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Somatropin Biopartners (somatropin) – Summary of product characteristics - H01AC01

Updated on site: 10-Oct-2017

Medication nameSomatropin Biopartners
ATC CodeH01AC01
Substancesomatropin
ManufacturerBioPartners GmbH

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1.NAME OF THE MEDICINAL PRODUCT

Somatropin Biopartners 2 mg powder and solvent for prolonged-release suspension for injection

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial delivers 2 mg of somatropin* (corresponding to 6 IU).

After reconstitution, 0.2 mL of suspension contains 2 mg somatropin (10 mg/mL).

*produced in Saccharomyces cerevisiae by recombinant DNA technology

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

White or almost white powder. The solvent is a clear, oily liquid.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Somatropin Biopartners is indicated for the replacement therapy of endogenous growth hormone in adults with childhood- or adult-onset growth hormone deficiency (GHD).

Adult-onset: Patients with GHD in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one additional known deficiency of a pituitary hormone excluding prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a GHD.

Childhood-onset: In patients with childhood-onset isolated GHD (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be performed after completion of growth, except for those having low insulin-like growth factor-I (IGF-I) concentrations (< -2 standard deviation score (SDS)), who may be considered for one test. The cut-off point of the dynamic test should be strict.

4.2Posology and method of administration

Diagnosis and therapy with this medicinal product should be initiated and monitored by physicians adequately experienced in the diagnosis and management of patients with GHD.

Posology

Somatropin Biopartners should be administered subcutaneously at a concentration of 10 mg/mL.

Starting dose

Generally, 2 mg once a week for all patients apart from female patients receiving oral oestrogen therapy who should receive 3 mg once a week. In older or overweight patients, lower doses may be necessary.

Gender

Starting dose

Male

2 mg (6 IU)

Female (not on oral oestrogen)

2 mg (6 IU)

Female (on oral oestrogen)

3 mg (9 IU)

Dose adjustment

Initially, patients should have their IGF-I levels assessed at 3- to 4-weekly intervals until IGF-I SDS is in the target range of -0.5 to +1.5. Samples should be drawn 4 days after the previous dose (Day 4). Repeated adjustments in dose may be required, dependent on patients’ IGF-I response. IGF-I levels should be acted upon, as indicated below.

IGF-I SDS

Action on

Dose change at a time

previous dose

 

 

IGF-I SDS lower than -1

Increase

+1.5 mg (female on oral oestrogen)

+1.0 mg (all other patients)

 

 

IGF-I SDS in the range of -1 to +1 and

Increase

+1.5 mg (female on oral oestrogen)

less than 1SDS increase from Baseline

+1.0 mg (all other patients)

 

IGF-I SDS in the range of -1 to +1 and

Maintain

None

more than 1 SDS increase from Baseline

 

 

 

Maintain or

 

IGF-I SDS in the range of +1 to +2

decrease

None or -0.5 mg (all patients)

depending on

 

 

 

clinical status

 

IGF-I SDS greater than +2

Decrease

-0.5 mg (all patients)

 

 

 

IGF-I = insulin-like growth factor-I, SDS = standard deviation score.

Conversion from required dose to injection volume and vial strength

Somatropin dose

vials and solvent required for preparation of

Injection volume

(mg)

one dose*

(mL)

one 2-mg vial reconstituted

0.1

1.5

0.15

with 0.4 mL solvent

0.2

 

* Each vial contains an

overfill of somatropin powder to allow the withdrawal of the required amount

of somatropin when reconstituted (see section 6.6).

 

For other doses vials with 4 or 7 mg somatropin are available.

 

The minimum effective dose should be used. The treatment goal should be IGF-I concentrations within -0.5 and +1.5 SDS of the age corrected mean.

In order to reach the defined treatment goal, men may need lower growth hormone doses than women. Oral oestrogen administration increases the dose requirements in women. An increasing sensitivity to growth hormone (expressed as change in IGF-I per growth hormone dose) over time may be observed, particularly in men. The accuracy of the growth hormone dose should therefore be controlled every

6 months.

The dosage of somatropin should be decreased in cases of persistent oedema or severe paraesthesia, in order to avoid the development of carpal tunnel syndrome.

The dose may be reduced in steps of 0.5 mg at a time. If the symptoms leading to the dose reduction disappear, at the judgment of the physician, the dose may be maintained at the decreased level or increased according to the dose adjustment scheme described above. If the symptom reappears after the dose increase, then the dose should be maintained at the previous lower dose.

Special populations

Older people

Experience with somatropin treatment in patients above 60 years of age is limited. Dose requirements may decline with increasing age.

Renal/hepatic impairment

No information in patients with renal or hepatic impairment is available and particular dose recommendations cannot be given.

Paediatric population

There is no relevant use of Somatropin Biopartners 2 mg in the paediatric population in the indication of long-term treatment of growth failure due to insufficient secretion of endogenous growth hormone. For the treatment of children and adolescents aged 2 to 18 years the 10 mg and 20 mg vials of this medicinal product should be used.

Method of administration

The patient or carer should receive training to ensure understanding of the administration procedure before being allowed to (self-) inject.

Somatropin Biopartners is administered subcutaneously once a week. After reconstitution the injection should be administered immediately.

The subcutaneous injection should always be administered at the same time of the day to increase compliance and the site of injection must be varied to prevent lipoatrophy.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somatropin must not be used when there is any evidence of tumour activity. Intracranial tumours must be inactive and antitumour therapy must be completed prior to the initiation of growth hormone therapy. Treatment should be discontinued if there is evidence of tumour (re)growth.

Somatropin treatment must not be started in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure or similar conditions.

4.4Special warnings and precautions for use

Malignancies

Patients with prior malignancies should be examined routinely for progression or recurrence.

Benign intracranial hypertension

In cases of severe or recurrent headache, visual problems, nausea, and/or vomiting, a fundoscopy 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 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.

Insulin sensitivity

Because human growth hormone (hGH) may induce a state of insulin resistance and hyperglycaemia, patients treated with this medicinal product should be monitored for evidence of glucose intolerance. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin treatment is initiated. 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. Hypothyroidism may develop in patients with central subclinical hypothyroidism after initiating therapy with growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to somatropin.

In patients with hypopituitarism receiving thyroxin replacement therapy, hyperpituitarism may develop. Thyroid function should therefore be closely monitored in all patients.

Adrenal function

Treatment with growth hormone may facilitate the development of adrenal insufficiency and potentially fatal adrenal crises in patients with organic GHD or idiopathic panhypopituitarism. It is therefore crucial to assess baseline and stress doses of glucocorticoids which may need to be adjusted when growth hormone therapy is initiated.

Adults with childhood-onset of GHD

Young adult patients with closed epiphyses who have previously been treated as children for GHD should be re-evaluated for GHD using the criteria for adult patients (see section 4.1) before replacement therapy is commenced at the doses recommended for adults.

Other precautions

This medicinal product is not indicated for the treatment of patients with growth failure due to Prader-Willi syndrome unless they also have a diagnosis of GHD. There have been reports of sleep apnoea and sudden death after initiating growth hormone therapy in 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.

After accidental intramuscular injection, hypoglycaemia may occur.

Antibodies

Some patients may develop antibodies to this medicinal product. Somatropin Biopartners has given rise to the formation of antibodies in approximately 4% of adult patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.

4.5Interaction with other medicinal products and other forms of interaction

Excessive glucocorticoid therapy can inhibit the actions of hGH. Patients receiving concomitant glucocorticoid therapy should have their dose carefully adjusted.

Growth hormone increases the extrathyroidal conversion of thyroxin (T4) to triiodothyronine (T3) and may unmask central hypothyroidism. Thyroxine replacement therapy may therefore need to be initiated or adjusted.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective. In women taking oral oestrogens, a higher dose of somatropin may be required to achieve the treatment goal, see section 4.2.

Patients taking insulin for diabetes mellitus should be carefully monitored during treatment with somatropin. Because hGH may induce a state of insulin resistance, an adjustment of the insulin dose may be required.

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 cyclosporine) may be increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6Fertility, pregnancy and lactation

Women of childbearing potential

Somatropin Biopartners is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no data on the use of this medicinal product in pregnant women. Very limited data on exposure to other somatropin preparations during early pregnancy did not indicate an adverse pregnancy outcome. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

During normal pregnancy, levels of pituitary growth hormone fall markedly after 20 weeks of gestation, being replaced almost entirely by placental growth hormone by 30 weeks. In view of this, it is unlikely that continued replacement therapy with somatropin would be necessary in growth hormone deficient women in the third trimester of pregnancy. Somatropin Biopartners is not recommended during pregnancy.

Breast-feeding

No clinical studies have been conducted with Somatropin Biopartners in breast-feeding women. It is unknown whether somatropin or its metabolites are excreted in human breast milk; however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely. Caution should be exercised when this medicinal product is administered to breast-feeding women.

Fertility

Animal studies with other somatropin formulations have shown adverse effects but the available nonclinical data are considered insufficient to draw firm conclusions on the use in humans (see section 5.3).

4.7Effects on ability to drive and use machines

Somatropin has no or negligible influence on the ability to drive and use machines.

4.8Undesirable effects

Summary of the safety profile

Clinical trials included approximately 530 patients treated with Somatropin Biopartners. When adverse reactions occurred, they tended to be transient and severity was generally mild to moderate. The safety profile of Somatropin Biopartners is generally consistent with the well known safety profile of daily growth hormone treatments. The adverse reactions most commonly reported were injection site related reactions, peripheral oedema, headache, myalgia, arthralgia, paraesthesia, hypothyroidism and decreased free thyroxine.

Tabulated list of adverse reactions

The following adverse reactions have been observed under treatment with Somatropin Biopartners in a 6-month controlled clinical study with 151 adult patients with GHD of adult- or childhood-onset and in a 6-month extension study. Additional reports based on published information for daily growth hormone treatments are listed with asterisks.

The frequency of adverse reactions listed below is defined 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), not known (cannot be estimated from the available data):

Infections and infestations

Common: Herpes simplex

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: Neoplasm progression (1 case of neoplasm progression in a female patient with a history of neurofibromatosis and radiation treatment), acrochordon, craniopharyngioma

Blood and the lymphatic system disorders

Common: Decreased or increased white blood cell count, increased glycosylated haemoglobin, decreased haemoglobin

Immune system disorders

Common: Formation of antibodies against growth hormone

Endocrine disorders

Common: Adrenal insufficiency, decreased free thyroxine, decreased free tri-iodothyronine, increased blood TSH, hypothyroidism*

Metabolism and nutrition disorders

Very common: Mild hyperglycaemia*

Common: Impaired fasting glucose, hyperlipidaemia, increased blood insulin, increased blood cholesterol, decreased blood sodium, increased blood triglycerides, increased blood glucose, increased or decreased HDL, increased LDL

Not known: Insulin resistance*

Psychiatric disorders

Common: Insomnia

Nervous system disorders

Very common: Headache

Common: Paraesthesia, hypoaesthesia, carpal tunnel syndrome, dizziness, somnolence Rare: Benign intracranial hypertension*

Eye disorders

Common: Conjunctivitis, visual acuity reduced

Ear and labyrinth disorders

Common: Vertigo

Cardiac disorders

Common: Tachycardia, heart rate abnormal/irregular

Vascular disorders

Common: Hypertension,increased blood pressure

Respiratory, thoracic and mediastinal disorders

Common: Epistaxis

Gastrointestinal disorders

Common: Nausea

Hepatobiliary disorders

Common: Hyperbilirubinaemia, cholecystitis, liver test abnormal

Skin and subcutaneous tissue disorders

Common: Swelling face, acne, allergic dermatitis, hyperhidrosis, urticaria, rash

Musculoskeletal and connective tissue disorders

Common: Back pain, pain in extremities, arthralgia, shoulder pain, musculoskeletal stiffness, bone pain, muscular weakness, sensation of heaviness, tendonitis, joint swelling, arthritis, musculosceletal pain, myalgia*

Renal and urinary disorders

Common: Haematuria, increased blood uric acid, increased blood creatinine

Reproductive system and breast disorders

Common: Nipple pain

Uncommon: Gynaecomastia*

General disorders and administration site conditions

Very common: Oedema peripheral, oedema (local and generalised)*

Common: Fatigue, pain, asthenia, face oedema, local swelling, oedema, thirst, malaise, chest pain, increased weight, injection site pain

Investigations

Common: Increased blood phosphorus, increased or decreased IGF

Description of selected adverse reactions

Immunogenicity

Some patients may develop antibodies to rhGH. Somatropin Biopartners has given rise to the formation of antibodies in approximately 4% of adult patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation.

