Download shared care policy - recombinant human growth hormone

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)