NUTROPINAQ 10mg / 2ml injectible solution medication leaflet

NutropinAq 10 mg/2 ml (30 IU) solution for injection.

One ml contains 5 mg of somatropin*

One cartridge contains 10 mg (30 IU) of somatropin

* Somatropin is a human growth hormone produced in Escherichia coli cells by recombinant DNAtechnology.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear and colourless solution.

- Long-term treatment of children with growth failure due to inadequate endogenous growthhormone secretion.

- Long-term treatment of girls from 2 years old with growth failure associated with Turnersyndrome.

- Treatment of prepubertal children with growth failure associated with chronic renalinsufficiency up to the time of renal transplantation.

Adult population

- Replacement of endogenous growth hormone in adults with growth hormone deficiency ofeither childhood or adult-onset etiology. Growth hormone deficiency should be confirmedappropriately prior to treatment.

In adults with growth hormone deficiency the diagnosis should be established depending onthe etiology:

Adult-onset: The patient must have growth hormone deficiency as a result of hypothalamic orpituitary disease, and at least one other hormone deficiency diagnosed (except for prolactin).

Test for growth hormone deficiency should not be performed until adequate replacementtherapy for other hormone deficiencies have been instituted.

Childhood-onset: Patients who have had growth hormone deficiency as a child should beretested to confirm growth hormone deficiency in adulthood before replacement therapy with

NutropinAq is started.

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 thetherapeutic indication of use.

The NutropinAq dosage and administration schedule should be individualised for each patient.

Growth failure in children due to inadequate growth hormone secretion0.025 - 0.035 mg/kg bodyweight given as a daily subcutaneous injection.

Somatropin therapy should be continued in children and adolescents until their epiphysis are closed.

Growth failure associated with Turner syndrome

Up to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.

Somatropin therapy should be continued in children and adolescents until their epiphysis are closed.

Growth failure associated with chronic renal insufficiency

Up to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.

Somatropin therapy should be continued in children and adolescents until their epiphysis are closed,or up to the time of renal transplantation.

Adult population

Growth hormone deficiency in adults

At the start of somatropin therapy, low initial doses of 0.15 - 0.3 mg are recommended, given as adaily subcutaneous injection. The dose should be adjusted stepwise, controlled by serum Insulin-like

Growth Factor-1 (IGF-I) values. The recommended final dose seldom exceeds 1.0 mg/day. Ingeneral, the lowest efficacious dose should be administered. In older or overweight patients, lowerdoses may be necessary.

Women may require higher doses than men, with men showing an increasing IGF-I sensitivity overtime. This means that there is a risk that women, especially those on oral oestrogen therapy, are under-treated while men are over-treated.

The solution for injection should be administered subcutaneously each day. The site of injectionshould be changed.

NutropinAq is supplied as a multi-dose solution. After removal from the refrigerator, if the solution iscloudy, the content must not be injected. Gently swirl. Do not shake vigorously as it could denaturethe protein. NutropinAq is intended for use only with the NutropinAq Pen.

For instructions for use and handling of the medicinal product, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Somatropinshould not be used for growth promotion in patients with closed epiphyses.

Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumoursmust be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatmentshould be discontinued if there is evidence of tumour growth.

Growth hormone should not be initiated to treat patients with acute critical illness due tocomplications following open-heart or abdominal surgery, multiple accidental traumas or to treatpatients having acute respiratory failure.

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

Neoplasm

In patients with previous malignant disease, special attention should be given to signs and symptomsof relapse.

Patients with pre-existing tumors or growth hormone deficiency secondary to an intracranial lesionshould be examined routinely for progression or recurrence of the underlying disease process. Inchildhood cancer survivors, an increased risk of a second neoplasm has been reported in patientstreated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, inpatients treated with radiation to the head for their first neoplasm, were the most common of thesesecond neoplasms.

