Valtropin (somatropin) – Summary of product characteristics - H01AC01

1. NAME OF THE MEDICINAL PRODUCT

Valtropin 5 mg/1.5 ml powder and solvent for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of powder contains 5 mg somatropin (corresponding to 15 IU).

technology.

Patients with severe growth hormone deficiency in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one additional known deficiency of a pituitary hormone not being prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a growth hormone deficiency. In patients with childhood-onset isolated growth hormone deficiency (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be recommended, except for those having low insulin-like growth factor-1 (IGF-1) concentrations (< 2 standard deviation score (SDS)), who may be considered for one test. The cut-off point of the dynamic test should be strict.

4.2 Posology and method of administration

Therapy with Valtropin should be initiated and monitored by physicians adequately experienced in the diagnosis and management of patients with growth hormone deficiency.

Posology

The dosage and administration schedule should be individualised for each patient.

Dosage in paediatric population

Growth hormone deficiency in children

The recommended dosage is 0.025 - 0.035 mg/kg body weight per day.

Children with Turner syndrome

The recommended dosage is 0.045 - 0.050 mg/kg body weight per day, given as a subcutaneous injection.

Pre-pubertal children with chronic renal insufficiency

The recommended dosage is 0.045 - 0.050 mg/kg body weight per day, given as a subcutaneous injection.

The recommended starting dose is 0.15 - 0.30 mg/day, given as a subcutane us injection. A lower starting dose may be necessary in older and obese patients.

This dose should be gradually increased according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. Total daily dose usually does not exceed 1 mg. IGF-1 concentrations should be maintained below the upper limit of the age-specific normal range.

The minimum effective dose should be used.

Experience of prolonged treatment (over 5 years) with somatropin in adults is limited.

Renal impairment

Currently available data on renal insufficiency are described in section 4.4, but no recommendation on a posology can be made.

Hepatic impairment

In patients with severe liver dysfunction a reduction of somatropin clearance has been noted. The clinical significance of this decrease is unknown.

Method of administration

Valtropin is administered by subcutaneous injection.

The injection sites should be varied in order to avoid lipo-atrophy.

For further information on reconstitution and administration see section 6.6.

4.3 Contraindications

-Hypersensitivity to the active substance or to any of the excipients (e.g. metacresol) (see section 4.4).

-Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.

-Valtropin should not be used for growth promotion in children with closed epiphyses.

-Patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or patients having acute respiratory failure.

4.4 Special warnings and precautions for use

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

Pituitary

There is no evidence to suspect that growth hormone replacement influences the recurrence rate or

regrowth of intracranial neoplasms, but standard clinical practice requiresauthorisedregular pituitary imaging in

patients with a history of pituitary pathology. A baseline scan is recommended in th se patients before instituting growth hormone replacement therapy.

Tumour control

If the patient has had a brain tumour, the patient should be re-examined frequently to make sure that the tumour has not come back.

In childhood cancer survivors, a higher risk of a second neoplasm (benign malignant) has been reported in patients treated with somatropin. Intracraniallongertumou s, in particular, were the most common of these second neoplasms.

Intracranial hypertension

In cases of severe or recurrent headache, visualnopr blems, nausea, and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is c nfirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth hormone treatment should be discontinued. At present, there isproductinsufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertensi n is necessary.

Insulin sensitivity

Thyroid function

Because humanMedicinalgrowth hormone may induce a state of insulin resistance, patients treated with somatropin should be mo itored for evidence of glucose intolerance.

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.

Slipped capital epiphyse

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 deficiency after epiphyseal closure

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.

Treatment after the end of growth in children

For children, 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.

Prader-Willi syndrome

Valtropin is not indicated for the treatment of patients with growth failure due to Prader-Willi syndrome unless they also have a diagnosis of growth hormone deficiency. There have been reports of sleep apnoea and sudden death after initiating growth hormone 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.

