OMNITROPE 10mg / 1.5ml injection solution in the cartridge medication leaflet

Omnitrope 5 mg/1.5 ml solution for injection in cartridge

Omnitrope 10 mg/1.5 ml solution for injection in cartridge

Omnitrope 5 mg/1.5 ml solution for injection

Each ml of solution contains 3.3 mg of somatropin* (corresponding to 10 IU)

One cartridge contains 1.5 ml corresponding to 5 mg somatropin* (15 IU).

This medicine contains 9 mg benzyl alcohol in each ml.

Benzyl alcohol may cause allergic reactions.

Omnitrope 10 mg/1.5 ml solution for injection

Each ml of solution contains 6.7 mg of somatropin* (corresponding to 20 IU)

One cartridge contains 1.5 ml corresponding to 10 mg somatropin* (30 IU).

* produced in Escherichia coli by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection.

The solution is clear and colourless.

Infants, children and adolescents

- Growth disturbance due to insufficient secretion of growth hormone (growth hormonedeficiency, GHD).

- Growth disturbance associated with Turner syndrome.

- Growth disturbance associated with chronic renal insufficiency.

- Growth disturbance (current height standard deviation score (SDS) < -2.5 and parental adjustedheight SDS < -1) in short children/adolescents born small for gestational age (SGA), with abirth weight and/or length below -2 standard deviation (SD), who failed to show catch-upgrowth (height velocity (HV) SDS < 0 during the last year) by 4 years of age or later.

- Prader-Willi syndrome (PWS), for improvement of growth and body composition. Thediagnosis of PWS should be confirmed by appropriate genetic testing.

- Replacement therapy in adults with pronounced growth hormone deficiency.

- Adult onset: Patients who have severe growth hormone deficiency associated with multiplehormone deficiencies as a result of known hypothalamic or pituitary pathology, and who have atleast one known deficiency of a pituitary hormone not being prolactin. These patients shouldundergo an appropriate dynamic test in order to diagnose or exclude a growth hormonedeficiency.

- Childhood onset: Patients who were growth hormone deficient during childhood as a result ofcongenital, genetic, acquired, or idiopathic causes. Patients with childhood onset GHD shouldbe re-evaluated for growth hormone secretory capacity after completion of longitudinal growth.

In patients with a high likelihood for persistent GHD, i.e. a congenital cause or GHD secondaryto a hypothalamic-pituitary disease or insult, an insulin-like growth factor-I (IGF-I) SDS < -2off growth hormone treatment for at least 4 weeks should be considered sufficient evidence ofprofound GHD.

All other patients will require IGF-I assay and one growth hormone stimulation test.

Diagnosis and therapy with somatropin should be initiated and monitored by physicians who areappropriately qualified and experienced in the diagnosis and management of patients with growthdisorders.

The posology and administration schedule should be individualised.

Growth disturbance due to insufficient secretion of growth hormone in paediatric patients

Generally a dose of 0.025 - 0.035 mg/kg body weight per day or 0.7 - 1.0 mg/m2 body surface area perday is recommended. Even higher doses have been used.

Where childhood onset GHD persists into adolescence, treatment should be continued to achieve fullsomatic development (e.g. body composition, bone mass). For monitoring, the attainment of a normalpeak bone mass defined as a T score > -1 (i.e. standardized to average adult peak bone mass measuredby dual energy X-ray absorptiometry taking into account sex and ethnicity) is one of the therapeuticobjectives during the transition period. For guidance on dosing see adult section below.

Prader-Willi syndrome, for improvement of growth and body composition in paediatric patients

Generally a dose of 0.035 mg/kg body weight per day or 1.0 mg/m2 body surface area per day isrecommended. Daily doses of 2.7 mg should not be exceeded. Treatment should not be used inpaediatric patients with a growth velocity less than 1 cm per year and near closure of epiphyses.

Growth disturbance due to Turner syndrome

A dose of 0.045 - 0.050 mg/kg body weight per day or 1.4 mg/m2 body surface area per day isrecommended.

Growth disturbance in chronic renal insufficiency

A dose of 0.045 - 0.050 mg/kg body weight per day (1.4 mg/m2 body surface area per day) isrecommended. Higher doses may be needed if growth velocity is too low. A dose correction can beneeded after six months of treatment (see section 4.4).