Prader-Willi syndrome

NutropinAq is not indicated for the long-term treatment of paediatric patients who have growthfailure due to genetically confirmed Prader-Willi syndrome, unless they also have a diagnosis ofgrowth hormone deficiency. There have been reports of sleep apnoea and sudden death afterinitiating therapy with growth hormone in paediatric patients with Prader-Willi syndrome who hadone or more of the following risk factors: severe obesity, history of upper airway obstruction or sleepapnoea, or unidentified respiratory infection.

Acute critical illness

The effects of growth hormone on recovery were studied in two placebo-controlled clinical trialsinvolving 522 adult patients who were critically ill due to complications following open-heart orabdominal surgery, multiple accidental traumas, or who were having acute respiratory failure.

Mortality was higher (41.9 % vs. 19.3 %) among growth hormone treated patients (doses 5.3 -8 mg/day) compared to those receiving placebo.

The safety of continuing somatropin treatment in patients with acute critical illness in intensive careunits due to complications following open-heart or abdominal surgery, multiple accidental trauma oracute respiratory failure receiving replacement doses for approved indications has not beenestablished. Therefore, the benefit-risk assessment for continuing treatment should be performedcarefully.

Chronic renal insufficiency

Patients with growth hormone failure secondary to CRI should be examined periodically for evidenceof progression of renal osteodystrophy. Slipped capital femoral epiphyses and aseptic necrosis of thefemoral head may be seen in children with advanced renal osteodystrophy and in growth hormonedeficiency, and it is uncertain whether these problems are affected by GH therapy.

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. A patient treated with somatropin whodevelops a limp or complains of hip or knee pain should be evaluated by a physician.

Scoliosis

Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitoredduring treatment. However, growth hormone treatment has not been shown to increase the incidenceor severity of scoliosis.

Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence ofglucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after

NutropinAq therapy is instituted. Patients with diabetes or glucose intolerance should be monitoredclosely during somatropin therapy. Somatropin therapy is not indicated in diabetic patients withactive proliferative or severe non-proliferative retinopathy.

Intracranial hypertension

Intracranial hypertension with papilloedema, visual changes, headache, nausea and/or vomiting hasbeen reported in a small number of patients treated with somatropin. Symptoms usually occur withinthe first eight weeks of the initiation of NutropinAq therapy. In all reported cases, intracranialhypertension-associated signs and symptoms resolved after reduction of the somatropin dose ortermination of the therapy. Funduscopic examination is recommended at the initiation andperiodically during the course of treatment.

Hypothyroidism may develop during treatment with somatropin, and untreated hypothyroidism mayprevent optimal response to NutropinAq. Therefore, patients should have periodic thyroid functiontests and should be treated with thyroid hormone when indicated. Patients with severehypothyroidism should be treated accordingly prior to the start of NutropinAq therapy.

Renal transplantation

Since somatropin therapy following renal transplantation has not been adequately tested, NutropinAqtreatment should be terminated after that surgery.

Glucocorticoids use

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

Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefullyadjusted to avoid any inhibitory effect on growth. The use of NutropinAq in patients with chronicrenal insufficiency receiving glucocorticoid therapy has not been evaluated.

Leukaemia

Leukaemia has been reported in a small number of growth hormone deficient patients treated withgrowth hormone. A causal relationship to somatropin therapy has not been established.

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

Use with oral oestrogen therapy

If a woman taking NutropinAq begins oral oestrogen therapy, the dose of NutropinAq may need tobe increased to maintain the serum IGF-1 levels within the normal age appropriate range.

Conversely, if a woman on NutropinAq discontinues oral oestrogen therapy, the dose of NutropinAqmay need to be reduced to avoid excess of growth hormone and/or side effects (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per cartridge, i.e. essentially“sodium- free‟.

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

Limited published data indicate that growth hormone treatment increases cytochrome P450 mediatedantipyrine clearance in man. Monitoring is advisable when somatropin is administered incombination with medicinal products known to be metabolised by CYP450 liver enzymes, such ascorticosteroids, sex steroids, anticonvulsants, and cyclosporin.

