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THE SHEFFIELD AREA PRESCRIBING COMMITTEE Shared Care Protocol for the treatment of Children with Recombinant Human Growth Hormone Devised by: Dr JK Wales, Dr NP Wright and Dr H Davies, Sheffield Children’s Hospital Date approved: 27 January 2004 Review Date: On publication of NICE guidance Dear Dr Re (Patient’s Name Date of Birth Address) Your patient is being started on treatment with medication. This treatment can be prescribed by GPs under the Traffic Light System under the “shared care” arrangements. I enclose a copy of the shared care protocol/This protocol is can be obtained from www. (delete as appropriate) This shared care protocol has been approved by the Sheffield Area Prescribing Committee and the Sheffield LMC. Please will you undertake to prescribe for your patient. I will assume your willingness to help unless you inform me otherwise. Yours sincerely PS No reply necessary unless you are unwilling to prescribe for your patient Sheffield Children’s NHS Trust/ Sheffield Primary Care Trusts Shared Care Guidelines for the Treatment of Children with Recombinant Human Growth Hormone Background Recombinant Human growth hormone (hGH) is licensed for children with growth hormone deficiency, Turner Syndrome, Prader-Willi syndrome and chronic renal impairment. These indications have been approved by NICE. HGH has also recently received a license for children who meet specific criteria born with intrauterine growth retardation. Although this indication has yet to be reviewed by NICE, it is included in these shared care guidelines (NICE review date: June 2005). There are currently six preparations of hGH (somatropin) available, in many different presentations. All products have equivalent efficacy. The most common side effects of hGH are transient local skin reactions at the injection site, symptoms of fluid retention, carpal tunnel syndrome, arthralgia, myalgia, hypothyroidism and hypoglycaemia. HGH has been reported to interact with anticonvulsants and ciclosporin, increasing the clearance of these drugs. Diabetic patients may need to adjust their therapy to maintain their glycaemic control and patients with co-existing ACTH deficiency should have their glucocorticoid replacement therapy reviewed. Summary Following a detailed assessment, only a consultant with expertise in the management of children with growth hormone disorder will initiate and monitor hGH treatment. Once a shared care agreement has been made between the consultant and the GP, continuation of treatment can then be maintained by the GP The consultant must inform the GP of the brand, dose and frequency of hGH used. He should also be kept up to date with the patient’s response to treatment and notified of any therapy changes. Although hGH products are clinically interchangeable, changes should only be made by the consultant at the specialist centre to allow the necessary patient training to take place. The GP will be responsible for prescribing maintenance therapy and reporting any adverse events or significant medical conditions to the consultant. The GP will also inform the consultant of any other medication prescribed to the patient. If the GP wishes, he may discuss sharing in the monitoring of the child’s response to treatment. The patient will continue to be reviewed regularly by the consultant at a maximum interval of 6 months. Based on National Shared Care Guidelines, British Society for Paediatric Endocrinology and Diabetes, Dec 2003 Treatment of Children with Recombinant Human Growth Hormone National Shared Care Guidelines based on NICE guidance May 2002 Adapted for use between Sheffield Children’s NHS Trust and Sheffield Primary Care Trusts British Society for Paediatric Endocrinology and Diabetes SHARED CARE OF PATIENTS ON hGH THERAPY Children undergoing recombinant human growth hormone (hGH) therapy will require regular assessment of progress by specialists in child growth and therefore full discharge of the patients from the hospital to the general practitioner is not possible. A system of shared care, involving both primary and back-up care is therefore necessary. These guidelines outline the suggested areas of responsibility of the hospital and the general practitioner for patients who have shared care and expand upon the guidance to the NHS issued by NICE in May 2002. The dosage required of hGH and other therapy will need to be determined by the specialist following the NICE and pharmaceutical industry’s guidance. The patient’s general practitioner will receive an initial letter, giving full clinical details and full details of treatment. The patient and their