Paediatric population

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

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

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

Adult population

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

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

Adult-onset: The patient must have growth hormone deficiency as a result of hypothalamic or pituitary disease, and at least one other hormone deficiency diagnosed (except for prolactin). Test for growth hormone deficiency should not be performed until adequate replacement therapy for other hormone deficiencies have been instituted.

Childhood-onset: Patients who have had growth hormone deficiency as a child should be retested 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 are appropriately qualified and experienced in the diagnosis and management of patients with the therapeutic indication of use.

Posology

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

Paediatric population

Growth failure in children due to inadequate growth hormone secretion

0.025 - 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 a daily 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. In general, the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.

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

Method of administration

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

Precaution to be taken before manipulating or administering the product

NutropinAq is supplied as a multi-dose solution. After removal from the refrigerator, if the solution is cloudy, the content must not be injected. Gently swirl. Do not shake vigorously as it could denature the 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. Somatropin should 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 tumours must be inactive and anti-tumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.

Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open-heart or abdominal surgery, multiple accidental traumas or to treat patients 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 symptoms of relapse.

Patients with pre-existing tumours or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumours, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms.

Prader-Willi syndrome

NutropinAq is not indicated for the long-term treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome, unless they also have a diagnosis of growth hormone deficiency. There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in paediatric 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.

Acute critical illness

The effects of growth hormone on recovery were studied in two placebo-controlled clinical trials involving 522 adult patients who were critically ill due to complications following open-heart or abdominal 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 care units due to complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure receiving replacement doses for approved indications has not been established. Therefore, the benefit-risk assessment for continuing treatment should be performed carefully.

Chronic renal insufficiency

Patients with growth hormone failure secondary to CRI should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphyses and aseptic necrosis of the femoral head may be seen in children with advanced renal osteodystrophy and in growth hormone deficiency, 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 the hip may occur more frequently than in the general population. A patient treated with somatropin who develops 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 monitored during treatment. However, growth hormone treatment has not been shown to increase the incidence or severity of scoliosis.

Glycaemic control

Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose 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 monitored closely during somatropin therapy. Somatropin therapy is not indicated in diabetic patients with active proliferative or severe non-proliferative retinopathy.

Intracranial hypertension

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

Hypothyroidism

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

Renal transplantation

Since somatropin therapy following renal transplantation has not been adequately tested, NutropinAq treatment 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 carefully adjusted to avoid any inhibitory effect on growth. The use of NutropinAq in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated.

Leukaemia

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

Pancreatitis

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

Use with oral oestrogen therapy

If a woman taking NutropinAq begins oral oestrogen therapy, the dose of NutropinAq may need to be 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 NutropinAq may need to be reduced to avoid excess of growth hormone and/or side effects (see section 4.5).

Excipients

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

Traceability

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

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

In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment (see section 4.4).

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral hypoglycaemic medicinal product may require adjustment when somatropin therapy is initiated (see section 4.4).

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

Pregnancy

There are no or limited data from the use of somatropin in pregnant women. Thus, the risk for humans 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.

Breast-feeding

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

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

Fertility

The effect of NutropinAq has not been assessed in conventional animal fertility studies (see section 5.3) or clinical studies.

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

Summary of the safety profile

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 trials all approved indications (642 patients) and post-marketing sources which included a surveillance survey (National Cooperative Growth Study [NCGS] in 35,344 patients). Approximately 2.5 % of patients from the NCGS have experienced drug related adverse reactions.

The most frequently reported adverse reactions from the pivotal and supportive clinical trials were hypothyroidism, impaired glucose tolerance, headache, hypertonia, arthralgia, myalgia, peripheral oedema, 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 and intracranial hypertension.

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

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

NutropinAq reduces insulin sensitivity; glucose tolerance impairment was reported in both the pivotal and supportive clinical trials and the post-marketing surveillance survey. Events of diabetes mellitus and 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 the pivotal and supportive clinical trials and/or the post-marketing surveillance survey. These events can be avoided by correct injection technique and rotation of injection sites.