In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism maybe unmasked requiring glucocorticoid replacement therapy. In addition, patients treated withglucocortocoid replacement therapy for previously diagnosed hypoadrenalism may require anincrease in their maintenance or stress doses, following initiation of somatropin treatment (seesection 4.4).

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oralhypoglycemic medicinal product may require adjustment when somatropin therapy is initiated (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).

There are no or limited data from the use of somatropin in pregnant women. Thus, the risk forhumans is unknown.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Somatropin is not recommended during pregnancy and should be discontinued if pregnancy occurs.

During pregnancy, maternal somatropin will largely be replaced by placental growth hormone.

It is unknown whether somatropin/metabolites are excreted in human milk. No animal data areavailable.

Caution should be exercised while breast-feeding during treatment with NutropinAq.

The effect of NutropinAq has not been assessed in conventional animal fertility studies (see section5.3) or clinical studies.

Somatropin has no known effect on the ability to drive or to use machines.

The adverse reactions reported in both adults and children receiving Nutropin, NutropinAq, Nutropin

Depot or Protropin (somatrem) are listed in the table below, based on experience from clinical trialsall approved indications (642 patients) and post-marketing sources which included a surveillancesurvey (National Cooperative Growth Study [NCGS] in 35,344 patients). Approximately 2.5 % ofpatients from the NCGS have experienced drug related adverse reactions.

The most frequently reported adverse reactions from the pivotal and supportive clinical trials werehypothyroidism, impaired glucose tolerance, headache, hypertonia, arthralgia, myalgia, peripheraloedema, oedema, asthenia, injection site reaction and the presence of drug specific antibodies.

The most serious adverse reactions from the pivotal and supportive clinical trials were neoplasm andintracranial hypertension.

Neoplasms (malignant and benign) were reported in both the pivotal and supportive clinical trials andin the post-marketing surveillance survey (see sections 4.3 and 4.4). The majority of neoplasmsreported were recurrence of previous neoplasms and second neoplasms.

Intracranial hypertension was reported in the post-marketing surveillance survey. It is typicallyassociated with papilloedema, visual changes, headache, nausea, and/or vomiting and symptomsusually occur within eight weeks of initiation of therapy with NutropinAq.

NutropinAq reduces insulin sensitivity; glucose tolerance impairment was reported in both the pivotaland supportive clinical trials and the post-marketing surveillance survey. Events of diabetes mellitusand hyperglycaemia were reported in the post-marketing surveillance survey (see section 4.4).

Injection site reactions such as haemorrhage, atrophy, urticaria and pruritus were reported in thepivotal and supportive clinical trials and/or the post-marketing surveillance survey. These events canbe avoided by correct injection technique and rotation of injection sites.

A small percentage of patients may develop antibodies to the protein somatropin. The binding capacityof growth hormone antibodies was lower than 2 mg/l in NutropinAq subjects tested, which has notbeen associated with adversely affected growth rate.

Table 1 contains very common (≥ 1/10), common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100);rare (≥ 1/10,000, < 1/1,000) adverse reactions which occurred in clinical trials and a post-marketingsurveillance survey. Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness. Other adverse reactions have been identified during post approval use of

NutropinAq. Because these reactions are reported voluntarily from a population of uncertain size, it isnot possible to reliably estimate their frequency.

System Organ Class Reactions observed in Pivotal and Reactions observed from the post

Supportive Clinical Trials (in 642 marketing environmentpatients)

Neoplasms benign, Uncommon: Neoplasm malignant, Rare: Neoplasm malignantmalignant and neoplasm benign recurrence, melanocytic naevusunspecified (includingcysts and polyps)

Blood and lymphatic Uncommon: Anaemiasystem disorders

Endocrine disorders Common: Hypothyroidism Rare: Hypothyroidism

Metabolism and Common: Glucose tolerance impaired Rare: Diabetes mellitus,nutrition disorders Uncommon: Hypoglycaemia, hyperglycaemia, hypoglycaemia,hyperphosphatemia glucose tolerance impaired

Psychiatric disorders Uncommon: Personality disorder Rare: Abnormal behaviour,depression, insomnia

