Zomacton 4mg, powder and solvent for solution for injection

Somatropin* …..……………………………………………………………..4mg

(1.3mg/ml or 3.3mg/ml after reconstitution)

* Produced in Escherichia coli cells by recombinant DNA technology

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Zomacton is a white to off-white lyophilised powder in a vial. The solvent in ampoule is clear and colorless.

Zomacton is indicated for the longterm treatment of children who have growth failure due to inadequate secretion of growth hormone and for the long-term treatment of growth retardation due to Turner's Syndrome confirmed by chromosome analysis.

Zomacton therapy should be used only under the supervision of a qualified physician experienced in the management of patients with growth hormone deficiency.

The dosage and schedule of administration of Zomacton should be individualized for each patient.

The duration of treatment, usually a period of several years, will depend on maximum achievable therapeutic benefit.

The subcutaneous administration of growth hormone may lead to loss or increase of adipose tissue at the injection site. Therefore, injection sites should be alternated.

Growth Hormone Deficiency

Generally a dose of 0.17 - 0.23mg/kg bodyweight (approximating to 4.9mg/m²– 6.9mg/m² body surface area) per week divided into 6 - 7 s.c. injections is recommended (corresponding to a daily injection of 0.02 – 0.03mg/kg bodyweight or 0.7 - 1.0mg/m² body surface area). The total weekly dose of 0.27mg/kg or 8mg/m² body surface area should not be exceeded (corresponding to daily injections of up to about 0.04mg/kg).

Turner's Syndrome

Generally a dose of 0.33mg/kg/bodyweight (approximating to 9.86mg/m²/body surface area) per week divided into 6 - 7 s.c. injections are recommended (corresponding to daily injection of 0.05mg/kg/bodyweight or 1.40-1.63mg/m²/body surface area).

Zomacton should not be used in children with closed epiphyses.

Patients with evidence of progression of an underlying intra-cranial lesion or other active neoplasms should not receive Zomacton, since the possibility of a tumor growth promoting effect cannot be excluded. Prior to the initiation of therapy with Zomacton, neoplasms must be inactive and anti-tumor therapy completed.

Hypersensitivity to somatropin or to any of the excipients.

Zomacton must not be given to premature babies or neonates as the solvent contains benzyl alcohol.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure, or similar conditions should not be treated with Zomacton (see section 4.4).

Due to the presence of benzyl alcohol as excipient, Zomacton may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates.

Patients should be observed for evidence of glucose intolerance because growth hormone may induce a state of insulin resistance. Zomacton should be used with caution in patients with diabetes mellitus or with a family history predisposition for the disease. Strict monitoring of urine and blood glucose is necessary in these patients. In children with diabetes, the dose of insulin may need to be increased to maintain glucose control during Zomacton therapy.

In patients with growth hormone deficiency secondary to an intra-cranial lesion, frequent monitoring for progression or recurrence of the underlying disease process is advised.

Discontinue Zomacton therapy if progression or recurrence of the lesion occurs.

In patients with previous malignant diseases special attention should be given to signs and symptoms of relapse.

Zomacton is not indicated for the long term treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome, unless they also have a diagnosis of GH deficiency. There have been reports of sleep apnoea and sudden death associated with the use of growth hormone in paediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of respiratory impairment or unidentified respiratory infection.

Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during somatropin treatment.

Treatment with Zomacton should be discontinued at renal transplantation.

Rare cases of benign intra-cranial hypertension have been reported. In the event of severe or recurring headache, visual problems, and nausea/vomiting, a funduscopy for papilla edema is recommended. If papilla edema is confirmed, diagnosis of benign intra-cranial hypertension should be considered and if appropriate growth hormone treatment should be discontinued (see also section 4.8).

During treatment with somatropin an enhanced T4 to T3 conversion has been found which may result in a reduction in serum T4 and an increase in serum T3 concentrations. In general, the peripheral thyroid hormone levels have remained within the reference ranges for healthy subjects. The effects of somatropin on thyroid hormone levels may be of clinical relevance in patients with central subclinical hypothyroidism in whom hypothyroidism theoretically may develop. Conversely, in patients receiving replacement therapy with thyroxin mild hyperthyroidism may occur. It is therefore particularly advisable to test thyroid function after starting treatment with somatropin and after dose adjustments.