Growth disturbance in short children/adolescents born small for gestational age (SGA)

A dose of 0.035 mg/kg body weight per day (1 mg/m2 body surface area per day) is usuallyrecommended until final height is reached (see section 5.1). Treatment should be discontinued afterthe first year of treatment if the height velocity SDS is below + 1. Treatment should be discontinued ifheight velocity is < 2 cm/year and, if confirmation is required, bone age is > 14 years (girls) or> 16 years (boys), corresponding to closure of the epiphyseal growth plates.

Dose recommendations in paediatric patients

Indication mg/kg body weight dose mg/m² body surfaceper day area dose per day

Growth hormone deficiency 0.025 - 0.035 0.7 - 1.0

Prader-Willi syndrome 0.035 1.0

Turner syndrome 0.045 - 0.050 1.4

Chronic renal insufficiency 0.045 - 0.050 1.4

Children/adolescents born small forgestational age (SGA) 0.035 1.0

Growth hormone deficient adult patients

In patients who continue growth hormone therapy after childhood GHD, the recommended dose torestart is 0.2 - 0.5 mg per day. The dose should be gradually increased or decreased according toindividual patient requirements as determined by the IGF-I concentration.

In adults with adult-onset GHD, therapy should start with a low dose, 0.15 - 0.3 mg per day. The doseshould be gradually increased according to individual patient requirements as determined by the IGF-Iconcentration.

In both cases treatment goal should be insulin-like growth factor (IGF-I) concentrations within 2 SDSfrom the age corrected mean. Patients with normal IGF-I concentrations at the start of the treatmentshould be administered growth hormone up to an IGF-I level into the upper range of normal, notexceeding the 2 SDS. Clinical response and side effects may also be used as guidance for dosetitration. It is recognized that there are patients with GHD who do not normalize IGF-I levels despite agood clinical response, and thus do not require dose escalation. The maintenance dose rarely exceeds1.0 mg per day. Women may require higher doses than men, with men showing an increasing IGF-Isensitivity over time. This means that there is a risk that women, especially those on oral oestrogenreplacement are under-treated while men are over-treated. The accuracy of the growth hormone doseshould therefore be controlled every 6 months. As normal physiological growth hormone productiondecreases with age, dose requirements may be reduced.

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

The injection should be given subcutaneously and the site varied to prevent lipoatrophy.

For instructions for use and handling see section 6.6.

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 activity of a tumour. Intracranial tumoursmust be inactive and anti-tumour therapy must be completed prior to starting GH therapy. Treatmentshould be discontinued if there is evidence of tumour growth.

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

Patients with acute critical illness suffering complications following open heart surgery, abdominalsurgery, multiple accidental trauma, acute respiratory failure or similar conditions must not be treatedwith somatropin (regarding patients undergoing substitution therapy, see section 4.4).

The maximum recommended daily dose should not be exceeded (see section 4.2).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypoadrenalism

Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisolconcentrations. In patients treated with somatropin, previously undiagnosed central (secondary)hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In addition,patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalismmay require an increase in their maintenance or stress doses, following initiation of somatropintreatment (see section 4.5).

Use with oral oestrogen therapy

If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to beincreased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, ifa woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to bereduced to avoid excess of growth hormone and/or side effects (see section 4.5).

Insulin sensitivity

Somatropin may reduce insulin sensitivity. For patients with diabetes mellitus, the insulin dose mayrequire adjustment after somatropin therapy is instituted. Patients with diabetes, glucose intolerance,or additional risk factors for diabetes should be monitored closely during somatropin therapy.

Thyroid function

Growth hormone increases the extrathyroidal conversion of T4 to T3 which may result in a reductionin serum T4 and an increase in serum T3 concentrations. Whereas the peripheral thyroid hormonelevels have remained within the reference ranges for healthy subjects, hypothyroidism theoreticallymay develop in subjects with subclinical hypothyroidism. Consequently monitoring of thyroidfunction should therefore be conducted in all patients. In patients with hypopituitarism on standardreplacement therapy, the potential effect of growth hormone treatment on thyroid function must beclosely monitored

Neoplasms

In growth hormone deficiency, secondary to treatment of malignant disease, it is recommended to payattention to signs of relapse of the malignancy. In childhood cancer survivors, an increased risk of asecond neoplasm has been reported in patients treated with somatropin after their first neoplasm.