With regard to antibodies against host cell proteins, low anti-S. cerevisiae protein antibody titres similar to levels in the normal untreated population were found in some patients treated with this medicinal product. The generation of such antibodies with low binding activity is unlikely to be clinically relevant.

Malignancies/tumours

Cases of malignant and benign tumour recurrences, de-novo and secondary tumours have been reported in temporal relationship with somatropin therapy.

Paediatric population

With the exception of injection site related reactions and the formation of antibodies to rhGH which were reported more frequently in children than in adults the safety profile of Somatropin Biopartners is similar for children and adults.

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 national reporting system listed in Appendix V.

4.9Overdose

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Due to the prolonged-release characteristics of this medicinal product peak levels of growth hormone can be expected approximately 15 hours after injection, see section 5.2. Long term over-dosing could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of hGH excess.

Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and agonists, ATC code: H01AC01

The somatropin in this medicinal product is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 Daltons. The amino acid sequence of the active substance is identical to that of hGH of pituitary origin. The somatropin in this medicinal product is synthesised in yeast (Saccharomyces cerevisiae).

Mechanism of action

The biological effects of somatropin are equivalent to those of hGH of pituitary origin.

Somatropin promotes cellular protein synthesis and nitrogen retention. The most prominent effect of somatropin in children is the stimulation of the growth plates of long bones.

Pharmacodynamic effects

Somatropin stimulates lipid metabolism; it increases plasma fatty acids and high-density lipoprotein (HDL)-cholesterols, and decreases total plasma cholesterol.

Somatropin therapy has a beneficial effect on body composition in patients with -GHD, in that body fat stores are reduced and lean body mass is increased. Long-term therapy in growth hormone-deficient patients increases bone mineral density.

Somatropin may induce insulin resistance. Large doses of somatropin may impair glucose tolerance.

Clinical efficacy and safety

Safety and efficacy in adults with GHD was assessed in a phase III, double-blind, randomized, placebo-controlled, parallel-group, multicentre study. This pivotal phase III study comprised 151 adult patients with GHD of adult- or childhood-onset and lasted 6 months. After 6 months of weekly treatment with Somatropin Biopartners, there was a statistically significant reduction of 1.6 kg in fat mass in the Somatropin Biopartners group compared to the placebo group. A similar improvement was observed for the secondary efficacy endpoints namely increase in lean body mass, serum IGF-I and IGF-I SDS. Effects were maintained throughout the 6-month follow-up period.

5.2Pharmacokinetic properties

Absorption

Following repeated weekly subcutaneous administration of a mean dose of 4.4 mg prolonged release

somatropin to adults with GHD the Cmax and tmax of plasma hGH were about 4.5 ng/mL and 15 h respectively. The apparent terminal half-life was about 16.8 h in adults, presumably reflecting slow

absorption from the site of injection.

The tmax was later and the half-life longer following the administration of Somatropin Biopartners than when immediate release products had been previously administered once daily to the same subjects reflecting the slower and more prolonged release of hGH from the site of injection of Somatropin Biopartners.

Distribution

No accumulation of hGH following multiple dosing of this medicinal product has been observed.

Biotransformation / Elimination

The metabolic fate of hGH involves classical protein catabolism in both the liver and kidney.

5.3Preclinical safety data

Non-clinical pharmacokinetic and pharmacodynamic studies in dogs and juvenile monkeys showed that Somatropin Biopartners released recombinant hGH in a prolonged manner and increased serum IGF-I for an extended period up to 5-6 days.

Non-clinical data revealed no specific hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity.

Animal studies with this medicinal product are not sufficient to fully assess the reproductive toxicity potential. From reproductive toxicity studies performed with other somatropin products there is no evidence of an increased risk of adverse reactions to the embryo or foetus. Doses in excess of human therapeutic doses have shown adverse effects on reproductive function in male and female rats and male dogs, possibly through disruption of hormonal regulation. In rabbits and monkeys no adverse effects were observed.

Long term carcinogenicity studies with Somatropin Biopartners have not been conducted. There are no specific studies which address local tolerance in animals after subcutaneous injection, but data available from the repeated-dose toxicity studies revealed swelling and inflammatory infiltrate at the injection sites.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Powder:

Sodium hyaluronate

Egg phospholipids

Sodium dihydrogen phosphate anhydrous

Disodium phosphate anhydrous.

Solvent:

Medium chain triglycerides.

6.2Incompatibilities

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

6.3Shelf life

3 years

After reconstitution: From a microbiological point of view, the product must be used immediately.

6.4Special precautions for storage

Store in a refrigerator (2 - 8°C). Do not freeze.

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

6.5Nature and contents of container

Powder: Vial (type I glass) closed with a rubber stopper (butyl) and a yellow flip-off cap (aluminium and plastic).

Solvent: Vial (Type I glass) closed with a rubber stopper (butyl) and a flip-off cap (aluminium and plastic).

Each vial of powder delivers 2 mg somatropin; each vial of solvent contains 1.5 mL liquid. Pack size: 4 vials of powder and 4 vials of solvent.

6.6Special precautions for disposal and other handling

Reconstitution

Somatropin Biopartners 2 mg should be reconstituted with 0.4 mL solvent.

The suspension should appear uniform and white.

The vial contains an overfill of somatropin powder to allow the withdrawal of up to 2 mg (0.2 mL suspension) of somatropin when reconstituted.

Each vial is for single use only.

Reconstitution and dilution should be performed using aseptic techniques to ensure the sterility of the prepared suspension. The solvent vial should be warmed to room temperature and the powder vial should be tapped and shaken to ensure the powder is moving freely. After removal of the protective caps from the top of both vials the rubber stoppers should be cleaned with an alcohol swab. A 1 mL graduated syringe with 19 Gauge or wider needle should be used for withdrawing the solvent from its

vial. The syringe should be filled with a volume of air equal to the required volume of the solvent for injection and the air injected into the solvent vial to make it easier to withdraw the solvent. The vial should be turned upside down, with the syringe in and the tip of the needle should be placed in the solvent. To remove any bubbles, the syringe should be tapped gently. The plunger should be pushed up gently, until all bubbles are removed from the syringe and needle. The syringe should be filled with the correct volume of the solvent for injection as listed above and the syringe needle withdrawn from the vial subsequently. Any remaining solvent should not be used for a second preparation.

Holding the needle against the inside vial wall, the entire contents of the syringe should be injected into the powder vial. Without touching the rubber top the vial should be swirled vigorously until the content is completely mixed. This usually takes approximately 60 seconds but can take up to

90 seconds. The swirling should only be stopped once the suspension appears uniform, white and all the powder on the bottom is dispersed. After reconstitution the medicinal product should be used immediately before the suspension settles. If not used immediately, the suspension must be reconstituted again by swirling immediately before injection. The appropriate volume should be withdrawn in a sterile syringe via a sterile 26-gauge needle: The vial should be turned upside down, with the syringe in, and the tip of the needle should be placed in the suspension which is then slowly withdrawn. To remove small air bubbles the syringe should be tapped gently. The powder should be homogenously suspended in the injection vehicle prior to administration. The syringe should be held upright and gentle pressure applied to the plunger until a small drop of suspension appears at the end of the needle. The injection site should be cleaned with an alcohol swab and the suspension injected over a period of 5 seconds.

Detailed information on how to administer this medicinal product is provided in section 3 of the patient leaflet.

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

7.MARKETING AUTHORISATION HOLDER

BioPartners GmbH

Kaiserpassage 11 D-72764 Reutlingen Germany

Tel: +49 (0) 7121 948 7756 Fax:+49 (0) 7121 346 255 e-mail: info@biopartners.de

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/13/849/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 August 2013

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Somatropin Biopartners 4 mg powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial delivers 4 mg of somatropin* (corresponding to 12 IU)

After reconstitution, 0.4 mL of suspension contains 4 mg somatropin (10 mg/mL).

*produced in Saccharomyces cerevisiae by recombinant DNA technology

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

White or almost white powder. The solvent is a clear, oily liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Somatropin Biopartners is indicated for the replacement therapy of endogenous growth hormone in adults with childhood- or adult-onset growth hormone deficiency (GHD).

Adult-onset: Patients with GHD in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one additional known deficiency of a pituitary hormone excluding prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a GHD.

Childhood-onset: In patients with childhood-onset isolated GHD (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be performed after completion of growth, except for those having low insulin-like growth factor-I (IGF-I) concentrations (< -2 standard deviation score (SDS)), who may be considered for one test. The cut-off point of the dynamic test should be strict.

4.2 Posology and method of administration

Diagnosis and therapy with this medicinal product should be initiated and monitored by physicians adequately experienced in the diagnosis and management of patients with GHD.

Posology

Somatropin Biopartners should be administered subcutaneously at a concentration of 10 mg/mL.

Starting dose

Generally, 2 mg once a week for all patients apart from female patients receiving oral oestrogen therapy who should receive 3 mg once a week. In older or overweight patients, lower doses may be necessary.

Gender

Starting dose

Male

2 mg (6 IU)

Female (not on oral oestrogen)

2 mg (6 IU)

Female (on oral oestrogen)

3 mg (9 IU)

Dose adjustment

Initially, patients should have their IGF-I levels assessed at 3- to 4-weekly intervals until IGF-I SDS is in the target range of -0.5 to +1.5. Samples should be drawn 4 days after the previous dose (Day 4). Repeated adjustments in dose may be required, dependent on patients’ IGF-I response. IGF-I levels should be acted upon, as indicated below.

IGF-I SDS

Action on

Dose change at a time

previous dose

 

 

IGF-I SDS lower than -1

Increase

+1.5 mg (female on oral oestrogen)

+1.0 mg (all other patients)

 

 

IGF-I SDS in the range of -1 to +1 and

Increase

+1.5 mg (female on oral oestrogen)

less than 1SDS increase from Baseline

+1.0 mg (all other patients)

 

IGF-I SDS in the range of -1 to +1 and

Maintain

None

more than 1 SDS increase from Baseline

 

 

 

Maintain or

 

IGF-I SDS in the range of +1 to +2

decrease

None or -0.5 mg (all patients)

depending on

 

 

 

clinical status

 

IGF-I SDS greater than +2

Decrease

-0.5 mg (all patients)

 

 

 

IGF-I = insulin-like growth factor-I, SDS = standard deviation score.

Conversion from required dose to injection volume and vial strength

Somatropin dose

vials and solvent required for preparation of

Injection volume

(mg)

one dose*

(mL)

2.5

one 4-mg vial reconstituted

0.25

0.3

3.5

with 0.6 mL solvent

0.35

 

0.4

* Each vial contains an overfill of somatropin powder to allow the withdrawal of the required amount of somatropin when reconstituted (see section 6.6).

For other doses vials with 2 or 7 mg somatropin are available.

The minimum effective dose should be used. The treatment goal should be IGF-I concentrations within -0.5 and +1.5 SDS of the age corrected mean.

In order to reach the defined treatment goal, men may need lower growth hormone doses than women. Oral oestrogen administration increases the dose requirements in women. An increasing sensitivity to growth hormone (expressed as change in IGF-I per growth hormone dose) over time may be observed, particularly in men. The accuracy of the growth hormone dose should therefore be controlled every

6 months.

The dosage of somatropin should be decreased in cases of persistent oedema or severe paraesthesia, in order to avoid the development of carpal tunnel syndrome.

The dose may be reduced in steps of 0.5 mg at a time. If the symptoms leading to the dose reduction disappear, at the judgment of the physician, the dose may be maintained at the decreased level or increased according to the dose adjustment scheme described above. If the symptom reappears after the dose increase, then the dose should be maintained at the previous lower dose.

Special populations

Older people

Experience with somatropin treatment in patients above 60 years of age is limited. Dose requirements may decline with increasing age.

