Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Children treated with somatropin should be regularly assessed by a specialist in child growth.
Somatropin 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, SGA, and Noonan syndrome. Data of final adult height following the use of Norditropin are limited for children with Noonan Syndrome and are not available for children with chronic renal disease.

The maximum recommended daily dose should not be exceeded (see section 4.2).

The stimulation of longitudinal growth in children can only be expected until epiphyseal closure.

Children

Treatment of growth hormone deficiency in patients with Prader-Willi syndrome There have been reports of sudden death after initiating somatropin 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.

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 somatropin is recommended, and a dose reduction to the lower part of the dose range should be considered if increased growth is observed.

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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 somatropin 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 somatropin 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 somatropin treatment, renal function should be monitored for an excessive decline or increase in the glomerular filtration rate (which could imply hyperfiltration).

Scoliosis
Scoliosis is known to be more frequent in some of the patient groups treated with somatropin for example Turner syndrome and Noonan syndrome. In addition, rapid growth in any child can cause progression of scoliosis. Somatropin has not been shown to increase the incidence or severity of scoliosis. Signs of scoliosis should be monitored during treatment.

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, somatropin should not be administered.

Somatropin has been found to influence carbohydrate metabolism, therefore, patients should be observed for evidence of glucose intolerance.

IGF-1
In Turner syndrome and SGA children it is recommended to measure the IGF-1 level before start of treatment and twice a year thereafter. If on repeated measurements IGF-1 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.
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.

Adults

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.

Adults and Children

Pancreatitis
Although rare, pancreatitis should be considered in somatropin-treated patients who develop abdominal pain, especially in children.


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General

Neoplasms
There is no evidence for increased risk of new primary cancers in children or in adults treated with somatropin.

In patients in complete remission from tumours or malignant disease, somatropin therapy has not been associated with an increased relapse rate.

An overall slight increase in second neoplasms has been observed in childhood cancer survivors treated with growth hormone, with the most frequent being intracranial tumours.
The dominant risk factor for second neoplasms seems to be prior exposure to radiation.

Patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of somatropin therapy.

Leukaemia
Leukaemia has been reported in a small number of growth hormone deficient patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in somatropin 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 somatropin treatment should be discontinued.

At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If somatropin 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
Somatropin 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 somatropin therapy patients should have their thyroid function tested regularly and should receive replacement therapy with thyroid hormone when indicated.

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.

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 
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effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Acute adrenal insufficiency
Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required.
In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment (see section 4.5).

Use with oral oestrogen therapy
If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects (see section 4.5).

Slipped capital femoral epiphysis
In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population. A patient treated with somatropin who develops a limp or complains of hip or knee pain should be evaluated by a physician.

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 somatropin 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 somatropin in patients having acute critical illnesses should be weighed against the potential risk.

One open-label, randomised clinical trial (dose range 0.045-0.090 mg/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.

Excipients
Norditropin contains less than 1 mmol sodium (23 mg) per 1.5 ml, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Norditropin NordiFlex has no or negligible influence on the ability to drive and use machines.