fatalities associated with overdose have been reported Overdose Management There is no specific antidote for teriparatide Treatment of suspected overdose should include discontinuation of FORTEO monitoring of serum calcium and phosphorus and implementation of appropriate supportive measures such as hydration 11 DESCRIPTION FORTEO teriparatide rDNA origin injection contains recombinant human parathyroid hormone 1 34 and is also called rhPTH 1 34 It has an identical sequence to the 34 N terminal amino acids the biologically active region of the 84 amino acid human parathyroid hormone Teriparatide has a molecular weight of 4117 8 daltons and its amino acid sequence is shown below Teriparatide rDNA origin is manufactured using a strain of Escherichia coli modified by recombinant DNA technology FORTEO is supplied as a sterile colorless clear isotonic solution in a glass cartridge which is pre assembled into a disposable delivery device pen for subcutaneous injection Each prefilled delivery device is filled with eith
325. n E 2002 359 93 20 1841 1850 Metabolism of parathyroid J Clin hormone by isolated rat Invest 1981 kupffer cells and hepatocytes Feb 67 449 57 Biochemical markers of bone Osteoporos turnover potential use in the Int investigation and management 2008 19 168 of postmenopausal 3 1704 osteoporosis Prevention and management WHO of osteoporosis Technical Report Series No 921 Systematic review Ann Intern bisphosphonates and Med osteonecrosis of the jaws 2006 144 10 753 761 Effect of Teriparatide J Bone recombinant human Miner Res parathyroid hormone 1 34 2003 18 3 on cortical bone in 539 543 postmenopausal women with osteoporosis REFR RE OO 82 WAYE lt 2000 2001 18 76 82 2008 HERE OO 6 LI 2005 42 596 608 35 LY333334 HORE EBM
326. n should be returned to the refrigerator immediately after use Do not freeze Do not store the injection device with the needle attached 6 5 Nature and contents of container 2 4 ml solution in cartridge siliconised Type I glass with a plunger halobutyl rubber disc seal polyisoprene bromobutyl rubber laminate aluminium assembled into a disposable pen FORSTEO is available in pack sizes of 1 or 3 pens Each pen contains 28 doses of 20 micrograms per 80 microliters Not all pack sizes may be marketed 6 6 Special precautions for disposal FORSTEO is supplied in a pre filled pen Each pen should be used by only one patient A new sterile needle must be used for every injection Each FORSTEO pack is provided with a user manual that fully describes the use of the pen No needles are supplied with the product The device can be used with insulin pen injection needles After each injection the FORSTEO pen should be returned to the refrigerator FORSTEO should not be used if the solution is cloudy coloured or contains particles Please also refer to the User Manual for instructions on how to use the pen Any unused product or waste material should be disposed of in accordance with local requirements 7 MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B V Grootslag 1 5 NL 3991 RA Houten The Netherlands 8 MARKETING AUTHORISATION NUMBER S EU 1 03 247 001 002 9 DATE OF FIRST AUTHORISATION RENEWAL OF THE AUTHORISATION Date
327. ntinue nursing or FORTEO taking into account the importance of treatment to the mother 8 3 e Pediatric Use FORTEO should not be used in pediatric and young adult patients with open epiphyses due to increased baseline risk of osteosarcoma 5 1 8 4 See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised 07 2009 FULL PRESCRIBING INFORMATION CONTENTS WARNING POTENTIAL RISK OF OSTEOSARCOMA 1 INDICATIONS AND USAGE 1 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture 1 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture 1 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture 2 DOSAGE AND ADMINISTRATION 2 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture 2 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture 2 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture 24 Administration 2 5 Treatment Duration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 1 Osteosarcoma 52 Treatment Duration 5 3 Bone Metastases and Skeletal Malignancies 5 4 Metabolic Bone Diseases 5 5 Hypercalcemia and Hypercalcemic Disorders 5 6 Urolithiasis or Pre existing Hypercalciuria 5 7 Orthostatic Hypotension 5 8 Drug Interactions 6 ADVERSE REACTIONS 6 1 Clinical T