Oral oestrogen administration increases the dose requirements in women. An increasing sensitivity to growth hormone (expressed as change in IGF-1 per growth hormone dose) over time may be observed, particularly in men. The accuracy of the growth hormone dose should therefore be controlled every

6 months.

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.

Accidental intramuscularMedicinalinjection

After accidental intramuscular injection, hypoglycaemia may appear. Any unwanted reaction should be followed. No spe ial treatment is recommended.

Sensitivity to metacresol

Valtropin should not be reconstituted with the supplied solvent for patients with a known sensitivity to metacresol. If sensitivity to the accompanying solvent occurs, the vials should be reconstituted with water for injections and used as a single use vial (see section 6.3).

4.5Interaction with other medicinal products and other forms of interaction

Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human growth hormone. Patients with co-existing adrenocorticotropic hormone (ACTH) deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth.

In women taking oral oestrogens, a higher dose of somatropin may be required to achieve the treatment goal.

Patients taking insulin for diabetes mellitus should be carefully monitored during treatment with somatropin. An adjustment of the insulin dose may be required.

Description of selected adverse reactions

In a clinical study with Valtropin, 3% of children with growth hormone deficiency developed antibodies to somatropin. The binding capacity of these antibodies was low and there was no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Anti-host cell protein (anti-S. cerevisiae) antibodies were uncommon in patients treated with Valtropin. The generation of such antibodies with low binding capacity is unlikely to be clinically relevant. In contrast to bacteria (E. coli), yeast has not been described to elicit adjuvant effects modifying the immunological response.

Paediatric population

Mild and transient oedema was observed early during the course of treatment with somatropin.

Adult patients

In adult patients with adult-onset growth hormone deficiency, oedema, muscle pain, joint pain and

disorders were reported early in therapy and tended to be transient.

excess human growth hormone. Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

Acute overdose could lead initially to hypoglycaemia and subsequentlyauthorisedto hyperglycaemia. Long-term overdose could result in signs and symptoms of acromegaly consistent wi known effects of

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and somatropin agonists; ATC code: H01AC01

Somatropin is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and

The biological effects of somatropin are equivalent to those of human growth hormone of pituitary origin.

The most promin nt effect of somatropin is that it stimulates the growth plates of long bones. Additionally, it promotes cellular protein synthesis and nitrogen retention.

Somatropin stimulates lipid metabolism; it increases plasma fatty acids and high-density lipoprotein (HDL)-cholesterols, and decreases total plasma cholesterol.

Somatropin 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.

Somatropin may induce insulin resistance. Large doses of somatropin may impair glucose tolerance.

Clinical studies

The efficacy and safety of Valtropin has been assessed in a randomised, double-blind, parallel, controlled Phase III study in children with growth hormone deficiency. There were no relevant

differences between Valtropin and the reference medicinal product with regard to height velocity and height velocity SDS.

An open single-arm Phase III study investigating the efficacy and safety of treatment with Valtropin in girls with short stature associated with Turner syndrome showed a significant effect of study treatment on height velocity.

5.2 Pharmacokinetic properties

A double-blind, randomised, single dose, crossover study in 24 healthy volunteers showed that the pharmacokinetic profile of Valtropin was comparable to that of the reference medicinal product. Subcutaneous administration of 0.073 mg/kg body weight of Valtropin resulted in a Cmax of 43.97 ng/ml and an AUC0-24 h of 369.90 ng·h/ml. Cmax was reached at 4 h and t½ was 3 h.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studi s with Valtropin of repeated dose toxicity, genotoxicity and reproductive toxicity studies.

Animal studies with Valtropin are not sufficient to assess the reproductive xicity potential. From

Powder:

Glycine

Mannitol

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment).

Sodium dihydrogenMedicinalphosph te nhydrous

Disodium phosphate hydrous

Solvent:

Metacresol

Water for injections.

6.2Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3Shelf life

3 years

After first opening or following reconstitution with the solvent provided:

After reconstitution with the solvent provided, chemical and physical in-use stability has been demonstrated for 21 days at 2°C - 8°C (refrigerator).