ZOMACTON 4MG INJECTION

Active substance: SOMATROPIN

View full screen / Print PDF » Download PDF ⇩

Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Zomacton 4 mg, powder and solvent for solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial of powder contains :
Somatropin* …..………………………………………………………….4 mg
(corresponding to a concentration of 1.3 mg/ml or 3.3 mg/ml after
reconstitution)
* produced in Escherichia coli cells by recombinant DNA technology.
Excipient with known effect (in the solvent):
Benzyl alcohol: 9 mg/ml
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
Zomacton is a white to off-white powder. The solvent in ampoule is clear and
colorless.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic Indications
Zomacton® is indicated for the long-term 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.

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 and schedule 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.
4.3

Contraindications
Zomacton must not be given to premature babies or neonates as the solvent
contains benzyl alcohol.
Hypersensitivity to somatropin or to any of the excipients.
Somatropin must not be used when there is any evidence of activity of a
tumour. Intracranial tumours must be inactive and antitumor therapy must be
completed prior to starting GH therapy. Treatment should be discontinued if
there is evidence of tumour growth.
Somatropin should not be used for growth promotion in children with closed
epiphyses.
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 somatropin.
In children with chronic renal disease, treatment with somatropin should be
discontinued at renal transplantation.

4.4

Special warnings and precautions for use
The maximum recommended daily dose should not be exceeded (see section
4.2).
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.
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 after initiating therapy with
growth hormone in paediatric 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.
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). At present, there is insufficient evidence to guide clinical decision
making in patients with resolved intracranial hypertension. If growth hormone
treatment is restarted, careful monitoring for symptoms of intracranial
hypertension is necessary.
Leukaemia has been reported in a small number of growth hormone deficient
patients treated with somatropin as well as in untreated patients. However,
there is no evidence that leukaemia incidence is increased in growth hormone
recipients without predisposition factors.
As with all somatropin containing products, a small percentage of patients
may develop antibodies to somatropin. The binding capacity of these
antibodies is low and there is no effect on growth rate. Testing for antibodies
to somatropin should be carried out in any patient who fails to respond to
therapy.
Growth hormone increases the extrathyroidal conversion of T4 to T3 and may,
as such, unmask insipiens 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.
Because somatropin may reduce insuline sensitivity, patients should be
monitored for evidence of glucose intolerance. For patients with diabetes
mellitus, the insuline dose may require adjustment after somatropin containing
product therapy is initiated. Patients with diabetes or glucose intolerance
should be monitored closely during somatropin therapy. Zomacton should also

be used with caution in patients with a family history predisposing for the
disease.
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. In childhood cancer survivors, an increased risk of
a second neoplasm has been reported in patients treated with somatropin after
their first neoplasm. Intracranial tumours, in particular meningiomas, in
patients treated with radiation to the head for their first neoplasm, were the
most common of these second neoplasms
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.
Scoliosis may progress in any child during rapid growth. Signs of scoliosis
should be monitored during somatropin treatment.
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.
Although rare, pancreatitis should be considered in somatropin-treated
patients, especially children who develop abdominal pain.
4.5

Interaction with other medicinal products and other forms of interaction
Concomitant treatment with glucocorticoide inhibits the growth-promoting
effects of somatropin containing products. Patients with ACTH deficiency
should have their glucocorticoid replacement therapy carefully adjusted to
avoid any inhibitory effect on growth hormone.
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. There is
no data from the use of Zomacton during pregnancy in animals. (See section
Preclinical safety data 5.3)
Therefore, Zomacton is not recommended during pregnancy and in woman of
childbearing potential not using contraception.
There have been no clinical studies conducted with somatropin containing
products in breast-feeding women. It is not known whether somatropin is
excreted in human milk. Therefore caution should be exercised when
somatropin containing products are administered to breast-feeding women.

4.7

Effects on ability to drive and use machines
Somatropin containing products have no influence on the ability to drive and
use machines.
Undesirable effects
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.

Gastroinyestinal



Ear and labyrinth
disorders
Endocrine
disorders
Eye disorders

Uncommon
( 1/1000, to
<1/100)
anemia

Rare
( 1/10,000
to <1/1,000)

tachycardia,
(adult)
hypertension
vertigo

Common
( 1/100 to
<1/10)



Blood and
lymphatic system
disorders
Cardiac disorders

Very
Common
( 1/10)

(children)
hypertension



System Organ
Class



4.8

hypothyroidism
papilloedema,
diplopia
vomiting,

diarrhoea

Very rare
(<1/10,00
0)

disorders

General disorders
and
administration
site conditions

(adults)
oedema,
(adults)
peripheral
oedema

Immune system
disorders
Investigations

Metabolism and
nutrition
disorders
Musculoskeletal
and connective
tissue disorders

(adult)
mild
hyperglyc
aemia
(adults)
arthralgia;
(adults)
myalgia

(children)
oedema,
(children)
peripheral
oedema,
injection site
reactions,
asthenia
antibody
building

(children)
glucose tolerance
impaired
(children)
arthralgia;
(children)
myalgia
(Adults)
Stiffness in the
extremities

