1. Name Of The Medicinal Product
ZOMACTON 10 mg/ml, powder and solvent for solution for injection in pre-filled syringe.
2. Qualitative And Quantitative Composition
Somatropin*.10mg
(10mg/ml after reconstitution for one vial)
* Produced in Escherichia coli cells using recombinant DNA technology
For full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection in pre-filled syringe.
Zomacton is a white to off-white lyophilised powder. The solvent in prefilled syringe is clear and colourless.
4. Clinical Particulars
4.1 Therapeutic Indications
Zomacton is indicated for:
- the long
- the long-term treatment of growth retardation due to Turner's Syndrome confirmed by chromosome analysis.
4.2 Posology And Method Of Administration
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 of administration of Zomacton should be individualised 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 – 0.23 mg/kg bodyweight (approximating to 4.9 mg/m2– 6.9 mg/m2 body surface area) per week divided into 6 - 7 s.c. injections is recommended (corresponding to a daily injection of 0.02 – 0.03 mg/kg bodyweight or 0.7 – 1.0 mg/m2 body surface area).
The total weekly dose of 0.27 mg/kg or 8 mg/m2 body surface area should not be exceeded (corresponding to daily injections of up to about 0.04 mg/kg).
TURNER'S SYNDROME
Generally a dose of 0.33 mg/kg/bodyweight (approximating to 9.86 mg/m2/body surface area) per week divided into 6 - 7 s.c. injections are recommended (corresponding to daily injection of 0.05 mg/kg/bodyweight or 1.40-1.63 mg/m2/body surface area).
Instructions for preparation, see section 6.6.
Administration
The required dose of ZOMACTON 10 mg/ml is administered with a ZOMAJET VISION X needle-free device or with an ordinary syringe.
Specific instructions for the use of the ZOMAJET VISION X device are given in a booklet supplied with the device.
4.3 Contraindications
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.
Pregnancy and lactation (see section 4.6).
Hypersensitivity to somatropin or to any of the excipients.
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).
4.4 Special Warnings And Precautions For Use
Very rare cases of myositis have been observed and may be due to the metacresol used as preservative. In the case of myalgia or disproportionate pain at the injection site, myositis should be considered and, if confirmed, a Zomacton presentation without metacresol should be used.
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 predisposing 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 8 mg/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.
Experience of local tolerability to administration of ZOMACTON 10 mg/ml with Zomajet Vision X needle-free device has been studied before marketing authorisation in a 12 week study including only Caucasian children.
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
Zomacton has no influence on the ability to drive and use machines.
4.8 Undesirable Effects
The subcutaneous administration of growth hormone may lead to loss or increase of adipose tissue as well as punctual haemorrhage and bruising 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.
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4.9 Overdose
The recommended dose of Zomacton should not be exceeded.
Although there have been no reports of overdose with Zomacton, acute overdose 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).
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Somatropin and somatropin agonists
ATC code: H 01 AC 01
Pharmacodynamic properties:
Identical to pituitary
Skeletal system:
Growth hormone produces a generally proportional growth of the skeletal bone in man. Increased linear growth in children with confirmed deficiency of pit
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 nitrogen retaining 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.
5.2 Pharmacokinetic Properties
Twenty-four (24) healthy adult subjects received 1.67 mg somatropin either by conventional s.c. injection or by ZomaJet Vision needle free device. Peak plasma levels of around 20 ng/ml were observed 3.5 to 4 hours after administration of the medicinal product.
A terminal half-life 2.6 hours was observed when the compound was administered with Zomajet vision needle-free device which is likely to be due to a rate limiting absorption process.
Data from other somatropin containing products suggest that the bioavailability subcutaneously administered somatropin is approximately 80% in healthy adults and that both liver and kidney have been shown to be important protein catabolism organs eliminating the compound.
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated-dose toxicity and genotoxicity.
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, studies on safety pharmacology, toxicity to reproduction and carcinogenicity have not been conducted as no such effects are anticipated.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Powder
Mannitol
Disodium phosphate dodecahydrate
Sodium dihydrogen phosphate dihydrate
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
2 years
After reconstitution, the solution must be stored for a maximum of 28 days in a refrigerator at 2°C - 8°C.
After reconstitution, store vials in an upright position.
6.4 Special Precautions For Storage
Store in a refrigerator ( 2°C to - 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.
6.5 Nature And Contents Of Container
Zomacton is supplied in various packs subject to national approvals:
a) Sets for use for needle injection:
Powder: Vial (type I glass) with closure (rubber, halobutyl polymer) in combination with an aluminium seal and “Flip-off” cap (plastic).
Solvent: Pre-filled syringe (type I glass) with tip cap (rubber, halobutyl polymer), plunger stopper (rubber, halobutyl polymer) and a solvent transfer connector (polycarbonate).
Packs: 1, 3 and 5
b) Sets for use with the needle free device Zomajet Vision X:
Powder: Vial (type I glass) with closure (rubber, halobutyl polymer) in combination with an aluminium seal and “Flip-off” cap (plastic).
Solvent: Pre-filled syringe (type I glass) with tip cap (rubber, halobutyl polymer), plunger stopper (rubber, halobutyl polymer) and vial adaptor (polycarbonate and silicone rubber).
Packs: 1, 3 and 5
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Reconstitution
The powder should be reconstituted only by introducing the provided solvent contained in the prefilled syringe into the vial.
See the package leaflet for detailed instructions for reconstitution.
The following is a general description of the reconstitution and administration process. Reconstitution should be performed in accordance with good practice rules, particularly in the respect of asepsis.
1. Hands should be washed.
2. Flip off the yellow plastic protective caps from the vial.
3. The top of the vial should be wiped with an antiseptic solution to prevent contamination of the content.
4. Place the vial adaptor or the solvent transfer connector over the centre of the vial with the spike facing downwards then push down firmly until it clicks into place. Remove the adaptor cap.
5. Take the prefilled syringe. Remove the grey cap. Place the syringe into the adaptor / connector of the vial and inject the solvent slowly into the vial aiming the stream of liquid against the glass wall in order to avoid foam.
6. Place the adaptor cap / connector cap back on the adaptor / connector.
7. Gently swirl the vial a few times until the content is completely dissolved. Do not shake; this may cause denaturation of the active substance.
8. If the solution is cloudy or contains particulate matter, it should not be used. In the case of cloudiness after refrigeration, the product should be allowed to warm to room temperature. If cloudiness persists, discard the vial and its contents. The content must be clear and colourless after reconstitution.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Ferring Pharmaceuticals Ltd
The Courtyard,
Waterside Drive
Langley
Berkshire SL3 6EZ
8. Marketing Authorisation Number(S)
PL 03194/0104
9. Date Of First Authorisation/Renewal Of The Authorisation
21st November 2008
10. Date Of Revision Of The Text
21st November 2008
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