Intracranial tumours, in particular meningiomas, in patients treated with radiation to the head for theirfirst neoplasm, were the most common of these second neoplasms.

Slipped capital femoral epiphysis

In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of thehip may occur more frequently than in the general population. Patients limping during treatment withsomatropin should be examined clinically.

Benign intracranial hypertension

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a fundoscopy forpapilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranialhypertension should be considered and, if appropriate, the growth hormone treatment should bediscontinued. At present there is insufficient evidence to give specific advice on the continuation ofgrowth hormone treatment in patients with resolved intracranial hypertension. If growth hormonetreatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Leukaemia

Leukaemia has been reported in a small number of growth hormone deficiency patients, some ofwhom have been treated with somatropin. However, there is no evidence that leukaemia incidence isincreased in growth hormone recipients without predisposition factors.

Antibodies

A small percentage of patients may develop antibodies to Omnitrope. Omnitrope has given rise to theformation of antibodies in approximately 1% of patients. The binding capacity of these antibodies islow and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out inany patient with otherwise unexplained lack of response.

Although rare, pancreatitis should be considered in somatropin-treated patients who developabdominal pain, especially in children.

Scoliosis

Scoliosis is known to be more frequent in some of the patient groups treated with somatropin. Inaddition, rapid growth in any child can cause progression of scoliosis. Somatropin has not been shownto increase the incidence or severity of scoliosis. Signs of scoliosis should be monitored duringtreatment.

Acute critical illness

The effects of somatropin on recovery were studied in two placebo controlled trials involving522 critically ill adult patients suffering complications following open heart surgery, abdominalsurgery, multiple accidental trauma or acute respiratory failure. Mortality was higher in patientstreated with 5.3 or 8 mg somatropin daily compared to patients receiving placebo, 42% vs. 19%.

Based on this information, these types of patients should not be treated with somatropin. As there is noinformation available on the safety of growth hormone substitution therapy in acutely critically illpatients, the benefits of continued treatment in this situation should be weighed against the potentialrisks involved.

In all patients developing other or similar acute critical illness, the possible benefit of treatment withsomatropin must be weighed against the potential risk involved.

Experience in patients above 80 years is limited. Elderly patients may be more sensitive to the actionof Omnitrope, and therefore may be more prone to develop adverse reactions.

Prader-Willi syndrome

In patients with PWS, treatment should always be in combination with a calorie-restricted diet.

There have been reports of fatalities associated with the use of growth hormone in paediatric patientswith PWS who had one or more of the following risk factors: severe obesity (those patients exceedinga weight/height of 200%), history of respiratory impairment or sleep apnoea or unidentifiedrespiratory infection. Patients with PWS and one or more of these risk factors may be at greater risk.

Before initiation of treatment with somatropin patients with PWS should be evaluated for upperairway obstruction, sleep apnoea or respiratory infections should be assessed.

If during the evaluation of upper airway obstruction, pathological findings are observed, the childshould be referred to an Ear, nose and throat (ENT) specialist for treatment and resolution of therespiratory disorder prior to initiating growth hormone treatment.

Sleep apnoea should be assessed before onset of growth hormone treatment by recognised methodssuch as polysomnography or overnight oxymetry, and monitored if sleep apnoea is suspected.

If during treatment with somatropin patients show signs of upper airway obstruction (including onsetof or increased snoring), treatment should be interrupted, and a new ENT assessment performed.

All patients with PWS should be evaluated for sleep apnoea and monitored if sleep apnoea issuspected.Patients should be monitored for signs of respiratory infections, which should be diagnosedas early as possible and treated aggressively.

All patients with PWS should have effective weight control before and during growth hormonetreatment.

Experience with prolonged treatment in adults and in patients with PWS is limited.

Small for gestational age

In short children/adolescents born SGA, other medical reasons or treatments that could explain growthdisturbance should be ruled out before starting treatment.

In SGA children/adolescents it is recommended to measure fasting insulin and blood glucose beforestart of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g.familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucosetolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should notbe administered.