Renal/hepatic impairment

No information in patients with renal or hepatic impairment is available and particular dose recommendations cannot be given.

Paediatric population

There is no relevant use of Somatropin Biopartners 4 mg in the paediatric population in the indication of long-term treatment of growth failure due to insufficient secretion of endogenous growth hormone. For the treatment of children and adolescents aged 2 to 18 years the 10 mg and 20 mg vials of this medicinal product should be used.

Method of administration

The patient or carer should receive training to ensure understanding of the administration procedure before being allowed to (self-) inject.

Somatropin Biopartners is administered subcutaneously once a week. After reconstitution the injection should be administered immediately.

The subcutaneous injection should always be administered at the same time of the day to increase compliance and the site of injection must be varied to prevent lipoatrophy.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somatropin must not be used when there is any evidence of tumour activity. Intracranial tumours must be inactive and antitumour therapy must be completed prior to the initiation of growth hormone therapy. Treatment should be discontinued if there is evidence of tumour (re)growth.

Somatropin treatment must not be started in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure or similar conditions.

4.4 Special warnings and precautions for use

Malignancies

Patients with prior malignancies should be examined routinely for progression or recurrence.

Benign intracranial hypertension

In cases of severe or recurrent headache, visual problems, nausea, and/or vomiting, a fundoscopy 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 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.

Insulin sensitivity

Because human growth hormone (hGH) may induce a state of insulin resistance and hyperglycaemia, patients treated with this medicinal product should be monitored for evidence of glucose intolerance. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin treatment is initiated. 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. Hypothyroidism may develop in patients with central subclinical hypothyroidism after initiating therapy with growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to somatropin.

In patients with hypopituitarism receiving thyroxin replacement therapy, hyperpituitarism may develop. Thyroid function should therefore be closely monitored in all patients.

Adrenal function

Treatment with growth hormone may facilitate the development of adrenal insufficiency and potentially fatal adrenal crises in patients with organic GHD or idiopathic panhypopituitarism. It is therefore crucial to assess baseline and stress doses of glucocorticoids which may need to be adjusted when growth hormone therapy is initiated.

Adults with childhood-onset of GHD

Young adult patients with closed epiphyses who have previously been treated as children for GHD should be re-evaluated for GHD using the criteria for adult patients (see section 4.1) before replacement therapy is commenced at the doses recommended for adults.

Other precautions

This medicinal product is not indicated for the treatment of patients with growth failure due to Prader-Willi syndrome unless they also have a diagnosis of GHD. There have been reports of sleep apnoea and sudden death after initiating growth hormone therapy in 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.

After accidental intramuscular injection, hypoglycaemia may occur.

Antibodies

Some patients may develop antibodies to this medicinal product. Somatropin Biopartners has given rise to the formation of antibodies in approximately 4% of adult patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Excessive glucocorticoid therapy can inhibit the actions of hGH. Patients receiving concomitant glucocorticoid therapy should have their dose carefully adjusted.

Growth hormone increases the extrathyroidal conversion of thyroxin (T4) to triiodothyronine (T3) and may unmask central hypothyroidism. Thyroxine replacement therapy may therefore need to be initiated or adjusted.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective. In women taking oral oestrogens, a higher dose of somatropin may be required to achieve the treatment goal, see section 4.2.

Patients taking insulin for diabetes mellitus should be carefully monitored during treatment with somatropin. Because hGH may induce a state of insulin resistance, an adjustment of the insulin dose may be required.

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 cyclosporine) may be increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Somatropin Biopartners is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no data on the use of this medicinal product in pregnant women. Very limited data on exposure to other somatropin preparations during early pregnancy did not indicate an adverse pregnancy outcome. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

During normal pregnancy, levels of pituitary growth hormone fall markedly after 20 weeks of gestation, being replaced almost entirely by placental growth hormone by 30 weeks. In view of this, it is unlikely that continued replacement therapy with somatropin would be necessary in growth hormone deficient women in the third trimester of pregnancy. Somatropin Biopartners is not recommended during pregnancy.

Breast-feeding

No clinical studies have been conducted with Somatropin Biopartners in breast-feeding women. It is unknown whether somatropin or its metabolites are excreted in human breast milk; however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely. Caution should be exercised when this medicinal product is administered to breast-feeding women.

Fertility

Animal studies with other somatropin formulations have shown adverse effects but the available nonclinical data are considered insufficient to draw firm conclusions on the use in humans (see section 5.3).

4.7 Effects on ability to drive and use machines

Somatropin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Clinical trials included approximately 530 patients treated with Somatropin Biopartners. When adverse reactions occurred, they tended to be transient and severity was generally mild to moderate. The safety profile of Somatropin Biopartners is generally consistent with the well known safety profile of daily growth hormone treatments. The adverse reactions most commonly reported were injection site related reactions, peripheral oedema, headache, myalgia, arthralgia, paraesthesia, hypothyroidism and decreased free thyroxine.

Tabulated list of adverse reactions

The following adverse reactions have been observed under treatment with Somatropin Biopartners in a 6-month controlled clinical study with 151 adult patients with GHD of adult- or childhood-onset and in a 6-month extension study. Additional reports based on published information for daily growth hormone treatments are listed with asterisks.

The frequency of adverse reactions listed below is defined 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), not known (cannot be estimated from the available data):

Infections and infestations

Common: Herpes simplex

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: Neoplasm progression (1 case of neoplasm progression in a female patient with a history of neurofibromatosis and radiation treatment), acrochordon, craniopharyngioma

Blood and the lymphatic system disorders

Common: Decreased or increased white blood cell count, increased glycosylated haemoglobin, decreased haemoglobin

Immune system disorders

Common: Formation of antibodies against growth hormone

Endocrine disorders

Common: Adrenal insufficiency, decreased free thyroxine, decreased free tri-iodothyronine, increased blood TSH, hypothyroidism*

Metabolism and nutrition disorders

Very common: Mild hyperglycaemia*

Common: Impaired fasting glucose, hyperlipidaemia, increased blood insulin, increased blood cholesterol, decreased blood sodium, increased blood triglycerides, increased blood glucose, increased or decreased HDL, increased LDL

Not known: Insulin resistance*

Psychiatric disorders

Common: Insomnia

Nervous system disorders

Very common: Headache

Common: Paraesthesia, hypoaesthesia, carpal tunnel syndrome, dizziness, somnolence Rare: Benign intracranial hypertension*

Eye disorders

Common: Conjunctivitis, visual acuity reduced

Ear and labyrinth disorders

Common: Vertigo

Cardiac disorders

Common: Tachycardia, heart rate abnormal/irregular

Vascular disorders

Common: Hypertension,increased blood pressure

Respiratory, thoracic and mediastinal disorders

Common: Epistaxis

Gastrointestinal disorders

Common: Nausea

Hepatobiliary disorders

Common: Hyperbilirubinaemia, cholecystitis, liver test abnormal

Skin and subcutaneous tissue disorders

Common: Swelling face, acne, allergic dermatitis, hyperhidrosis, urticaria, rash

Musculoskeletal and connective tissue disorders

Common: Back pain, pain in extremities, arthralgia, shoulder pain, musculoskeletal stiffness, bone pain, muscular weakness, sensation of heaviness, tendonitis, joint swelling, arthritis, musculosceletal pain, myalgia*

Renal and urinary disorders

Common: Haematuria, increased blood uric acid, increased blood creatinine

Reproductive system and breast disorders

Common: Nipple pain

Uncommon: Gynaecomastia*

General disorders and administration site conditions

Very common: Oedema peripheral, oedema (local and generalised)*

Common: Fatigue, pain, asthenia, face oedema, local swelling, oedema, thirst, malaise, chest pain, increased weight, injection site pain

Investigations

Common: Increased blood phosphorus, increased or decreased IGF

Description of selected adverse reactions

Immunogenicity

Some patients may develop antibodies to rhGH. Somatropin Biopartners has given rise to the formation of antibodies in approximately 4% of adult patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation.

With regard to antibodies against host cell proteins, low anti-S. cerevisiae protein antibody titres similar to levels in the normal untreated population were found in some patients treated with this medicinal product. The generation of such antibodies with low binding activity is unlikely to be clinically relevant.

Malignancies/tumours

Cases of malignant and benign tumour recurrences, de-novo and secondary tumours have been reported in temporal relationship with somatropin therapy.

Paediatric population

With the exception of injection site related reactions and the formation of antibodies to rhGH which were reported more frequently in children than in adults the safety profile of Somatropin Biopartners is similar for children and adults.

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 national reporting system listed in Appendix V.

4.9 Overdose

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Due to the prolonged-release characteristics of this medicinal product peak levels of growth hormone can be expected approximately 15 hours after injection, see section 5.2. Long term over-dosing could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of hGH excess.

Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and agonists, ATC code: H01AC01

The somatropin in this medicinal product is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 Daltons. The amino acid sequence of the active substance is identical to that of hGH of pituitary origin. The somatropin in this medicinal product is synthesised in yeast (Saccharomyces cerevisiae).

Mechanism of action

The biological effects of somatropin are equivalent to those of hGH of pituitary origin.

Somatropin promotes cellular protein synthesis and nitrogen retention. The most prominent effect of somatropin in children is the stimulation of the growth plates of long bones.

Pharmacodynamic effects

Somatropin stimulates lipid metabolism; it increases plasma fatty acids and high-density lipoprotein (HDL)-cholesterols, and decreases total plasma cholesterol.

Somatropin therapy has a beneficial effect on body composition in patients with -GHD, in that body fat stores are reduced and lean body mass is increased. Long-term therapy in growth hormone-deficient patients increases bone mineral density.

Somatropin may induce insulin resistance. Large doses of somatropin may impair glucose tolerance.

Clinical efficacy and safety

Safety and efficacy in adults with GHD was assessed in a phase III, double-blind, randomized, placebo-controlled, parallel-group, multicentre study. This pivotal phase III study comprised 151 adult patients with GHD of adult- or childhood-onset and lasted 6 months. After 6 months of weekly treatment with Somatropin Biopartners, there was a statistically significant reduction of 1.6 kg in fat mass in the Somatropin Biopartners group compared to the placebo group. A similar improvement was observed for the secondary efficacy endpoints namely increase in lean body mass, serum IGF-I and IGF-I SDS. Effects were maintained throughout the 6-month follow-up period.

5.2 Pharmacokinetic properties

Absorption

Following repeated weekly subcutaneous administration of a mean dose of 4.4 mg prolonged release

somatropin to adults with GHD the Cmax and tmax of plasma hGH were about 4.5 ng/mL and 15 h respectively. The apparent terminal half-life was about 16.8 h in adults, presumably reflecting slow

absorption from the site of injection.

The tmax was later and the half-life longer following the administration of Somatropin Biopartners than when immediate release products had been previously administered once daily to the same subjects reflecting the slower and more prolonged release of hGH from the site of injection of Somatropin Biopartners.

Distribution

No accumulation of hGH following multiple dosing of this medicinal product has been observed.

Biotransformation / Elimination

The metabolic fate of hGH involves classical protein catabolism in both the liver and kidney.

5.3 Preclinical safety data

Non-clinical pharmacokinetic and pharmacodynamic studies in dogs and juvenile monkeys showed that Somatropin Biopartners released recombinant hGH in a prolonged manner and increased serum IGF-I for an extended period up to 5-6 days.

Non-clinical data revealed no specific hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity.

Animal studies with this medicinal product are not sufficient to fully assess the reproductive toxicity potential. From reproductive toxicity studies performed with other somatropin products there is no evidence of an increased risk of adverse reactions to the embryo or foetus. Doses in excess of human therapeutic doses have shown adverse effects on reproductive function in male and female rats and male dogs, possibly through disruption of hormonal regulation. In rabbits and monkeys no adverse effects were observed.

Long term carcinogenicity studies with Somatropin Biopartners have not been conducted. There are no specific studies which address local tolerance in animals after subcutaneous injection, but data available from the repeated-dose toxicity studies revealed swelling and inflammatory infiltrate at the injection sites.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Sodium hyaluronate

Egg phospholipids

Sodium dihydrogen phosphate anhydrous

Disodium phosphate anhydrous.

