GENOTROPIN 5.3 MG POWDER AND SOLVENT FOR SOLUTION FOR INJECTION

Active substance: SOMATROPIN (RBE)

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
GENOTROPIN 5.3mg powder and solvent for solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
GENOTROPIN 5.3 mg powder and solvent for solution for injection, with
preservative. One cartridge contains 5.3 mg somatropin*. After reconstitution
the concentration of somatropin is 5.3 mg/ml.
* produced in Escherichia coli 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. In the two-chamber cartridge there is a
white powder in the front compartment and a clear solution in the rear compartment.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Children
Growth disturbance due to insufficient secretion of growth hormone (growth
hormone deficiency, GHD) and growth disturbance associated with Turner
syndrome or chronic renal insufficiency.
Growth disturbance [current height standard deviation score (SDS) < - 2.5
and parental adjusted height SDS < - 1] in short children born small for
gestational age (SGA), with a birth weight and/or length below - 2 SD, who
failed to show catch-up growth [height velocity (HV) SDS < 0 during the last
year] by 4 years of age or later.
Prader-Willi syndrome (PWS), for improvement of growth and body
composition. The diagnosis of PWS should be confirmed by appropriate
genetic testing.

Adults
Replacement therapy in adults with pronounced growth hormone deficiency.
Adult Onset: Patients who have severe growth hormone deficiency associated
with multiple hormone deficiencies as a result of known hypothalamic or
pituitary pathology, and who have at least one known deficiency of a pituitary
hormone not being prolactin. These patients should undergo an appropriate
dynamic test in order to diagnose or exclude a growth hormone deficiency.
Childhood Onset: Patients who were growth hormone deficient during
childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients with childhood onset GHD should be re-evaluated for growth
hormone secretory capacity after completion of longitudinal growth. In
patients with a high likelihood for persistent GHD, i.e. a congenital cause or
GHD secondary to a pituitary/hypothalamic disease or insult, an Insulin-like
Growth Factor-I (IGF-I) SDS < - 2 off growth hormone treatment for at least 4
weeks should be considered sufficient evidence of profound GHD.
All other patients will require IGF-I assay and one growth hormone
stimulation test.
4.2

Posology and method of administration
The dosage and administration schedule should be individualized.
The injection should be given subcutaneously and the site varied to prevent
lipoatrophy.
Growth disturbance due to insufficient secretion of growth hormone in
children: Generally a dose of 0.025 - 0.035 mg/kg body weight per day or 0.7
- 1.0 mg/m² body surface area per day is recommended. Even higher doses
have been used.
Where childhood onset GHD persists into adolescence, treatment should be
continued to achieve full somatic development (e.g. body composition, bone
mass). For monitoring, the attainment of a normal peak bone mass defined as a
T score > - 1 (i.e. standardized to average adult peak bone mass measured by
dual energy X-ray absorptiometry taking into account sex and ethnicity) is one
of the therapeutic objectives during the transition period. For guidance on
dosing see adult section below.
Prader-Willi syndrome, for improvement of growth and body composition in
children: Generally a dose of 0.035 mg/kg body weight per day or 1.0 mg/m2
body surface area per day is recommended. Daily doses of 2.7 mg should not
be exceeded. Treatment should not be used in children with a growth velocity
of less than 1 cm per year and near closure of epiphyses.
Growth disturbance due to Turner syndrome: A dose of 0.045 - 0.050 mg/kg
body weight per day or 1.4 mg/m² body surface area per day is recommended.

