cachexia AGHD AGHD AGHD ISS Daily Daily Monthly* Daily Daily Daily Daily Daily Daily

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1 Growth Hormone Product Review Date: 8/11/2003 Products Nutropin Approved Indications Dosing frequency Nutropin AQ Nutropin Depo Protropin Genotropin Norditropin Humatrope Saizen Serostim GHD GHD GHD GHD GHD GHD GHD GHD AIDS CRI CRI PWS Turner wasting or Turner Turner SGA AGHD cachexia AGHD AGHD AGHD ISS Daily Daily Monthly* Daily Daily Daily Daily Daily Daily GHD=Growth Hormone Deficiency; AGHD=Adult Growth Hormone Deficiency; CRI=Chronic Renal Insufficiency; PWS=Prader-Willi Syndrome; SGA=Small for Gestational Age; ISS=idiopathic short stature *May need more than one injection, may be taken twice monthly Product Comparisons Somatrem and somatropin are synthetic growth hormones of recombinant DNA origin and considered therapeutically equivalent to endogenous GH. All GH products vary in dosage strengths and form, added preservatives, length of stability after mixing, and approved product-specific indications; however they are considered interchangeable by their dosing equivalents based on international units (I.U.). Somatropin is a preferred option due to development of antibodies with somatrem (Protropin ) (30-40%), which can cause treatment failure. The somatropin depot product does not offer additional clinical benefit over current growth hormone products. The depot product actually produces lower growth responses. Cost per vial/strength per product ranges from $200 - $1080; cost of therapy per patient per year can range from $10,000 - $75,000. Contraindications GH is contraindicated in patients with active malignant disease, benign intracranial hypertension, and proliferative or preproliferative diabetic retinopathy. 30 GH should be discontinued when pregnancy is confirmed. 30 GH should not be used in critically ill patients with acute catabolism who are in an intensive-care unit. 30 Children whose short stature is due to a certain congenital disorder and who are severely obese or have severe breathing problems must not receive Genotropin, according to a manufacturer s letter circulated in July 2003 by the FDA. Pfizer had received seven reports describing the deaths of children with Prader-Willi syndrome who received Genotropin. Two of the seven reports were from the United States, and the other five from elsewhere in the world. The Pfizer letter noted that the patients who died had at least one of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea, or unidentified respiratory-tract infection. 31 Side effects Common side effects are fluid retention in conjunction with edema of the extremities, arthralgias, myalgias, and carpal tunnel syndrome. 30 Arthralgia, myalgia, and carpal tunnel syndrome are more frequent in adults but occur occasionally in GH-treated children. Slipped capital femoral epiphysis may occur more frequently in children with GHD than in others

2 GH induces transient resistance to the actions of insulin. In patients with limited insulin reserve, glucose intolerance may result. 30 Transient gynecomastia has been described in children and adults during GH replacement therapy. 30 Growth Hormone Therapy in Children Turner s Syndrome GH therapy improves short stature associated with Turner s Syndrome. Clinical trials showed that final height could be improved in most patients with TS and normalized in some. GH produced mean adult height increases of 5 cm to 8.3 cm compared to controls. 1,2,3 A final height of 150 cm is now an achievable goal for most patients. 1 Recommended starting dose 0.05 mg/kg/day (0.15IU/kg/day); up to mg/kg (1.125 IU/kg) divided into equal doses given subcutaneously every day or on 3 alternate days. 1,2,3 Pre-Transplant Chronic Renal Insufficiency GH therapy improves growth velocity (7.6 to 10.8 cm/year) and the acquired height deficit associated with chronic renal insufficiency prior to transplantation. 2,4,5,6,7 Clinical studies showed that GH improve growth velocity in both pre- and post-transplant children; however, patients treated pre-transplant demonstrated the most significant improvement in growth velocity. 2,4,5,6,7 There are insufficient data regarding the impact on final adult height or benefits beyond 3 years of therapy. 2,4 Recommended dose of a weekly dose of 0.35 mg/kg divided into daily subcutaneous injections. 