Nervous system Common: Headache, hypertonia, Uncommon: Headache Rare: Benigndisorders Uncommon: Carpal tunnel syndrome, intracranialsomnolence, nystagmus hypertension, intracranial pressureincreased, migraine, carpal tunnelsyndrome, paraesthesia, dizziness

Eye disorders Uncommon: Papilloedema, diplopia Rare: Papilloedema, vision blurred

Ear and labyrinth Uncommon: Vertigodisorders

Cardiac disorders Uncommon: Tachycardia

Vascular disorders Uncommon: Hypertension Rare: Hypertension

Respiratory thoracic Rare: Tonsillar hypertrophyand mediastinal Uncommon: Adenoidal hypertrophydisorders

Gastrointestinal Uncommon: Abdominal pain, Rare: Abdominal pain, diarrhoea,disorders vomiting, nausea, flatulence nausea, vomiting

Skin and subcutaneous Uncommon: Exfoliative dermatitis, Rare: Generalised pruritus, urticaria,tissue disorders skin atrophy, skin hypertrophy, rashhirsutism, lipodystrophy, urticaria

Musculoskeletal and Very common in adults, common in Uncommon: Slipped capital femoralconnective tissue children: Arthralgia, myalgia epiphysis, scoliosis progression,disorders Uncommon: Muscle atrophy, bone arthralgiapain Rare: Bone development abnormal,osteochondrosis, muscular weakness,pain in extremity

Renal and urinary Uncommon: Urinary incontinence,disorders pollakiuria, polyuria, urineabnormality

Reproductive system Uncommon: Uterine haemorrhage, Uncommon: Gynaecomastiaand breast disorders genital discharge

General disorders and Very common in adults, common in Uncommon: Peripheral oedema,administration site children: Peripheral oedema, oedema oedema, injection site reactionconditions Common: Asthenia, injection site (irritation, pain)reaction Rare: Asthenia, face oedema, fatigue,

Uncommon: Injection site irritability, pain, pyrexia, injectionhaemorrhage, injection site atrophy, site reaction (haemorrhage,injection site mass, hypertrophy haematoma, atrophy, urticaria,pruritus, swelling, erythema)

Investigations Common: Drug specific antibody Rare: Blood glucose increased,present weight increased

Neoplasm

There is a risk of neoplasia due to treatment with GH. The underlying risk varies according to theunderlying cause for growth hormone deficiency (e.g. secondary to intracranial lesion), associatedco- morbidities and treatment(s) undertaken. NutropinAq therapy must not be initiated when there isevidence of tumour activity. Patients with pre-existing tumours or growth hormone deficiencysecondary to an intracranial lesion should be examined routinely for progression or recurrence of theunderlying disease process. Treatment must be discontinued if there is evidence of tumour growth.

Intracranial hypertension

In all reported cases, intracranial hypertension associated signs and symptoms resolved afterreduction of the NutropinAq dose or termination of therapy (see section 4.4). Fundoscopicexamination is recommended at the initiation and periodically during the course of treatment.

Hypothyroidism may develop during treatment with NutropinAq and untreated hypothyroidism mayprevent optimal response to NutropinAq. Patients should have periodic thyroid function tests andshould be treated with thyroid hormone when required. Patients with pre-existing hypothyroidismshould be treated prior to the start of NutropinAq therapy.

As NutropinAq may reduce insulin sensitivity, patients should be monitored for evidence of glucoseintolerance. For patients with diabetes mellitus, the dose of insulin may need adjustment after

NutropinAq therapy is initiated. Patients with diabetes or glucose intolerance should be monitoredclosely during somatropin therapy.

Injection site reactions may be avoided by using the correct injection technique and rotation ofinjection sites.

Slipped capital femoral epiphysis

Patients with endocrinological disorders are more prone to develop a slipped capital femoralepiphysis.

Indication-specific adverse drug reactions from clinical trials

Children with growth failure due to inadequate growth hormone secretion (n=236)

Common: central nervous system neoplasm (2 patients experienced a recurrent medulloblastoma, 1patient experienced a histiocytoma). See also section 4.4.

