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4.4 Special warnings and precautions for use
Previous paediatric subjects, who had been treated with growth hormone during childhood until final height was attained, should be re-evaluated for growth hormone deficiency after epiphyseal closure before replacement therapy is commenced at the doses recommended for adults.
Diagnosis and therapy with HUMATROPE should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with growth hormone deficiency.
There is so far no evidence to suspect that growth hormone replacement influences the recurrence rate or regrowth of intracranial neoplasms, but standard clinical practice requires regular pituitary imaging in patients with a history of pituitary pathology. A baseline scan is recommended in these patients before instituting growth hormone replacement therapy.
In childhood cancer survivors, a higher risk of a second neoplasm (benign or malignant) has been reported in patients treated with somatropin. Intracranial tumours, in particular, were the most common of these second neoplasms.
In cases of severe or recurrent headache, visual problems, nausea and/or vomiting, a fundoscopy 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.
Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any child with the onset of a limp during growth hormone therapy should be evaluated.
Growth 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.
For paediatric patients, the treatment should be continued until the end of the growth has been reached. It is advisable not to exceed the recommended dosage in view of the potential risks of acromegaly, hyperglycaemia and glucosuria.
Before instituting treatment with somatropin for growth retardation secondary to chronic renal insufficiency, patients should have been followed for one year to verify growth disturbance. Conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status for one year prior to the treatment) should have been established and should be maintained during treatment. Treatment with somatropin should be discontinued at the time of renal transplantation.
The effects of growth hormone on recovery were studied in two placebo-controlled clinical trials involving 522 adult patients who were critically ill due to complications following open heart or abdominal surgery, multiple accidental trauma, or who were having acute respiratory failure. Mortality was higher (41.9% versus 19.3%) among growth hormone-treated patients (doses 5.3-8mg/day) compared to those receiving placebo. The safety of continuing growth hormone in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation in patients having acute critical illnesses should be weighed against the potential risks.
Depending on dose and route of administration, oestrogen therapy may affect the response to growth hormone treatment. Higher doses of growth hormone may be required to achieve an equivalent increase in serum IGF-I in women, as compared to men, especially in women receiving oral oestrogen replacement. If a change of the route of oestrogen administration (oral to transdermal or vice versa) is made, growth hormone should be newly titrated (see section 4.5). An increasing sensitivity to growth hormone (expressed as change in serum IGF-I per growth hormone dose) over time may be observed, particularly in men.
Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, HUMATROPE is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome. There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone 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.
Subjects with diabetes mellitus should be carefully monitored during treatment with HUMATROPE. An adjustment of the insulin dose may be required.
Elderly patients (age ≥ 65 years) are more sensitive to the action of HUMATROPE, they may be more prone to develop (severe) adverse events.
Experience in patients above 80 years is limited.
Experience with prolonged treatment in adults is lacking.
In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
In children born SGA it is recommended to measure fasting plasma 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 until the patient has been stabilized for diabetes care. Then growth hormone may be introduced with careful monitoring of the diabetic metabolic control. An increase in insulin dosage may be required.
In children born SGA it is recommended to measure the plasma IGF-I concentration before the start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for sex, age and pubertal status, the IGF-I / IGFBP-3 ratio should be taken into account to consider dose adjustment.
Initiating HUMATROPE treatment in children born SGA and in children with SHOX deficiency, near onset of puberty, is not recommended because of limited experience.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before reaching final height.
Pancreatitis in children
Children treated with somatropin have an increased risk of developing pancreatitis compared to adults treated with somatropin. Although rare, pancreatitis should be considered in somatropin-treated children who develop abdominal pain.
4.5 Interaction with other medicinal products and other forms of interaction
Because human growth hormone may induce a state of insulin resistance, patients should be monitored for evidence of glucose intolerance.
If glucocorticoid replacement therapy is required, glucocorticoid dosage and compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of growth promoting effects. In patients treated with somatropin, previously undiagnosed secondary hypoadrenalism may be unmasked, requiring glucocorticoid replacement therapy.
In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4).
Somatropin can increase cytochrome P450 (CYP) enzyme activity in humans and may result in reduced plasma concentrations and decreased effectiveness of drugs metabolized by CYP3A such as sex steroids, corticosteroids, cyclosporine and anticonvulsants.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: H01A C01.
Somatropin is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. It is synthesised in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.
The biological effects of HUMATROPE are equivalent to human growth hormone of pituitary origin.
The most prominent effect of HUMATROPE is that it stimulates the growth plates of long bones. Additionally, it promotes cellular protein synthesis and nitrogen retention.
HUMATROPE stimulates lipid metabolism; it increases plasma fatty acids and HDL-cholesterols and decreases total plasma cholesterol.
HUMATROPE therapy has a beneficial effect on body composition in growth hormone deficient patients, in that body fat stores are reduced and lean body mass is increased. Long-term therapy in growth hormone deficient patients increases bone mineral density.
HUMATROPE may induce insulin resistance. Large doses of human growth hormone may impair glucose tolerance.
The data available from clinical trials so far in patients with Turner syndrome indicate that, while some patients may not respond to this therapy, an increase over predicted height has been observed, the average being 3.3 ± 3.9cm.
In a clinical trial, patients born SGA (mean age 9.5 ± 0.9 yr) who were treated with a HUMATROPE dose of 0.067mg/kg/day for two years showed a mean gain in height SDS of + 1.2 during treatment. The results obtained in this trial with HUMATROPE are comparable with those described for other recombinant growth hormone preparations. Long-term safety data are still limited.
10. DATE OF REVISION OF THE TEXT
Changed to:
28 January 2011
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