Solvent:

Medium chain triglycerides.

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: From a microbiological point of view, the product must be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2 - 8°C). Do not freeze.

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

6.5 Nature and contents of container

Powder: Vial (type I glass) closed with a rubber stopper (butyl) and a pink flip-off cap (aluminium and plastic).

Solvent: Vial (Type I glass) closed with a rubber stopper (butyl) and a flip-off cap (aluminium and plastic).

Each vial of powder delivers 4 mg somatropin; each vial of solvent contains 1.5 mL liquid. Pack size: 4 vials of powder and 4 vials of solvent.

6.6 Special precautions for disposal and other handling

Reconstitution

Somatropin Biopartners 4 mg should be reconstituted with 0.6 mL solvent.

The suspension should appear uniform and white.

The vial contains an overfill of somatropin powder to allow the withdrawal of up to 4 mg (0.4 mL suspension) of somatropin when reconstituted.

Each vial is for single use only.

Reconstitution and dilution should be performed using aseptic techniques to ensure the sterility of the prepared suspension. The solvent vial should be warmed to room temperature and the powder vial should be tapped and shaken to ensure the powder is moving freely. After removal of the protective caps from the top of both vials the rubber stoppers should be cleaned with an alcohol swab. A 1 mL graduated syringe with 19 Gauge or wider needle should be used for withdrawing the solvent from its vial. The syringe should be filled with a volume of air equal to the required volume of the solvent for injection and the air injected into the solvent vial to make it easier to withdraw the solvent. The vial should be turned upside down, with the syringe in and the tip of the needle should be placed in the solvent. To remove any bubbles, the syringe should be tapped gently. The plunger should be pushed up gently, until all bubbles are removed from the syringe and needle. The syringe should be filled with the correct volume of the solvent for injection as listed above and the syringe needle withdrawn from the vial subsequently. Any remaining solvent should not be used for a second preparation.

Holding the needle against the inside vial wall, the entire contents of the syringe should be injected into the powder vial. Without touching the rubber top the vial should be swirled vigorously until the content is completely mixed. This usually takes approximately 60 seconds but can take up to

90 seconds. The swirling should only be stopped once the suspension appears uniform, white and all the powder on the bottom is dispersed. After reconstitution the medicinal product should be used immediately before the suspension settles. If not used immediately, the suspension must be reconstituted again by swirling immediately before injection. The appropriate volume should be withdrawn in a sterile syringe via a sterile 26-gauge needle: The vial should be turned upside down, with the syringe in, and the tip of the needle should be placed in the suspension which is then slowly withdrawn. To remove small air bubbles the syringe should be tapped gently. The powder should be homogenously suspended in the injection vehicle prior to administration. The syringe should be held upright and gentle pressure applied to the plunger until a small drop of suspension appears at the end of the needle. The injection site should be cleaned with an alcohol swab and the suspension injected over a period of 5 seconds.

Detailed information on how to administer this medicinal product is provided in section 3 of the patient leaflet.

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

7. MARKETING AUTHORISATION HOLDER

BioPartners GmbH

Kaiserpassage 11 D-72764 Reutlingen Germany

Tel: +49 (0) 7121 948 7756 Fax:+49 (0) 7121 346 255 e-mail: info@biopartners.de

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/849/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 August 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Somatropin Biopartners 7 mg powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial delivers 7 mg of somatropin* (corresponding to 21 IU)

After reconstitution, 0.7 mL of suspension contains 7 mg somatropin (10 mg/mL).

*produced in Saccharomyces cerevisiae by recombinant DNA technology

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

White or almost white powder. The solvent is a clear, oily liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Somatropin Biopartners is indicated for the replacement therapy of endogenous growth hormone in adults with childhood- or adult-onset growth hormone deficiency (GHD).

Adult-onset: Patients with GHD in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one additional known deficiency of a pituitary hormone excluding prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a GHD.

Childhood-onset: In patients with childhood-onset isolated GHD (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be performed after completion of growth, except for those having low insulin-like growth factor-I (IGF-I) concentrations (< -2 standard deviation score (SDS)), who may be considered for one test. The cut-off point of the dynamic test should be strict.

4.2 Posology and method of administration

Diagnosis and therapy with this medicinal product should be initiated and monitored by physicians adequately experienced in the diagnosis and management of patients with GHD.

Posology

Somatropin Biopartners should be administered subcutaneously at a concentration of 10 mg/mL.

Starting dose

Generally, 2 mg once a week for all patients apart from female patients receiving oral oestrogen therapy who should receive 3 mg once a week. In older or overweight patients, lower doses may be necessary.

Gender

Starting dose

Male

2 mg (6 IU)

Female (not on oral oestrogen)

2 mg (6 IU)

Female (on oral oestrogen)

3 mg (9 IU)

Dose adjustment

Initially, patients should have their IGF-I levels assessed at 3- to 4-weekly intervals until IGF-I SDS is in the target range of -0.5 to +1.5. Samples should be drawn 4 days after the previous dose (Day 4). Repeated adjustments in dose may be required, dependent on patients’ IGF-I response. IGF-I levels should be acted upon, as indicated below.

IGF-I SDS

Action on

Dose change at a time

previous dose

 

 

IGF-I SDS lower than -1

Increase

+1.5 mg (female on oral oestrogen)

+1.0 mg (all other patients)

 

 

IGF-I SDS in the range of -1 to +1 and

Increase

+1.5 mg (female on oral oestrogen)

less than 1SDS increase from Baseline

+1.0 mg (all other patients)

 

IGF-I SDS in the range of -1 to +1 and

Maintain

None

more than 1 SDS increase from Baseline

 

 

 

Maintain or

 

IGF-I SDS in the range of +1 to +2

decrease

None or -0.5 mg (all patients)

depending on

 

 

 

clinical status

 

IGF-I SDS greater than +2

Decrease

-0.5 mg (all patients)

 

 

 

IGF-I = insulin-like growth factor-I, SDS = standard deviation score.

Conversion from required dose to injection volume and vial strength

Somatropin dose

vials and solvent required for preparation of

Injection volume

(mg)

one dose*

(mL)

4.5

 

0.45

one 7-mg vial reconstituted

0.5

5.5

0.55

with 0.9 mL solvent

0.6

6.5

 

0.65

 

0.7

* Each vial contains an overfill of somatropin powder to allow the withdrawal of the required amount of somatropin when reconstituted (see section 6.6).

For other doses vials with 2 or 4 mg somatropin are available.

The minimum effective dose should be used. The treatment goal should be IGF-I concentrations within -0.5 and +1.5 SDS of the age corrected mean.

In order to reach the defined treatment goal, men may need lower growth hormone doses than women. Oral oestrogen administration increases the dose requirements in women. An increasing sensitivity to growth hormone (expressed as change in IGF-I per growth hormone dose) over time may be observed, particularly in men. The accuracy of the growth hormone dose should therefore be controlled every

6 months.

The dosage of somatropin should be decreased in cases of persistent oedema or severe paraesthesia, in order to avoid the development of carpal tunnel syndrome.

The dose may be reduced in steps of 0.5 mg at a time. If the symptoms leading to the dose reduction disappear, at the judgment of the physician, the dose may be maintained at the decreased level or increased according to the dose adjustment scheme described above. If the symptom reappears after the dose increase, then the dose should be maintained at the previous lower dose.

Special populations

Older people

Experience with somatropin treatment in patients above 60 years of age is limited. Dose requirements may decline with increasing age.

Renal/hepatic impairment

No information in patients with renal or hepatic impairment is available and particular dose recommendations cannot be given.

Paediatric population

There is no relevant use of Somatropin Biopartners 7 mg in the paediatric population in the indication of long-term treatment of growth failure due to insufficient secretion of endogenous growth hormone. For the treatment of children and adolescents aged 2 to 18 years the 10 mg and 20 mg vials of this medicinal product should be used.

Method of administration

The patient or carer should receive training to ensure understanding of the administration procedure before being allowed to (self-) inject.

Somatropin Biopartners is administered subcutaneously once a week. After reconstitution the injection should be administered immediately.

The subcutaneous injection should always be administered at the same time of the day to increase compliance and the site of injection must be varied to prevent lipoatrophy.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somatropin must not be used when there is any evidence of tumour activity. Intracranial tumours must be inactive and antitumour therapy must be completed prior to the initiation of growth hormone therapy. Treatment should be discontinued if there is evidence of tumour (re)growth.

Somatropin treatment must not be started in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure or similar conditions.

4.4 Special warnings and precautions for use

Malignancies

Patients with prior malignancies should be examined routinely for progression or recurrence.

Benign intracranial hypertension

In cases of severe or recurrent headache, visual problems, nausea, and/or vomiting, a fundoscopy 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 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.

Insulin sensitivity

Because human growth hormone (hGH) may induce a state of insulin resistance and hyperglycaemia, patients treated with this medicinal product should be monitored for evidence of glucose intolerance. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin treatment is initiated. 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. Hypothyroidism may develop in patients with central subclinical hypothyroidism after initiating therapy with growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to somatropin.

In patients with hypopituitarism receiving thyroxin replacement therapy, hyperpituitarism may develop. Thyroid function should therefore be closely monitored in all patients.

Adrenal function

Treatment with growth hormone may facilitate the development of adrenal insufficiency and potentially fatal adrenal crises in patients with organic GHD or idiopathic panhypopituitarism. It is therefore crucial to assess baseline and stress doses of glucocorticoids which may need to be adjusted when growth hormone therapy is initiated.

Adults with childhood-onset of GHD

Young adult patients with closed epiphyses who have previously been treated as children for GHD should be re-evaluated for GHD using the criteria for adult patients (see section 4.1) before replacement therapy is commenced at the doses recommended for adults.

Other precautions

This medicinal product is not indicated for the treatment of patients with growth failure due to Prader-Willi syndrome unless they also have a diagnosis of GHD. There have been reports of sleep apnoea and sudden death after initiating growth hormone therapy in 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.

After accidental intramuscular injection, hypoglycaemia may occur.

Antibodies

Some patients may develop antibodies to this medicinal product. Somatropin Biopartners has given rise to the formation of antibodies in approximately 4% of adult patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Excessive glucocorticoid therapy can inhibit the actions of hGH. Patients receiving concomitant glucocorticoid therapy should have their dose carefully adjusted.

Growth hormone increases the extrathyroidal conversion of thyroxin (T4) to triiodothyronine (T3) and may unmask central hypothyroidism. Thyroxine replacement therapy may therefore need to be initiated or adjusted.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective. In women taking oral oestrogens, a higher dose of somatropin may be required to achieve the treatment goal, see section 4.2.

Patients taking insulin for diabetes mellitus should be carefully monitored during treatment with somatropin. Because hGH may induce a state of insulin resistance, an adjustment of the insulin dose may be required.

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 cyclosporine) may be increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Somatropin Biopartners is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no data on the use of this medicinal product in pregnant women. Very limited data on exposure to other somatropin preparations during early pregnancy did not indicate an adverse pregnancy outcome. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

During normal pregnancy, levels of pituitary growth hormone fall markedly after 20 weeks of gestation, being replaced almost entirely by placental growth hormone by 30 weeks. In view of this, it is unlikely that continued replacement therapy with somatropin would be necessary in growth hormone deficient women in the third trimester of pregnancy. Somatropin Biopartners is not recommended during pregnancy.

Breast-feeding

No clinical studies have been conducted with Somatropin Biopartners in breast-feeding women. It is unknown whether somatropin or its metabolites are excreted in human breast milk; however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely. Caution should be exercised when this medicinal product is administered to breast-feeding women.

Fertility

Animal studies with other somatropin formulations have shown adverse effects but the available nonclinical data are considered insufficient to draw firm conclusions on the use in humans (see section 5.3).

4.7 Effects on ability to drive and use machines

Somatropin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Clinical trials included approximately 530 patients treated with Somatropin Biopartners. When adverse reactions occurred, they tended to be transient and severity was generally mild to moderate. The safety profile of Somatropin Biopartners is generally consistent with the well known safety profile of daily growth hormone treatments. The adverse reactions most commonly reported were injection site related reactions, peripheral oedema, headache, myalgia, arthralgia, paraesthesia, hypothyroidism and decreased free thyroxine.

