Medical description of Genotropin

Pharmacodynamics

Somatropin is a potent metabolic hormone that plays an important role in lipid, carbohydrate and protein metabolism. Somatropin is produced in Escherichia coli cells using recombinant DNA technology. In children with endogenous growth hormone deficiency, somatropin accelerates linear skeletal growth and growth velocity. In adults and children, somatropin maintains a normal physique by increasing nitrogen uptake, accelerating skeletal muscle growth and mobilising body fat. Visceral adipose tissue is particularly sensitive to somatropin. As well as stimulating lipolysis, somatropin reduces the entry of triglycerides into fat deposits. Serum concentrations of IGF-1 (insulin-like growth factor type 1) and IGFBP-3 (insulin-like growth factor binding protein type 3) increase under the influence of somatropin. In addition, the actions described below have been demonstrated.

Pharmacokinetics

Absorption. The bioavailability of somatropin administered subcutaneously is approximately 80% in healthy volunteers and in patients with growth hormone deficiency. A dose of 0.035 mg/kg of somatropin administered subcutaneously gives the following plasma Cmax and tmax values: 13-35 ng/ml and 3-6 hours, respectively.

Conclusions. The mean marginal half-life after administration of somatropin to adults with growth hormone deficiency is approximately 0.4 hours. However, after subcutaneous administration, the half-life can reach 2 to 3 hours. The difference observed is probably due to slower absorption from the injection site after subcutaneous administration.

Subpopulation. The absolute bioavailability of somatropin by subcutaneous administration is similar in men and women.

There is no or incomplete information on the pharmacokinetics of somatropin in elderly and paediatric patients, in patients of different races and in patients with renal and hepatic dysfunction or heart failure.

Preclinical safety data.

No clinically relevant effects were observed in the general toxicity, local tolerance and reproductive toxicity studies.

In vitro and in vivo genotoxicity studies on genetic mutations and induction of chromosomal aberrations were negative.

In an in vitro study, an increase in chromosomal fragility was observed in lymphocytes taken from patients after long-term treatment with somatropin and subsequent administration of an additional radiomimetic drug, bleomycin. The clinical significance of this finding is unclear.

In another study, no chromosomal abnormalities were found in lymphocytes collected from patients following long-term treatment with somatropin.

Contraindications
Hypersensitivity to the active substance or to one of the excipients of the medicinal product.

Somatropin should not be administered in the presence of signs of tumour activity. Intracranial tumours must be inactive and anti-tumour treatment must be completed before treatment with growth hormone is started. If there are signs of tumour growth, treatment should be discontinued.

Genotropin should not be used to stimulate growth in children with closed epiphyseal growth zones.

Treatment with Genotropin is contraindicated in patients in acute critical condition due to complications of open heart surgery, abdominal cavity surgery, multiple trauma, acute respiratory failure or other similar conditions.

Interaction with other medicinal products and other types of interaction
Concomitant use of glucocorticoids inhibits the growth-promoting effect of somatropin preparations. Patients with adrenocorticotropic hormone deficiency must be carefully selected for glucocorticoid replacement therapy to avoid any inhibitory effect on growth.

Therefore, the growth of patients treated with glucocorticoids should be carefully monitored to assess the potential effects of glucocorticoid use on growth.

Growth hormone reduces the conversion of cortisone to cortisol and may lead to the development of previously undiagnosed central adrenal hypofunction or render ineffective the use of low-dose glucocorticoids as part of replacement therapy (see “Administration”).

Data from a drug interaction study involving adult patients with growth hormone deficiency suggest that somatropin administration may increase the clearance of compounds metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (such as sex steroid hormones, corticosteroids, anticonvulsants and cyclosporine) may be excessively increased, resulting in a decrease in the plasma concentration of these substances. The clinical significance of this phenomenon is unknown.

For more information on diabetes mellitus and thyroid dysfunction, see the “Administration details” section.

Women receiving oral oestrogen replacement therapy may require a higher dose of growth hormone to achieve the treatment goal (see “Administration”).

Particularities of use

Diagnosis, initiation of treatment with Genotropin and subsequent monitoring should be carried out by qualified physicians experienced in the diagnosis and treatment of patients in accordance with the indications for use.

Myositis is a very rare side effect, which may be caused by the action of the preservative contained in the m-cresol preparation. In the event of myalgia or increased pain at the injection site, myositis should be assumed. If this is confirmed, the m-cresol-free form of Genotropin should be used.

Insulin sensitivity.

Somatropin may reduce insulin sensitivity. In patients with diabetes mellitus, adjustment of the insulin dose may be necessary after the start of treatment with somatropin. Patients with diabetes mellitus, impaired glucose tolerance or other risk factors for diabetes mellitus should be monitored during treatment with somatropin.

Thyroid function.

Growth hormone accelerates the peripheral conversion of T4 to T3, which may result in a decrease in serum T4 concentration and an increase in serum T3 concentration. Although peripheral thyroid hormone concentrations remain normal in most healthy volunteers, it is theoretically possible for patients with subclinical hypothyroidism to develop hypothyroidism. Therefore, thyroid function should be monitored in all patients. In patients with hypopituitarism receiving standard replacement therapy, the possible effect of growth hormone treatment on thyroid function should be carefully monitored.