328. o endpoint at the lumbar spine femoral neck total hip and total body see Table 3 Table 3 Mean Percent Change in BMD from Baseline to Endpoint in Postmenopausal Women with Osteoporosis Treated with FORTEO or Placebo for a Median of 19 Months FORTEO Placebo N 541 N 544 Lumbar spine BMD 9 7 1 1 Femoral neck BMD 2 8 0 7 Total hip BMD 2 6 1 0 Trochanter BMD 3 5 0 2 Intertrochanter BMD 2 6 1 3 12 Ward s triangle BMD 4 2 0 8 Total body BMD 0 6 0 5 Distal 1 3 radius BMD 2 1 1 3 Ultradistal radius BMD 0 1 1 6 a b Intent to treat analysis last observation carried forward p lt 0 001 compared with placebo px0 05 compared with placebo FORTEO treatment increased lumbar spine BMD from baseline in 96 of postmenopausal women treated Seventy two percent of patients treated with FORTEO achieved at least a 5 increase in spine BMD and 44 gained 10 or more Both treatment groups lost height during the trial The mean decreases were 3 61 and 2 81 mm in the placebo and FORTEO groups respectively Bone Histology The effects of teriparatide on bone histology were evaluated in iliac crest biopsies of 35 postmenopausal women treated for 12 to 24 months with calcium and vitamin D and teriparatide 20 or 40 mcg day Normal mineralization was observed with no evidence of cellular toxicity The new bone formed with teriparatide was of normal quality as evidenc
329. oadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied see Clinical Pharmacology 12 3 7 3 Furosemide Coadministration of intravenous furosemide 20 to 100 mg with teriparatide 40 mcg in healthy people and patients with mild moderate or severe renal impairment CrCl 13 to 72 mL min resulted in small increases in the serum calctum 2 and 24 hour urine calcium 37 responses to teriparatide that did not appear to be clinically important see Clinical Pharmacology 12 3 8 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy Pregnancy Category C There are no adequate and well controlled studies of FORTEO in pregnant women In animal studies teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose FORTEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus In animal studies pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose At doses 60 times the human dose the fetuses showed an increased incidence of skeletal deviations or var
330. ographic vertebral fractures and men had a mean age of 57 years mean lumbar spine BMD T score of 2 2 median prednisone equivalent dose of 10 mg day and 24 had one or more radiographic vertebral fractures Sixty nine percent of patients completed the 18 month primary phase At the 18 month endpoint FORSTEO significantly increased lumbar spine BMD 7 2 compared with alendronate 3 4 p lt 0 001 FORSTEO increased BMD at the total hip 3 6 compared with alendronate 2 2 p lt 0 01 as well as at the femoral neck 3 7 compared with alendronate 2 1 p lt 0 05 In patients treated with teriparatide lumbar spine total hip and femoral neck BMD increased between 18 and 24 months by an additional 1 7 0 9 and 0 4 respectively At 36 months analysis of spinal X rays from 169 alendronate patients and 173 FORSTEO patients showed that 13 patients in the alendronate group 7 7 had experienced a new vertebral fracture compared with 3 patients in the FORSTEO group 1 7 p 0 01 In addition 15 of 214 patients in the alendronate group 7 0 had experienced a nonvertebral fracture compared with 16 of 214 patients in the FORSTEO group 7 5 p 0 84 In premenopausal women the increase in BMD from baseline to 18 month endpoint was significantly greater in the FORSTEO group compared with the alendronate group at the lumbar spine 4 2 versus 1 9 p lt 0 001 and total hip 3 8 versus 0 9 p 0 005 However no significant effect
331. on the skeleton of adult osteopenic ovariectomized rats Animal models for in vivo experimentation in osteoporosis research hormone PTH related peptide 1 34 and bovine PTH 1 34 4 3 22 4 3 23 4 3 24 4 3 25 4 3 26 4 3 30 4 3 31 4 3 32 Hock JM enhance the anabolic effect of rats induced by ovariectomy post menopausal osteoporotic analog of human parathyroid Kimmel DB 1 12 RE Mech Ageing Dev 1995 85 2 3 183 197 J Musculoskel Neuron Interact 2001 2 33 47 Bone Miner 1988 3 3 1 B 93 199 il p i 4 B Int J Pharm 2006 317 2 144 154 J Clin Invest 1999 104 4 439 446 Bone 2007 40 143 4 1446 Mech Ageing Dev 1990 56 1 49 62 Bone Miner 1990 11 2 217 235 Endocrinolo gy 1993 132 4 21577 1584 Osteoporosi s 1996 671 690 Endocrinolo gy 1995 136 8 73624 3631 LY333334 Metabolic stability of human parathyroid hormone peptide hPTH 1 34 in rat tissue homogenates kinetics and products of proteolytic degradation Age related changes of cancellous and cortical bone histomorphometry in female Sprague Dawley rats Parathyroid hormone monotherapy and cotherapy with antiresorptive