2,4 GH is not recommended for posttransplant patients unless it is given as part of a research study. 30 Growth Hormone Deficiency Long-term GH treatment may be considered medically necessary for children that exhibit decreased growth velocity caused by a deficiency of pituitary growth hormone. 8 The goal of GH therapy is to increase growth rate in order to achieve normal adult height. 8 Recommended dosing range mcg/kg/day. 8 After attainment of final height or epiphyseal closure has been documented, standard GH stimulation tests should be performed after an appropriate interval of 1-3 months off GH therapy to confirm adult 8, 30 GHD diagnosis. Prader-Willi Syndrome (PWS) GH treatment in children with PWS accelerates growth, decreases percent body fat, and increases fat oxidation which may be of benefit in reducing the physical disabilities associated with PWS. 9 Research data showed substantial improvement in near-final adult height after GH therapy in children with PWS. 30 Recommended dose 0.24mg/kg/week divided into 6 or 7 subcutaneous injections. 9 15

3 Intrauterine Growth Retardation (IUGR)/Small for Gestational Age (SGA) Children with SGA usually do not have deficiencies in GH or IGF-I. While several studies report that GH increases growth velocity in IUGR/SGA children, there is limited data documenting final adult height of GH-treated children compared to a control population The available data suggest that GH does not increase adult height of children with SGA. 10,14,15,16 Well-designed trials are necessary in order to establish benefits derived from GH therapy in this population. Neonatal Hypoglycemia Associated with Growth Hormone Deficiency Treatment of hypoglycemia in newborns resulting from hypopituitarism and diagnosed with GHD requires replacement with growth hormone and cortisol. 17 Cystic Fibrosis GH therapy in cystic fibrosis patients showed significant improvement in height and height velocity compared to the controls. It showed significant improvement in %FVC but no significant change in %FEV 1. Hospitalization in GH therapy group decreased insignificantly during the year of study. 18 Long-term benefits are not known at this time. 19 Idiopathic Short Stature These are children with short stature who do not have growth hormone deficiency according to the standard diagnostic testing of GHD but have the same growth-retardation findings as children with GHD. Short stature has been defined as height more than 2 SD below the mean for age and sex. 32 Huamtrope was approved in July 2003 by the FDA for the long-term treatment of children with idiopathic short stature. This new indication restricts therapy to children who are more than 2.25 SD below the mean for age and sex, or the shortest 1.2% of children. 33 The approval of Huamtrope for this new indication was based on 2 randomized, double-blind studies in 71 children aged 9-15 years. Humatrope or placebo was given three times weekly to subjects until adult heights were reached. Thirty-three subjects contributed final height measurements out of the 71 children that participated. The mean treatment duration was 4.4 years. The mean final height of the Humatrope subjects exceeded that of the placebo subjects by approximately 1.5 inches. 33 In the second dose-response study, subjects who received the high-dose Humatrope had mean final height exceeded mean height predicted at baseline by nearly three inches. 33 Majority of other previous clinical trials involving the use of GH for children with idiopathic short stature have shown only modest results on final height attainment. 34 There is a need to critically evaluate the real clinical or psychosocial importance of actual attainment of final height in normal, short children treated with growth hormone. Studies have shown that there are no differences in the levels of self-esteem and self-image between normal, short-stature children treated for five years with growth hormone and similar untreated children. 34,35 GH is not recommended for children with idiopathic short stature at this time until further evidence of long-term clinically important health outcomes becomes available. 16