Leukaemia has been reported in a small number of growth hormone deficient patients treated with somatropin as well as in untreated patients. Based on clinical experience of more than 10 years, the incidence of leukaemia in GH-treated patients without risk factors is not greater than that in the general population.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders. A patient treated with Zomacton who develops a limp or complains of hip or knee pain should be evaluated by a physician.

The effects of treatment with growth hormone on recovery were studied in two placebo controlled trials involving 522 critically ill adult patients suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, or acute respiratory failure.

Mortality was higher (42% vs. 19%) among patients treated with growth hormones (doses 5.3 to 8mg/day) compared to those receiving placebo. Based on this information, such patients should not be treated with growth hormones. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued treatment in this situation should be weighed against the potential risks involved.

In all patients developing other or similar acute critical illness, the possible benefit of treatment with growth hormone must be weighed against the possible risk involved.

Glucocorticoid therapy may inhibit the growth promoting effect of Zomacton. Patients with coexisting ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid impairment of the growth promoting effect of Zomacton.

High doses of androgens, oestrogens, or anabolic steroids can accelerate bone maturation and may, therefore, diminish gain in final height.

Because somatropin can induce a state of insulin resistance, insulin dose may have to be adjusted in diabetic patients receiving concomitant Zomacton.

Data from an interaction study performed in GH 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 P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporin) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

For Zomacton no clinical data on exposed pregnancies are available. Thus, the risk for humans is unknown. Although animal studies do not point to a potential risk of somatropin applied during pregnancy, Zomacton should be discontinued if pregnancy occurs. During pregnancy, maternal somatropin will largely be replaced by placental growth hormone.

It is not known whether somatropin is excreted in human milk, however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely.

Zomacton has no influence on the ability to drive and use machines.

The subcutaneous administration of growth hormone may lead to loss or increase of adipose tissue at the injection site. On rare occasions patients have developed pain and an itchy rash at the site of injection.

Somatropin has given rise to the formation of antibodies in approximately 1% of the patients. The binding capacity of these antibodies has been low and no clinical changes have been associated with their formation.

Rare cases of benign intra-cranial hypertension have been reported with somatropin (see section 4.4).

Very rare cases of leukaemia have been reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

The recommended dose of Zomacton should not be exceeded.

Although there have been no reports of overdosage with Zomacton, acute overdosage may result in an initial hypoglycaemia followed by a subsequent hyperglycaemia.

The effects of long-term, repeated use of Zomacton in doses exceeding those recommended, are unknown. However, it is possible that such use might produce signs and symptoms consistent with the known effects of excess human growth hormone (e.g. acromegaly).

Pharmacotherapeutic group: Somatropin and somatropin agonists

ATC code: H 01 AC 01

Identical to pituitaryderived human growth hormone (pithGH) in amino acid sequence, chain length (191 amino acids) and pharmacokinetic profile. Zomacton can be expected to produce the same pharmacological effects as the endogenous hormone.

Skeletal system:

Growth hormone produces a generally proportional growth of the skeletal bone in man. Increased linear growth in children with confirmed deficiency of pithGH has been demonstrated after exogenous administration of Zomacton. The measurable increase in height after administration of Zomacton results from an effect on the epiphyseal plates of long bones. In children who lack adequate amounts of pithGH, Zomacton produces increased growth rates and increased IGF1 (Insulinlike Growth Factor/Somatomedin-C) concentrations that are similar to those seen after therapy with pit- hGH. Elevations in mean serum alkaline phosphatase concentrations are also involved.

Other organs and tissues:

An increase in size, proportional to total increase in body weight, occurs in other tissues in response to growth hormone, as well. Changes include: increased growth of connective tissues, skin and appendages; enlargement of skeletal muscle with increase in number and size of cells; growth of the thymus; liver enlargement with increased cellular proliferation; and a slight enlargement of the gonads, adrenals, and thyroid. Disproportionate growth of the skin and flat bones, and accelerated sexual maturation have not been reported in association with the growth hormone replacement therapy.