family will be instructed in injection technique, use of injection devices, storage and management of growth hormone supplies by the Regional Specialist Paediatric Endocrine Nurse or deputy who will liaise with the General Practitioner and/or practice nurse. Regular administration of hGH maximises the growth response and as an aid to family compliance it is helpful if prescriptions written by the general practitioner could be for a minimum period of 1-2 months. Local Contacts In case of any queries related to the prescription of hGH or clinical matters relating to the patients please contact Dr JK Wales, Dr NP Wright or Dr H Davies, Paediatric endocrinologists at Sheffield Children’s Hospital 0114-2717508 or 2717118 Responsibilities for Monitoring of hGH therapy by the specialist The principal method for determining the success or otherwise of hGH treatment is by careful and accurate estimation of the child’s growth. * Regular assessment of growth response by a specialist in child growth at intervals - usually three to four months during the first year. * If the response to treatment is satisfactory, the interval between assessments may be extended to six months. * Thyroid function annually or when indicated. * Bone age assessment annually or when indicated. * Assessment of pituitary status as other deficiencies may be unmasked by treatment with hGH if indicated. * Sex hormone replacement to induce puberty at the normal timing if indicated. * Examining patients with GH deficiency secondary to an intracranial lesion for evidence of progression or recurrence of underlying disease. * Regular communication with the general practitioner to update about response and developments and any change in treatment. * Co-ordinate hGH treatment in children with chronic renal failure who have undergone a renal transplant. Stopping and re-starting treatment as indicated. * Discontinue hGH treatment or collaborate transition to adult care when appropriate Aspects of care for which the GP will be responsible * Reporting of adverse events or significant medical conditions presented by the patient to the specialist centre. * Prescribing maintenance therapy, minimum one month at a time. * Reporting of changes or additions to patient’s other medication. * Sharing in the monitoring of the child’s response to treatment if the GP so wishes. Further Information about Growth Hormone Somatropin (recombinant human Growth Hormone, hGH) is genetically engineered growth hormone which is structurally, chemically and biologically identical to the endogenous hormone. There are six manufacturers of hGH and all six products are licensed for the replacement of GH in children whose output from the anterior pituitary is deficient or absent, leading to the failure to attain normal stature. All six products are identical to the naturally-occurring hormone and differ only in their methods of production. The six products and their manufacturers are given below. Genotropin Norditropin Simplexx NutropinAq Saizen Zomacton Humatrope Pfizer (prev Pharmacia) Novo Nordisk Ipsen Serono Ferring Lilly Product Development Somatropin (human growth hormone) was first used as a treatment for growth hormone deficiency in children in 1958. Supplies of the hormone, which relied on the availability of pituitary gland from human cadavers, were therefore limited. In 1985, an association was made between the development of Creutzfeldt-Jacob disease in four young adults and their previous exposure to pituitary-derived growth hormone. The product was withdrawn when it was discovered that some batches may have been contaminated with the Creutzfeldt-Jacob “slow virus” pathogen. There have been subsequent cases of Creutzfeldt-Jacob disease. DNA technology enabled the production of the first biosynthetic hGH (met-hGH, somatrem) by E. coli bacteria and this was made available in the UK in late 1985. Subsequently, natural sequence hGH (somatropin) was introduced in the UK in December 1988 following further refinements in the production process. It is structurally, chemically and biologically identical to pituitary-source hGH and in addition, its immunogenicity has been shown to be lower than any previous exogenous hGH. Growth Hormone and Growth Linear growth is influenced by a number of endocrinological factors but growth hormone (GH) plays a predominant role due to both direct and indirect effects on the epiphyseal growth plate. It also affects carbohydrate and lipid metabolism, nitrogen metabolism and the growth of tissue Growth hormone deficiency can result from a number of causes; the common ones are given below. It may occur as an isolated deficiency or part of