Tabulated list of adverse reactions

The following adverse reactions have been observed under treatment with Somatropin Biopartners in a 6-month controlled clinical study with 151 adult patients with GHD of adult or childhood-onset and in a 6-month extension study. Additional reports based on published information for daily growth hormone treatments are listed with asterisks.

The frequency of adverse reactions listed below is defined 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), not known (cannot be estimated from the available data):

Infections and infestations

Common: Herpes simplex

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: Neoplasm progression (1 case of neoplasm progression in a female patient with a history of neurofibromatosis and radiation treatment), acrochordon, craniopharyngioma

Blood and the lymphatic system disorders

Common: Decreased or increased white blood cell count, increased glycosylated haemoglobin, decreased haemoglobin

Immune system disorders

Common: Formation of antibodies against growth hormone

Endocrine disorders

Common: Adrenal insufficiency, decreased free thyroxine, decreased free tri-iodothyronine, increased blood TSH, hypothyroidism*

Metabolism and nutrition disorders

Very common: Mild hyperglycaemia*

Common: Impaired fasting glucose, hyperlipidaemia, increased blood insulin, increased blood cholesterol, decreased blood sodium, increased blood triglycerides, increased blood glucose, increased or decreased HDL, increased LDL

Not known: Insulin resistance*

Psychiatric disorders

Common: Insomnia

Nervous system disorders

Very common: Headache

Common: Paraesthesia, hypoaesthesia, carpal tunnel syndrome, dizziness, somnolence Rare: Benign intracranial hypertension*

Eye disorders

Common: Conjunctivitis, visual acuity reduced

Ear and labyrinth disorders

Common: Vertigo

Cardiac disorders

Common: Tachycardia, heart rate abnormal/irregular

Vascular disorders

Common: Hypertension,increased blood pressure

Respiratory, thoracic and mediastinal disorders

Common: Epistaxis

Gastrointestinal disorders

Common: Nausea

Hepatobiliary disorders

Common: Hyperbilirubinaemia, cholecystitis, liver test abnormal

Skin and subcutaneous tissue disorders

Common: Swelling face, acne, allergic dermatitis, hyperhidrosis, urticaria, rash

Musculoskeletal and connective tissue disorders

Common: Back pain, pain in extremities, arthralgia, shoulder pain, musculoskeletal stiffness, bone pain, muscular weakness, sensation of heaviness, tendonitis, joint swelling, arthritis, musculosceletal pain, myalgia*

Renal and urinary disorders

Common: Haematuria, increased blood uric acid, increased blood creatinine

Reproductive system and breast disorders

Common: Nipple pain

Uncommon: Gynaecomastia*

General disorders and administration site conditions

Very common: Oedema peripheral, oedema (local and generalised)*

Common: Fatigue, pain, asthenia, face oedema, local swelling, oedema, thirst, malaise, chest pain, increased weight, injection site pain

Investigations

Common: Increased blood phosphorus, increased or decreased IGF

Description of selected adverse reactions

Immunogenicity

Some patients may develop antibodies to rhGH. Somatropin Biopartners has given rise to the formation of antibodies in approximately 4% of adult patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation.

With regard to antibodies against host cell proteins, low anti-S. cerevisiae protein antibody titres similar to levels in the normal untreated population were found in some patients treated with this medicinal product. The generation of such antibodies with low binding activity is unlikely to be clinically relevant.

Malignancies/tumours

Cases of malignant and benign tumour recurrences, de-novo and secondary tumours have been reported in temporal relationship with somatropin therapy.

Paediatric population

With the exception of injection site related reactions and the formation of antibodies to rhGH which were reported more frequently in children than in adults the safety profile of Somatropin Biopartners is similar for children and adults.

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 national reporting system listed in Appendix V.

4.9 Overdose

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Due to the prolonged-release characteristics of this medicinal product peak levels of growth hormone can be expected approximately 15 hours after injection, see section 5.2. Long term over-dosing could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of hGH excess.

Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and agonists, ATC code: H01AC01

The somatropin in this medicinal product is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 Daltons. The amino acid sequence of the active substance is identical to that of hGH of pituitary origin. The somatropin in this medicinal product is synthesised in yeast (Saccharomyces cerevisiae).

Mechanism of action

The biological effects of somatropin are equivalent to those of hGH of pituitary origin.

Somatropin promotes cellular protein synthesis and nitrogen retention. The most prominent effect of somatropin in children is the stimulation of the growth plates of long bones.

Pharmacodynamic effects

Somatropin stimulates lipid metabolism; it increases plasma fatty acids and high-density lipoprotein (HDL)-cholesterols, and decreases total plasma cholesterol.

Somatropin therapy has a beneficial effect on body composition in patients with -GHD, in that body fat stores are reduced and lean body mass is increased. Long-term therapy in growth hormone-deficient patients increases bone mineral density.

Somatropin may induce insulin resistance. Large doses of somatropin may impair glucose tolerance.

Clinical efficacy and safety

Safety and efficacy in adults with GHD was assessed in a phase III, double-blind, randomized, placebo-controlled, parallel-group, multicentre study. This pivotal phase III study comprised 151 adult patients with GHD of adult- or childhood-onset and lasted 6 months. After 6 months of weekly treatment with Somatropin Biopartners, there was a statistically significant reduction of 1.6 kg in fat mass in the Somatropin Biopartners group compared to the placebo group. A similar improvement was observed for the secondary efficacy endpoints namely increase in lean body mass, serum IGF-I and IGF-I SDS. Effects were maintained throughout the 6-month follow-up period.

5.2 Pharmacokinetic properties

Absorption

Following repeated weekly subcutaneous administration of a mean dose of 4.4 mg prolonged release

somatropin to adults with GHD the Cmax and tmax of plasma hGH were about 4.5 ng/mL and 15 h respectively. The apparent terminal half-life was about 16.8 h in adults, presumably reflecting slow

absorption from the site of injection.

The tmax was later and the half-life longer following the administration of Somatropin Biopartners than when immediate release products had been previously administered once daily to the same subjects reflecting the slower and more prolonged release of hGH from the site of injection of Somatropin Biopartners.

Distribution

No accumulation of hGH following multiple dosing of this medicinal product has been observed.

Biotransformation / Elimination

The metabolic fate of hGH involves classical protein catabolism in both the liver and kidney.

5.3 Preclinical safety data

Non-clinical pharmacokinetic and pharmacodynamic studies in dogs and juvenile monkeys showed that Somatropin Biopartners released recombinant hGH in a prolonged manner and increased serum IGF-I for an extended period up to 5-6 days.

Non-clinical data revealed no specific hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity.

Animal studies with this medicinal product are not sufficient to fully assess the reproductive toxicity potential. From reproductive toxicity studies performed with other somatropin products there is no evidence of an increased risk of adverse reactions to the embryo or foetus. Doses in excess of human therapeutic doses have shown adverse effects on reproductive function in male and female rats and male dogs, possibly through disruption of hormonal regulation. In rabbits and monkeys no adverse effects were observed.

Long term carcinogenicity studies with Somatropin Biopartners have not been conducted. There are no specific studies which address local tolerance in animals after subcutaneous injection, but data available from the repeated-dose toxicity studies revealed swelling and inflammatory infiltrate at the injection sites.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Sodium hyaluronate

Egg phospholipids

Sodium dihydrogen phosphate anhydrous

Disodium phosphate anhydrous.

Solvent:

Medium chain triglycerides.

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: From a microbiological point of view, the product must be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2 - 8°C). Do not freeze.

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

6.5 Nature and contents of container

Powder: Vial (type I glass) closed with a rubber stopper (butyl) and a light-blue flip-off cap (aluminium and plastic).

Solvent: Vial (Type I glass) closed with a rubber stopper (butyl) and a flip-off cap (aluminium and plastic).

Each vial of powder delivers 7 mg somatropin; each vial of solvent contains 1.5 mL liquid. Pack size: 4 vials of powder and 4 vials of solvent.

6.6 Special precautions for disposal and other handling

Reconstitution

Somatropin Biopartners 7 mg should be reconstituted with 0.9 mL solvent.

The suspension should appear uniform and white.

The vial contains an overfill of somatropin powder to allow the withdrawal of up to 7 mg (0.7 mL suspension) of somatropin when reconstituted.

Each vial is for single use only.

Reconstitution and dilution should be performed using aseptic techniques to ensure the sterility of the prepared suspension. The solvent vial should be warmed to room temperature and the powder vial should be tapped and shaken to ensure the powder is moving freely. After removal of the protective caps from the top of both vials the rubber stoppers should be cleaned with an alcohol swab. A 1 mL graduated syringe with 19 Gauge or wider needle should be used for withdrawing the solvent from its vial. The syringe should be filled with a volume of air equal to the required volume of the solvent for injection and the air injected into the solvent vial to make it easier to withdraw the solvent. The vial should be turned upside down, with the syringe in and the tip of the needle should be placed in the solvent. To remove any bubbles, the syringe should be tapped gently. The plunger should be pushed up gently, until all bubbles are removed from the syringe and needle. The syringe should be filled with the correct volume of the solvent for injection as listed above and the syringe needle withdrawn from the vial subsequently. Any remaining solvent should not be used for a second preparation.

Holding the needle against the inside vial wall, the entire contents of the syringe should be injected into the powder vial. Without touching the rubber top the vial should be swirled vigorously until the content is completely mixed. This usually takes approximately 60 seconds but can take up to

90 seconds. The swirling should only be stopped once the suspension appears uniform, white and all the powder on the bottom is dispersed. After reconstitution the medicinal product should be used immediately before the suspension settles. If not used immediately, the suspension must be reconstituted again by swirling immediately before injection. The appropriate volume should be withdrawn in a sterile syringe via a sterile 26-gauge needle: The vial should be turned upside down, with the syringe in, and the tip of the needle should be placed in the suspension which is then slowly withdrawn. To remove small air bubbles the syringe should be tapped gently. The powder should be homogenously suspended in the injection vehicle prior to administration. The syringe should be held upright and gentle pressure applied to the plunger until a small drop of suspension appears at the end of the needle. The injection site should be cleaned with an alcohol swab and the suspension injected over a period of 5 seconds.

Detailed information on how to administer this medicinal product is provided in section 3 of the patient leaflet.

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

7. MARKETING AUTHORISATION HOLDER

BioPartners GmbH

Kaiserpassage 11 D-72764 Reutlingen Germany

Tel: +49 (0) 7121 948 7756 Fax:+49 (0) 7121 346 255 e-mail: info@biopartners.de

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/849/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 August 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Somatropin Biopartners 10 mg powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial delivers 10 mg of somatropin* (corresponding to 30 IU)

After reconstitution, 0.5 mL of suspension contains 10 mg somatropin (20 mg/mL).

*produced in Saccharomyces cerevisiae by recombinant DNA technology

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

White or almost white powder. The solvent is a clear, oily liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Somatropin Biopartners is indicated in children and adolescents aged 2 to 18 years for long-term treatment of growth failure due to insufficient secretion of endogenous growth hormone.

4.2 Posology and method of administration

Diagnosis and therapy with this medicinal product should be initiated and monitored by physicians adequately experienced in the diagnosis and management of patients with growth hormone deficiency (GHD).

Posology

The recommended and maximum dose is 0.5 mg/kg/week and should not be exceeded. In children, Somatropin Biopartners should be administered subcutaneously at a concentration of 20 mg/mL. For dosage instruction, see table below.

It is recommended that a maximum injection volume of 1 mL per injection site, corresponding to a dose of 20 mg of somatropin, should not be exceeded.

For children heavier than 20 kg, Somatropin Biopartners 20 mg powder and solvent for prolonged-release suspension for injection is available.

For children heavier than 40 kg, two vials (a 10 mg and a 20 mg vial or two vials of 20 mg) can be used according to the body weight as indicated in the table below. The maximum injection volume per injection site should not exceed 1 mL. Therefore, in children weighing more than 40 kg the overall

injection volume must be divided into equal parts between two injection sites, as more than 1 mL of suspension is required.