In SGA children/adolescents it is recommended to measure the IGF-I level before start of treatmentand twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared toreferences for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account toconsider dose adjustment.

Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore notrecommended to initiate treatment near onset of puberty. Experience in patients with Silver-Russellsyndrome is limited.

Some of the height gain obtained with treating short children/adolescents born SGA with growthhormone may be lost if treatment is stopped before final height is reached.

Chronic renal insufficiency

In chronic renal insufficiency, renal function should be below 50 percent of normal before institutionof therapy. To verify growth disturbance, growth should be followed for a year preceding institution oftherapy. During this period, conservative treatment for renal insufficiency (which includes control ofacidosis, hyperparathyroidism and nutritional status) should have been established and should bemaintained during treatment.

The treatment should be discontinued at renal transplantation.

To date, no data on final height in patients with chronic renal insufficiency treated with Omnitrope areavailable.

Omnitrope 5 mg/1.5 ml solution for injection contains benzyl alcohol:

This medicine contains 9 mg benzyl alcohol in each ml.

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse events anddeath in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicitymay occur is not known.

Advise the parents or legal guardian to not use more than a week in young children (less than 3 yearsold) without a physician or pharmacist permission.

Advise pregnant or breast feeding patients that large amounts of benzyl alcohol can be build up intheir body and may cause sides effects (called “metabolic acidosis”).

Advise patients who have a liver or kidney disease that large amounts of benzyl alcohol can be buildup in their body and may cause sides effects (called “metabolic acidosis”).

This medicine contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium- free’.

Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of Omnitrope.

Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefullyadjusted to avoid any inhibitory effect on growth.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previouslyundiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective (seesection 4.4).

In women on oral oestrogen replacement, a higher dose of growth hormone may be required toachieve the treatment goal (see section 4.4).

Data from an interaction study performed in growth hormone deficient adults suggests that somatropinadministration 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. sexsteroids, corticosteroids, anticonvulsants and ciclosporin) may be especially increased resulting inlower plasma levels of these compounds. The clinical significance of this is unknown.

Also see section 4.4 for statements regarding diabetes mellitus and thyroid disorder and section 4.2 forstatement on oral oestrogen replacement therapy.

There are no or limited amount of data from the use of somatropin in pregnant women. Animal studiesare insufficient with respect to reproductive toxicity (see section 5.3). Somatropin is not recommendedduring pregnancy and in women of childbearing potential not using contraception.

There have been no clinical studies conducted with somatropin containing products in breast-feedingwomen. It is not known if somatropin is excreted into breast milk, but absorption of intact proteinfrom the gastrointestinal tract of the infant is extremely unlikely. Therefore caution should beexercised when Omnitrope is administered to breast-feeding women.

Fertility studies with Omnitrope have not been performed.

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

Patients with growth hormone deficiency are characterised by extracellular volume deficit. Whentreatment with somatropin is started this deficit is rapidly corrected. Adverse reactions related to fluidretention, such as peripheral oedema and arthralgia are very common; musculoskeletal stiffness,myalgia and paraesthesia are common.

In general these adverse reactions are mild to moderate, arise within the first months of treatment andsubside spontaneously or with dose-reduction.

The incidence of these adverse reactions is related to the administered dose, the age of patients, andpossibly inversely related to the age of patients at the onset of growth hormone deficiency.

Omnitrope has given rise to the formation of antibodies in approximately 1% of the patients. Thebinding capacity of these antibodies has been low and no clinical changes have been associated withtheir formation, see section 4.4.

Table 1 shows the adverse reactions ranked under headings of System Organ Class and frequencyusing the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot beestimated from the available data) for each of the indicated conditions.