Girls with growth failure associated with Turner syndrome (n=108)

Common: menorrhagia.

Children with growth failure associated with chronic renal insufficiency (n=171)

Common: renal failure, peritonitis, osteonecrosis, blood creatinine increase. Children with chronicrenal insufficiency receiving NutropinAq are more likely to develop intracranial hypertension,although children with organic GHD and Turner syndrome also have an increased incidence. Thegreatest risk is at the beginning of treatment.

Adult population

Adults with growth hormone deficiency (n=127)

Very common: paraesthesia.

Common: hyperglycaemia, hyperlipidaemia, insomnia, synovial disorder, arthrosis, muscularweakness, back pain, breast pain, gynaecomastia.

Reporting of suspected adverse reactions after authorization 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 to hyperglycaemia. Long-term overdose could result in signs andsymptoms of gigantism and/or acromegaly consistent with the known effects of excess growthhormone.

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

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, Somatropin andanalogues, ATC Code: H01 AC 01

Somatropin stimulates growth rate and increases adult height in children who lack endogenousgrowth hormone and in children who have growth failure due to Turner Syndrome or CRI. Treatmentof growth hormone deficient adults with somatropin results in reduced fat mass, increased lean bodymass and increased spine bone mineral density. Metabolic alterations in these patients includenormalisation of IGF-I serum levels.

In vitro and in vivo preclinical and clinical tests have demonstrated that somatropin is therapeuticallyequivalent to human growth hormone of pituitary origin.

Actions that have been demonstrated for human growth hormone include:

Tissue Growth1. Skeletal growth: growth hormone and its mediator IGF-I stimulate skeletal growth in growthhormone deficient children by an effect on the epiphyseal plates of long bones. This results in ameasurable increase in body length until these growth plates fuse at the end of puberty.2. Cell growth: Treatment with somatropin results in an increase in both the number and size ofskeletal muscle cells.3. Organ growth: Growth hormone increases the size of internal organs, including kidneys, andincreases red blood cell mass.

Protein metabolism

Linear growth is facilitated in part by growth hormone-stimulated protein synthesis. This is reflectedby nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood ureanitrogen during growth hormone therapy.

Carbohydrate metabolism

Patients with inadequate growth hormone secretion sometimes experience fasting hypoglycaemia thatis improved by treatment with somatropin. Growth hormone therapy may decrease insulin sensitivityand impair glucose tolerance.

Mineral metabolism

Somatropin induces retention of sodium, potassium and phosphorus. Serum concentration ofinorganic phosphorus are increased in patients with growth hormone deficiency after NutropinAqtherapy due to metabolic activity associated with bone growth and increased tubular reabsorption inthe kidney. Serum calcium is not significantly altered by somatropin. Adults with growth hormonedeficiency show low bone mineral density and in the childhood-onset patient, NutropinAq has beenshown to increase spine bone mineral density in a dose-dependent manner.

Connective tissue metabolism

Somatropin stimulates the synthesis of chondroitin sulphate and collagen as well as the urinaryexcretion of hydroxyproline.

Body composition

Adult growth hormone deficient patients treated with somatropin at a mean dosage of 0.014 mg/kgbodyweight daily demonstrate a decrease in fat mass and increase in lean body mass. When thesealterations are coupled with the increase in total body water and bone mass, the overall effect ofsomatropin therapy is to modify body composition, an effect that is maintained with continuedtreatment.

