Valtropin - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

After reconstitution with 1.5 ml solvent, 1 ml contains: somatropin* 3.33 mg (corresponding to 10 IU)

* produced in Saccharomyces cerevisiae cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

White or almost white powder. The solvent is a clear solution.

After reconstitution with the solvent provided, Valtropin has a pH of approximately 7.5 and an osmolality of approximately 320 mOsm/kg.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Paediatric population

• – Long-term treatment of children and adolescents (12 to 18 years old) with growth failure due to an inadequ of normal endogenous growth hormone.

• – Treatment of short stature in children with Turner syndrome, confirmed by chromosome analysis.

• – Treatment of growth retardation in pre-pubertal children with chronic renal insufficiency.

Adult patients

• – Replacement therapy in adults with pronounced growth hormone deficiency of either childhood-or adult-onset aetiology.

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.

Dosage in adult patients

Growth hormone deficiency in adults

The recommended starting dose is 0.15 – 0.30 mg/day, given as a subcutaneous 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.

The dosage of somatropin should be decreased in cases of persistent oedema or severe paresthesia, in order to avoid the development of carpal tunnel syndrome.

Special populations

ent in patients above 60 years of age is limited. A lower starting dose ts. Dose requirements may decline with increasing age.

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 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.

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 or malignant) has been reported in patients treated with somatropin. Intracranial tumours, in particular, were the most common of these second neoplasms.

Intracranial hypertension

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 insufficie with resolved intracranial hypertension for symptoms of intracranial hypertensi

Insulin sensitivity

Because human growth hormone may induce a state of insulin resistance, patients treated with somatropin should be monitored for evidence of glucose intolerance.

Thyroid function

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.

Renal insufficiency

Before instituting treatment with somatropin for growth retardation secondary to chronic renal insufficiency, children 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.

Gender and dosing

In order to reach the defined treatment goal, men may need lower gro

Oral oestrogen administration increases the dose requirements in wom

growth hormone (expressed as change in IGF-1 per growth horm particularly in men. The accuracy of the growth hormone dose sh 6 months.

Turner syndrome

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders.

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.

Accidental intramuscular injection

After accidental intramuscular injection, hypoglycaemia may appear. Any unwanted reaction should be followed. No special 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).

4.5 Interaction 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.

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 P 450 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

For Valtropin no clinical data on exposed pregnancies are available. Animal studies are insufficient with respect to effects on pregnancy, embryofoetal development, parturition or postnatal development (see section 5.3). Therefore Valtropin should not be used during pregnancy unless clearly necessary.

Breast-feeding                             k

There have been no clinical studies conducted with Valtropin in breast-feeding women. It is not known whether somatropin is excreted in human milk. Therefore caution should be exercised when Valtropin is administered to breast-feeding women.

ameters.

4.7 Effects on ability to drive and use machinesuse machines.

Valtropin has no or negligible influence on the

4.8 Undesirable effects

Summary of the safety profile

The most common frequent adverse reactions are associated with the injection site, of endocrine nature, and headache, paresthesia and joint pain and disorder (arthralgia) in adults.

During clinical studies 128 children hildren with growth hormone deficiency and 30 with Turner syndrome) were exposed to Valtropie safety profile of Valtropin observed in these clinical studies was consistent with that reported with the reference medicinal product used in these studies and other somatropin containing medicinal products.

ctions and their frequencies have been observed under treatment with shed information:

/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare

(> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data), including isolated reports

Tabulated summary of adverse reactions

Neoplasms benign, malignant and unspecified (including cysts and polyps)	Uncommon: Neoplasm malignant, neoplasm
Blood and lymphatic system disorders	Uncommon: Anaemia
Immune system disorders	Common: Antibody building
	Not known: Single case of acute hypersensitivity involving urticaria and pruritus
Endocrine disorders	Common: Hypothyroidism
Metabolism and nutrition disorders	Common: Glucose tolerance impaired
	Common: Mild hyperglycaemia (1% in children;