Growth disturbance in chronic renal insufficiency: A dose of 0.045 - 0.050
mg/kg body weight per day (1.4 mg/m² body surface area per day) is
recommended. Higher doses can be needed if growth velocity is too low. A
dose correction can be needed after six months of treatment.
Growth disturbance in short children born small for gestational age: A dose
of 0.035 mg/kg body weight per day (1 mg/m² body surface area per day) is
usually recommended until final height is reached (see section 5.1). Treatment
should be discontinued after the first year of treatment if the height velocity
SDS is below + 1. Treatment should be discontinued if height velocity is < 2
cm/year and, if confirmation is required, bone age is > 14 years (girls) or > 16
years (boys), corresponding to closure of the epiphyseal growth plates.
Dosage recommendations in Pediatric Patients
mg/kg body weight
mg/m² body surface area
Indication
dose per day
dose per day
Growth hormone
0.025 - 0.035
0.7 - 1.0
deficiency in children
Prader-Willi
0.035
1.0
syndrome in children
Turner syndrome
0.045 - 0.050
1.4
Chronic renal
0.045 - 0.050
1.4
insufficiency
Children born small
0.035
1.0
for gestational age
Growth hormone deficient adult patients: In patients who continue growth
hormone therapy after childhood GHD, the recommended dose to restart is 0.2
– 0.5 mg per day. The dose should be gradually increased or decreased
according to individual patient requirements as determined by the IGF-I
concentration.
In patients with adult-onset GHD, therapy should start with a low dose, 0.15 –
0.3 mg per day. The dose should be gradually increased according to
individual patient requirements as determined by the IGF-I concentration.
In both cases treatment goal should be IGF-I concentrations within 2 SDS
from the age corrected mean. Patients with normal IGF-I concentrations at the
start of the treatment should be administered growth hormone up to an IGF-I
level into upper range of normal, not exceeding the 2 SDS. Clinical response
and side effects may also be used as guidance for dose titration. It is
recognised that there are patients with GHD who do not normalize IGF-I
levels despite a good clinical response, and thus do not require dose escalation.
The maintenance dose seldom exceeds 1.0 mg per day. Women may require
higher doses than men, with men showing an increasing IGF-I sensitivity over
time. This means that there is a risk that women, especially those on oral
oestrogen replacement are under-treated while men are over-treated. The
accuracy of the growth hormone dose should therefore be controlled every 6
months. As normal physiological growth hormone production decreases with

age, dose requirements are reduced. In patients above 60 years, therapy should
start with a dose of 0.1 - 0.2 mg per day and should be slowly increased
according to individual patient requirements. The minimum effective dose
should be used. The maintenance dose in these patients seldom exceeds 0.5
mg per day.
4.3

Contraindications

Hypersensitivity to the active substance 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 antitumour therapy must be completed prior
to starting growth hormone therapy. Treatment should be discontinued if there is
evidence of tumour growth.
GENOTROPIN 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 GENOTROPIN(regarding patients
undergoing substitution therapy, see section 4.4).
4.4

Special warnings and precautions for use

Diagnosis and therapy with GENOTROPIN should be initiated and monitored by
physicians who are appropriately qualified and experienced in the diagnosis and
management of patients with the therapeutic indication of use.

Myositis is a very rare adverse event that may be related to the preservative
metacresol. In the case of myalgia or disproportionate pain at injection site, myositis
should be considered and if confirmed, a GENOTROPIN presentation without
metacresol should be used.
The maximum recommended daily dose should not be exceeded (see section 4.2).
Insulin sensitivity
Somatropin may reduce insulin sensitivity. For patients with diabetes mellitus, the
insulin dose may require adjustment after somatropin therapy is instituted. Patients
with diabetes, glucose intolerance, or additional risk factors for diabetes should be
monitored closely during somatropin therapy.
Thyroid function
Growth hormone increases the extrathyroidal conversion of T4 to T3 which may
result in a reduction in serum T4 and an increase in serum T3 concentrations.
Whereas the peripheral thyroid hormone levels have remained within the reference
ranges in the majority of healthy subjects, hypothyroidism theoretically may develop
in subjects with subclinical hypothyroidism. Consequently, monitoring of thyroid

