Somatropin Biopartners - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS4.1 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.

Dose adjustment

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

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

Conversion from required dose to injection volume and vial strength

* 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 unders 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.

Hypersensitivity tive 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 resul in serum T4 and an increase in serum T3 concentrations. Hypothyroidism may develo with central subclinical hypothyroidism after initiating therapy with growth hormone. treatment of hypothyroidism may prevent optimal response to somatropin.

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

Adrenal function

Treatment with growth hormone may facilitate the development 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.

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 wi 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

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

pituitary growth hormone fall markedly after 20 weeks of

irely 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-feed ing^^

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 injecti site related reactions, peripheral oedema, headache, myalgia, arthralgia, paraesthesia, hypothyroi 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 info n 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

Common: Adrenal insufficiency, decreased free thyroxine, decreased free tri-iodothyronine, increased

Metabolis m 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 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 PROPERTIES5.1 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 PARTICULARS6.1 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 wit 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 medicin

6.5 Nature 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.

6.6 Special precautions for disposal and other handling

Reconstit

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

spension 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 948 775

Fax:+49 (0) 7121 346 255

e-mail: info@biopartners.d

NG AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 August 2013