A small percentage of patients may develop antibodies to the protein somatropin. The binding capacity of growth hormone antibodies was lower than 2 mg/l in NutropinAq subjects tested, which has not been associated with adversely affected growth rate.

Tabulated summary of adverse reactions

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-marketing surveillance survey. Within each frequency grouping, undesirable effects are presented in order of decreasing 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 is not possible to reliably estimate their frequency.

Description of selected adverse reactions

Neoplasm

There is a risk of neoplasia due to treatment with GH. The underlying risk varies according to the underlying cause for growth hormone deficiency (e.g. secondary to intracranial lesion), associated co- morbidities and treatment(s) undertaken. NutropinAq therapy must not be initiated when there is evidence of tumour activity. Patients with pre-existing tumours or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying 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 after reduction of the NutropinAq dose or termination of therapy (see section 4.4). Fundoscopic examination is recommended at the initiation and periodically during the course of treatment.

Hypothyroidism

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

Glycaemic control

As NutropinAq may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. 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 monitored closely during somatropin therapy.

Injection site reactions

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

Slipped capital femoral epiphysis

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

Indication-specific adverse drug reactions from clinical trials

Paediatric population

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

Common: central nervous system neoplasm (2 patients experienced a recurrent medulloblastoma, 1 patient 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 chronic renal insufficiency receiving NutropinAq are more likely to develop intracranial hypertension, although children with organic GHD and Turner syndrome also have an increased incidence. The greatest 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, muscular weakness, back pain, breast pain, gynaecomastia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization 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 below:

In Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: [email protected]

In the United Kingdom via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

Acute overdose could lead to hyperglycaemia. Long-term overdose could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone.

Management

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

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

Mechanism of action

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

Pharmacodynamic effects

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

Actions that have been demonstrated for human growth hormone include:

Tissue Growth

1. Skeletal growth: growth hormone and its mediator IGF-I stimulate skeletal growth in growth hormone deficient children by an effect on the epiphyseal plates of long bones. This results in a measurable 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 of skeletal muscle cells.

3. Organ growth: Growth hormone increases the size of internal organs, including kidneys, and increases red blood cell mass.

Protein metabolism

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

Carbohydrate metabolism

Patients with inadequate growth hormone secretion sometimes experience fasting hypoglycaemia that is improved by treatment with somatropin. Growth hormone therapy may decrease insulin sensitivity and impair glucose tolerance.

Mineral metabolism

Somatropin induces retention of sodium, potassium and phosphorus. Serum concentration of inorganic phosphorus are increased in patients with growth hormone deficiency after NutropinAq therapy due to metabolic activity associated with bone growth and increased tubular reabsorption in the kidney. Serum calcium is not significantly altered by somatropin. Adults with growth hormone deficiency show low bone mineral density and in the childhood-onset patient, NutropinAq has been shown 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 urinary excretion of hydroxyproline.

Body composition

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

Clinical efficacy and safety

Growth failure in children

Two pivotal, open label, uncontrolled, multicentre studies have been conducted, one exclusively in 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 0.043 mg/kg/day, administered subcutaneously (s.c.). Doses used in these US based studies are consistent with the US approved dose regimen. Of the 139 patients included, 128 completed the first 12 months of therapy, with an average treatment time of 3.2 and 4.6 years and a total exposure of 542 patient years. In both studies there was a significant improvement in growth rate in the naï ve patients, increasing from 4.2 to 10.9 cm/year in one study and from 4.8 to 11.2 cm/year in the other at 12 months. The growth rate decreased after the first year in both studies, but continued to be greater than pretreatment levels for up to 48 months treatment (7.1 cm/year). The height standard deviation 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 bone age, which would jeopardise future growth potential. Predicted adult height (PAH) increased from 157.7-161.0 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 0.3 or 0.6 mg/kg/week either as a daily injection or three times per week, or 0.029 mg/kg/day. The data 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 years in males and 5 years in females, the mean near-adult height SDS was -0.7 in males and -1.2 in females.