Conversion from patient body weight to dose, number of vials, total injection volume and number of injections in paediatric patients

Patient

Dose

Vials and solvent required

Injection volume

Number of

bodyweight

injections

(mg)

for preparation of one dose*

(mL)

(kg)

per dose

 

 

 

 

0.1

 

 

0.15

 

 

0.2

 

One 10-mg vial reconstituted

0.25

 

0.3

 

with 0.7 mL solvent

 

0.35

 

 

 

 

0.4

 

 

0.45

 

 

0.5

 

0.55

 

 

 

0.6

 

 

0.65

 

One 20-mg vial reconstituted

0.7

 

0.75

 

with 1.2 mL solvent

 

0.8

 

 

 

 

0.85

 

 

0.9

 

 

0.95

 

 

1.0

 

 

1.05

 

One 10-mg vial reconstituted

1.1

 

1.15

 

with 0.7 mL solvent

1.2

 

and

1.25

 

One 20-mg vial reconstituted

1.3

 

with 1.2 mL solvent

1.35

 

 

1.4

 

 

1.45

 

 

1.5

 

1.55

 

 

 

1.6

 

 

1.65

 

Two 20-mg vials reconstituted

1.7

 

1.75

 

with 1.2 mL solvent each

 

1.8

 

 

 

 

1.85

 

 

1.9

 

 

1.95

 

 

2.0

 

* Each vial contains an overfill of somatropin powder to allow the withdrawal of the required amount of somatropin when reconstituted. (see section 6.6).

Treatment with this medicinal product should be continued until final height has been reached or until epiphyseal closure.

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. standardised to average adult peak bone mass measured by dual energy X-ray absorptiometry taking into account gender and ethnicity) is one of the therapeutic objectives during the transition period. Once a normal peak bone mass is attained patients should be switched to Somatropin Biopartners for adults, if clinically indicated, and the dosing recommendation for adults should be followed.

Special populations

Renal/hepatic impairment

No information in patients with renal or hepatic impairment is available and particular dose recommendations cannot be given.

Paediatric population (below 2 years of age)

Somatropin Biopartners should not be used in infants below the age of 2 years.

Method of administration

The patient or carer should receive training to ensure understanding of the administration procedure before being allowed to (self-) inject.

Somatropin Biopartners is administered subcutaneously once a week. After reconstitution the injection should be administered immediately.

The subcutaneous injection should always be administered at the same time of the day to increase compliance and the site of injection must be varied to prevent lipoatrophy.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somatropin must not be used when there is any evidence of tumour activity. Intracranial tumours must be inactive and antitumour therapy must be completed prior to the initiation of growth hormone therapy. Treatment should be discontinued if there is evidence of tumour (re)growth.

Somatropin must not be used for growth promotion in children with closed epiphyses.

Somatropin treatment must not be started in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure or similar conditions.

4.4 Special warnings and precautions for use

Malignancies

Patients with prior malignancies should be examined routinely for progression or recurrence.

In paediatric patients there is no evidence that growth hormone replacement influences the recurrence rate or regrowth of intracranial neoplasms, but standard clinical practice requires regular pituitary imaging in patients with a history of pituitary pathology. A baseline scan is recommended in these patients before instituting growth hormone replacement therapy.

There is an increased risk that paediatric patients with prior malignancies may develop second neoplasm when treated with growth hormone, especially if treatment of the primary malignancy involved radiotherapy. These patients should be counselled on risks before initiating therapy.

Benign intracranial hypertension

In cases of severe or recurrent headache, visual problems, nausea, and/or vomiting, a fundoscopy 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 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.

Insulin sensitivity

Because human growth hormone (hGH) may induce a state of insulin resistance and hyperglycaemia, patients treated with this medicinal product should be monitored for evidence of glucose intolerance. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin treatment is initiated. 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. Hypothyroidism may develop in patients with central subclinical hypothyroidism after initiating therapy with growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to somatropin.

In patients with hypopituitarism receiving thyroxin replacement therapy, hyperpituitarism may develop. Thyroid function should therefore be closely monitored in all patients.

Adrenal function

Treatment with growth hormone may facilitate the development of adrenal insufficiency and potentially fatal adrenal crises in patients with organic GHD or idiopathic panhypopituitarism. It is therefore crucial to assess baseline and stress doses of glucocorticoids which may need to be adjusted when growth hormone therapy is initiated.

Other precautions

This medicinal product is not indicated for the treatment of patients with growth failure due to Prader-Willi syndrome unless they also have a diagnosis of GHD. There have been reports of sleep apnoea and sudden death after initiating growth hormone therapy in 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.

After accidental intramuscular injection, hypoglycaemia may occur.

Paediatric patients with endocrine disorders, including GHD, may develop slipped capital femoral epiphyses more frequently. Any child with the onset of a limp during growth hormone therapy should be evaluated.

The recommended weekly dose in children (i.e. 0.5 mg/kg/week) should not be exceeded as there is limited experience with higher doses in this patient group.

Leukaemia

Leukaemia has been reported in a small number of GHD 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.

Scoliosis

Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. Somatropin has not been shown to increase the incidence or severity of scoliosis.

Antibodies

Some patients may develop antibodies to this medicinal product. Somatropin Biopartners has given rise to the formation of antibodies in approximately 33% of the paediatric patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation. Testing for antibodies to somatropin may be considered in patients with otherwise unexplained lack of growth response.

Injection site reactions

Injection site related reactions, mostly swelling at the injection site, were reported in approximately 43% of the paediatric patients. Few patients discontinued treatment due to injections site reactions, see section 4.8.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Excessive glucocorticoid therapy will inhibit the growth-promoting effect of hGH. Patients receiving concomitant glucocorticoid therapy should have their dose carefully adjusted to avoid an inhibitory effect on growth.

Growth hormone increases the extrathyroidal conversion of thyroxin (T4) to triiodothyronine (T3) and may unmask central hypothyroidism. Thyroxine replacement therapy may therefore need to be initiated or adjusted.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective.

Patients taking insulin for diabetes mellitus should be carefully monitored during treatment with somatropin. Because hGH may induce a state of insulin resistance, an adjustment of the insulin dose may be required.

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 cyclosporine) may be increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Somatropin Biopartners is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no data on the use of this medicinal product in pregnant women. Very limited data on exposure to other somatropin preparations during early pregnancy did not indicate an adverse pregnancy outcome. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

During normal pregnancy, levels of pituitary growth hormone fall markedly after 20 weeks of gestation, being replaced almost entirely by placental growth hormone by 30 weeks. In view of this, it is unlikely that continued replacement therapy with somatropin would be necessary in growth hormone deficient women in the third trimester of pregnancy. Somatropin Biopartners is not recommended during pregnancy.

Breast-feeding

No clinical studies have been conducted with Somatropin Biopartners in breast-feeding women. It is unknown whether somatropin or its metabolites are excreted in human breast milk; however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely. Caution should be exercised when this medicinal product is administered to breast-feeding women.

Fertility

Animal studies with other somatropin formulations have shown adverse effects but the available nonclinical data are considered insufficient to draw firm conclusions on the use in humans (see section 5.3).

4.7 Effects on ability to drive and use machines

Somatropin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Clinical trials included approximately 530 patients treated with Somatropin Biopartners. When adverse reactions occurred, they tended to be transient and severity was generally mild to moderate. The safety profile of Somatropin Biopartners is generally consistent with the well known safety profile of daily growth hormone treatments. The adverse reactions most commonly reported were injection site related reactions, peripheral oedema, headache, myalgia, arthralgia, paraesthesia, hypothyroidism and decreased free thyroxine.

Tabulated list of adverse reactions

The following adverse reactions have been observed under treatment with Somatropin Biopartners in a 12-month controlled comparative clinical study in 178 treatment naïve children with growth failure due to insufficient secretion of endogenous growth hormone and in a dose finding study. Additional reports based on published information for daily growth hormone treatments are listed with asterisks. The frequency of adverse reactions listed below is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data):

Immune system disorders

Very common: Formation of antibodies against growth hormone (33%), see section “Descriptions of selected adverse reactions”, under “Immunogenicity”.

Endocrine disorders

Common: Hypercortisolism (7.7%), hypothyroidism (2.2%), adrenal cortical insufficiency (3.3%), hypothyreosis secondary to TSH deficiency (2.6%), decreased free thyroxine (4.4%), increased blood TSH (2.2%)

Metabolism and nutrition disorders

Common: Mild hyperglycaemia*

Not known: Insulin resistance*

Psychiatric disorders

Very rare: insomnia*

Nervous system disorders

Common: headache (4.4%), lethargy (1.1%), dizziness (2.6%)

Rare: paraesthesia*

Vascular disorders

Rare: hypertension*

Gastrointestinal disorders

Common: vomitting (1.1%), abdominal pain (1.1%)

Skin and subcutaneous tissue disorders

Common: pigmentation disorder (1.1%)

Musculoskeletal and connective tissue disorders

Common: arthralgia (1.1%), pain in extremities (5.1%)

Reproductive system and breast disorders

Very rare: gynaecomastia*

General disorders and administration site conditions

Very common: injection site swelling (30.8%)

Common: injection site pain (9.9%), injection site discolouration (8.8%), injection site erythema (7.7%), injection site nodule (4.4%), injection site reaction (1.1%), injection site warmth (1.1%), pyrexia (2.6%), oedema (local and generalised)*

Investigations

Common: decreased blood cortisol (2.2%)

Description of selected adverse reactions

Injection site reactions

The most frequently reported adverse reactions in children were injection site related reactions, most of them being mild to moderate in intensity. Few patients discontinued treatment due to injections site reactions.

Immunogenicity

In the pivotal paediatric study, antibody responses to somatropin at two or more consecutive visits were observed in 33% of the patients. No effect on safety or efficacy was observed. It is unlikely that the antibody responses to treatment with Somatropin Biopartners are of clinical relevance.

With regard to antibodies against host cell proteins, low anti-S. cerevisiae protein antibody titres similar to levels in the normal untreated population were found in some patients treated with this medicinal product. The generation of such antibodies with low binding activity is unlikely to be clinically relevant.

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 national reporting system listed in Appendix V.

4.9 Overdose

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Due to the prolonged-release characteristics of this medicinal product peak levels of growth hormone can be expected approximately 15 hours after injection, see section 5.2. Long term over-dosing could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of hGH excess.

Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and agonists, ATC code: H01AC01

The somatropin in this medicinal product is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 Daltons. The amino acid sequence of the active substance is identical to that of hGH of pituitary origin. The somatropin in this medicinal product is synthesised in yeast (Saccharomyces cerevisiae).

Mechanism of action

The biological effects of somatropin are equivalent to those of hGH of pituitary origin.

The most prominent effect of somatropin in children is the stimulation of the growth plates of long bones. Additionally, it promotes cellular protein synthesis and nitrogen retention.

Pharmacodynamic effects

Somatropin stimulates lipid metabolism; it increases plasma fatty acids and high-density lipoprotein (HDL)-cholesterols, and decreases total plasma cholesterol.

Somatropin therapy has a beneficial effect on body composition in patients with -GHD, in that body fat stores are reduced and lean body mass is increased. Long-term therapy in growth hormone-deficient patients increases bone mineral density.

Somatropin may induce insulin resistance. Large doses of somatropin may impair glucose tolerance.

Clinical efficacy and safety

In a randomized, parallel-group, multicentre Phase III study, 178 children between 3 and 12 years of age with organic and/or idiopathic GHD were randomised to receive either weekly administered Somatropin Biopartners (0.5 mg/kg/week) or daily administered recombinant hGH (0.03 mg/kg/day) for 12 months. The results showed weekly administered Somatropin Biopartners to be non inferior to daily administered recombinant hGH with respect to the primary endpoint of height velocity after 12 months. Similar results were achieved for all other parameters assessed including height SDS (standard deviation score), bone maturation, IGF-I and IGF BP-3. In the children receiving

Somatropin Biopartners a higher incidence of (non-serious) injection site reactions and a higher rate of formation of (non-neutralising) antibodies against somatropin as compared to children with daily administered recombinant growth hormone were observed (see also sections 4.4 and 4.8).