Growth failure in children

Two pivotal, open label, uncontrolled, multicentre studies have been conducted, one exclusivelyin previously untreated patients (n=67), and the other in previously untreated patients (n=63)and in children previously treated with somatropin (n=9). The dose in both studies was 0.043mg/kg/day, administered subcutaneously (s.c.). Doses used in these US based studies are consistentwith the US approved dose regimen. Of the 139 patients included, 128 completed the first 12months of therapy, with an average treatment time of 3.2 and 4.6 years and a total exposure of 542patient years. In both studies there was a significant improvement in growth rate in the naïvepatients, increasing from 4.2 to 10.9 cm/year in one study and from 4.8 to 11.2 cm/year in the otherat 12 months. The growth rate decreased after the first year in both studies, but continued to begreater than pretreatment levels for up to 48 months treatment (7.1 cm/year). The height standarddeviation score (SDS) improved each year, increasing from -3.0 to -2.7 at baseline to -1.0 to -0.8 at

Month 36. The improvements in growth were not accompanied by undue advancement of boneage, which would jeopardise future growth potential. Predicted adult height (PAH) increased from157.7-161.0 cm at baseline to 161.4-167.4 cm at Month 12 and 166.2-171.1 cm at Month 36.

Supportive data are provided by two other studies, in which patients were given a dose of 0.3or 0.6 mg/kg/week either as a daily injection or three times per week, or 0.029 mg/kg/day. Thedata on growth rate and height SDS were broadly similar to those observed in the pivotal studies.

For 51 patients who achieved near-adult height after an average duration of treatment of 6 yearsin males and 5 years in females, the mean near-adult height SDS was -0.7 in males and -1.2 infemales.

IGF-I levels increased from a baseline of 43 ng/ml to 252 ng/ml at 36 months, which approximateto the normal levels expected in children of this age.

The most common adverse events (AEs) observed in the pivotal studies were infection,headache, otitis media, fever, pharyngitis, rhinitis and gastroenteritis and vomiting.

Growth failure associated with chronic renal insufficiency

Two pivotal, multicentre, controlled studies have been conducted in patients with growthfailure associated with chronic renal insufficiency (CRI). Each study had a two year treatmentperiod which included a placebo arm, followed by an open label uncontrolled extension inwhich all patients received somatropin. The dose was 0.05 mg/kg/day s.c. in both studies. Theresults of both studies were similar.

In total, 128 patients received somatropin over the 24 month controlled phase of the 2 studies,and 139 patients were treated with somatropin in the open extension phases. Overall, 171 patientswere exposed to somatropin for an average of 3.5 or 2.8 years.

Both studies demonstrated a statistically significant increase in growth rate compared to placeboover the first year (9.1-10.9 cm/year vs 6.2-6.6 cm/year), which decreased slightly in thesecond year (7.4-7.9 cm/year vs 5.5-6.6 cm/year). There was also a significant increase in height

SDS in somatropin-treated patients, from -2.9 to -2.7 at baseline to -1.6 to -1.4 at 24 months.

Height gains were maintained in the patients treated for 36 or 48 months. A total of 58% and65% of somatropin-treated patients, who were below normal range at baseline, had reached heightswithin the normal range by Month 24.

The results to Month 60 show continued improvement, and more patients reached height SDS inthe normal range. The average change in height SDS after 5 years of treatment was close to 2standard deviations (SDs). A statistically significant increase in mean PAH SDS was observed,from -1.6 or

- 1.7 at baseline to -0.7 or -0.9 at Month 24. This continued to increase in those patients treated for36 and 48 months.

IGF-I levels, which were low at study entry, were restored to within the normal range withsomatropin therapy.

The most frequently reported AEs were associated with both NutropinAq and placebo and werefever, infection, vomiting, cough increased, pharyngitis, rhinitis and otitis media. There was a highincidence of urinary tract infections.

Growth failure associated with Turner Syndrome

One pivotal, multicentre, open label, controlled study has been conducted in Turner Syndrome.

Patients received an s.c. dose of 0.125 mg/kg three times a week or 0.054 mg/kg/day, both regimensgiving a cumulative weekly dose of approximately 0.375 mg/kg. Patients under 11 years of age werealso randomised to receive oestrogen therapy, either in late (aged 15 years) or early (aged 12 years)adolescence.

A total of 117 patients were treated with somatropin; 36 received somatropin 0.125 mg/kg three timesa week and 81 patients received 0.054 mg/kg somatropin daily. The average treatment time was 4.7years in the somatropin three times a week group and 4.6 years in the somatropin daily group.