332. ormone 1 34 in Human Serum by Immunoradiometric Assay 952069 LY THIRD REVISION The Quantitative Determination of LY333334 Biosynthetic Human Parathyroid Hormone 1 34 in Human Serum by Immunoradiometric Assay IRMA 011591 Quantification of LY333334 Biosynthetic Human Parathyroid Hormone PTH 1 34 in Human Serum by Immunoratiometric Assay IRMA 23 LY333334 5 3 3 PK 5 3 3 1 PK GR B3D JE GHCO A Randomized Single Blind Placebo Controlled Study to Evaluate the Safety and Pharmacokinetics of Teriparatide in Healthy Older Japanese and Caucasian Women B3D LC GHAB LY333334 Single Dose Dose Ranging Study Pharmacokinetic and Pharmacodynamic Properties B3D LC GHAD The Effect of LY333334 on Calcium Homeostasis in Healthy Postmenopausal Women B3D FW GHBO Assessment of LY333334 on Cardiac Conduction and Repolarisation B3D FW GHBO 2 Abbreviated Report Assessment of LY333334 on Cardiac Conduction and Repolarisation 5 3 3 3 PK
333. ould not be prescribed for patients at increased baseline risk of osteosarcoma These include Paget s disease of bone Unexplained elevations of alkaline phosphatase may indicate Paget s disease of bone e Pediatric and young adult patients with open epiphyses e Prior external beam or implant radiation therapy involving the skeleton Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO Enrollment information can be obtained by calling 1 866 382 6813 or by visiting www forteoregistry rti org 52 Treatment Duration The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment Consequently use of the drug for more than 2 years during a patients lifetime is not recommended 5 3 Bone Metastases and Skeletal Malignancies Patients with bone metastases or a history of skeletal malignancies should not be treated with FORTEO 5 4 Metabolic Bone Diseases Patients with metabolic bone diseases other than osteoporosis should not be treated with FORTEO 5 5 Hypercalcemia and Hypercalcemic Disorders FORTEO has not been studied in patients with pre existing hypercalcemia These patients should not be treated with FORTEO because of the possibility of exacerbating hypercalcemia Patients known to have an underlying hypercalcemic disorder such as primary hyperparathyroidism shou
334. porosis FORTEO 20 mcg n 541 All women received 1000 mg of calcium and at least 400 IU of vitamin D per day Baseline and endpoint spinal radiographs were evaluated using the semiquantitative scoring Ninety percent of the women in the study had 1 or more radiographically diagnosed vertebral fractures at baseline The primary efficacy endpoint was the occurrence of new radiographically diagnosed vertebral fractures defined as changes in the height of previously undeformed vertebrae Such fractures are not necessarily symptomatic Effect on Fracture Incidence New Vertebral Fractures FORTEO when taken with calcium and vitamin D and compared with calcium and vitamin D alone reduced the risk of 1 or more new vertebral fractures from 14 3 of women in the placebo group to 5 0 in the FORTEO group This difference was statistically significant p 0 001 the absolute reduction in risk was 9 3 and the relative reduction was 65 FORTEO was effective in reducing the risk for vertebral fractures regardless of age baseline rate of bone turnover or baseline BMD see Table 2 Table 2 Effect of FORTEO on Risk of Vertebral Fractures in Postmenopausal Women with Osteoporosis Percent of Women With Fracture Absolute Risk Reduction Relative Risk Reduction FORTEO Placebo 90 95 CI 9o 95 CI N 444 N 448 New fracture 21 5 0 14 3 9 3 5 5 13 1 65 45 78 1 fracture 3 8 9 4 2 fractures 0 9 2 9 23 fractures 0 2 2
335. ractions 7 2 Furosemide In a study of 9 healthy people and 17 patients with mild moderate or severe renal impairment CrCl 13 to 72 mL min coadministration of intravenous furosemide 20 to 100 mg with teriparatide 40 mcg resulted in small increases in the serum calcium 296 and 24 hour urine calcium 3796 responses to teriparatide that did not appear to be clinically important see Drug Interactions 7 3 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility Carcinogenesis Two carcinogenicity bioassays were conducted in Fischer 344 rats In the first study male and female rats were given daily subcutaneous teriparatide injections of 5 30 or 75 mcg kg day for 24 months from 2 months of age These doses resulted in systemic exposures that were respectively 3 20 and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg based on AUC comparison Teriparatide treatment resulted in a marked dose related increase in the incidence of osteosarcoma a rare malignant bone tumor in both male and female rats Osteosarcomas were observed at all doses and the incidence reached 40 to 50 in the high dose groups Teriparatide also caused a dose related increase in 10 osteoblastoma and osteoma in both sexes No osteosarcomas osteoblastomas or osteomas were observed in untreated control rats The bone tumors in rats occurred in association with a large
336. rcumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur see Warnings and Precautions 5 7 e Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit FORTEO is a clear and colorless liquid Do not use if solid particles appear or if the solution is cloudy or colored Patients and caregivers who administer FORTEO should receive appropriate training and instruction on the proper use of the FORTEO delivery device from a qualified health professional see Patient Counseling Information 17 5 2 5 Treatment Duration The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment Consequently use of the drug for more than 2 years during a patient s lifetime is not recommended 3 DOSAGE FORMS AND STRENGTHS Multi dose prefilled delivery device pen for subcutaneous injection containing 28 daily doses of 20 mcg 4 CONTRAINDICATIONS Do not use FORTEO in patients with e Hypersensitivity to teriparatide or to any of its excipients Reactions have included angioedema and anaphylaxis see Adverse Reactions 6 2 5 WARNINGS AND PRECAUTIONS 5 1 Osteosarcoma In male and female rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor that was dependent on dose and treatment duration see Boxed Warning and Nonclinical Toxicology 13 1 FORTEO sh
337. rials Experience 6 2 Postmarketing Experience 7 DRUG INTERACTIONS 7 1 Digoxin AD Hydrochlorothiazide 7 3 Furosemide 8 USEIN 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 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action 12 2 Pharmacodynamics 12 3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility 17 1 Potential Risk of Osteosarcoma and Voluntary FORTEO Patient 13 2 Animal Toxicology Registry 14 CLINICAL STUDIES 17 2 Orthostatic Hypotension 17 3 Hypercalcemia 17 4 Other Osteoporosis Treatment Modalities 17 5 Use of Delivery Device 17 6 Availability of Medication Guide and User Manual 14 1 X Treatment of Osteoporosis in Postmenopausal Women 14 2 Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis 14 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis 16 HOW SUPPLIED STORAGE AND HANDLING Sections or subsections omitted from the full prescribing information are not 16 1 How Supplied listed 16 2 Storage and Handling 17 PATIENT COUNSELING INFORMATION FULL PRESCRIBING INFORMATION WARNING POTENTIAL RISK OF OSTEOSARCOMA In male and female rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor that was dependent on dose and treatment duration The effect was ob
338. ry in Healthy Subjects 5 3 1 2 3 B3D EW GHAS ID i3 E LY333334 A Relative dx Bioavailability Study of the m NA Pulmonary Route of Administration compared with the Subcutaneous Route and Single and Multiple Dose Safety and Pharmacokinetics of LY333334 by Inhalation 22 LY333334 1 12 T SAY B3D EW GHAT Evaliation of the Nasal Absorption and Tolerability of LY333334 following the Administration of a Noval Nasal Formulation to Healthy Volunteers B3D EW GHBF A Multiple Dose Safety Study of Inhaled LY333334 and Relative Bioavailability to the Subcutaneous Route B3D EW GHCE A Single Dose Study to Compare the Pharmacokinetics of Teriparatide Administered by Two Different Injection Techniques 5 3 14 an PERO Sat 5 952069 LY FIRST REVISION The Quantitative Determination of LY333334 Biosynthetic Human Parathyroid H
339. s from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality FORTEO Placebo N 691 N 691 Event Classification Body as a Whole Pain 21 3 20 5 Headache 7 5 7 4 Asthenia 8 7 6 8 Neck pain 3 0 2 7 Cardiovascular Hypertension 7 1 6 8 Angina pectoris 2 5 1 6 Syncope 2 6 1 4 Digestive System Nausea 8 5 6 7 Constipation 5 4 4 5 Diarrhea 54 4 6 Dyspepsia 52 4 1 Vomiting 3 0 2 3 Gastrointestinal disorder 2 3 2 0 Tooth disorder 2 0 1 3 Musculoskeletal Arthralgia 10 1 8 4 Leg cramps 2 6 1 3 Nervous System Dizziness 8 0 5 4 Depression 4 1 2 1 Insomnia 4 3 3 6 Vertigo 3 8 2 7 Respiratory System Rhinitis 9 6 8 8 Cough increased 6 4 5 5 Pharyngitis 5 5 4 8 Dyspnea 3 6 2 6 Pneumonia 3 9 33 Skin and Appendages Rash 4 9 4 5 Sweating 2 2 1 7 Immunogenicity In the clinical trial antibodies that cross reacted with teriparatide were detected in 3 of women 15 541 receiving FORTEO Generally antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy There was no evidence of hypersensitivity reactions or allergic reactions among these patients Antibody formation did not appear to have effects on serum calcium or on bone mineral density BMD response Laboratory Findings Serum Calcium
