In children with chronic renal disease, treatment with Norditropin SimpleXx should be discontinued at renal transplantation.
4.4 Special warnings and precautions for use
Children treated with Norditropin SimpleXxsomatropin should be regularly assessed by a specialist in child growth. Norditropin SimpleXxSomatropin treatment should always be instigated by a physician with special knowledge of growth hormone insufficiency and its treatment. This is true also for the management of Turner syndrome, chronic renal disease and SGA. Data of final adult height following the use of Norditropin for children with chronic renal disease are not available.
The stimulation of longitudinal growth in children can only be expected until epiphyseal closure.
The dosage in children with chronic renal disease is individual and must be adjusted according to the individual response to therapy. The growth disturbance should be clearly established before Norditropin SimpleXx treatment by following growth on optimal treatment for renal disease over one year. Conservative management of uraemia with customary medicinal product and if needed dialysis should be maintained during Norditropin SimpleXx therapy.
Patients with chronic renal disease normally experience a decline in renal function as part of the natural course of their illness. However, as a precautionary measure during Norditropin SimpleXx treatment renal function should be monitored for an excessive decline, or increase in the glomerular filtration rate (which could imply hyperfiltration).
Treatment of growth hormone deficiency in patients with Prader-Willi syndrome
There have been reports of sudden death after initiating growth hormonesomatropin therapy in patients with Prader-Willi syndrome, who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.
Growth hormone deficiency in adults
Growth hormone deficiency in adults is a lifelong disease and needs to be treated accordingly, however, experience in patients older than 60 years and in patients with more than five years of treatment in adult growth hormone deficiency is still limited.
Small for Gestational Age
In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty.
Experience with patients with Silver-Russell syndrome is limited.
Turner syndrome
Monitoring of growth of hands and feet in Turner syndrome patients treated with somatropingrowth hormone is recommended and a dose reduction to the lower part of the dose range should be considered if increased growth is observed.
Girls with Turner syndrome generally have an increased risk of otitis media, which is why otological evaluation is recommended on at least an annual basis.
Chronic renal disease
The dosage in children with chronic renal disease is individual and must be adjusted according to the individual response to therapy (see section 4.2). The growth disturbance should be clearly established before somatropinNorditropin SimpleXx treatment by following growth on optimal treatment for renal disease over one year. Conservative management of uraemia with customary medicinal product and if needed dialysis should be maintained during somatropinNorditropin SimpleXx therapy.
Patients with chronic renal disease normally experience a decline in renal function as part of the natural course of their illness. However, as a precautionary measure during somatropinNorditropin SimpleXx treatment, renal function should be monitored for an excessive decline, or increase in the glomerular filtration rate (which could imply hyperfiltration).
IGF-I
In Turner syndrome and SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the dose should be reduced to achieve an IGF-I level within the normal range.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before final height is reached.
Tumours and malignancies
In patients in complete remission from tumours or malignant disease, somatropingrowth hormone therapy has not been associated with an increased relapse rate. Nevertheless, patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of Norditropin SimpleXx therapy.
Leukaemia
Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in somatropingrowth hormone recipients without predisposition factors.
Benign intracranial hypertension
In the event of severe or recurrent headache, visual problems, nausea, and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and if appropriate the somatropingrowth hormone treatment should be discontinued.
At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If somatropingrowth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.
Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process.
Thyroid function
SomatropinGrowth hormone increases the extrathyroidal conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.
In patients with a pituitary disease in progression, hypothyroidism may develop.
Patients with Turner syndrome have an increased risk of developing primary hypothyroidism associated with anti-thyroid antibodies. As hypothyroidism interferes with the response to somatropinNorditropin SimpleXx therapy patients should have their thyroid function tested regularly, and should receive replacement therapy with thyroid hormone when indicated.
Scoliosis
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment. However, somatropingrowth hormone treatment has not been shown to increase the incidence or severity of scoliosis.
Insulin sensitivity
Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance (see section 4.5). For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin containing product therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.
Blood glucose and insulin
In Turner syndrome and SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk of diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, somatropingrowth hormone should not be administered.
Somatropin has been found to influence carbohydrate metabolism, therefore, patients should be observed for evidence of glucose intolerance.
IGF-I
In Turner syndrome and SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the dose should be reduced to achieve an IGF-I level within the normal range.
Some of the height gain obtained with treating short children born SGA with somatropin may be lost if treatment is stopped before final height is reached.
Antibodies
As with all somatropin containing products, a small percentage of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.
Somatropin has been found to influence carbohydrate metabolism, therefore, patients should be observed for evidence of glucose intolerance.
In Turner syndrome and SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.
In Turner syndrome and SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the dose should be reduced to achieve an IGF-1 level within the normal range.Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty.
Experience with patients with Silver-Russell syndrome is limited.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before final height is reached.
Serum thyroxine levels may fall during treatment with Norditropin SimpleXx due to the increased peripheral deiodination of T4 to T3.
In patients with a pituitary disease in progression, hypothyroidism may develop.
Patients with Turner syndrome have an increased risk of developing primary hypothyroidism associated with anti-thyroid antibodies. As hypothyroidism interferes with the response to Norditropin SimpleXx therapy patients should have their thyroid function tested regularly, and should receive replacement therapy with thyroid hormone when indicated.
Monitoring of growth of hands and feet in Turner syndrome patients treated with growth hormone is recommended and a dose reduction to the lower part of the dose range should be considered if increased growth is observed.
Girls with Turner syndrome generally have an increased risk of otitis media, why otological evaluation is recommended on at least an annual basis.
In insulin treated patients adjustment of insulin dose may be needed after initiation of Norditropin SimpleXx treatment.
Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process.
Leukaemia has been reported in a small number of growth hormone deficient patients some of whom have been treated with somatropin. Based on 10 years global assessment there is no increased risk of development of leukaemia during somatropin treatment. In patients in complete remission from tumours or malignant disease, growth hormone therapy has not been associated with an increased relapse rate. Nevertheless, patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of Norditropin SimpleXx therapy.
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment. However, growth hormone treatment has not been shown to increase the incidence or severity of scoliosis.
In the event of severe or recurrent headache, visual problems, nausea, and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and if appropriate the growth hormone treatment should be discontinued.
At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.
Growth hormone deficiency in adults is a lifelong disease and needs to be treated accordingly, however, experience in patients older than 60 years and in patients with more than five years of treatment in adult growth hormone deficiency is still limited.
Clinical trial experience
Two placebo-controlled clinical trials of patients in intensive care units have demonstrated an increased mortality among patients suffering from acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure, who were treated with somatropin in high doses (5.3-8 mg/day). The safety of continuing somatropingrowth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropingrowth hormone in patients having acute critical illnesses should be weighed against the potential risk.
One open-label, randomised clinical trial (dose range 45-90 µg/kg/day) with patients with Turner syndrome indicated a tendency for a dose-dependent risk of otitis externa and otitis media. The increase in ear infections did not result in more ear operations/ tube insertions compared to the lower dose group in the trial.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin containing products. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on somatropingrowth hormone.Concomitant glucocorticoid therapy may inhibit growth and thereby oppose the growth promoting effect of Norditropin SimpleXx. The effect of growth hormone on final height can also be influenced by additional therapy with other hormones, e.g. gonadotrophin, anabolic steroids, estrogen and thyroid hormone.
Data from an interaction study performed in growth hormone deficient adults, suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.
The effect of somatropingrowth hormone on final height can also be influenced by additional therapy with other hormones, e.g. gonadotrophin, anabolic steroids, estrogen and thyroid hormone.
In insulin treated patients adjustment of insulin dose may be needed after initiation of somatropin treatment (see section 4.4).
4.6 Fertility, Ppregnancy and lactation
Animal studies are insufficient with regard to effects on pregnancy, embryofoetal development, parturition or postnatal development. No clinical data on exposed pregnancies are available.
Therefore, somatropin containing products are not recommended during pregnancy and in woman of childbearing potential not using contraception.
There have been no clinical studies conducted with somatropin containing products in breast-feeding women. It is not known whether somatropin is excreted in human milk. Therefore caution should be exercised when somatropin containing products are administered to breast-feeding women.Currently there is insufficient evidence of safety of somatropin therapy during pregnancy. The possibility that somatropin is secreted in breast milk cannot be discounted.
4.7 Effects on ability to drive and use machines
No influence on the ability to drive and use machines.
4.8 Undesirable effects
Growth hormone deficient patients are characterised by extracellular volume deficit. When treatment with somatropin is initiated, this deficit is corrected. Fluid retention with peripheral oedema may occur especially in adults. Carpal tunnel syndrome is uncommon, but may be seen in adults. The symptoms are usually transient, dose dependeant and may require transient dose reduction.
Mild arthralgia, muscle pain and paresthesia may also occur, but are usually self-limiting.
Adverse reactions in children are uncommon or rare.
Clinical trial experience:
|
System organ classes
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Very common
(≥> 1/10)
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Common
(≥> 1/100; to << 1/10)
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Uncommon
(≥> 1/1,000; to << 1/100)
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Rare
(≥> 1/10,000; to << 1/1,000)
|
|
Metabolism and nutrition disorders
|
|
|
In adults Diabetes mellitus type 2 (See Post-marketing experience)
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|
|
Nervous system disorders
|
|
In adults headache and paraesthesia
|
In adults carpal tunnel syndrome. In children headache
|
|
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Skin and subcutaneous tissue disorders
|
|
|
In adults pruritus
|
In children rash NOS
|
|
Musculoskeletal, connective tissue and bone disorders
|
|
In adults arthralgia, joint stiffness and myalgia
|
In adults muscle stiffness
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In children arthralgia and myalgia
|
|
General disorders and administration site conditions
|
In adults peripheral oedema (see text above)
|
|
In adults and children injection site pain. In children injection site reaction NOS
|
In children peripheral oedema
|
In children with Turner syndrome increased growth of hands and feet has been reported during somatropinGH therapy.
A tendency for increased incidence of otitis media in Turner syndrome patients treated with high doses of Norditropin has been observed in one open-label randomised clinical trial. However, the increase in ear infections did not result in more ear operations/ tube insertions compared to the lower dose group in the trial.
Post-marketing experience:
In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported and are by an overall judgement considered possibly related to Norditropin treatment.
Neoplasms benign and malignant (inluding cysts and polyps)
Leukaemia has been reported in a small number of growth hormone deficiency patients (see section 4.4).
Immune system disorders
Hypersensitivity (see section 4.3).
Formation of antibodies directed against somatropin. The titres and binding capacities of these antibodies have been very low and have not interfered with the growth response to Norditropin administration.
Endocrine disorders
Hypothyroidism. Decrease in serum thyroxin levels (please refer tosee section 4.4).
Metabolism and nutrition disorders
Hyperglycemia, (see section 4.4).
Nervous system disorders
Benign intracranial hypertension (see section 4.4).
Musculoskeletal and connective tissue disorders
Slipped capital femoral epiphysis. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders.
Legg-Calvé-Perthes disease. Legg-Calvé-Perthes disease may occur more frequently in patients with short stature.
Investigations
Increase in blood alkaline phosphatase level.
