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1 CTD 2.7 Page (1) GDDQ 1) GDDQ AGHD GH GDDQ GDDQ * GDDQ * ) GDDQ AGHD

2 CTD 2.7 Page GDDQ GDDQ *1 *1 *2 AO CO GH *2 AGHD *2 * * ± µg/l : AO µg/l : AO µg/l: CO µg/l : CO µg/l : AO µg/l : AO µg/l : CO µg/l : CO GDDQ < < *1 * ) (a) 1% %4.9% 3.8% 194

3 CTD 2.7 Page GDDQ 274 * % *2 Musculoskeletal and connective tissue disorders Arthralgia Myalgia Back pain Peripheral swelling Nervous system disorders Headache Paraesthesia Carpal tunnel syndrome Dizziness General disorders and administration site conditions Oedema peripheral Fatigue NOS Oedema NOS Influenza like illness Infections and infestations Influenza Gastrointestinal disorders Respiratory, thoracic and nediastinal disorders Nasopharyngitis Skin and subcutaneous tissue disorders Sweating increased Investigations Vascular disorders NOS Hypertension NOS Metabolism and nutrition disorders * *2 MedDRA(J) 5.1 SOC, PT %

4 CTD 2.7 Page GDDQ () 274 * % *2 Psychiatric disorders Depression Surgical and medical procedures Neoplasms benign, malignant and unspecified (inclcysts and polyps) Cardiac disorders Eye disorders Reproductive system and breast disorders Injury, poisoning and procedural complications Ear and labyrinth disorder Endocrine disorders Renal and urinary disorders * *2 MedDRA(J) 5.1 SOC, PT % (b) GDDQ

5 CTD 2.7 Page GDDQ IU/ IU/ IU/ IU/ IU/ *1 *2 *1 20 mg 250 mg THYREX 0.1 mg CENTYL-KCL ELTROXIN OSTRADIOL MINIRIN SEMPREX HEXAHYDROBENZOATE 250 ADALAT OROS BURINEX CACIT SINTROM ZOCOR BURINEX MIXTARD 30/70 * 1 MedDRA(J) 5.1 PT *

6 CTD 2.7 Page GDDQ () *1 *2 * IU/ LASCAL THYRAX ADALAT OROS CAPOTEN THYRAX ASCAL TEMA ZAPAN FEROFUMMATE TRYPTISOL 2 2 IU/ IU/ IU/ 7 1 IU/ * 1 MedDRA(J) 5.1 PT * DIDROVIT DYTAC 50 mg 40 mg IMPORTAL10 g 250 mg LEVAXIN MINIRIN LEVAXIN MINIRIN

7 CTD 2.7 Page GDDQ () IU/ IU/ *1 *2 *1 LEVAXIN TROMBYL LEVAXIN MINIRIN T IU/ 50 mg IU/ 8 1 IU/ IU/ 5 mg T LEVAXIN 0.5 mg T MINIRIN 0.1 mg T 5 mg LEVAXIN NITROMEX SELOKEN ZOC TROMBYL FURIX MINDIAB T MINDIAB 5 mg 0.5 mg INSULATARD 100 U/mL 6 1 IU/ 1418 * 1 MedDRA(J) 5.1 PT *

8 CTD 2.7 Page GDDQ () IU/ IU/ IU/ 498 *1 *2 *1 ANUSOL CREAM C GTN SPRAY IU/ IU/ *1 MedDRA(J) 5.1 PT *2 2002

9 CTD 2.7 Page 201 (c) d 144 GDDQ *1 N=1715 N=1307 N=408 % % % * NOS Pituitary tumour NOS Transient ischaemic attack Craniopharyngioma Angina pectoris Cardiac failure NOS Pneumonia NOS NOS Cerebrovascular accident NOS NOS Pituitary tumour benign NOS Pituitary tumour removal NOS Vomiting NOS Chest pain NOS Neoplasm NOS NOS Headache NOS Cerebral infarction NOS Hemianopia NOS NOS Gastroenteritis NOS NOS Death NOS * *2 MedDRA(J) 5.1 PT 201

10 CTD 2.7 Page GDDQ Appendicitis Ovarian cyst Adrenocortical insufficiency acute *1 N=1715 N=1307 N=408 % % % * *2 MedDRA(J) 5.1 PT (d) GH C6 mg C12 mg % GH GH IGF-I IGFBP-3 IGF-I GH AGHD AGHD