340. served at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20 mcg dose Because of the uncertain relevance of the rat osteosarcoma finding to humans prescribe FORTEO only for patients for whom the potential benefits are considered to outweigh the potential risk FORTEO should not be prescribed for patients who are at increased baseline risk for osteosarcoma including those with Paget s disease of bone or unexplained elevations of alkaline phosphatase pediatric and young adult patients with open epiphyses or prior external beam or implant radiation therapy involving the skeleton see Warnings and Precautions 5 1 Adverse Reactions 6 2 and Nonclinical Toxicology 13 1 1 INDICATIONS AND USAGE 1 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture FORTEO is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy In postmenopausal women with osteoporosis FORTEO reduces the risk of vertebral and nonvertebral fractures see Clinical Studies 14 1 1 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture d
341. sn Leu Gly Lys His Leu Asn Ser Met Glu o 0H 7 Non Arg Val Glu Trp Leu Arg ire HANCH CHCH C Lys Lys Leu Gln Asp Val i K is His Asn Phe 600 ug 60 mg 5 mg FERJE 1 1 qr Amd o HFE ella och del 2 Gk Far fy amp x En ae att LY333334 1 7 1 7 1 1 1 1 1 60mg 3mg 1 1 4 20 pg
342. steady state a single FORSTEO dose did not alter the cardiac effect of digoxin However sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity Because FORSTEO transiently increases serum calcium FORSTEO should be used with caution in patients taking digitalis 4 6 Pregnancy and lactation General recommendation Studies in rabbits have shown reproductive toxicity see section 5 3 The effect of teriparatide on human foetal development has not been studied The potential risk for humans is unknown It is not known whether teriparatide is excreted in human milk FORSTEO is contraindicated for use during pregnancy or breast feeding Women of childbearing potential Contraception in females Women of childbearing potential should use effective methods of contraception during use of FORSTEO If pregnancy occurs FORSTEO should be discontinued 4 7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed However transient orthostatic hypotension or dizziness was observed in some patients These patients should refrain from driving or the use of machines until symptoms have subsided 4 8 Undesirable effects Of patients in the teriparatide trials 82 8 of the FORSTEO patients and 84 5 of the placebo patients reported at least 1 adverse event The most commonly reported adverse reactions in patients treated with FORST
343. steoblastic activity over osteoclastic activity In monkey studies teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone In humans the anabolic effects of teriparatide manifest as an increase in skeletal mass an increase in markers of bone formation and resorption and an increase in bone strength By contrast continuous excess of endogenous PTH as occurs in hyperparathyroidism may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation 12 2 Pharmacodynamics Pharmacodynamics in Men and Postmenopausal Women with Osteoporosis Effects on Mineral Metabolism Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH e g increases serum calcium and decreases serum phosphorus Serum Calcium Concentrations When teriparatide 20 mcg is administered once daily the serum calcium concentration increases transiently beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours median increase 0 4 mg dL The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16 to 24 hours after each dose In a clinical study of postmenopausal women with osteoporosis the median peak serum calcium concentration measured 4 to 6 hours after dosing with FORTEO