function should therefore be conducted in all patients. In patients with
hypopituitarism on standard replacement therapy, the potential effect of growth
hormone treatment on thyroid function must be closely monitored.
In growth hormone deficiency secondary to treatment of malignant disease, it is
recommended to pay attention to signs of relapse of the malignancy. 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.
In patients with endocrine disorders, including growth hormone deficiency, slipped
epiphyses of the hip may occur more frequently than in the general population.
Children limping during treatment with somatropin, should be examined clinically.
Benign intracranial hypertension
In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a
funduscopy 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
insufficient evidence to give specific advice on the continuation of growth hormone
treatment in patients with resolved intracranial hypertension. If growth hormone
treatment is restarted, careful monitoring for symptoms of intracranial hypertension is
necessary.
Leukaemia
Leukaemia has been reported in a small number of growth hormone deficiency
patients, some of whom have been treated with somatropin. However, there is no
evidence that leukaemia incidence is increased in growth hormone recipients without
predisposition factors.
Antibodies
As with all somatropin containing products, a small percentage of patients may
develop antibodies to GENOTROPIN. GENOTROPIN has given rise to the
formation of antibodies in approximately 1% of patients. 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 with otherwise unexplained lack of
response.
Elderly patients
Experience in patients above 80 years is limited. Elderly patients may be more
sensitive to the action of GENOTROPIN, and therefore may be more prone to
develop adverse reactions.
Acute critical illness
The effects of GENOTROPIN 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 in patients treated with 5.3 or 8 mg GENOTROPIN
daily compared to patients receiving placebo, 42% vs. 19%. Based on this
information, these types of patients should not be treated with GENOTROPIN. 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 Genotropin must be weighed against the potential risk involved.
Pancreatitis
Although rare, pancreatitis should be considered in somatropin-treated patients,
especially children who develop abdominal pain.
Prader-Willi syndrome
In patients with Prader-Willi syndrome, treatment should always be in combination
with a calorie-restricted diet.
There have been reports of fatalities associated with the use of growth hormone in
pediatric patients with Prader-Willi syndromewho had one or more of the following
risk factors: severe obesity (those patients exceeding a weight/height of 200 %),
history of respiratory impairment or sleep apnoea, or unidentified respiratory
infection. Patients with one or more of these factors may be at increased risk.
Before initiation of treatment with somatropin in patients with Prader-Willi
syndrome, signs for upper airway obstruction, sleep apnoea, or respiratory infections
should be assessed.
If during the evaluation of upper airway obstruction, pathological findings are
observed, the child should be referred to an Ear, nose and throat (ENT) specialist for
treatment and resolution of the respiratory disorder prior to initiating growth hormone
treatment.
Sleep apnoea should be assessed before onset of growth hormone treatment by
recognised methods such as polysomnography or overnight oxymetry, and monitored
if sleep apnoea is suspected.
If during treatment with somatropin patients show signs of upper airway obstruction
(including onset of or increased snoring), treatment should be interrupted, and a new
ENT assessment performed.
All patients with Prader-Willi syndromeshould be monitored if sleep apnoea is
suspected.
Patients should be monitored for signs of respiratory infections, which should be
diagnosed as early as possible and treated aggressively.
All patients with Prader-Willi syndromeshould also have effective weight control
before and during growth hormone treatment.
Scoliosis is common in patients with Prader-Willi syndrome. Scoliosis may progress
in any child during rapid growth. Signs of scoliosis should be monitored during
treatment.
Experience with prolonged treatment in adults and in patients with Prader-Willi
syndrome is limited.
Small for gestational age
In short children born SGA other medical reasons or treatments that could explain
growth disturbance should be ruled out before starting treatment.

In SGA children it is recommended to measure fasting insulin and blood glucose
before start of treatment and annually thereafter. In patients with increased risk for
diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance,
acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If
overt diabetes occurs, growth hormone should not be administered.
In SGA children it is recommended to measure the IGF-I level before start of
treatment and twice a year thereafter. If on repeated measurements IGF-I levels
exceed +2 SD compared to references for age and pubertal status, the IGF-I / IGFBP3 ratio could be taken into account to consider dose adjustment.
Experience in initiating treatment in SGA patients near onset of puberty is limited. It
is therefore not recommended to initiate treatment near onset of puberty. Experience
in patients with Silver-Russell syndrome is limited.
Some of the height gain obtained with treating short children born SGA with growth
hormone may be lost if treatment is stopped before final height is reached.
Chronic renal insufficiency
In chronic renal insufficiency, renal function should be below 50 percent of normal
before institution of therapy. To verify growth disturbance, growth should be
followed for a year preceding institution of therapy. During this period, conservative
treatment for renal insufficiency (which includes control of acidosis,
hyperparathyroidism and nutritional status) should have been established and should
be maintained during treatment. The treatment should be discontinued at renal
transplantation.
To date, no data on final height in patients with chronic renal insufficiency treated
with Genotropin are available.

4.5

Interaction with other medicinal products and other forms of interaction
Concomitant treatment with glucocorticoids may inhibit the growth-promoting
effects of somatropin containing products. Therefore, patients treated with
glucocorticoids should have their growth monitored carefully to assess the
potential impact of glucocorticoid treatment on growth.
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 ciclosporin) may be especially
increased resulting in lower plasma levels of these compounds. The clinical
significance of this is unknown.
Also see section 4.4 for statements regarding diabetes mellitus and thyroid
disorder and section 4.2 for statement on oral oestrogen replacement therapy.