11 CTD 2.7 Page GDDQ 274 * % *2 % NOS Pituitary tumour NOS NOS Neoplasm NOS Craniopharyngioma NOS Pituitary tumour benign NOS NOS Prostate cancer NOS Basal cell carcinoma Skin papilloma NOS Carcinoma NOS NOS Breast cancer NOS NOS Cyst NOS NOS Skin carcinoma NOS NOS Skin neoplasm NOS NOS Adenoma benign NOS Bronchial carcinoma NOS Colon cancer NOS 0 Colon carcinoma stage 0 Colon adenoma NOS Thyroid adenoma NOS NOS Lipoma NOS NOS Gastrointestinal neoplasm NOS Glioma * *2 MedDRA J 5.1 PT 203

12 CTD 2.7 Page GDDQ 274 * % *2 % Polycythaemia vera Astrocytoma Fibromatosis NOS Adenocarcinoma NOS Fibroadenoma of breast Papillary thyroid cancer Lipoma of breast NOS Breast neoplasm NOS NOS Brain neoplasm NOS NOS Bladder cancer NOS NOS Non-Hodgkin s lymphoma NOS NOS Lymphoma NOS * *2 MedDRA(J) 5.1 PT 204

13 CTD 2.7 Page 205 4) (a) % 3%5.5%4.6% 4.1% 3.7%3.7%3.2%3.2% 5% 9.2%2.3% GDED T002 GH

14 CTD 2.7 Page GDDQ *1 N=2253 *2 Nervous system disorders 65 N=217 % N=2036 % Headache Transient ischaemic attack Paraesthesia Sciatica Cerebral infarction Dizziness Carpal tunnel syndrome Musculoskeletal and connective tissue disorders Arthralgia Back pain Myalgia Peripheral swelling General disorders and administration site conditions Oedema peripheral Fatigue NOS Oedema NOS Influenza like illness Infections and infestations Influenza NOS Pneumonia NOS NOS Urinary tract infection NOS NOS Infection NOS Respiratory, thoracic and nediastinal disorders Nasopharyngitis Hyperventilation Cardiac disorders Angina pectoris Atrial fibrillation NOS Cardiac failure NOS Myocardial infarction Investigations *1 MedDRA J 5.1 SOC, PT *

15 CTD 2.7 Page GDDQ *1 N=2253 *2 Gastrointestinal disorders 65 N=217 % N=2036 % Nausea Vascular disorders NOS Hypertension NOS Skin and subcutaneous tissue disorders Sweating increased NOS Rash NOS Neoplasms benign, malignant and unspecified (incl cysts and polyps) NOS Pituitary tumour NOS NOS Prostate cancer NOS Surgical and medical procedures NOS Operation NOS Matabolism and nutrition disorders NOS Diabetes mellitus NOS Injury, poisoning and procedural complications Renal and urinary disorders Eye disorders Ear and Labyrinth disorders Vertigo Reproductive system and breast disorders Blood and lymphatic system disorder NOS(Anaemia NOS Psychiatric disorders Depression Endocrine disorders *1 MedDRA J 5.1 SOC, PT *

16 CTD 2.7 Page 208 (2) MedDRA Version / / N=60600 / N=17667 / * *1 // 208

17 CTD 2.7 Page *1 - - *2 1 *4 NA * *3 1 3 NOS *4 NA *5 NOS NOS 1 *4 NA *5 NOS 1 4 NA *5 NOS 1 NA *5 NOS 2 *4 NOS NOS 3 *4 NA *5 1 3 NOS *4 NOS 11 *4 NA *5 NOS 1 NA *5 NOS *4 *1 MedDRA(J) ver.6.0 *2 *3 *4 / *5 NA:

18 CTD 2.7 Page *1 - * * *4 NA *5 1 *4 NA *5 1 *4 NA *5 NOS 0 *4 NA * NA* *4 NA * NA *5 1 1 *3 NOS NOS *4 NOS NOS NOS NOS NOS NOS *1 MedDRA(J) ver.6.0 *2 *3 *4 : / *5 NA:

19 CTD 2.7 Page *1 - *2 NOS NOS *4 NA *5 NOS GH *3 NA *4 1 NOS 1 NA *4-1 *3 NA * NOS 1 *3 NA *4 NOS *3 NA * NOS *3 NA *4 NOS 2 NA *4 NOS NA * NA *4 NOS *3 NA *4 1 NA *4 *1 MedDRA(J) ver.6.0 *2 *3 / *4 NA:

20 CTD 2.7 Page * *2 NOS 2 2 *3 NA * NOS NA *4 1 NOS 6 *3 NA *4 - NOS 1 3 *3 NA *4 3 2 NOS NOS NOS 1 *3 NA *4 NOS *3 NOS *3 NOS GH NOS 5 NOS 4 NOS 4 *3 NOS 1 6 *3 NA *4 1 1 *3 NOS *1 MedDRA(J) ver.6.0 *2 *3 / *4 NA:

21 CTD 2.7 Page *1 * NA *3 1 2 NA * NA *3 1 NA *3 NOS NOS NA *3 3 2 * / NOS NA *3 NOS 2 1 NA *3 *1 MedDRA(J) ver.6.0 *2 *3 NA: *4

22 CTD 2.7 Page *1 - *2 1 NA *3 1 2 NA *3 1 2 NA *3 1 NA *3 1 NA *3 2 NA *3 NOS 1 NA *3 1 NA * NA *3 2 NOS NOS 1 2 NA *3 1 2 NA * NA *3 1 1 NA *3 1 2 NA * NA * NA *3 1 *1 MedDRA(J) ver.6.0 *2 *3 NA:

23 CTD 2.7 Page *1 - *1 MedDRA(J) ver.6.0 *2 *3 NA: *2 4 1 NA * NOS NA *3 NOS 1 1 NA *3 NOS 1 2 NOS NA *3 1 1 NOS 5 2 NOS 2 2 NOS 5 1 2

24 CTD 2.7 Page *1 - *1 MedDRA(J) ver.6.0 *2 *3 NA: *2 NOS NOS NOS 4 2 NOS NOS 4 2 NOS NOS 5 1 NOS 3 1 NOS NOS 4 2 NOS NOS NOS 6 1 NOS 5 1 NOS 5 1 NOS NOS 5 NOS NOS 4 2 NOS 4 1 NOS NOS 4 1 NOS 4 1 NOS NA *3 NOS 5 2 NOS 6 2

25 CTD 2.7 Page *1 - *1 MedDRA(J) ver.6.0 *2 *2 NOS 5 1 NOS NOS NOS NOS 5 1 NOS 6 2 NOS 4 1 NOS 6 2 NOS NOS 6 2 NOS NOS NOS NOS NOS NOS 6 NOS

26 CTD 2.7 Page *1 - *2 NOS NOS NOS 6 NOS *3 NOS NOS 6 NOS 7 2 NOS 7 2 NOS 7 1 NOS NOS 7 2 NOS 7 2 NOS NOS NOS NOS NA *4 1 NOS 1 1 NA *1 MedDRA(J) ver.6.0 *2 *3 *4 NA:

27 CTD 2.7 Page *1 - *2 NOS 1 1 NOS NOS NOS / *1 MedDRA(J) ver.6.0 *2 *3 NA: NOS 1 NA * NA 1 1 NOS NOS 1 NA *3 NOS 1 NA *3 NOS 1 NOS 5 1

28 CTD 2.7 Page Shalet SM, Shavrikova E, Cromer M, Child CJ, Keller E, Zapletalova J, et al. Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: A 2-year randomized, controlled, dose-ranging study. J Clin Endocrinol Metab; 2003; 88: Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson BA, et al: Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab 1996; 81: Ito H, Ohshima A, Ohto N, Ogasawara M, Tsuzuki M, Takao K, et al. Relation between body composition and age in healthy Japanese subjects. Eur J Clin Nutr; 2001:55: Vahl N, Juul A, Jorgensen JOL, Orskov H, Skakkebaek NE, Chiristiansen JS. Continuation of growth hormone (GH) replacement in GH-deficient patients during transition from childhood to adulthood: A two-year placebo-controlled study. J Clin Endocrinol Metab 2000; 85: Rudling M, Parini P, Angelin B. Effects of growth hormone on hepatic cholesterol metabolism. Lessons from studies in rats and humans. Growth Hormone & IGF Research 1999; 9: Leonsson M, Oscarsson J, Bosaeus I, Lundgren BK, Johannsson G, Wiklund O, et al: Growth hormone (GH) therapy in GH-deficient adults influences the response to a dietary load of cholesterol and saturated fat in terms of cholesterol synthesis, but not serum low density lipoprotein cholesterol levels. J Clin Endocrinol Metab 1999; 84: De Boer H, Blok GJ, van der Veen EA. Clinical aspects of growth hormone deficiency in adults. Endocrine Rev 1995; 16: Florakis D, Hung V, Kaltsas G, Coyte D, Jenkins PJ, Chew SL, et al: Sustained reduction in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy: A two year study. Clin Endocrinol 2000; 53: Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: Jφrgensen JOL, Pedersen SA, Laurberg P, Weeke J, Skakkebaek NE, Chiristiansen JS. Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. J Clin Endocrinol Metab 1989; 69: Bengtsson BA, Eden S, Lonn L, Kvist H, Stokland A, Lindstedt G, et al: Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 1993; 76: Drake WM, Coyte D, Camacho-Hubner C, Jivanji NM, Kaltsas G, Wood DF, et al. Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab 1998;83: De Boer H, Blok GJ, Popp-Snijders C, Stuurman L, Baxter RC, Van Der Veen E. Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers. J Clin Endocrinol Metab 1996;81: Span JPT, Pieters GFFM, Sweep CGJ, Hermus ARMM, Smals AGH. Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: Role of sex hormone replacement. J Clin Endocrinol Metab 2000; 85: ,,,,,. IRMA IGF-I, IGF-II, IGFBP ; 44: Grφfte T, Wolthers T, Jensen SA, Moller N, Jorgensen JOL, Tygstrup N, et al. Effects of growth 220