5.2 Pharmacokinetic properties

Absorption

Following repeated weekly subcutaneous administration of a mean dose of 0.5 mg/kg prolonged release somatropin to prepubertal children with GHD the Cmax and tmax of plasma hGH were about 60.7 ng/mL and 12.0 h respectively. In general, Cmax and AUC increased approximately proportionally with dose over a dose range of 0.2 to 0.7 mg/kg in prepubertal children with GHD. The apparent terminal half-life was about 7.4 h in children, presumably reflecting slow absorption from the site of injection.

The tmax was later and the half-life longer following the administration of Somatropin Biopartners than when immediate release products had been previously administered once daily to the same subjects reflecting the slower and more prolonged release of hGH from the site of injection of Somatropin Biopartners.

Distribution

No accumulation of hGH following multiple dosing of this medicinal product has been observed.

Biotransformation / Elimination

The metabolic fate of hGH involves classical protein catabolism in both the liver and kidney.

5.3 Preclinical safety data

Non-clinical pharmacokinetic and pharmacodynamic studies in dogs and juvenile monkeys showed that Somatropin Biopartners released recombinant hGH in a prolonged manner and increased serum IGF-I for an extended period up to 5-6 days.

Non-clinical data revealed no specific hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity.

Animal studies with this medicinal product are not sufficient to fully assess the reproductive toxicity potential. From reproductive toxicity studies performed with other somatropin products there is no evidence of an increased risk of adverse reactions to the embryo or foetus. Doses in excess of human therapeutic doses have shown adverse effects on reproductive function in male and female rats and male dogs, possibly through disruption of hormonal regulation. In rabbits and monkeys no adverse effects were observed.

Long term carcinogenicity studies with Somatropin Biopartners have not been conducted. There are no specific studies which address local tolerance in animals after subcutaneous injection, but data available from the repeated-dose toxicity studies revealed swelling and inflammatory infiltrate at the injection sites.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Sodium hyaluronate

Egg phospholipids

Sodium dihydrogen phosphate anhydrous

Disodium phosphate anhydrous.

Solvent:

Medium chain triglycerides.

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: From a microbiological point of view, the product must be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2 - 8°C). Do not freeze.

For storage conditions of the reconstituted medicinal product, see section 6.3

6.5 Nature and contents of container

Powder: Vial (type I glass) closed with a rubber stopper (butyl) and a light-green flip-off cap (aluminium and plastic).

Solvent: Vial (Type I glass) closed with a rubber stopper (butyl) and a flip-off cap (aluminium and plastic).

Each vial of powder delivers 10 mg somatropin; each vial of solvent contains 1.5 mL liquid.

Pack sizes:

1 vial of powder and 1 vial of solvent.

4 vials of powder and 4 vials of solvent.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Reconstitution

Somatropin Biopartners 10 mg should be reconstituted with 0.7 mL solvent.

The suspension should appear uniform and white.

The 10-mg vial contains an overfill of somatropin powder to allow the withdrawal of up to 10 mg (0.5 mL suspension) of somatropin when reconstituted.

Each vial is for single use only.

Reconstitution and dilution should be performed using aseptic techniques to ensure the sterility of the prepared suspension. The solvent vial should be warmed to room temperature and the powder vial should be tapped and shaken to ensure the powder is moving freely. After removal of the protective caps from the top of both vials the rubber stoppers should be cleaned with an alcohol swab. A 1 mL graduated syringe with 19 Gauge or wider needle should be used for withdrawing the solvent from its vial. The syringe should be filled with a volume of air equal to the required volume of the solvent for injection and the air injected into the solvent vial to make it easier to withdraw the solvent. The vial should be turned upside down, with the syringe in and the tip of the needle should be placed in the solvent. To remove any bubbles, the syringe should be tapped gently. The plunger should be pushed up gently, until all bubbles are removed from the syringe and needle. The syringe should be filled with the correct volume of the solvent for injection as listed above and the syringe needle withdrawn from the vial subsequently. Any remaining solvent should not be used for a second preparation.

Holding the needle against the inside vial wall, the entire contents of the syringe should be injected into the powder vial. Without touching the rubber top the vial should be swirled vigorously until the content is completely mixed. This usually takes approximately 60 seconds but can take up to

90 seconds. The swirling should only be stopped once the suspension appears uniform, white and all the powder on the bottom is dispersed. After reconstitution the medicinal product should be used immediately before the suspension settles. If not used immediately, the suspension must be reconstituted again by swirling immediately before injection. The appropriate volume should be withdrawn in a sterile syringe via a sterile 26-gauge needle: The vial should be turned upside down, with the syringe in, and the tip of the needle should be placed in the suspension which is then slowly withdrawn. To remove small air bubbles the syringe should be tapped gently. The powder should be homogenously suspended in the injection vehicle prior to administration.

The syringe should be held upright and gentle pressure applied to the plunger until a small drop of suspension appears at the end of the needle. The injection site should be cleaned with an alcohol swab and the suspension injected over a period of 5 seconds.

Detailed information on how to administer this medicinal product is provided in section 3 of the patient leaflet.

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

7. MARKETING AUTHORISATION HOLDER

BioPartners GmbH

Kaiserpassage 11 D-72764 Reutlingen Germany

Tel: +49 (0) 7121 948 7756 Fax: +49 (0) 7121 346 255 e-mail: info@biopartners.de

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/849/004

EU/1/13/849/005

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 August 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Somatropin Biopartners 20 mg powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial delivers 20 mg of somatropin* (corresponding to 60 IU)

After reconstitution, 1 mL of suspension contains 20 mg somatropin (20 mg/mL).

*produced in Saccharomyces cerevisiae by recombinant DNA technology

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

White or almost white powder. The solvent is a clear, oily liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Somatropin Biopartners is indicated in children and adolescents aged 2 to 18 years for long-term treatment of growth failure due to insufficient secretion of endogenous growth hormone.

4.2 Posology and method of administration

Diagnosis and therapy with this medicinal product should be initiated and monitored by physicians adequately experienced in the diagnosis and management of patients with growth hormone deficiency (GHD).

Posology

The recommended and maximum dose is 0.5 mg/kg / week and should not be exceeded. In children, Somatropin Biopartners should be administered subcutaneously at a concentration of 20 mg/mL. For dosage instruction, see table below.

It is recommended that a maximum injection volume of 1 mL per injection site, corresponding to a dose of 20 mg of somatropin, should not be exceeded.

For children up to 20 kg Somatropin Biopartners 10 mg powder and solvent for prolonged-release suspension for injection is available.

The maximum retrievable amount of somatropin in one vial of suspension is 20 mg which is sufficient for administration in children of up to 40 kg bodyweight. For children heavier than 40 kg, two vials (a 10 mg and a 20 mg vial or two vials of 20 mg) can be used according to the body weight as indicated in the table below. The maximum injection volume per injection site should not exceed 1 mL.

Therefore, in children weighing more than 40 kg the overall injection volume must be divided into equal parts between two injection sites, as more than 1 mL of suspension is required.

Conversion from patient body weight to dose, number of vials, total injection volume and number of injections in paediatric patients

Patient

Dose

Vials and solvent required

Injection volume

Number of

bodyweight

injections

(mg)

for preparation of one dose*

(mL)

(kg)

per dose

 

 

 

 

0.1

 

 

0.15

 

 

0.2

 

One 10-mg vial reconstituted

0.25

 

0.3

 

with 0.7 mL solvent

 

0.35

 

 

 

 

0.4

 

 

0.45

 

 

0.5

 

0.55

 

 

 

0.6

 

 

0.65

 

One 20-mg vial reconstituted

0.7

 

0.75

 

with 1.2 mL solvent

 

0.8

 

 

 

 

0.85

 

 

0.9

 

 

0.95

 

 

1.0

 

 

1.05

 

One 10-mg vial reconstituted

1.1

 

1.15

 

with 0.7 mL solvent

1.2

 

and

1.25

 

One 20-mg vial reconstituted

1.3

 

with 1.2 mL solvent

1.35

 

 

1.4

 

 

1.45

 

 

1.5

 

1.55

 

 

 

1.6

 

 

1.65

 

Two 20-mg vials reconstituted

1.7

 

1.75

 

with 1.2 mL solvent each

 

1.8

 

 

 

 

1.85

 

 

1.9

 

 

1.95

 

 

2.0

 

* Each vial contains an overfill of somatropin powder to allow the withdrawal of the required amount of somatropin when reconstituted. (see section 6.6).

Treatment with this medicinal product should be continued until final height has been reached or until epiphyseal closure.

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. standardised to average adult peak bone mass measured by dual energy X-ray absorptiometry taking into account gender and ethnicity) is one of the therapeutic objectives during the transition period. Once a normal peak bone mass is attained patients should be switched to Somatropin Biopartners for adults, if clinically indicated, and the dosing recommendation for adults should be followed.

Special populations

Renal/hepatic impairment

No information in patients with renal or hepatic impairment is available and particular dose recommendations cannot be given.

Paediatric population (below 2 years of age)

Somatropin Biopartners should not be used in infants below the age of 2 years.

Method of administration

The patient or carer should receive training to ensure understanding of the administration procedure before being allowed to (self-) inject.

Somatropin Biopartners is administered subcutaneously once a week. After reconstitution the injection should be administered immediately.

The subcutaneous injection should always be administered at the same time of the day to increase compliance and the site of injection must be varied to prevent lipoatrophy.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somatropin must not be used when there is any evidence of tumour activity. Intracranial tumours must be inactive and antitumour therapy must be completed prior to the initiation of growth hormone therapy. Treatment should be discontinued if there is evidence of tumour (re)growth.

Somatropin must not be used for growth promotion in children with closed epiphyses.

Somatropin treatment must not be started in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure or similar conditions.

4.4 Special warnings and precautions for use

Malignancies

Patients with prior malignancies should be examined routinely for progression or recurrence.

In paediatric patients there is no evidence that growth hormone replacement influences the recurrence rate or regrowth of intracranial neoplasms, but standard clinical practice requires regular pituitary imaging in patients with a history of pituitary pathology. A baseline scan is recommended in these patients before instituting growth hormone replacement therapy.

There is an increased risk that paediatric patients with prior malignancies may develop second neoplasm when treated with growth hormone, especially if treatment of the primary malignancy involved radiotherapy. These patients should be counselled on risks before initiating therapy.

Benign intracranial hypertension

In cases of severe or recurrent headache, visual problems, nausea, and/or vomiting, a fundoscopy 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 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.

Insulin sensitivity

Because human growth hormone (hGH) may induce a state of insulin resistance and hyperglycaemia, patients treated with this medicinal product should be monitored for evidence of glucose intolerance. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin treatment is initiated. 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. Hypothyroidism may develop in patients with central subclinical hypothyroidism after initiating therapy with growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to somatropin.

In patients with hypopituitarism receiving thyroxin replacement therapy, hyperpituitarism may develop. Thyroid function should therefore be closely monitored in all patients.

Adrenal function

Treatment with growth hormone may facilitate the development of adrenal insufficiency and potentially fatal adrenal crises in patients with organic GHD or idiopathic panhypopituitarism. It is therefore crucial to assess baseline and stress doses of glucocorticoids which may need to be adjusted when growth hormone therapy is initiated.

Other precautions

This medicinal product is not indicated for the treatment of patients with growth failure due to Prader-Willi syndrome unless they also have a diagnosis of GHD. There have been reports of sleep apnoea and sudden death after initiating growth hormone therapy in 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.

After accidental intramuscular injection, hypoglycaemia may occur.

Paediatric patients with endocrine disorders, including GHD, may develop slipped capital femoral epiphyses more frequently. Any child with the onset of a limp during growth hormone therapy should be evaluated.

The recommended weekly dose in children (i.e. 0.5 mg/kg/week) should not be exceeded as there is limited experience with higher doses in this patient group.

Leukaemia

Leukaemia has been reported in a small number of GHD 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.

Scoliosis

Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. Somatropin has not been shown to increase the incidence or severity of scoliosis.

Antibodies

Some patients may develop antibodies to this medicinal product. Somatropin Biopartners has given rise to the formation of antibodies in approximately 33% of the paediatric patients. The binding activity of these antibodies has been low and no clinical consequences have been associated with their formation. Testing for antibodies to somatropin may be considered in patients with otherwise unexplained lack of growth response.