IGF-I levels increased from a baseline of 43 ng/ml to 252 ng/ml at 36 months, which approximate to 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 growth failure associated with chronic renal insufficiency (CRI). Each study had a two year treatment period which included a placebo arm, followed by an open label uncontrolled extension in which all patients received somatropin. The dose was 0.05 mg/kg/day s.c. in both studies. The results 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 patients were 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 placebo over the first year (9.1-10.9 cm/year vs 6.2-6.6 cm/year), which decreased slightly in the second 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% and 65% of somatropin-treated patients, who were below normal range at baseline, had reached heights within the normal range by Month 24.

The results to Month 60 show continued improvement, and more patients reached height SDS in the normal range. The average change in height SDS after 5 years of treatment was close to 2 standard 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 for 36 and 48 months.

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

The most frequently reported AEs were associated with both NutropinAq and placebo and were fever, infection, vomiting, cough increased, pharyngitis, rhinitis and otitis media. There was a high incidence 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 regimens giving a cumulative weekly dose of approximately 0.375 mg/kg. Patients under 11 years of age were also 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 times a week and 81 patients received 0.054 mg/kg somatropin daily. The average treatment time was 4.7 years 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 significant increase 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 Month 48. 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 therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29). Thus, the greatest improvement in adult height 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 and otitis 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 patients diagnosed with adult growth hormone deficiency (AGHD), one in adult-onset AGHD (n=166) and the other 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 total body % 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 in both 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. No significant 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, although there was no statistically significant dose response for total body BMD. Lumbar spine BMD had statistically 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 the pivotal 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 AEs was also high in the placebo groups.

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

General characteristics

Absorption

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

Distribution

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 in healthy adult males is about 50 ml/kg bodyweight, approximating the serum volume.

Biotransformation

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

Elimination

After subcutaneous bolus administration, the mean terminal half-life t½ of somatropin is about 2.3 hours. After intravenous bolus administration of somatropin, the mean terminal half-life t½ β or t½ γ is about 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.

Special populations

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

Paediatric population

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 plasma concentration of somatropin may not be different between young and elderly patients.

Race

Reported values for half-lives for endogenous GH in normal adult black males are not different from observed 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 hormone deficient patients are similar to those observed in healthy subjects.

Renal impairment

Children and adults with chronic renal failure and end-stage renal disease tend to have decreased clearance compared to normal subjects. Endogenous growth hormone production may also increase in some individuals with end-stage renal disease. However, no somatropin accumulation has been reported in children with chronic renal failure or end-stage renal disease dosed with current regimens.

Turner syndrome

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

Hepatic impairment

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

Gender

No gender-specific pharmacokinetic studies have been done with NutropinAq. The available literature 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-dose toxicity studies.

Carcinogenic potential

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

Toxicity to reproduction and development

No conventional reproduction studies were performed. Somatropin is known to be associated with inhibition 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 at 10 IU/kg/day (3.3 mg/kg/day). Long-term treatment of monkeys during pregnancy and lactation and of newborn animals until adolescence, sexual maturity and reproduction did not indicate substantial disturbances of fertility, pregnancy, delivery, nursing or development of progeny.

Environmental risk assessment (ERA)

Under the proposed indications, the use of somatropin is not expected to result in an unacceptable risk 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 other medicinal 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 28 days at 2° C - 8° C. NutropinAq is designed to withstand a nominal (one hour maximum) period of time 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 local requirements.

Instructions for use and handling

NutropinAq is supplied as a multi-dose solution. After removal from the refrigerator, if the solution is cloudy, the content must not be injected. Gently swirl. Do not shake vigorously as it could denature 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 contents by 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 of 4.0 mg, in 0.1 mg increments.

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