4.6

Pregnancy and lactation

Pregnancy

Animal studies are insufficient with regard to effects on pregnancy, embryofoetal
development, parturition or postnatal development (See section 5.3). No clinical
studies on exposed pregnancies are available. Therefore, somatropin containing
products are not recommended during pregnancy and in women of childbearing
potential not using contraception.
Lactation
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,
but absorption of intact protein from the gastrointestinal tract of the infant is
extremely unlikely. 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
GENOTROPIN has no influence on the ability to drive and use machines.

Undesirable effects

Patients with growth hormone deficiency are characterized by extracellular volume
deficit. When treatment with somatropin is started this deficit is rapidly corrected. In
adult patients adverse effects related to fluid retention, such as oedema peripheral,
musculoskeletal stiffness, arthralgia, myalgia and paraesthesia are common. In
general these adverse effects are mild to moderate, arise within the first months of
treatment and subside spontaneously or with dose-reduction.
The incidence of these adverse effects is related to the administered dose, the age of
patients, and possibly inversely related to the age of patients at the onset of growth
hormone deficiency. In children such adverse effects are uncommon.
Genotropin 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, see section 4.4.
Tabulated list of adverse reactions
Tables 1-6 show the adverse reactions ranked under headings of System Organ Class
and frequency using the following convention: very common ( 1/10); 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) for
each of the indicated conditions.









4.8

Clinical Trials in Children with GHD
Table 1
Long-term Treatment of Children with Growth Disturbance due to insufficient secretion of growth
hormone
System Organ
Class

Very
Common
≥1/10

Common

Uncommon

Rare

≥1/100 to
<1/10

≥1/1,000 to
<1/100

≥1/10,000 to
<1/1,000

Very
Rare
<1/10,000

Not Known
(cannot be
estimated from
available data)

Leukaemia†

Neoplasms
Benign,
Malignant and
Unspecified
(including cysts
and polyps)
Metabolism and
Nutrition
Disorders

Type 2 diabetes
mellitus

Nervous System
Disorders

Paraesthesia*
Benign
intracranial
hypertension
Arthralgia*

Musculoskeletal,
Connective
Tissue and Bone
Disorders
General
Disorders and
Administration
Site Conditions

Myalgia*
Musculoskeletal
stiffness*

Injection
site
reaction$

Investigations

Oedema
peripheral*

Blood cortisol
decreased‡

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside
spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered
dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth
hormone deficiency.
$ Transient injection site reactions in children have been reported.
‡ Clinical significance is unknown
† Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be
similar to that in children without growth hormone deficiency.

Clinical Trials in children with Turner Syndrome
Table 2
Long-term Treatment of Children with Growth Disturbance due to Turner syndrome
System Organ
Class

Very
Common
≥1/10

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
available data)

Neoplasms
Benign,
Malignant and
Unspecified
(including cysts
and polyps)

Leukaemia†

Metabolism and
Nutrition
Disorders

Type 2 diabetes
mellitus

Nervous System
Disorders

Paraesthesia*

Musculoskeletal,
Connective
Tissue and Bone
Disorders

Benign
intracranial
hypertension
Arthralgia*

Myalgia*
Musculoskeletal
stiffness*

General
Disorders and
Administration
Site Conditions

Oedema
peripheral*

Investigations

Blood cortisol
decreased‡

Injection site
reaction$

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside
spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered
dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth
hormone deficiency.
$ Transient injection site reactions in children have been reported.
‡ Clinical significance is unknown
† Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be
similar to that in children without growth hormone deficiency.