Injection site reactions

Injection site related reactions, mostly swelling at the injection site, were reported in approximately 43% of the paediatric patients. Few patients discontinued treatment due to injections site reactions, see section 4.8.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Excessive glucocorticoid therapy will inhibit the growth-promoting effect of hGH. Patients receiving concomitant glucocorticoid therapy should have their dose carefully adjusted to avoid an inhibitory effect on growth.

Growth hormone increases the extrathyroidal conversion of thyroxin (T4) to triiodothyronine (T3) and may unmask central hypothyroidism. Thyroxine replacement therapy may therefore need to be initiated or adjusted.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective.

Patients taking insulin for diabetes mellitus should be carefully monitored during treatment with somatropin. Because hGH may induce a state of insulin resistance, an adjustment of the insulin dose may be required.

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 cyclosporine) may be increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Somatropin Biopartners is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no data on the use of this medicinal product in pregnant women. Very limited data on exposure to other somatropin preparations during early pregnancy did not indicate an adverse pregnancy outcome. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

During normal pregnancy, levels of pituitary growth hormone fall markedly after 20 weeks of gestation, being replaced almost entirely by placental growth hormone by 30 weeks. In view of this, it is unlikely that continued replacement therapy with somatropin would be necessary in growth hormone deficient women in the third trimester of pregnancy. Somatropin Biopartners is not recommended during pregnancy.

Breast-feeding

No clinical studies have been conducted with Somatropin Biopartners in breast-feeding women. It is unknown whether somatropin or its metabolites are excreted in human breast milk; however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely. Caution should be exercised when this medicinal product is administered to breast-feeding women.

Fertility

Animal studies with other somatropin formulations have shown adverse effects but the available nonclinical data are considered insufficient to draw firm conclusions on the use in humans (see section 5.3).

4.7 Effects on ability to drive and use machines

Somatropin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Clinical trials included approximately 530 patients treated with Somatropin Biopartners. When adverse reactions occurred, they tended to be transient and severity was generally mild to moderate. The safety profile of Somatropin Biopartners is generally consistent with the well known safety profile of daily growth hormone treatments. The adverse reactions most commonly reported were injection site related reactions, peripheral oedema, headache, myalgia, arthralgia, paraesthesia, hypothyroidism and decreased free thyroxine.

Tabulated list of adverse reactions

The following adverse reactions have been observed under treatment with Somatropin Biopartners in a 12-month controlled comparative clinical study in 178 treatment naïve children with growth failure due to insufficient secretion of endogenous growth hormone and in a dose finding study. Additional reports based on published information for daily growth hormone treatments are listed with asterisks. The frequency of adverse reactions listed below is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data):

Immune system disorders

Very common: Formation of antibodies against growth hormone (33%), see section “Descriptions of selected adverse reactions”, under “Immunogenicity”

Endocrine disorders

Common: Hypercortisolism (7.7%), hypothyroidism (2.2%), adrenal cortical insufficiency (3.3%), hypothyreosis secondary to TSH deficiency (2.6%), decreased free thyroxine (4.4%), increased blood TSH (2.2%)

Metabolism and nutrition disorders

Common: Mild hyperglycaemia*

Not known: Insulin resistance*

Psychiatric disorders

Very rare: insomnia*

Nervous system disorders

Common: headache (4.4%), lethargy (1.1%), dizziness (2.6%)

Rare: paraesthesia*

Vascular disorders

Rare: hypertension*

Gastrointestinal disorders

Common: vomitting (1.1%), abdominal pain (1.1%)

Skin and subcutaneous tissue disorders

Common: pigmentation disorder (1.1%)

Musculoskeletal and connective tissue disorders

Common: arthralgia (1.1%), pain in extremities (5.1%)

Reproductive system and breast disorders

Very rare: gynaecomastia*

General disorders and administration site conditions

Very common: injection site swelling (30.8%)

Common: injection site pain (9.9%), injection site discolouration (8.8%), injection site erythema (7.7%), injection site nodule (4.4%), injection site reaction (1.1%), injection site warmth (1.1%), pyrexia (2.6%), oedema (local and generalised)*

Investigations

Common: decreased blood cortisol (2.2%)

Description of selected adverse reactions

Injection site reactions

The most frequently reported adverse reactions in children were injection site related reactions, most of them being mild to moderate in intensity. Few patients discontinued treatment due to injections site reactions.

Immunogenicity

In the pivotal paediatric study, antibody responses to somatropin at two or more consecutive visits were observed in 33% of the patients. No effect on safety or efficacy was observed. It is unlikely that the antibody responses to treatment with Somatropin Biopartners are of clinical relevance.

With regard to antibodies against host cell proteins, low anti-S. cerevisiae protein antibody titres similar to levels in the normal untreated population were found in some patients treated with this medicinal product. The generation of such antibodies with low binding activity is unlikely to be clinically relevant.

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 national reporting system listed in Appendix V.

4.9 Overdose

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Due to the prolonged-release characteristics of this medicinal product peak levels of growth hormone can be expected approximately 15 hours after injection, see section 5.2. Long term over-dosing could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of hGH excess.

Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and agonists, ATC code: H01AC01

The somatropin in this medicinal product is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 Daltons. The amino acid sequence of the active substance is identical to that of hGH of pituitary origin. The somatropin in this medicinal product is synthesised in yeast (Saccharomyces cerevisiae).

Mechanism of action

The biological effects of somatropin are equivalent to those of hGH of pituitary origin.

The most prominent effect of somatropin in children is the stimulation of the growth plates of long bones. Additionally, it promotes cellular protein synthesis and nitrogen retention.

Pharmacodynamic effects

Somatropin stimulates lipid metabolism; it increases plasma fatty acids and high-density lipoprotein (HDL)-cholesterols, and decreases total plasma cholesterol.

Somatropin therapy has a beneficial effect on body composition in patients with -GHD, in that body fat stores are reduced and lean body mass is increased. Long-term therapy in growth hormone-deficient patients increases bone mineral density.

Somatropin may induce insulin resistance. Large doses of somatropin may impair glucose tolerance.

Clinical efficacy and safety

In a randomized, parallel-group, multicentre Phase III study, 178 children between 3 and 12 years of age with organic and/or idiopathic GHD were randomised to receive either weekly administered Somatropin Biopartners (0.5 mg/kg/week) or daily administered recombinant hGH (0.03 mg/kg/day) for 12 months. The results showed weekly administered Somatropin Biopartners to be non inferior to daily administered recombinant hGH with respect to the primary endpoint of height velocity after 12 months. Similar results were achieved for all other parameters assessed including height SDS

(standard deviation score), bone maturation, IGF-I and IGF BP-3. In the children receiving Somatropin Biopartners a higher incidence of (non-serious) injection site reactions and a higher rate of formation of (non-neutralising) antibodies against somatropin as compared to children with daily administered recombinant growth hormone were observed (see also sections 4.4 and 4.8).

5.2 Pharmacokinetic properties

Absorption

Following repeated weekly subcutaneous administration of a mean dose of 0.5 mg/kg prolonged release somatropin to prepubertal children with GHD the Cmax and tmax of plasma hGH were about 60.7 ng/mL and 12.0 h respectively. In general, Cmax and AUC increased approximately proportionally with dose over a dose range of 0.2 to 0.7 mg/kg in prepubertal children with GHD. The apparent terminal half-life was about 7.4 h in children, presumably reflecting slow absorption from the site of injection.

The tmax was later and the half-life longer following the administration of Somatropin Biopartners than when immediate release products had been previously administered once daily to the same subjects reflecting the slower and more prolonged release of hGH from the site of injection of Somatropin Biopartners.

Distribution

No accumulation of hGH following multiple dosing of this medicinal product has been observed.

Biotransformation / Elimination

The metabolic fate of hGH involves classical protein catabolism in both the liver and kidney.

5.3 Preclinical safety data

Non-clinical pharmacokinetic and pharmacodynamic studies in dogs and juvenile monkeys showed that Somatropin Biopartners released recombinant hGH in a prolonged manner and increased serum IGF-I for an extended period up to 5-6 days.

Non-clinical data revealed no specific hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity.

Animal studies with this medicinal product are not sufficient to fully assess the reproductive toxicity potential. From reproductive toxicity studies performed with other somatropin products there is no evidence of an increased risk of adverse reactions to the embryo or foetus. Doses in excess of human therapeutic doses have shown adverse effects on reproductive function in male and female rats and male dogs, possibly through disruption of hormonal regulation. In rabbits and monkeys no adverse effects were observed.

Long term carcinogenicity studies with Somatropin Biopartners have not been conducted. There are no specific studies which address local tolerance in animals after subcutaneous injection, but data available from the repeated-dose toxicity studies revealed swelling and inflammatory infiltrate at the injection sites.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Sodium hyaluronate

Egg phospholipids

Sodium dihydrogen phosphate anhydrous

Disodium phosphate anhydrous.

Solvent:

Medium chain triglycerides.

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: From a microbiological point of view, the product must be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2 - 8°C). Do not freeze.

For storage conditions of the reconstituted medicinal product, see section 6.3

6.5 Nature and contents of container

Powder: Vial (type I glass) closed with a rubber stopper (butyl) and a green flip-off cap (aluminium and plastic).

Solvent: Vial (Type I glass) closed with a rubber stopper (butyl) and a flip-off cap (aluminium and plastic).

Each vial of powder delivers 20 mg somatropin; each vial of solvent contains 1.5 mL liquid.

Pack sizes:

1 vial of powder and 1 vial of solvent.

4 vials of powder and 4 vials of solvent.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Reconstitution

Somatropin Biopartners 20 mg should be reconstituted with 1.2 mL solvent.

The suspension should appear uniform and white.

The 20-mg vial contains an overfill of somatropin powder to allow the withdrawal of up to 20 mg (1 mL suspension) of somatropin when reconstituted.

Each vial is for single use only.

Reconstitution and dilution should be performed using aseptic techniques to ensure the sterility of the prepared suspension. The solvent vial should be warmed to room temperature and the powder vial should be tapped and shaken to ensure the powder is moving freely. After removal of the protective caps from the top of both vials the rubber stoppers should be cleaned with an alcohol swab. A 1 mL graduated syringe with 19 Gauge or wider needle should be used for withdrawing the solvent from its vial. The syringe should be filled with a volume of air equal to the required volume of the solvent for injection and the air injected into the solvent vial to make it easier to withdraw the solvent. The vial should be turned upside down, with the syringe in and the tip of the needle should be placed in the solvent. To remove any bubbles, the syringe should be tapped gently. The plunger should be pushed up gently, until all bubbles are removed from the syringe and needle. The syringe should be filled with the correct volume of the solvent for injection as listed above and the syringe needle withdrawn from the vial subsequently. Any remaining solvent should not be used for a second preparation.

Holding the needle against the inside vial wall, the entire contents of the syringe should be injected into the powder vial. Without touching the rubber top the vial should be swirled vigorously until the content is completely mixed. This usually takes approximately 60 seconds but can take up to

90 seconds. The swirling should only be stopped once the suspension appears uniform, white and all the powder on the bottom is dispersed. After reconstitution the medicinal product should be used immediately before the suspension settles. If not used immediately, the suspension must be reconstituted again by swirling immediately before injection. The appropriate volume should be withdrawn in a sterile syringe via a sterile 26-gauge needle: The vial should be turned upside down, with the syringe in, and the tip of the needle should be placed in the suspension which is then slowly withdrawn. To remove small air bubbles the syringe should be tapped gently. The powder should be homogenously suspended in the injection vehicle prior to administration.

The syringe should be held upright and gentle pressure applied to the plunger until a small drop of suspension appears at the end of the needle. The injection site should be cleaned with an alcohol swab and the suspension injected over a period of 5 seconds.

Detailed information on how to administer this medicinal product is provided in section 3 of the patient leaflet.

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

7. MARKETING AUTHORISATION HOLDER

BioPartners GmbH

Kaiserpassage 11 D-72764 Reutlingen Germany

Tel: +49 (0) 7121 948 7756 Fax: +49 (0) 7121 346 255 e-mail: info@biopartners.de

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/849/006

EU/1/13/849/007

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 August 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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