panhypopituitarism (TSH, ACTH, LH, FSH and/or diabetes insipidus). Congenital Acquired Midline embryonic defect eg septo- Tumours of the pituitary, hypothalamus optic (especially craniopharyngiomas) and dysplasia , cleft palate, absence or pinealomas. hypoplasia of the pituitary. Head injury - perinatal Genetic, usually autosomal recessive. - road traffic accident. Occasionally x-linked or dominant. Histiocytosis Haemorrhagic infarction at birth. Post irradiation to the head e.g. intracranial, nasopharyngeal tumours. Cranial or cranio-spinal irradiation in acute leukaemia. Temporary failure due to emotional deprivation or hypothyroidism. Diagnosis of GH Deficiency In children, growth hormone deficiency manifests with slow growth. Growth in utero is usually normal. Small genitalia may be noted at birth, or hypoglycaemia may occur in infancy. The condition often remains unrecognised until the child starts school and other clinical manifestations at this stage are rare. In congenital deficiency, after two years of age, the annual increment in growth is usually less than 4cm per year irrespective of the patient’s height. Puberty is usually delayed even in the absence of associated gonadotrophin deficiency. The children are plump with immature faces, small hands, feet and genitalia. Diagnosis requires documented growth velocity below the 25th centile for at least one year. The diagnosis is confirmed biochemically by low IGF-1 levels and a peak plasma GH level below a locally defined level to two provocative tests. Random GH levels are of no diagnostic value and all laboratory test results need specialist interpretation. A single provocative test is only required for certain specified conditions, e.g. previous cranial radiotherapy, pituitary tumour. Growth retardation may be caused by many processes apart from GH deficiency. However, some of these may be responsive to hGH therapy eg Turner’s syndrome, children with chronic renal failure before or after transplantation and children with intrauterine growth retardation and Prader-Willi syndrome. Treatment of GH deficiency. HGH is the treatment of choice for short stature caused by decreased secretion of growth hormone. Treatment is successful when started early (especially in those with congenital deficiency) and the majority of children show a good response. As in any catch-up growth situation, growth velocity is greatest during the first year of treatment and therefore declines towards the average velocity for a given chronological age. Treatment with hGH does not always restore loss of growth potential present at the time of diagnosis. Continuing treatment improves growth velocity until epiphysial fusion at the end of puberty. A product licence is available for the use of growth hormone in children with growth hormone deficiency, Turner’s syndrome, Prader Willi syndrome and chronic renal failure and use of growth hormone in these conditions has been endorsed by NICE (May 2002). HGH treatment has recently received a licence for growth disturbance in short children born small for gestational age, with a birth weight and/or length below –2 SD, who fail to show catch-up growth by 4 years of age or later. It is anticipated that NICE will review this indication when they review their guidance on the use of hGH in children in June 2005. Growth hormone accelerates growth in the short term in short normal children but produces no improvement in final adult stature. Growth hormone is not currently licensed for this indication and hence its use for this indication has not been endorsed by NICE. Research is continuing in other conditions such as skeletal dysplasia, juvenile rheumatoid arthritis and other severe conditions to assess the response to treatment with hGH. Treatment on the indication of growth failure alone is merited in some children. Similarly, these indications have not been endorsed by NICE, a national audit will be conducted. Other aspects of hGH therapy. Hypothyroidism has been reported in 5-10% of patients undergoing treatment with hGH. This may be a result of the natural history of hypopituitarism due to the associated deficiency of TSH. It is essential to correct any deficiency with thyroxine if a response to GH treatment is to be achieved. Adverse Effects. hGH therapy is safe and adverse effects are uncommon with recommended dosages but include these listed below. 1.Local discomfort at the site of injection has been reported and frequent subcutaneous injection into the same site may result in tissue atrophy. This can be avoided by varying the injection site. 2.Headache may be noted transiently in some patients on higher dosage regimens. Rarely benign intracranial hypertension has been reported but this can be detected by fundoscopy. 