Protein, carbohydrate and lipid metabolism:

Growth hormone exerts a nitrogenretaining effect and increases the transport of amino acids into tissue. Both processes augment the synthesis of protein. Carbohydrate use and lipogenesis are depressed by growth hormone. With large doses or in the absence of insulin, growth hormone acts as a diabetogenic agent, producing effects seen typically during fasting (i.e. intolerance to carbohydrate, inhibition of lipogenesis, mobilisation of fat and ketosis).

Mineral metabolism:

Conservation of sodium, potassium, and phosphorous occurs after treatment with growth hormone. Increased calcium loss by the kidney is offset by increased absorption in the gut. Serum calcium concentrations are not significantly altered in patients treated with Zomacton or with pit-hGH. Increased serum concentrations of inorganic phosphates have been shown to occur both after Zomacton and pit-hGH. Accumulation of these minerals signals an increased demand during tissue synthesis.

Eight healthy subjects received 0.1mg somatropin/kg body weight. Peak plasma levels of about 64ng/ml were found 6 hours after administration.

Single dose toxicity:

Single dose toxicity studies were performed in rats (intramuscular application of 10mg/kg), dogs and monkeys (intramuscular dose of 5mg/kg, corresponding to the 50 - 100 fold of the human therapeutic dose). There was no evidence of drug-related toxicity in any of these species.

Repeated dose toxicity:

No relevant toxicological signs were observed in a rat study in which doses of 1.10mg/kg/day for 30 days and 0.37mg/kg/day for 90 days were administered to the animals.

Reproduction toxicology, mutagenic and carcinogenic potential

Genetically engineered somatropin is identical to endogenous human pituitary growth hormone. It has the same biological properties and it is usually administered in physiological doses. Therefore, it was not deemed necessary to perform the full range of such toxicological studies. Untoward effects on reproduction organs, on pregnancy and lactation are unlikely and also no carcinogenic potential has to be expected. A mutagenicity study showed the absence of mutagenic potential.

The solution contains benzyl alcohol 9mg/ml.

Powder

Mannitol

Solvent

Sodium chloride

Benzyl alcohol

Water for injections

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

3 years

After reconstitution, may be stored for a maximum of 14 days in a refrigerator at

2°C - 8°C.

Store vials in an upright position.

Store in a refrigerator (2 °C - 8 °C); keep in the outer carton in order to protect from light.

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

Zomacton is supplied in various packs subject to national approvals:

Not all pack sizes may be marketed.

Reconstitution

Two concentrations can be prepared: 3.3 mg/ml for use with the ZomaJet 2 Vision, Ferring-Pen or conventional syringes and 1.3 mg/ml for conventional syringes only.

The 3.3 mg/ml solution is prepared by reconstituting the Zomacton powder with 1.3 ml benzyl alcohol preserved saline solvent using a graduated disposable syringe, when the 1.3 mg/ml solution is prepared with 3.2 ml of solvent.

After reconstitution the solvent forms a clear and colorless solution for injection.

To prevent foaming of the solution, the stream of solvent should be aimed against the side of the vial. The vial must then be swirled with a gentle rotary motion until the contents are completely dissolved and a clear, colorless solution is produced. Since Zomacton is a protein, shaking or vigorous mixing is not recommended. If after mixing, the solution is cloudy or contains particulate matter, the contents must be discarded. In the case of cloudiness after refrigeration, the product should be allowed to warm to room temperature. If cloudiness persists or coloration appears, discard the vial and its contents.

Administration

The required Zomacton dose is administered by using the ZomaJet 2 Vision (a needle free device), the Ferring-Pen (a needle device) or alternatively a conventional syringe.

Specific instructions for use of the ZomaJet 2 Vision and the Ferring-Pen are given in a brochure supplied with the device.

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

Ferring Pharmaceuticals Ltd

The Courtyard

Waterside Drive

Langley

Berkshire

SL3 6EZ

PL 03194/0052

05/01/2007

October 2009