Table 1

System Organ Class Frequency

Neoplasms Benign, Uncommon: Leukaemia†1

Malignant and Not known: Leukaemia†2,3,4,5

Unspecified(including cysts andpolyps)

Endocrine disorders Not known: Hypothyroidism**

Metabolism and Not known: Type II diabetes mellitus

Nutrition Disorders

Nervous System Common: Paraesthesia*, Benign intracranial

Disorders hypertension 5, Carpal Tunnel Syndrome6

Not known: Benign intracranial hypertension1,2,3,4,6

Not known: Headache**

Skin and Subcutaneaous Common: Rash**, Urticaria**

Tissues disorders Uncommon: Pruritus**

Musculoskeletal, Very common: Arthralgia*

Connective Tissue and Common: Myalgia*, Musculoskeletal stiffness*

Bone Disorders

Reproductive system Uncommon: Gynaecomastia**and breast disorders

General Disorders and Very common: Injection site reaction$, Oedema

Administration Site peripheral*

Conditions Not known: Face oedema*

Investigations Not known: Blood cortisol decreased‡1 Clinical trials in children with GHD2 Clinical trials in children with Turner syndrome3 Clinical trials in children with chronic renal insufficiency4 Clinical trials in children with SGA5 Clinical trials in PWS6 Clinical trials in adults with GHD

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, andsubside spontaneously or with dose-reduction. The incidence of these adverse effects is related to theadministered dose, the age of the patients, and possibly inversely related to the age of the patients atthe onset of growth hormone deficiency.

**Adverse drug reaction (ADR) identified post-marketing.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown† Reported in growth hormone deficient children treated with somatropin, but the incidence appears tobe similar to that in children without growth hormone deficiency.

c. Description of selected adverse reactions

Reduced serum cortisol levels

Somatropin has been reported to reduce serum cortisol levels, possibly by affecting carrier proteins orby increased hepatic clearance. The clinical relevance of these findings may be limited. Nevertheless,corticosteroid replacement therapy should be optimised before initiation of therapy.

Prader-Willi syndrome

In the post-marketing experience rare cases of sudden death have been reported in patients affected by

Prader-Willi syndrome treated with somatropin, although no causal relationship has beendemonstrated.

Leukaemia

Cases of leukaemia (rare or very rare) have been reported in growth hormone deficient children treatedwith somatropin and included in the post-marketing experience. However, there is no evidence of anincreased risk of leukaemia without predisposition factors, such as radiation to the brain or head.

Slipped capital femoral epiphysis and Legg-Calvé-Perthes disease

Slipped capital femoral epiphysis and Legg-Calvé-Perthes disease have been reported in childrentreated with GH. Slipped capital femoral epiphysis occurs more frequently in case of endocrinedisorders and Legg-Calvé-Perthes is more frequent in case of short stature. But it is unknown if these2 pathologies are more frequent or not while treated with somatropin. Their diagnosis should beconsidered in a child with a discomfort or pain in the hip or knee.

Other adverse drug reactions

Other adverse drug reactions may be considered somatropin class effects, such as possiblehyperglycaemia caused by decreased insulin sensitivity, decreased free thyroxin level and benignintra-cranial hypertension.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia.

Long-term overdose could result in signs and symptoms consistent with the known effects of humangrowth hormone excess.

Pharmacotherapeutic group: Anterior pituitary lobe hormones and analogues, ATC code: H01AC01.

Omnitrope is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu

Somatropin is a potent metabolic hormone of importance for the metabolism of lipids, carbohydratesand proteins. In children with inadequate endogenous growth hormone, somatropin stimulates lineargrowth and increases growth rate. In adults as well as in children, somatropin maintains a normal bodycomposition by increasing nitrogen retention and stimulation of skeletal muscle growth, and bymobilisation of body fat. Visceral adipose tissue is particularly responsive to somatropin. In additionto enhanced lipolysis, somatropin decreases the uptake of triglycerides into body fat stores. Serumconcentrations of IGF-I (Insulin-like Growth Factor-I) and IGFBP3 (Insulin-like Growth Factor

Binding Protein 3) are increased by somatropin. In addition, the following actions have beendemonstrated.

Lipid metabolism

Somatropin induces hepatic LDL cholesterol receptors, and affects the profile of serum lipids andlipoproteins. In general, administration of somatropin to growth hormone deficient patients results inreduction in serum LDL and apolipoprotein B. A reduction in serum total cholesterol may also beobserved.

Carbohydrate metabolism

Somatropin increases insulin but fasting blood glucose is commonly unchanged. Children withhypopituitarism may experience fasting hypoglycaemia. This condition is reversed by somatropin.