4 Transition to Adult Management The effectiveness, benefits and risks of continuing GH in patients with GHD deficiency who have attained closed growth plates has not been established. 2,3,4,8 Patients who were treated with GH- replacement therapy in childhood should be re-evaluated before continuation of GH therapy for GH-deficient adults. 2,3,4,8 Growth Hormone Therapy in Adults Adult Growth Hormone Deficiency (AGHD) Life expectancy is significantly decreased in hypopituitary patients with GHD, with cardiovascular disease a common cause of death. 20,21 Replacement dosages of GH in adults have not been well defined; studies have suggested 0.1 to 1 mg/day. Furthermore, the dose requirements may decrease with time as the patient ages. If no benefits are seen, a withdrawal period should be considered. 30 Treatment with GH reverses abnormalities in abnormal body composition and may reduce cardiovascular risk factors; however, the long-term treatment outcomes on cardiovascular morbidity and mortality reduction or bone fracture reduction are unknown. 4,20,21,22 Acute and Chronic Catabolic Illnesses Use of high doses of GH in critically ill patients with wasting is associated with increased morbidity and mortality (44% in GH treated patients vs. 18% in placebo patients). 23 GH is not recommended for treatment of patients with acute catabolism, including preoperative and postoperative patients, critically ill patients, and burn patients. 30 AIDS Wasting Clinical trials using GH in AIDS-wasting patients has been limited to 12-weeks of therapy Limited data suggest that patients with AIDS wasting have resistance to the action of GH as demonstrated by high serum GH concentrations and low serum insulin-like growth factor I concentrations. 28 In a randomized, double-blind, multicenter study, 178 patients with HIV infection and a documented weight loss of >10% or with weight <90% of ideal was treated with GH (0.1mg/kg SC QD) or placebo for 12 weeks. After 12 weeks, subjects in the GH group had an increase of body weight by a mean +/-SD of 1.6 +/-3.7kg and lean body mass by 3 +/-3kg significantly better than the results with subjects in the placebo group (0.1 +/-3.1kg and 0.1 +/-2kg, respectively). The mean body fat mass also decreased significantly better in the GH group than the placebo group (-1.7 +/-1.7kg vs /- 2.2kg, respectively). There was an improvement in functional performance determined by work output during treadmill exercise in the GH treated subjects. However, the quality of life, as assessed by an HIV-specific questionnaire, was unaffected by GH treatment. Similarly, days of disability and use of medical services did not differ between the GH and placebo groups. 25 To date, no long-term efficacy and safety studies of GH have been performed in patients with AIDS wasting. Higher rates of arthralgia, myalgia, and carpal tunnel syndrome were associated with GH compared with placebo in clinical trials In addition, concerns regarding the diabetogenic potential of GH, high frequency of growth hormone resistance among HIV-infected persons may result in a lack of 17

5 response in some patients, stimulation of HIV-associated malignancies with long-term high-dose GH dosing, and lack of improvement on overall quality of life or survival benefit have made the optimal use of GH in AIDS wasting undetermined Other uses There are many off-label uses of GH. These include antiaging, athletes performance-enhancing, chronic fatigue syndrome, fibromyalgia, battered-wife syndrome, HIV-associated lipodystrophy or obesity. None of these uses are FDA approved uses of GH and all remain in experimental categories. 30 There is a lack of scientific evidence concerning health outcomes for GH therapy in geriatric patients. Therefore, the use of GH in these patients is not recommended. References 1. Saenger P, Albertsson Wikland K, Conway GS, Davenport M, Gravholt CH, Hintz R et al. Recommendations for the diagnosis and management of Turner s Syndrome. J Clin Endo Metab 2001;86(7): Nutropin AQ Product Information, Genetech, Inc., San Francisco, December Nutropin Depot Product Information, Genetech, Inc., San Francisco, December Nutropin Product Information, Genetech, Inc., San Francisco, December Sanchez-Beatriz CP, Kuizon D, Goodman WG, Gales B, Ettenger RB, InezBoechat M et al. Growth hormone and the skeleton in pediatric renal allograft recipients. Pediatr Nephrol 2002;17: Fine RN, Stablein D, Cohen AH, Tejani A, Kohaut E. Recombinant human growth hormone post-renal transplantation in children: A randomized controlled study of the NAPRTCS. Kidney Int 2002;62: Qvist E, Marttinen E, Ronnholm K, Antikainen M, Jalanko H, Sipila I et al. Growth after renal transplantation in infancy or early childhood. Pediatr Nephrol 2002;17: GH Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endo Metab 2000;85(11): Genotropin Product Information, Genetech, Inc., San Francisco, Coutant R, Carel JC, Letrait M, Bouvattier C, Chatelain P, Coste J et al. Short stature associated with intrauterine growth retardation: final height of untreated and growth hormone-treated children. J Clin Endo Metab 1998;83(4): Sas T, de Waal W, Mulder P, Houdijk M, Jansen M, Reeser M et al. Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. J Clin Endo Metab 1999;84(9): Wilton P, Albertsson-Wikland K, Butenandt O, Chaussain JL, de Zegher F, Jonsson B et al. Growth hormone treatment induces a dose-dependent catch-up growth in short children born small for gestational age: a summary of four clinical trials. Horm Res 1997;48(Suppl 1): Ranke MB, Lindberg A. Growth hormone treatment of short children born small for gestational age or with Silver-Russell syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height. Acta Paediatr 1996 Oct;417: Kamp GA, Mul D, Waelkens JJJ, Jansen M, Delemarre-van de Waal HA, Verhoeven-Wind L, Frolich M et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endo Metab 2001;86(7): Root AW. Editorial: Dose growth hormone have a role in the management of children with nongrowth hormone deficient short stature and intrauterine growth retardation? J Clin Endo Metab 1998;83(4):

6 16. Mehta A, Hindmarsh PC. The use of somatropin (recombinant growth hormone) in children of short stature. Paediatr Drugs 2002;4(1): Lteif AN. Hypoglycemia in infants and children. Endo Metab Clin North Am 1999;28(3): Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Growth hormone improves clinical status in prepubertal children with cystic fibrosis: results of a randomized controlled trial. J Pediatr 2001;139: Bucuvalas JC, Chernausek SD. Growth hormone and cystic fibrosis: good for more than growth? [editorial] J Pediatr 2001;139(5): Vance ML, Kleinberg DL, Cook DM, Gordon T. Clinical and reimbursement issues in growth hormone use in adults. Am J Manage Care 2000;6(Suppl 15):S817-S Vance ML, Mauras N. Growth hormone therapy in adults and children. N Eng J Med 1999 Oct;341(16): Cummings DE, Merriam GR. Growth hormone therapy in adults. Annu Rev Med 2003;54: Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G et al. Increased mortality associated with growth hormone treatment in critically ill adults. New Eng J Med 1999 Sept;341(11): Mulligan K, Schambelan M. Anabolic treatment with GH, IGF-I, or anabolic steroids in patients with HIVassociated wasting. Int J Cardio 2002;85: Schambelan M, Mulligan K, Grunfeld C, Daar ES, LaMarca A, Kotler D et al. Recombinant human growth hormone in patients with HIV-associated wasting: a randomized, placebo-controlled trial. Ann Intern Med 1996;125(11): Lee PDK, Pivarnik JM, Bukar JG, Muurahainen N, Berry PS, Skolnik PR et al. A randomized, placebocontrolled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection. J Clin Endo Metab 1996;81(8): Waters D, Danska J, Hardy K, Koster F, Qualls C, Nickell D et al. Recombinant human growth hormone, insulin-like growth factor 1, and combination therapy in AIDS-associated wasting: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med 1996;125(11): Wood AJJ. Treatments for wasting in patients with the acquired immunodeficiency syndrome. New Eng J Med 1999;340(22): Grinspoon S, Gelato M. Editorial: the rational use of growth hormone in HIV-infected patients. J Clin Endo Metab 2001;86(8): American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Growth Hormone Use in Adults and Children 2003 Update. AACE Growth Hormone Task Force. Endocr Pract 2003;9(1): Hintz RL, Attie KM, Baptista J, Roche A et al. Effect of growth hormone treatment of adult height of children with idiopathic short stature. N Engl J Med 1999;340(7): Oberfield SE. Growth hormone use in normal, short children a plea for reason [Editorial]. N Engl J Med 1999;340(7): Theunissen NC, Kamp GA, Koopman HM, Zwinderman KA, Vogels T, Wit JM. Quality of life and selfesteem in children treated for idiopathic short stature. J Pediatr 2002;140(5): MMWR 1987;36(suppl 2S):3S-15S. 19