344. tatic hypotension were observed Typically an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours When transient orthostatic hypotension occurred it happened within the first several doses was relieved by placing subjects in a reclining position and did not preclude continued treatment Caution should be exercised in patients with moderate renal impairment Experience in the younger adult population including premenopausal women is limited see section 5 1 Treatment should only be initiated if the benefit clearly outweighs risks in this population Women of childbearing potential should use effective methods of contraception during use of FORSTEO If pregnancy occurs FORSTEO should be discontinued Studies in rats indicate an increased incidence of osteosarcoma with long term administration of teriparatide see section 5 3 Until further clinical data become available the recommended treatment time of 24 months should not be exceeded 4 5 Interactions with other medicinal products and other forms of interaction FORSTEO has been evaluated in pharmacodynamic interaction studies with hydrochlorothiazide No clinically significant interactions were noted Co administration of raloxifene or hormone replacement therapy with FORSTEO did not alter the effects of FORSTEO on serum or urine calcium or on clinical adverse events In a study of 15 healthy subjects administered digoxin daily to
345. teoporosi S Foundation 2008 Effects of two years of daily J Bone Teriparatide treatment on Miner Res BMD in postmenopausal i 2008 23 10 women with severe 71591 1600 osteoporosis with and without prior antiresorptive treatment Severely suppressed bone i J Clin turnover a potential Endocrinol complication of alendronate Metab therapy 2005 90 3 1294 1301 Diagnostic criteria of primary i J Bone osteoporosis Miner Metab 1998 16 139 150 Pathogenesis of osteoporosis i J Clin concepts conflicts and Invest prospects 2005 115 12 3318 A unitary model for i J Bone involutional osteoporosis Miner Res estrogen deficiency causes 1998 13 5 both type I and type II 763 773 osteoporosis in postmenopausal women and contributes to bone loss in aging men Drug used to treat i J Bone osteoporosis the critical need Miner Res for a uniform nomenclature 2005 20 2 based on their action on bone 177 184 remodeling 5 4 31 5 4 32 5 4 33 5 4 34 5 4 35 5 4 36 5 4 37 5 4 38 5 4 39 34 LY333334 1 12 ae EN G EV Vertebral fracture prevalence Ross PD Int J 2 in women in Hiroshima Epidemiol compared to Caucasians or 1995 24 6 Japanese in the US 1171 1177 Pathogenesis of bone fragility Seeman Lancet in women and me
346. thyroid hormone PTH is the primary regulator of calctum and phosphate metabolism in bone and kidney FORSTEO rhPTH 1 34 is the active fragment 1 34 of endogenous human parathyroid hormone Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells osteoblasts indirectly increasing the intestinal absorption of calcium and increasing the tubular re absorption of calcium and excretion of phosphate by the kidney Pharmacodynamic effects FORSTEO is a bone formation agent to treat osteoporosis The skeletal effects of FORSTEO depend upon the pattern of systemic exposure Once daily administration of FORSTEO increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity Clinical efficacy Risk Factors Independent risk factors for example low BMD age the existence of previous fracture family history of hip fractures high bone turnover and low body mass index should be considered in order to identify women and men at increased risk of osteoporotic fractures who could benefit from treatment Premenopausal women with glucocorticoid induced osteoporosis should be considered at high risk for fracture if they have a prevalent fracture or a combination of risk factors that place them at high risk for fracture e g low bone density e g T score lt 2 sustained high dose glucocorticoid therapy e g 27 5
347. u Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe 1 1 20pg R 4 0 2 4mL 1 13 S Bil 8 Bil 20 hg Cmax 118 9 pg mL AUC 135 9 pg hrmL 1 Arthritis Rheum 60 3346 2009 2 3 p you 4 5 6 BAA COR 7 FA pH BE SLE j THUTO fas fee Bil MARIE RA 203 8 iL DSRNA ELEN 20 pg 12 52 9 IKE
348. um value above the upper limit of normal 2 64 mmol L 10 6 mg dL compared with none of the men treated with placebo The percentage of men treated with FORTEO whose serum calcium was above the upper limit of normal on consecutive measurements was 1 3 2 men compared with none of the men treated with placebo Although calcium supplements and or FORTEO doses could have been reduced in these men only calcium supplementation was reduced see Warnings and Precautions 5 5 and Adverse Reactions 6 1 In a clinical study of women previously treated for 18 to 39 months with raloxifene n 26 or alendronate n 33 mean serum calcium gt 12 hours after FORTEO injection was increased by 0 09 to 0 14 mmol L 0 36 to 0 56 mg dL after 1 to 6 months of FORTEO treatment compared with baseline Of the women pretreated with raloxifene 3 11 5 had a serum calcium gt 2 76 mmol L 11 0 mg dL and of those pretreated with alendronate 3 9 1 had a serum calcium gt 2 76 mmol L 11 0 mg dL The highest serum calcium reported was 3 12 mmol L 12 5 mg dL None of the women had symptoms of hypercalcemia There were no placebo controls in this study In the study of patients with glucocorticoid induced osteoporosis the effects of FORTEO on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids Urinary Calcium Excretion In a clinical study of postmenopausal women with osteoporosis who received 1000 mg o