Clinical Trials in Children with Chronic Renal Insufficiency
Table 3
Long-Term Treatment of Children with Growth Disturbance due to Chronic Renal Insufficiency
System Organ
Class

Very
Common
≥1/10

Common
≥1/100 to
<1/10

Neoplasms
Benign,
Malignant, and
Unspecified
(including cysts
and polyps)

Uncommon
≥1/1000 to
<1/100

Rare
≥1/10,000
to
<1/1000

Very
Rare
<1/10,000

Not Known
(cannot be
estimated from
available data)
Leukaemia†

Metabolism and
Nutrition
Disorders

Type 2 diabetes
mellitus

Nervous System
Disorders

Paraesthesia*
Benign
intracranial
hypertension

Musculoskeletal,
Connective
Tissue, and Bone
Disorders

Arthralgia*
Myalgia*
Musculoskeletal
stiffness*

General
Disorders and
Administration
Site Conditions
Investigations

Injection site
reaction$

Oedema
peripheral*

Blood cortisol
decreased‡
*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside
spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered
dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth
hormone deficiency.
$ Transient injection site reactions in children have been reported.
‡ Clinical significance is unknown.
† Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be
similar to that in children without growth hormone deficiency.

Clinical Trials in children with SGA
Table 4
Long-term Treatment of Children with Growth Disturbance due to Born Small for Gestational Age
System Organ
Class

Very
Common
≥1/10

Common

Uncommon

Rare

≥1/100 to
<1/10

≥1/1,000 to
<1/100

≥1/10,000
to
<1/1,000

Very
Rare
<1/10,000

Not Known (cannot
be estimated from
available data)

Neoplasms
Benign,
Malignant and
Unspecified
(including cysts
and polyps)

Leukaemia†

Metabolism and
Nutrition
Disorders

Type 2 diabetes
mellitus

Nervous System
Disorders

Paraesthesia*
Benign intracranial
hypertension

Musculoskeletal,
Connective
Tissue and Bone
Disorders
General
Disorders and
Administration
Site Conditions

Arthralgia*

Myalgia*
Musculoskeletal
stiffness*

Injection
site
reaction$

Investigations

Oedema peripheral*

Blood cortisol
decreased‡

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside
spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered
dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth
hormone deficiency.
$ Transient injection site reactions in children have been reported.
‡ Clinical significance is unknown
† Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be
similar to that in children without growth hormone deficiency.

Clinical Trials in PWS
Table 5
Long-term Treatment and Improvement of Body Composition of Children with Growth Disturbance
due to Prader-Willi Syndrome
System Organ
Class

Very
Common

Common

Rare

≥1/100 to
<1/10

≥1/10

Uncommon
≥1/1,000 to
<1/100

≥1/10,000
to
<1/1,000

Very
Rare
<1/10,000

Not Known
(cannot be
estimated from
available data)

Neoplasms
Benign,
Malignant and
Unspecified
(including cysts
and polyps)

Leukaemia†

Metabolism and
Nutrition
Disorders

Type 2 diabetes
mellitus

Nervous System
Disorders

Paraesthesia*

Musculoskeletal,
Connective
Tissue and Bone
Disorders

Arthralgia*

General
Disorders and
Administration
Site Conditions

Oedema
peripheral*

Benign
intracranial
hypertension

Myalgia*

Investigations

Musculoskeletal
stiffness*

Injection site
reaction$

Blood cortisol
decreased‡

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside
spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered
dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth
hormone deficiency.
$ Transient injection site reactions in children have been reported.
‡ Clinical significance is unknown
† Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be
similar to that in children without growth hormone deficiency.

Clinical Trials in Adults with GHD
Table 6
Replacement Therapy in Adults with Growth Hormone Deficiency
System Organ
Class

Very
Common
≥1/10

Common

Uncommon

Rare

≥1/100 to <1/10

≥1/1,000 to
<1/100

≥1/10,000
to <1/1,000

Not Known
(cannot be
estimated
from
available
data)

Very
Rare
<1/10,000

Type 2
diabetes
mellitus

Metabolism and
Nutrition
Disorders
Nervous System
Disorders

Paraesthesia*
Carpal Tunnel
Syndrome

Musculoskeletal,
Connective
Tissue and Bone
Disorders

Arthralgia*

General
Disorders and
Administration
Site Conditions

Oedema
peripheral*

Benign
intracranial
hypertension

Myalgia*
Musculoskeletal
stiffness*

Investigations

Injection site
reaction$

Blood
cortisol
decreased‡

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside
spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered
dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth
hormone deficiency.
$ Transient injection site reactions in children have been reported.
‡ Clinical significance is unknown