Growth rate increased significantly from 3.6-4.1 cm/year at baseline to 6.7-8.1 cm/year at Month 12,6.7-6.8 cm/year at Month 24 and 4.5-5.1 cm/year at Month 48. This was accompanied by a significantincrease in height SDS from -0.1 to 0.5 at baseline to 0.0 to 0.7 at Month 12 and 1.6 to 1.7 at Month48. Compared with matched historical controls, early somatropin therapy (mean duration of 5.6 years)combined with oestrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm(n=26), whereas girls who initiated oestrogen at age 15 years (mean duration of somatropin therapy6.1 years) had a mean adult height gain of 8.3 cm (n=29). Thus, the greatest improvement in adultheight was observed in patients who received early GH treatment and oestrogen after age 14 years.

The most commonly reported AEs were flu syndrome, infection, headache, pharyngitis, rhinitis andotitis media. These events are expected in children and were mild/moderate AEs.

Growth hormone deficiency in adults

Two pivotal, multicentre, placebo-controlled, double-blind studies have been conducted in patientsdiagnosed with adult growth hormone deficiency (AGHD), one in adult-onset AGHD (n=166) and theother in childhood-onset AGHD (n=64). The dose of somatropin was 0.0125 mg/kg/day sc in adult-onset AGHD and 0.0125 or 0.025 mg/kg/day in childhood-onset AGHD.

In both studies, somatropin treatment resulted in significant changes compared to placebo in totalbody % fat (-6.3 to -3.6 vs +0.2 to-0.1), trunk % fat (-7.6 to -4.3 vs +0.6 to 0.0) and total body % lean(+3.6 to +6.4 vs -0.2 to +0.2). These changes were highly significant at the 12-month time point inboth studies, and at the 24-month time point in the childhood-onset study. At the 12-month time point,the percentage change was higher in the childhood-onset study than in the adult-onset study. Nosignificant changes in bone mineral density (BMD) were observed in adult-onset AGHD patients,however in the childhood-onset study, all groups had an increase in BMD at 24 months, althoughthere was no statistically significant dose response for total body BMD. Lumbar spine BMD hadstatistically significant increases in both treated groups, and the increase was dose dependent.

Supporting data from a study on adult-onset GHD patients were generally consistent with those of thepivotal studies, with some improvements in BMD.

The most frequently reported AEs in the two pivotal studies were headache, oedema,arthralgia/arthrosis, tenosynovitis, paraesthesia and allergic reaction/rash. The incidence of these AEswas also high in the placebo groups.

The pharmacokinetic properties of NutropinAq have only been investigated in healthy adult males.

General characteristics

The absolute bioavailability of recombinant human growth hormone after subcutaneousadministration is about 80%.

Animal studies with somatropin showed that growth hormone localises to highly perfused organs,particularly the liver and kidney. The volume of distribution at steady state for somatropin inhealthy adult males is about 50 ml/kg bodyweight, approximating the serum volume.

Both the liver and the kidney have been shown to be important protein catabolising organs forgrowth hormone. Animal studies suggest that the kidney is the dominant organ of clearance. Growthhormone is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleavedwithin renal cells into its constituent amino acids, which return to the systemic circulation.

After subcutaneous bolus administration, the mean terminal half-life t½ of somatropin is about 2.3hours. After intravenous bolus administration of somatropin, the mean terminal half-life t½ or t½isabout 20 minutes and the mean clearance is reported to be in the range of 116 - 174 ml/h/kg.

Available literature data suggest that somatropin clearance is similar in adults and children.

Information about the pharmacokinetics of somatropin in elderly and paediatric populations, indifferent races or genders and in patients with renal or hepatic impairment is incomplete.

Available literature data suggests that somatropin clearances are similar in adults and children.

Older people

Limited published data suggest that the plasma clearance and average steady-state plasmaconcentration of somatropin may not be different between young and elderly patients.

Reported values for half-lives for endogenous GH in normal adult black males are not different fromobserved values for normal adult white males. No data for other races are available.