349. utaneously to Male CD Rats tox15 A Segment I Reproduction Study in Female CD Rats Administered LY333334 Subcutaneously tox17 A Segment II Developmental Toxicity Study in Pregnant CD 1 Mice Given LY333334 Subcutaneously tox14 A Segment II Developmental Toxicity Study of LY333334 Administered Subcutaneously to Pregnant CD Rats 12 1 12 TUE LY333334 1 12 ap ap p agb LN EE Eas 798995 4 2 3 5 2 3 m08097 208 ERA Eli Lilly ES TARR BG PES A Pilot Teratology Study of and PTH LY333334 Company Administered Subcutaneously in Pregnant CD 1 Mice 4 2 3 5 2 4 r09997 r11997 IE Ep Eli Lilly A Pilot Teratology Study of and PTH
350. v tox22 A Chronic Toxicity Study of LY333334 Administered Subcutaneously to Cynomolgus Monkey for 1 Year genpharm03 The Acute Behavioral Profile of LY333334 Following Subcutaneous Administration 4 2 2 4 2 2 1 a DURUM nv ADME Report 1 Quantification of LY333334 PTH 1 34 in Rat Serum by Immunoradiometric Assay 4 2 2 2 GR ADME Report 3 Serum Pharmacokinetics of LY333334 in Male and Female F344 Rats Following Single Subcutaneous Administrations of 100 300 or 1000 pg kg Study R09495 ADME Report 2 Serum Pharmacokinetics of LY333334 in Male and Female F344 Rats Following a Single Intravenous Administration of 300 ug kg Study R07795 ADME Report 24 Serum Pharmacokinetics of LY333334 in Male and Female Fischer 344 Rats Following a Single Intravenous or Subcutaneous Dose of 10 ug kg ADME Report 25
351. y No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30 100 or 300 mcg kg day prior to mating and in females continuing through gestation Day 6 16 to 160 times the human dose of 20 meg based on surface area mcg m 13 2 Animal Toxicology In single dose rodent studies using subcutaneous injection of teriparatide no mortality was seen in rats given doses of 1000 mcg kg 540 times the human dose based on surface area mcg m or in mice given 10 000 mcg kg 2700 times the human dose based on surface area mcg m In a long term study skeletally mature ovariectomized female monkeys N 30 per treatment group were given either daily subcutaneous teriparatide injections of 5 mcg kg or vehicle Following the 18 month treatment period the monkeys were removed from teriparatide treatment and were observed for an additional 3 years The 5 mcg kg dose resulted in systemic exposures that were approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg based on AUC comparison Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study 14 CLINICAL STUDIES 14 1 Treatment of Osteoporosis in Postmenopausal Women The safety and efficacy of once daily FORTEO median exposure of 19 months were examined in a double blind multicenter placebo controlled clinical study of 1637 postmenopausal women with osteo
352. y 1 hour when administered by subcutaneous injection The longer half life following subcutaneous administration reflects the time required for absorption from the injection site Metabolism and Excretion No metabolism or excretion studies have been performed with teriparatide However the mechanisms of metabolism and elimination of PTH 1 34 and intact PTH have been extensively described in published literature Peripheral metabolism of PTH is believed to occur by non specific enzymatic mechanisms in the liver followed by excretion via the kidneys Pediatric Patients Pharmacokinetic data in pediatric patients are not available see Warnings and Precautions 5 1 Geriatric Patients No age related differences in teriparatide pharmacokinetics were detected range 31 to 85 years Gender Although systemic exposure to teriparatide was approximately 20 to 30 lower in men than women the recommended dose for both genders is 20 mcg day Race The populations included in the pharmacokinetic analyses were 98 5 Caucasian The influence of race has not been determined Renal Impairment No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment creatinine clearance CrCl 30 to 72 mL min administered a single dose of teriparatide In 5 patients with severe renal impairment CrCI lt 30 mL min the AUC and T of teriparatide were increased by 73 and 77 respectively Maximum serum concentration

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