Reduced serum cortisol levels
Somatropin has been reported to reduce serum cortisol levels, possibly by affecting
carrier proteins or by increased hepatic clearance. The clinical relevance of these
findings may be limited. Nevertheless, corticosteroid replacement therapy should be
optimised before initiation of GENOTROPIN therapy.
Prader-Willi syndrome
In the post-marketing experience rare cases of sudden death have been reported in
patients affected by Prader-Willi syndrome treated with somatropin, although no
causal relationship has been demonstrated.
Leukaemia

Cases of leukaemia (rare or very rare) have been reported in children with a GH
deficiency, some of whom were treated with somatropin and included in the postmarketing experience. However, there is no evidence of an increased risk of
leukaemia without predisposition factors, such as radiation to the brain or head.
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease
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. Their diagnosis
should be considered in a child with a discomfort or pain in the hip or knee.
Other adverse drug reactions
Other adverse drug reactions may be considered somatropin class effects, such as
possible hyperglycaemia caused by decreased insulin sensitivity, decreased free
thyroxin level and benign intra-cranial hypertension.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard
Malta
Healthcare professionals are asked to report any suspected adverse reactions via ADR
Reporting, The Medicines Authority , Post-Licensing Directorate, 203 Level 3, Rue,
D'Argens, GŻR-1368 Gżira, Website: www.medicinesauthority.gov.mt, e-mail:
postlicensing.medicinesauthority@gov.mt

4.9

Overdose
Symptoms:
Acute overdosage could lead initially to hypoglycaemia and subsequently to
hyperglycaemia.
Long-term overdosage could result in signs and symptoms consistent with the
known effects of human growth hormone excess.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Anterior pituitary lobe hormones and analogues,
ATC code: H01A C01
Somatropin is a potent metabolic hormone of importance for the metabolism
of lipids, carbohydrates and proteins. In children with inadequate endogenous
growth hormone, somatropin stimulates linear growth and increases growth
rate. In adults, as well as in children, somatropin maintains a normal body
composition by increasing nitrogen retention and stimulation of skeletal
muscle growth, and by mobilization of body fat. Visceral adipose tissue is
particularly responsive to somatropin. In addition to enhanced lipolysis,
somatropin decreases the uptake of triglycerides into body fat stores. Serum
concentrations of IGF-I and IGFBP3 (Insulin-like Growth Factor Binding
Protein 3) are increased by somatropin. In addition, the following actions have
been demonstrated:
-

-

-

-

Lipid metabolism: Somatropin induces hepatic LDL cholesterol receptors, and
affects the profile of serum lipids and lipoproteins. In general, administration
of somatropin to growth hormone deficient patients results in reductions in
serum LDL and apolipoprotein B. A reduction in serum total cholesterol may
also be observed.
Carbohydrate metabolism: Somatropin increases insulin but fasting blood
glucose is commonly unchanged. Children with hypopituitarism may
experience fasting hypoglycemia. This condition is reversed by somatropin.
Water and mineral metabolism: Growth hormone deficiency is associated with
decreased plasma and extracellular volumes. Both are rapidly increased after
treatment with somatropin. Somatropin induces the retention of sodium,
potassium and phosphorus.
Bone metabolism: Somatropin stimulates the turnover of skeletal bone. Longterm administration of somatropin to growth hormone deficient patients with
osteopenia results in an increase in bone mineral content and density at
weight-bearing sites.
Physical capacity: Muscle strength and physical exercise capacity are
improved after long-term treatment with somatropin. Somatropin also
increases cardiac output, but the mechanism has yet to be clarified. A decrease
in peripheral vascular resistance may contribute to this effect.
In clinical trials in short children born SGA doses of 0.033 and 0.067 mg/kg
body weight per day have been used for treatment until final height. In 56
patients who were continuously treated and have reached (near) final height,
the mean change from height at start of treatment was +1.90 SDS (0.033
mg/kg body weight per day) and +2.19 SDS (0.067 mg/kg body weight per
day). Literature data from untreated SGA children without early spontaneous
catch-up suggest a late growth of 0.5 SDS. Long-term safety data are still
limited.