Water and mineral metabolism

Growth hormone deficiency is associated with decreased plasma and extracellular volumes. Both arerapidly increased after treatment with somatropin. Somatropin induces the retention of sodium,potassium and phosphorus.

Bone metabolism

Somatropin stimulates the turnover of skeletal bone. Long-term administration of somatropin togrowth hormone deficient patients with osteopenia results in an increase in bone mineral content anddensity at weight-bearing sites.

Physical capacity

Muscle strength and physical exercise capacity are improved after long-term treatment withsomatropin. Somatropin also increases cardiac output, but the mechanism has yet to be clarified. Adecrease in peripheral vascular resistance may contribute to this effect.

In clinical trials in short children/adolescents born SGA doses of 0.033 and 0.067 mg/kg body weightper day have been used for treatment until final height is reached. In 56 patients who werecontinuously treated and have reached (near) final height, the mean change from height at start oftreatment was +1.90 SDS (0.033 mg/kg body weight per day) and +2.19 SDS (0.067 mg/kg bodyweight per day). Literature data from untreated SGA children/adolescents without early spontaneouscatch-up suggest a late growth of 0.5 SDS.

Post-marketing study experience:

An international, non-interventional, non-controlled, longitudinal, open and multicenter, voluntarycategory 3 PASS designed to record the safety and effectiveness data of 7359 pediatric patients treatedwith Omnitrope in various indications was conducted by Sandoz between 2006 and 2020 in 11

European countries, in North America, Canada, Australia and Taiwan.

The main pediatric indications were: GHD (57.9%), SGA (26.6%), TS (4.9%), ISS (3.3%), PWS(3.2%) and CRI (1.0%). Most patients were naïve of previous rhGH treatment (86.0%). Across allindications, the most frequent AEs with a suspected causal relationship to Omnitrope treatment inpatients were headache (1.6%), injection site pain (1.1%), injection site hematoma (1.1%) andarthralgia (0.6%), assessed in 7359 pediatric patients (SAF). The majority of AEs assessed as relatedto Omnitrope treatment were expected based on the SmPC and as known for this type of class ofmolecule (GH). The intensity of most AEs was mild or moderate.

The effectiveness results, assessed in 6589 pediatric patients (EFF consisting of 5671 naïve, 915 rhGHpretreated and 3 patients with missing pre-treatment information), show that Omnitrope treatment waseffective and resulted in a substantial catch-up growth which are consistent with those reported inobservational studies of other approved rhGH medicines: the median H SDS increased effectivelyfrom -2.64 at baseline to -1.97 after 1 year and to -0.98 after 5 years of treatment in naïve patients, anda median H SDS increased from -1.49 to -1.21 after 1 year and to -0.98 after 5 years of Omnitropetreatment in pre-treated patients. 1628/6589 (24.7%) patients of the EFF reached final heightaccording to physician’s opinion (naïve: 1289/5671, 22.7%); rhGH pretreated: 338/915, 36.9%).

Median (range) final H SDS in naïve patients -1.51 (-9.3 to 2.7) and -1.43 (-8.7 to 2.1) in pre-treatedpatients.

The bioavailability of subcutaneously administered somatropin is approximately 80% in both healthysubjects and growth hormone deficient patients.

A subcutaneous dose of 5 mg of Omnitrope 5 mg/1.5 ml solution for injection in healthy adults resultsin plasma Cmax and tmax values of 72 ± 28 µg/l and 4.0 ± 2.0 hours, respectively.

A subcutaneous dose of 5 mg of Omnitrope 10 mg/1.5 ml solution for injection in healthy adultsresults in plasma Cmax and tmax values of 74 ± 22 µg/l and 3.9 ± 1.2 hours, respectively.

The mean terminal half-life of somatropin after intravenous administration in growth hormonedeficient adults is about 0.4 hours. However, after subcutaneous administration of Omnitrope5 mg/1.5 ml, Omnitrope 10 mg/1.5 ml solution for injection, a half-life of 3 hours is achieved. Theobserved difference is likely due to slow absorption from the injection site following subcutaneousadministration.

The absolute bioavailability of somatropin seems to be similar in males and females followingsubcutaneous administration.

