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Statement from the Growth Hormone Research Society Keswick Hall Charlottesville, Virginia May 7 - 10, 2000 Keswick Safety Presentation-final2.ppt 6-19-00.

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Presentation on theme: "Statement from the Growth Hormone Research Society Keswick Hall Charlottesville, Virginia May 7 - 10, 2000 Keswick Safety Presentation-final2.ppt 6-19-00."— Presentation transcript:

1 Statement from the Growth Hormone Research Society Keswick Hall Charlottesville, Virginia May 7 - 10, 2000 Keswick Safety Presentation-final2.ppt 6-19-00

2 Critical Evaluation of the Safety of Recombinant Human Growth Hormone Administration Background Epidemiological and experimental data used to assess relationships of GH, IGF-I and cancer risk Safety aspects –GH therapy in children –GH replacement in adults –Pharmacological GH treatment in adults Closing remarks

3 Participants Robert Baxter Bengt Åke Bengtsson Sandra L. Blethen Werner F. Blum Bjorn Carlsson Lena Carlsson Paul V. Carroll Jens Sandahl Christiansen Peter E. Clayton David R. Clemmons Pinchas Cohen Christopher T. Cowell Gordon B. Cutler Judith E. Fradkin Joseph M. Gertner Sue Hankinson Raymond Hintz Jörgen Isgaard Gudmundur Johannsson Jens Otto Lunde Jørgensen Anne-Marie Kappelgaard Irene Langbakke Derek LeRoith Barbara Lippe Saul N. Malozowski Thomas Maneatis John P. Monson Yoshikazu Nishi Michael N. Pollak Iain Robinson Ron Rosenfeld Daniel E. Salazar Akira Shimatsu Peter H. Sönksen Peter Stein Christian J. Strasburger Elisabeth Svanberg Anthony Swerdlow Katsuhiko Tachibana Hiroaki Takahashi Jukka Takala Toshiaki Tanaka Michael O. Thorner Greet van den Berghe A.J. van der Lely Patrick Wilton Douglas Yee

4 Background Lessons learned since recombinant human GH was introduced to the market in 1985 Unprecedented level of scrutiny has lasted more than 15 years because –Jacob Creutzfeld disease relationship to pituitary-derived GH –Potential association between GH and leukemia –GH was the second recombinant protein brought to market

5 Epidemiological and experimental data used to assess relationships of GH, IGF-I and cancer risk

6 Epidemiological Data Active acromegaly, a disease characterized by raised serum GH, IGF-I, and IGFBP-3 levels has been reported to be associated with increased incidence of colonic neoplasia, although conflicting data exist no increased incidence of breast or prostate cancers

7 Recent epidemiological surveys, including case-control, as well as follow-up designs report Serum IGF-I levels in upper normal range may be associated with increased risk of developing prostate cancer and breast cancer in premenopausal, but not postmenopausal women High IGF-I and low IGFBP-3 levels in serum may be associated with increased risk of these two tumors, as well as risk of colon cancer High serum IGFBP-3 levels alone have also been related to reduced cancer risk Epidemiological Data

8 Consensus regarding background information A cause-effect relationship between serum IGF-I and development of cancer has not been demonstrated Serum IGF-I levels may be affected by additional factors other than GH status, including nutrition Epidemiological Data

9 Studies in vitro and in animal models Most cells, including cancer cells, possess IGF-I receptors and respond to IGF-I with increased growth IGF binding proteins (IGFBP) and IGFBP proteases also modulate cell growth, and over expression of IGF-I receptors induces tumor formation in animal models No evidence that systemic administration of IGF-I to animals stimulates tumor formation, although it can increase growth of some established tumors Experimental Data

10 Studies in vitro and in animal models No studies have evaluated direct (IGF-independent) effects of GH on tumor formation In GH transgenic animals, specific activation of GH receptors with concomitant elevations in circulating IGF-I did not result in breast, colon or prostate tumor formation Experimental Data

11 No data to suggest that IGF-I and IGFBP-3 modulate cancer risk in GH-treated patients Patients with previous malignancies or history of radiation therapy carry significant risk for recurrence and second malignancy Recommend measurement of serum IGF-I levels in patients receiving GH treatment; place of regular IGFBP-3 monitoring is not defined Recommend that IGF-I level be maintained within appropriate age- and gender-related normal range in GH-deficient adults during long-term therapy Epidemiological Data GH Replacement and Cancer Risk

12 Current labeling for GH states that active malignancy is a contraindication for GH treatment. There are, however, no data to support this labeling. Current knowledge does not warrant additional warning about cancer risk in the product label. Epidemiological Data Regulatory Aspects