Growth hormone deficiency

Clearance and mean terminal half-life t½ of somatropin in adult and paediatric growth hormonedeficient patients are similar to those observed in healthy subjects.

Children and adults with chronic renal failure and end-stage renal disease tend to have decreasedclearance compared to normal subjects. Endogenous growth hormone production may also increasein some individuals with end-stage renal disease. However, no somatropin accumulation has beenreported in children with chronic renal failure or end-stage renal disease dosed with currentregimens.

Turner syndrome

Limited published data for exogenously-administered somatropin suggest absorption and eliminationhalf-lives and time of maximum concentration tmax in Turner patients are similar to those observed inboth normal and growth hormone deficient populations.

In patients with severe liver dysfunction a reduction in somatropin clearance has been noted. Theclinical significance of this decrease is unknown.

No gender-specific pharmacokinetic studies have been done with NutropinAq. The availableliterature indicates that the pharmacokinetics of somatropin are similar in men and women.

Non-clinical data reveal no special hazard for human based on conventional acute and repeated-dosetoxicity studies.

Carcinogenic potential

Carcinogenicity and genotoxicity studies have not been conducted with Nutropin Aq. In genotoxicitystudies with other recombinant growth hormone preparations, there was no evidence of genemutation in bacterial reverse mutation assays, chromosomal damage in human lymphocyte andmouse bone marrow cells, gene conversion in yeast or unscheduled DNA synthesis in humancarcinoma cells. In carcinogenicity studies testing biologically recombinant active growth hormone inrats and mice, no increase in the incidence of tumors was shown.

Toxicity to reproduction and development

No conventional reproduction studies were performed. Somatropin is known to be associated withinhibition of the reproduction in male and female rats at doses of 3 IU/kg/day (1 mg/kg/day) or more,with reduced copulation and conception rates, lengthened or absent oestrous cycles, and at10 IU/kg/day (3.3 mg/kg/day). Long-term treatment of monkeys during pregnancy and lactation andof newborn animals until adolescence, sexual maturity and reproduction did not indicate substantialdisturbances of fertility, pregnancy, delivery, nursing or development of progeny.

Under the proposed indications, the use of somatropin is not expected to result in an unacceptablerisk to the environment.

Sodium Chloride

Liquified Phenol

Polysorbate 20

Sodium Citrate Dihydrate

Citric Acid, Anhydrous

Water for Injections

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

2 years

Chemical and physical in-use stability has been demonstrated for 28 days at 2°C - 8°C.

From a microbiological point of view, once opened, the product may be stored for a maximum of 28days at 2°C - 8°C. NutropinAq is designed to withstand a nominal (one hour maximum) period oftime outside of the refrigerator on a daily basis.

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

Keep the blister in the outer carton

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

2 ml of solution in a cartridge (Type I glass) closed with a stopper (butyl rubber) and a seal (rubber).

Pack sizes of 1, 3 and 6 cartridges.

Not all pack sizes may be marketed.

No special requirements.

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

Instructions for use and handling

NutropinAq is supplied as a multi-dose solution. After removal from the refrigerator, if the solutionis cloudy, the content must not be injected. Gently swirl. Do not shake vigorously as it coulddenature the protein.

NutropinAq is intended for use only with the NutropinAq Pen. Wipe the rubber seal of the

NutropinAq with rubbing alcohol or an antiseptic solution to prevent contamination of the contentsby microorganisms that may be introduced by repeated needle insertions. It is recommended that

NutropinAq be administered using sterile, disposable needles.

The NutropinAq Pen allows for administration of a minimum dose of 0.1 mg to a maximum dose of4.0 mg, in 0.1 mg increments.

A cartridge that is in the pen should not be removed during injections.

Ipsen Pharma65 quai Georges Gorse,92100 Boulogne-Billancourt,

France

EU/1/00/164/003

EU/1/00/164/004

EU/1/00/164/005

Date of first authorisation: 16 February 2001

Date of latest renewal: 16 February 2006

DD/MM/YYYY

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

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