Neoplasms
benign, malignant
and unspecified
Nervous system
disorders

Psychiatric
disorders
Renal and urinary
disorders

Reproductive
system and breast
disorders
Skin and
subcutaneous
tissue disorders

(adult)
headache,
(adult)
paresthesi
a

headache,
hypertonia,
(adult) insomnia

abdominal
pain,
flatulence,
nausea
weakness,
injection site
atrophy,
injection site
haemorrhage,
injection site
mass,
hypertrophy

hypoglycaemia
,
hyperphosphat
emia
muscle
atrophy, bone
pain, carpal
tunnel
syndrome
(Children)
Stiffness in the
extremities
neoplasm
malignant,
neoplasm
somnolence,
nystagmus

personality
disorders
urinary
incontinence,
haematuria,
polyuria, urine
frequency/poll
akiuria, urine
abnormality
genital
discharge,
(adult)
gynecomastia
lipodystrophy,
skin atrophy,
dermatitis
exfoliative,
urticaria,
hirsutism, skin

renal
function test
abnormal
diabetes
mellitus type
II

(children)
leukaemia
neuropathy,
intracranial
pressure
increased,
(children)
insomnia,
(children)
paresthesia

(children)
Gynecom
astia

hypertrophy

Pancreatitis has been reported post-marketing during GH therapy (frequency
unknown).
Antibodies anti-somatropin: the protein somatropin may give rise to the
formation of antibodies. Depending on the concerned product, these antibodies
have been identified in a definite percentage of the treated population. Their
binding capacity and their titres are generally low with no clinical
consequence. However, testing for antibodies to somatropin should be
performed in case of absence of response to somatropin therapy.
Leukaemia: cases of leukaemia (very rare) have been reported in children with
a GH deficiency, some of them being treated with somatropin and included in
the post-marketing experience. However, there is no evidence of an increased
risk of leukaemia without predisposition factors.
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease have been
reported in children treated with GH. Slipped capital femoral epiphysis occurs
more frequently in case of endocrine disorders and Legg-Calve-Perthes is
more frequent in case of short stature. But, it is unknown if these 2 pathologies
are more frequent or not while treated with somatropin. A discomfort, a pain
in the hip and/or the knee must evocate their diagnosis.
Other adverse drug reactions may be considered as class effect, as the
hyperglycaemia due to the decrease in insulin-sensitivity, the decreased of free
thyroxin level and the possible development of a benign intra-cranial
hypertension.
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
Identical to pituitary-derived human growth hormone (pit-hGH) 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
pit-hGH 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 pit-hGH, Zomacton produces increased growth rates and
increased IGF-1 (Insulin-like 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 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
Eight healthy subjects received 0.1 mg somatropin/kg body weight. Peak
plasma levels of about 64 ng/ml were found 6 hours after administration.

5.3

Preclinical safety data
Single dose toxicity:
Single dose toxicity studies were performed in rats (intramuscular application
of 10 mg/kg), dogs and monkeys (intramuscular dose of 5 mg/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
1.10 mg/kg/day for 30 days and 0.37 mg/kg/day for 90 days were administered
to the animals.
Reproduction toxicology, mutagenic and carcinogenic potential
Somatropin produced by recombinant DNA technology 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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Powder
Mannitol
Solvent
Sodium chloride
Benzyl alcohol
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 reconstitution, the solution may be stored for a maximum of 14 days in a
refrigerator (2 °C-8 °C).
Store the vial in an upright position.

6.4

Special precautions for storage
Unopened vial: 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.

6.5

Nature and contents of container
Powder in vial (type I glass) with a stopper (grey halobutyl rubber), a seal and
a “flip-off” top + 3.5 ml solvent in ampoule (type I glass):
Pack size of 1, 5 and 10
or
Powder in vial (type I glass) with a stopper (grey halobutyl rubber), a seal and
a “flip-off” top + 3.5 ml solvent in ampoule (type I glass), a syringe
(polypropylene) with a plunger (polypropylene), a seal, and needle (stainless
steel)
Pack size of 5
or
Powder in vial (type I glass) with a stopper (grey halobutyl rubber), a seal and
a “flip-off” top + 3.5 ml solvent in ampoule (type I glass), a syringe
(polypropylene) with a plunger (polypropylene), a seal, a needle (stainless
steel), and an adapter (polycarbonate resin with silicone rubber
membrane/seal) for use with the needle free device ZomaJet 2 Vision or the
needle device Ferring Pen.
Pack size of 1, 5 and 10.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Reconstitution
The powder should only be dissolved with the solvent provided.
Two concentrations can be prepared depending on the volume of solvent used:
• for administration using a syringe, ZomaJet 2 Vision or Ferring-Pen, use 1.3 ml of
solvent for a concentration of 3.3 mg/ml (taking into account the whole content of
the vial which is greater than 4 mg)
• for administration using a syringe only, use 3.2 ml of solvent for a concentration
of 1.3 mg/ml. (taking into account the whole content of the vial which is greater
than 4 mg)

To prevent foaming of the solution, inject the solvent against the side of the
vial.

The vial must then be swirled with a gentle rotary motion until the contents are
completely dissolved in order to obtain a clear and colorless solution.
Since the powder mainly contains proteins, shaking or vigorous mixing is not
recommended. If after mixing, the solution is cloudy or contains particles, the
vial and its contents should be disposed of.
In case of cloudiness after refrigeration, the solution should be allowed to
warm up to room temperature (25°C). If cloudiness still persist or coloration
appears, dispose of the vial and its contents.
The solution should be used within 14 days after reconstitution if stored in a
refrigerator.
Any unused solution in the vial should be disposed of at the end of the 14-day
storage period.
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 medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Ferring Pharmaceuticals Ltd
Drayton Hall
Church Road
West Drayton
UB7 7PS

8.

MARKETING AUTHORISATION NUMBER
PL 03194/0052

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/08/2006

10

DATE OF REVISION OF THE TEXT
22/10/2012

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide
(web3)