3.Oedema may be exacerbated in Turner’s syndrome but is rare in other patients. Other associations have been described but are not regularly encountered in practice. Diabetes mellitus hGH exerts effects on both carbohydrate and lipid metabolism. It is both anabolic and diabetogenic and, in theory, hyperglycaemia and ketosis may occur but is rarely seen in practice. In children with existing diabetes mellitus, glycaemia control and insulin therapy may need readjustment; the induction of insulin resistance is also a rare occurrence. Antibody development has been observed in some hGH patients. It rarely affects the clinical response to treatment. Slipped femoral epiphysis has been reported to occur with a slight increase in frequency. Acute leukaemia has been reported both in untreated GH-deficient children as well as hGH treated children. Studies show that there is no increased incidence over standard population data so these reports are chance associations. The incidence in treated children is not higher even in children who have had leukaemia previously or a bone marrow transplant. Overdose in the acute situation is likely to lead to transient hypoglycaemia followed by hyperglycaemia. The consequences of long-term treatment or overdose are unknown but carry the risk of pituitary gigantism or acromegaly. However, these occur only with higher sustained levels of growth hormone than standard therapeutic doses. Interaction with other medications Corticosteroids in supraphysiological doses may interfere with the growth promoting actions of growth hormone. Children with co-existing ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth. Titration of doses should be managed by a specialist consultant. Diabetic patients may require their glycaemic control measures reviewed (including oral hypoglycaemics and insulin therapy) to take into account the hyperglycaemic effects of growth hormone. Dose and route of administration The dosage is calculated on an individual basis but generally a dose of 0.025-0.035mg/kg/day (0.7 mg/m²/day) for Growth Hormone Deficiency. The recommended dose for Turner’s syndrome and chronic renal failure is 0.050mg/kg/day (1.4 mg/m²/day),and for Prader Willi syndrome and small for gestational age children 0.035 mg/kg/day (1.0 mg/m²/day). The hGH should be given as seven daily subcutaneous injections preferably in the evening. This method has been shown to produce the best response with minimal patient inconvenience. Parents or older children can be taught to administer the injections. This creates less social and educational disturbance. Regular review of injection technique is important to ensure accuracy and compliance - this is carried out by the Specialist Paediatric Endocrine Nurse. Choice of preparation There are no significant therapeutic differences between the preparations available but choice may be determined by patient preference for the injection technique required. It is important that the brand used should only be changed by the specialist centre since training in a new injection technique may be required. It also avoids duplication of reporting should side effects occur. Cost of hGH treatment Growth hormone is administered commonly using an injection pen device (Genotropin pen Pharmacia; NordiPen - Novo Nordisk; One.click pen – Serono; Humatrope pen – Lilly, NutropinAq Pen), or via a single use preloaded syringe (Miniquick). Administration from vials by needle and syringe (Humatrope, Saizen) is possible with or without the aid of an “autojector” automatic injection device. Needle free transjectors (Zomaject – Ferring; Cool.click – Serono; Genotropin Ziptip - Pharmacia) are also available. The costs are given below, and hence costs, will escalate with the increasing size of the child. Product Manufacturer *Cost of therapy £ per mg (local variations may occur) Vial sizes Available Genotropin Pharmacia 23.18 Norditropin Simplexx Saizen Zomacton Humatrope NutropinAq Novo Nordisk 23.18 5.3/12mg plus single dose miniquick vials 0.4-2 mg 5/10/15 mg Serono Ferring Lilly Ipsen 22.89 21.86 22.87 23.18** 1.33/3.33/8 mg 4 mg 6/12/24 mg 10mg *BNF Prices (September 2003) ** MIMS Price (May 2004) National Guidelines Adapted by Dr JK Wales, Dr NP Wright & Dr H Davies, Sheffield Children’s Hospital Reviewed by L Miller, Pharmacist, South West PCT, K Bourne, Pharmacist, Sheffield Children’s NHS Trust, S Alton Pharmacist, West PCT, Dr D Savage, LMC Chairman and Dr T Edney, LMC Vice-Chairman. December 2003 (Version 2 June 2004) Review Date September 2005 (on publication of NICE guidance)