Genotropin 5.3 Mg Powder And Solvent For Solution For Injection

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/m 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
Indication	mg/kg body weight dose per day	mg/m2 body surface area dose per day
Growth hormone deficiency in children	0.025 - 0.035	0.7 - 1.0
Prader-Willi syndrome in children	0.035	1.0
Turner syndrome	0.045 - 0.050	1.4
Chronic renal insufficiency	0.045 - 0.050	1.4
Children born small for gestational age	0.035	1.0

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 / IGFBP-3 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.

4.8 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.

Long-term Treatment of Children with Growth Disturbance due to insufficient secretion of growth hormone

System Organ Class	Very Common >1/10	Common >1/100 to <1/10	Uncommon Rare >1/1,000 to >1/10,000 to <1/100 <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)			Leukaemiaf
Metabolism and Nutrition Disorders					Type 2 diabetes mellitus
Nervous System Disorders					Paraesthesia¹ Benign intracranial hypertension
Musculoskeletal, Connective Tissue and Bone Disorders			Arthralgia¹		Myalgia¹ Musculoskeletal stiffness¹
General Disorders and Administration Site Conditions	Injection site reaction				Oedema peripheral¹
Investigations					Blood cortisol decreased¹

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)						Leukaemiaf
Metabolism and Nutrition Disorders						Type 2 diabetes mellitus
Nervous System Disorders						Paraesthesia² Benign intracranial hypertension
Musculoskeletal, Connective Tissue and Bone Disorders	Arthralgia²					Myalgia² Musculoskeletal stiffness²
General Disorders and Administration Site Conditions						Oedema peripheral² Injection site reaction
Investigations						Blood cortisol decreased¹

Table 3

Long-Term Treatment of Children with Growth Disturbance due to Chronic Renal Insufficiency

System Organ	Very	Common	Uncommon	Rare	Very	Not Known
Class	Common	>1/100 to	>1/1000 to	>1/10,000	Rare	(cannot be
	>1/10	<1/10	<1/100	to	<1/10,000	estimated from
				<1/1000		available data)
Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps)						Leukaemiaf
Metabolism and						Type 2 diabetes
Nutrition Disorders						mellitus
Nervous System						Paraesthesia³
Disorders						Benign intracranial hypertension
Musculoskeletal,						Arthralgia³
Connective						Myalgia³
Tissue, and Bone						Musculoskeletal
Disorders						stiffness³
General		Injection site				Oedema
Disorders and Administration Site Conditions		reaction^$				peripheral³
Investigations						Blood cortisol decreased¹

Long-term Treatment of Children with Growth Disturbance due to Born Small for Gestational Age

System Organ	Very	Common	Uncommon	Rare	Very	Not Known (cannot
Class	Common >1/10	>1/100 to <1/10	>1/1,000 to <1/100	>1/10,000 to <1/1,000	Rare <1/10,000	be estimated from available data)
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)						Leukaemiaf
Metabolism and						Type 2 diabetes
Nutrition Disorders						mellitus
Nervous System						Paraesthesia⁴
Disorders						Benign intracranial hypertension
Musculoskeletal,			Arthralgia⁴			Myalgia⁴
Connective Tissue and Bone Disorders						Musculoskeletal stiffness⁴
General		Injection				Oedema peripheral⁴
Disorders and		site
Administration		reaction^$

Site Conditions

Investigations Blood cortisol

decreased¹

Long-term Treatment and Improvement of Body Composition of Children with Growth Disturbance

due to Prader-Willi Syndrome

System Organ	Very	Common	Uncommon	Rare	Very	Not Known
Class	Common >1/10	>1/100 to <1/10	>1/1,000 to <1/100	>1/10,000 to <1/1,000	Rare <1/10,000	(cannot be estimated from available data)
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)						Leukaemiaf
Metabolism and						Type 2 diabetes
Nutrition Disorders						mellitus
Nervous System		Paraesthesia⁵
Disorders		Benign intracranial hypertension
Musculoskeletal,		Arthralgia⁵				Musculoskeletal
Connective Tissue and Bone Disorders		Myalgia⁵				stiffness⁵
General		Oedema				Injection site
Disorders and Administration Site Conditions		peripheral⁵				reaction^$
Investigations						Blood cortisol decreased¹

Replacement Therapy in Adults with Growth Hormone Deficiency

System Organ Class

Metabolism and

Nutrition

Disorders

Very

Common

Uncommon

Rare

Very

Not Known

Common

>1/10

>1/100 to <1/10

>1/1,000 to <1/100

>1/10,000 to <1/1,000

Rare

<1/10,000

(cannot be estimated from available data)

Type 2

diabetes

mellitus

Nervous System	Paraesthesia⁶
Disorders	Carpal Tunnel Syndrome
Musculoskeletal,	Arthralgia⁶ Myalgia⁶
Connective Tissue and Bone Disorders	Musculoskeletal stiffness⁶

Benign

intracranial

hypertension

Injection site reaction^$

General Oedema

Disorders and peripheral⁶

Administration Site Conditions

Investigations

Blood

cortisol

decreased¹

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, GZR-1368 Gzira, 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.

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 C_max and t_max 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

Powder: Front compartment	Solvent: Rear compartment
Glycine (E640), Sodium dihydrogen phosphate anhydrous (E339), Disodium phosphate anhydrous (E339), Mannitol (E421)	Water for injections, Metacresol, 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 2^oC -8^oC

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

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.