13 Safety - GH Therapy in Children Recombinant human GH has been used in an estimated 50,000 children. Significant adverse drug reactions rare Large international databases have been useful in quantifying adverse events, and hence, addressing safety issues Extended follow-up into adulthood of children who have discontinued GH treatment would be ideal - this may only be achievable in subset of patients

14 Children receiving GH, who have had a malignancy, account for approximately 20% of patients enrolled in international databases. Existing evidence does not indicate that GH treatment will increase tumor recurrence in those successfully treated for their primary lesion In patients who have been rendered GH deficient by tumor and/or its treatment, timing of initiation of GH treatment must be decided on basis of individual case, once tumor treatment is completed and condition is in remission Safety - GH Therapy in Children Malignancy Risk

15 All subjects who have had a malignancy and received treatment for it are at risk for a second malignancy. No evidence that GH treatment increases risk of this process based on limited data available No evidence that de-novo cancer and leukemia are increased in GH recipients In view of continuing evolution of oncology treatments, ongoing surveillance of GH recipients with appropriate age-related controls is important Safety - GH Therapy in Children Malignancy Risk

16 Certain patient groups who receive GH treatment carry an intrinsic risk of developing malignancies, including those with Neurofibromatosis type 1, Fanconi anemia, Downs and Bloom syndromes. Although no evidence that GH replacement poses increased cancer risk, we recommend that such children be carefully monitored with regard to tumor formation Safety - GH Therapy in Children Malignancy Risk

17 Has been reported in 1/1000 children receiving GH treatment; may be underestimate Headache in children on GH treatment should be carefully evaluated Fundoscopic examination should be performed before initiation of GH treatment and repeated when clinically indicated Safety - GH Therapy in Children Benign Intracranial Hypertension

18 Reduction of insulin sensitivity is physiologic effect of GH, however, glucose homeostasis is maintained in vast majority of patients Most available surveillance data do not demonstrate increased incidence of diabetes, either type 1 or type 2, associated with GH treatment There are, however, subgroups of patients inherently at risk of developing diabetes - these should be carefully monitored Safety - GH Therapy in Children Glucose Metabolism

19 Diabetes mellitus is not contraindication to GH treatment in children Diabetic care should follow standard clinical practice Safety - GH Therapy in Children Glucose Metabolism

20 Some underlying disorders that are treated with GH therapy can be associated with slipped capital femoral epiphysis, scoliosis and avascular necrosis No evidence these conditions are caused by GH treatment; however, scoliosis may be exacerbated when growth is accelerated Safety - GH Therapy in Children Skeletal Disorders

21 No compelling evidence that GH treatment has any adverse effect on pubertal development and gonadal function GH can affect metabolism of thyroid hormones and cortisol Safety - GH Therapy in Children Interaction with Other Hormones

22 No data to support discontinuation of GH replacement treatment during illness Risk of hypoglycemia should be considered in children with GH deficiency who discontinue GH treatment Safety - GH Therapy in Children GH Treatment and Intercurrent Illness

23 Issues related to GH treatment in patients with non-GH deficient disorders Monitoring glucose homeostasis in Turner syndrome and glucose homeostasis and lipid profiles in chronic renal failure should be undertaken at intervals determined by standard clinical practice In patients with chronic renal failure treated with GH who receive renal transplant, assessment of graft function and surveillance for development of malignancy should be carried out according to routine nephrology guidelines Safety - GH Therapy in Children

24 Prevalence of diabetes mellitus (DM) increased in hypopituitary adults Metabolic actions of GH include insulin antagonism THUS, recommend that glucose metabolism be assessed in all patients before and during GH replacement DM (or impaired glucose tolerance) not a contraindication to GH replacement; care of diabetes in GH-replaced adults should follow standard guidelines, but intensified monitoring of metabolic control is advocated in early phase of GH replacement of such patients Safety - GH Replacement in Adults Glucose Metabolism

25 Eye examination is indicated in case of overt diabetes and should be conducted in accordance with standard guidelines Stable background retinopathy should not lead to discontinuation of GH replacement Development of pre-proliferative changes and presence of proliferative retinopathy are contraindications to GH replacement Safety - GH Replacement in Adults Glucose Metabolism

26 Symptoms related to fluid retention may be encountered especially in early phase of GH replacement This partly reflects a GH-induced, dose-dependent normalization of tissue hydration Monitoring of hydration during GH replacement should include body weight measurement, patient interview and clinical examination Safety - GH Replacement in Adults Fluid Retention

27 In the case of persistent symptoms attributable to fluid retention, reduction of GH dose should be considered Increased awareness of such symptoms and signs are recommended in patients with congestive heart failure Safety - GH Replacement in Adults Fluid Retention