29 CTD 2.7 Page 221 hormone and insulin-like growth factor-i singly and in combination on in vivo capacity of urea synthesis, gene expression of urea cycle enzymes, and organ nitrogen contents in rats. Hepatology 1997; 25: Shim M, Cohen P. IGFs and human cancer: implications regarding the risk of growth hormone therapy. Horm Res 1999; 51: Porretti S, Giavoli C, Ronchi C, Lombardi G, Zaccaria M, Valle D, et al. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T4 therapy become mandatory? J Clin Endocrinol Metab 2002; 87: Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J 1991; 121: Aronow WS. The older man's heart and heart disease. Med Clin North Am 1999; 83: Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovascular Res 2002; 54: Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society workshop on adult growth hormone deficiency [invited report of a workshop]. J Clin Endocrinol Metab 1998; 83: Fernholm R, Bramnert M, Hagg E, Hilding A, Baylink DJ, Mohan S, et al. Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease. J Clin Endocrinol Metab 2000; 85: Toogood AA, Shalet SM. Growth hormone replacement therapy in the elderly with hypothalamic-pituitary disease: a dose-finding study. J Clin Endocrinol Metab 1999; 84: Wiren L, Boguszewski CL, Johannsson G. Growth hormone (GH) replacement therapy in GH-deficient women during pregnancy. Clin Endocrinol 2002; 57: McMillan CV, Bradley C, Gibney J, Healy ML, Russell-Jones DL, Sonksen PH. Psychological effects of withdrawal of growth hormone therapy from adults with growth hormone deficiency. Clin Endocrinol 2003; 59: Colao A, Di Somma C, Salerno M, Spinelli L, Orio F, Lombardi G. The cardiovascular risk of GH-deficient adolescents. J Clin Endocrinol Metab. 2002; 87: Kohno H, Ueyama N, Honda S. Unfavourable impact of growth hormone (GH) discontinuation on body composition and cholesterol profiles after the completion of height growth in GH-deficient young adults. Diabetes Obes Metab. 1999; 1: Underwood LE, Attie KM, Baptista J, the Genentech collaborative study group. Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study. J Clin Endocrinol Metab 2003; 88: Hartman ML, Crowe BJ, Kleinberg DL, Chipman JJ, Melmed S. Prospective multicenter safety surveillance of GH replacement in 2033 GH-deficient adults. Proceeding of ENDO The Endocrine Society 83rd Annual Meeting; 2001 June 20-23; Denver, USA. Chevy Chase: The Endocrine Society; Cohen P, Clemmons DR, Rosenfeld RG. Does the GH-IGF axis play a role in cancer pathogenesis? Growth Horm & IGF Res 2000; 10:

Microsoft Word _fiYŁt”‚Š¿‹êŠŠ-“ì‰ÆŠp.doc

Microsoft Word _fiYŁt”‚Š¿‹êŠŠ-“ì‰ÆŠp.doc 1.12 医薬品部会 2006.2 1.12 Page 1 1.12 CTD 5 5.3.3 PK 5.3.3.3 PK 5.3.3.3-1 ( GDFR) Comparison of hgh Pharmacokinetics Following Intravenous and Subcutaneous Administration of Humatrope in Japanese and Caucasian