Information about the pharmacokinetics of somatropin in geriatric and paediatric populations, indifferent races and in patients with renal, hepatic or cardiac insufficiency is either lacking orincomplete.

In studies with Omnitrope regarding subacute toxicity and local tolerance, no clinically relevanteffects have been observed.

In other studies with somatropin regarding general toxicity, local tolerance and reproduction toxicityno clinically relevant effects have been observed.

With somatropins, in vitro and in vivo genotoxicity studies on gene mutations and induction ofchromosome aberrations have been negative.

An increased chromosome fragility has been observed in one in vitro study on lymphocytes takenfrom patients after long term treatment with somatropin and following the addition of theradiomimetic drug bleomycin. The clinical significance of this finding is unclear.

In another study with somatropin, no increase in chromosomal abnormalities was found in thelymphocytes of patients who had received long-term somatropin therapy.

Omnitrope 5 mg/1.5 ml solution for injectiondisodium hydrogen phosphate heptahydratesodium dihydrogen phosphate dihydratemannitolpoloxamer 188benzyl alcoholwater for injections

Omnitrope 10 mg/1.5 ml solution for injectiondisodium hydrogen phosphate heptahydratesodium dihydrogen phosphate dihydrateglycinepoloxamer 188phenolwater for injections

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

Omnitrope 5 mg/1.5 ml solution for injection2 years

Omnitrope 10 mg/1.5 ml solution for injection18 months.

After first use the cartridge should remain in the pen and has to be kept in a refrigerator (2°C - 8°C)for a maximum of 28 days. Store and transport refrigerated (2°C - 8°C). Do not freeze. Store in theoriginal pen in order to protect from light.

Unopened cartridge

Store and transport refrigerated (2°C - 8°C). Do not freeze. Store in the original package in order toprotect from light.

For storage conditions of the in-use medicinal product, see section 6.3.

1.5 ml of solution in a cartridge (colourless type I glass) with plunger on one side (siliconisedbromobutyl), a disc (bromobutyl) and a cap (aluminium) on the other side.

Pack sizes of 1, 5 and 10.

Not all pack sizes may be marketed.

Omnitrope 5 mg/1.5 ml solution for injection is a sterile, ready-to-use solution for subcutaneousinjection filled in a glass cartridge.

This presentation is intended for multiple use. It should only be administered with the

Omnitrope Pen 5, an injection device specifically developed for use with Omnitrope 5 mg/1.5 mlsolution for injection. It has to be administered using sterile, disposable pen needles. Patients andcaregivers have to receive appropriate training and instruction on the proper use of the Omnitropecartridges and the pen from the physician or other suitable qualified health professionals.

Omnitrope 10 mg/1.5 ml solution for injection is a sterile, ready-to-use solution for subcutaneousinjection filled in a glass cartridge.

This presentation is intended for multiple use. It should only be administered with the

Omnitrope Pen 10, an injection device specifically developed for use with Omnitrope 10 mg/1.5 mlsolution for injection. It has to be administered using sterile, disposable pen needles. Patients andcaregivers have to receive appropriate training and instruction on the proper use of the Omnitropecartridges and the pen from the physician or other suitable qualified health professionals.

The following is a general description of the administration process. The manufacturer’s instructionswith each pen must be followed for loading the cartridge, attaching the injection needle and for theadministration.

1. Hands should be washed.2. If the solution is cloudy or contains particulate matter, it should not be used. The content mustbe clear and colourless.3. Disinfect the rubber membrane of the cartridge with a cleansing swab4. Insert the cartridge into the Omnitrope Pen following the instructions for use provided with thepen.5. Clean the site of injection with an alcohol swab.6. Administer the appropriate dose by subcutaneous injection using a sterile pen needle. Removethe pen needle and dispose of it in accordance with local requirements.

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

Sandoz GmbH

Biochemiestr. 10

A-6250 Kundl

Austria

Omnitrope 5 mg/1.5 ml solution for injection

EU/1/06/332/004

EU/1/06/332/005

EU/1/06/332/006

Omnitrope 10 mg/1.5 ml solution for injection

EU/1/06/332/007

EU/1/06/332/008

EU/1/06/332/009

Date of first authorisation: 12 April 2006

Date of latest renewal: 28 February 2011

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Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.