28 Growth hormone increases extrathyroidal conversion of T 4 to T 3 - thyroid function should be monitored in all patients GH may decrease serum total cortisol concentrations by decreasing circulating cortisol binding globulin Safety - GH Replacement in Adults Interaction with Other Hormones

29 Even though clinical implications for these observations are uncertain, increased awareness of glucocorticoid status is recommended in all patients Possibility that overt ACTH insufficiency may be unmasked during GH replacement (as a result of inhibition of 11bHSD1) should be considered Safety - GH Replacement in Adults Interaction with Other Hormones

30 Increased prevalence of cardiovascular disease in active acromegaly cannot be extrapolated to GH-replaced hypopituitary adult Monitoring of cardiovascular function should follow standard of care for normal population Safety - GH Replacement in Adults Heart Function and Lipoproteins

31 GH replacement in adults is known to increase serum levels of lipoprotein(a). Clinical implications - if any - are uncertain and should be weighed against beneficial effects of GH replacement on other cardiovascular risk factors Measurement of lipoprotein(a) not recommended as standard procedure in hypopituitary patients Safety - GH Replacement in Adults Heart Function and Lipoproteins

32 Increased incidence of certain malignancies has been reported in hypopituitary adults, but no evidence that it is associated with GH replacement Current recommendations for cancer prevention and early detection in general population should be implemented in GH- treated hypopituitary adult Safety - GH Replacement in Adults Cancer risk and Tumor Recurrence

33 To date no evidence to suspect that GH replacement influences recurrence rate or regrowth of pituitary/peripituitary neoplasms Standard clinical practice requires regular pituitary imaging in patients with history of pituitary pathology Baseline imaging study recommended in all patients before instituting GH replacement therapy Safety - GH Replacement in Adults Cancer Risk and Tumor Recurrence

34 Safety - Pharmacological GH Treatment in Adults ICU Trials Power of placebo-controlled trials has been demonstrated with intensive care unit (ICU) studies, which showed that mortality was doubled in severely ill patients treated with high doses of GH These studies have refuted clinical practice beliefs that high-dose GH is beneficial in this situation

35 ICU Trials Two placebo-controlled clinical trials (522 ICU patients) demonstrated that mortality increased from 19% (placebo-treated) to 42% (GH-treated) Prolonged stay ICU patients following complications from open heart or abdominal surgery, multiple accidental trauma or those with acute respiratory failure were included Safety - Pharmacological GH Treatment in Adults

36 ICU Trials Supraphysiological doses of GH (5.3-8 mg or 0.07-0.13mg/kg per day) were administered Most common causes of death were multi-organ failure, septic shock and uncontrolled infections Baseline patient characteristics, severity of illness and diagnostic category did not explain increased mortality Safety - Pharmacological GH Treatment in Adults

37 Any GH treatment, other than replacement in those who have GH deficiency, should be considered as pharmacological In specific conditions where pharmacological GH treatment is being considered, standard safety data should be collected and protocols for new drug development should be followed Detrimental outcome of high dose GH treatment in ICU patients cannot be extrapolated to other conditions, which may potentially benefit from GH treatment Safety - Pharmacological GH Treatment in Adults

38 At present, not recommended that pharmacological GH treatment be initiated in adult ICU patients In patients receiving pharmacological (in contrast to replacement) GH treatment, cessation of GH treatment should be considered when patient is critically ill ICU trials should not discourage new studies of GH treatment in groups who may benefit from GH Pharmacological doses used in such trials should be minimum effective dose for relevant endpoint Safety - Pharmacological GH Treatment in Adults

39 GH levels and critical illness GH-IGF system is dysregulated in critical illness Not known whether this has effect on outcome in such patients, nor whether GH-deficient adults, including those receiving replacement therapy, are at higher risk for adverse outcomes when critically ill Safety - Pharmacological GH Treatment in Adults

40 GH levels and critical illness GH deficiency in adults and children, however, is frequently part of a more extensive pituitary deficiency including adrenocortical deficiency, which should be considered during critical illness in such patients No data to support discontinuation of appropriate GH replacement in patients receiving intensive care treatment for critical illness, or during period of less severe illness or in relation to surgery Safety - Pharmacological GH Treatment in Adults

41 Extensive data collected on large numbers of children and adults treated with GH indicate that, for current approved indications, GH is safe Nevertheless, this workshop highlighted a number of areas where ongoing surveillance of long-term safety of GH replacement is important (cancer – glucose homeostasis – high dose pharmacological GH treatment) –Appropriately designed follow-up studies using adequate epidemiological tools and untreated controls are required Closing Remarks


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