5.2

Pharmacokinetic properties

Absorption
The bioavailability of subcutaneously administered somatropin is approximately 80
% in both healthy subjects and growth hormone deficient patients. A subcutaneous
dose of 0.035 mg/kg of somatropin results in plasma Cmax and tmax values in the range
of 13-35 ng/ml and 3-6 hours respectively.
Elimination
The mean terminal half-life of somatropin after intravenous administration in growth
hormone deficient adults is about 0.4 hours. However, after subcutaneous
administration, half-lives of 2-3 hours are achieved. The observed difference is likely
due to slow absorption from the injection site following subcutaneous administration.
Sub-populations
The absolute bioavailability of somatropin seems to be similar in males and females
following s.c. administration.
Information about the pharmacokinetics of somatropin in geriatric and paediatric
populations, in different races and in patients with renal, hepatic or cardiac
insufficiency is either lacking or incomplete.

5.3

Preclinical safety data
In studies regarding general toxicity, local tolerance and reproduction toxicity no
clinically relevant effects have been observed.
In vitro and in vivo genotoxicity studies on gene mutations and induction of
chromosome aberrations have been negative.
An increased chromosome fragility has been observed in one in-vitro study on
lymphocytes taken from patients after long term treatment with somatropin and
following the addition of the radiomimetic drug bleomycin.The clinical significance
of this finding is unclear.
In another study, no increase in chromosomal abnormalities was found in the
lymphocytes of patients who had received long term somatropin therapy.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Powder: Front compartment
Solvent: Rear compartment
Glycine (E640), Sodium
Water for injections,
dihydrogen phosphate anhydrous
Metacresol, Mannitol (E421)
(E339), Disodium phosphate
anhydrous (E339), Mannitol (E421)

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
Chemical and physical in-use stability has been demonstrated for 4 weeks at 2oC –
8oC
From a microbiological point of view, once reconstituted, the product may be stored
for 4 weeks at 2°C - 8°C.
Other in-use storage times and conditions are the responsibility of the user.

6.4

Special precautions for storage
Before reconstitution:
Store in a refrigerator (2°C – 8°C), or for a maximum of 1 month at or below 25°C.
Keep the two-chamber cartridge/pre-filled pen in the outer carton in order to protect
from light.
After reconstitution:
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the two-chamber
cartridge/pre-filled penin the outer carton in order to protect from light. For storage
conditions of the reconstituted medicinal product, see section 6.3.

6.5

Nature and contents of container
Powder and 1 ml solvent in a two-chamber glass cartridge (type I glass) separated by
a rubber plunger (bromobutyl). The cartridge is sealed at one end with a rubber disc
(bromobutyl) and an aluminium cap and at the other end by a rubber stopper
(bromobutyl). The two-chamber cartridge is supplied for use in a re-usable injection
device GENOTROPIN Pen, or reconstitution device, GENOTROPIN Mixer or sealed
in a disposable multidose pre-filled pen, GoQuick.
The GENOTROPIN Pens are colour coded, and must be used with the matching
colour coded GENOTROPIN two-chamber cartridge to give the correct dose. The
GENOTROPIN Pen 5.3 (blue) must be used with GENOTROPIN 5.3 mg cartridge
(blue).
The 5.3 mg pre-filled pen GoQuick is colour coded blue.
1x5.3 mg, 5x5.3 mg, 1x5.3 mg pre-filled pen, 5x5.3 mg pre-filled pens
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
Only reconstitute the powder with the solvent supplied.
Two-chamber cartridge:The solution is prepared by screwing the reconstitution
device or injection device or GoQuick pre-filled pen sections together so that the
solvent will be mixed with the powder in the two chamber cartridge. Gently dissolve
the powder with a slow, swirling motion. Do not shake vigorously, this might cause
denaturation of the active substance. The reconstituted solution is almost colourless or
slightly opalescent. The reconstituted solution for injection is to be inspected prior to
use and only clear solutions without particles should be used.
Comprehensive instructions for the preparation and administration of the
reconstituted Genotropin product are given in the package leaflet, section 3,
“Injecting genotropin” and in the relevant Instructions for Use provided with the
device being used.
When using an injection device the injection needle should be screwed on before
reconstitution.
Disposal instructions: Any unused product or waste material should be disposed of in
accordance with local requirements. Empty GoQuick pre-filled pens should never be
refilled and must be properly discarded.

7

MARKETING AUTHORISATION HOLDER
Pfizer Limited
Ramsgate Road,
Sandwich,
Kent CT13 9NJ, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 00057/0987

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
1 February 1995/ 21 April 2010

10

DATE OF REVISION OF THE TEXT
12/09/2014

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.

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