	1% – 10% in adults)
	Uncommon: Hypoglycaemia, hyperphosphatemia
	Rare: Diabetes mellitus
	Not known: Insulin resistance
Psychiatric disorders	Uncommon: Personality disorder
Nervous system disorders	Very common: Headache in adults
	Very common: Paresthesia in adults
	Common: Hypertonia
	Common: Insomnia in adults
	Common: Carpal tunnel syndrome in adults
	Uncommon: Carpal tunnel syndrome in children
	Uncommon: Nystagmus
	Rare: Neuropathy, intracranial pressure increased
	Rare: Benign intracranial hypertension?)
	Rare: Paresthesia in children
	Very rare: Insomnia in children^p
Eye disorders	Uncommon: PapilloedemOc­diplopia
Ear and labyrinth disorders	Uncommon: Vertigo
Cardiac disorders	Common: HvperteinsioMn adults
	Uncommon: Tachycardia
	Rare: Hypertension in children
Respiratory, thoracic and mediastinal disorders	xQr Common<Dyspnoea in adults
	Common: Sleep apnoea in adults
Gastrointestinal disorders                   *	^Uncommon: Vomiting, abdominal pain, flatulence, nausea
X	.Rre: Diarrhoea
Skin and subcutaneous tissue disorder^^	Uncommon: Lipodystrophy, skin atrophy, exfoliative dermatitis, urticaria, hirsutism, skin hypertrophy
Musculoskeletal and connective tissues disorders                 ­< ’v)	Very common: Arthralgia in adults
	Common: Arthralgia in children
JU	Common: Myalgia
	Uncommon: Muscle atrophy, bone pain
Renal and urinay&isorders	Uncommon: Urinary incontinence, haematuria, polyuria, urine frequency/polla­kiuria, urine abnormality
Reproductivesy'stem and breast disorders	Uncommon: Genital discharge
	Uncommon: Gynaecomastia in adults
	Very rare: Gynaecomastia in children
General disorders and administration site conditions	Very common: Oedema, peripheral oedema in adults
	Common: Oedema, peripheral oedema in children
	Common: Injection site reactions, asthenia
	Uncommon: Injection site atrophy, injection site haemorrhage, injection site mass, hypertrophy, weakness in children
Investigations	Rare: Renal function test abnormal

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.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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 a molecular weight of 22,125 daltons. The amino acid sequence of the medicinal product is identical to that of human growth hormone of pituitary origin. Valtropin is synthesised in yeast cells (Saccharomyces cerevisiae ).

atropin are equivalent to those of human growth hormone of pituitary

t effect of somatropin is that it stimulates the growth plates of long bones. motes 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 AUC0–24h of 369.90 ng^h/ml. Cmax was reached at 4 h and t/2 was 3 h.

5.3 Preclinical safety data

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

Animal studies with Valtropin are not sufficient to assess the reproductive toxicity potential. From reproductive toxicity studies performed with other somatropin medicinal products there is no evidence of an increased risk of adverse reactions for the embryo or foetus.

Long-term studies for carcinogenicity have not been performed. There are no specific local tolerance studies in animals after subcutaneous injection of Valtropin. However, in single and repeat-dose general toxicity studies no adverse reactions at the injection sites were reported.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder: Glycine Mannitol

Sodium dihydrogen phosph

Disodium phosphate anhydrous

Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment).

Solvent:

Metacresol

Water for injections.

6.2 Incompatibilities

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

6.3 Shelf 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).

Following reconstitution with water for injections:

After reconstitution with water for injections, the medicinal product must be used immediately and must be used as a single use vial. If not used immediately, in-use storage times and conditions prior to use would normally not be longer than 24 hours at 2°C – 8°C (refrigerator), unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

For the purpose of transport and/or ambulatory use, the non-reconstituted medicinal product can be kept at room temperature (not above 25°C) for one single period of up to 4 weeks before use.

The date of refrigerator removal and the new expiry date should be written on the outer carton. At the end of the new expiry date, the medicinal product should have been used or be disposed of.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container 5 mg of powder in a vial (Type I glass) closed with a stopper (butyl rubber) and a flip-off cap (aluminium plastic).

1.5 ml of solvent in a pre-filled syringe (Type I glass) closed with a tip cap (FluroTec coated butyl rubber)

Pack size of 1 vial and 1 pre-filled syringe.

6.6 Special precautions for disposal and other handlingDetailed instructions for the handling of the leaflet.cinal product are given at the end of the package

For use and handling

Valtropin should not be reconstituted with the supplied solvent for patients with a known sensitivity to metacresol (see section 4.3). If sensitivity to the accompanying solvent occurs, the vials should be reconstituted with water for injections and used as a single use vial.

Reconstitution with the solvent provided

Each vial of Valtropin should be reconstituted using the accompanying solvent. The solvent should not be used if it is discoloured or cloudy. The solvent should be injected into the vial by aiming the stream of liquid against the glass wall. Following reconstitution, the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The resulting solution should be clear, without particulate matter. If the solution is discoloured, cloudy or contains particulate matter, the contents MUST NOT be injected. Before and after every injection, the septum of the vial should be wiped with alcohol to prevent contamination of the contents by repeated needle insertions. If reconstituted with the solvent, then the solution is for multidose use (see section 6.3).

Reconstitution with water for injections

After reconstitution with water for injections the medicinal product must be used immediately (see section 6.3) and the solution is for single use only.

Administration

Sterile disposable syringes and needles should be used for administration of Valtropin. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

BioPartners GmbH

Kaiserpassage 11

D-72764 Reutlingen

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/335/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE

Date of first authorisation 24.04.2006

Date of latest renewal 24.04.2011