Ipsen Pharmaceuticals Ltd

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

One cartridge contains 10 mg (30 IU) of somatropin*

* human growth hormone produced in Escherichia coli cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

Solution for injection.

NutropinAq is a solution for subcutaneous use. The clear, colourless, sterile solution for multidose use is contained in a glass cartridge, closed with a rubber stopper and a rubber seal.

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

- Long-term treatment of 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.

- 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 (see section 4.4).

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.

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

Posology

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.

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-1) 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.

Method of administration

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

For instructions for use and handling, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Somatropin should not be used for growth promotion in patients with closed epiphyses.

Growth hormone should not be used in patients with active neoplasm. NutropinAq therapy should be discontinued if evidence of tumour growth develops.

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.

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.

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.

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.

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.

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. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in patients treated with NutropinAq.

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.

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 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 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.

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

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 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 in children

Children treated with somatropin have an increased risk of developing pancreatitis compared to adults treated with somatropin. Although rare, pancreatitis should be considered in somatropin-treated children who develop abdominal pain.

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 glucocortocoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment.

For NutropinAq, no clinical data on exposed pregnancies are available. Thus, the risk for humans is unknown. Although animal studies do not point to a potential risk during pregnancy, NutropinAq should be discontinued if pregnancy occurs. During pregnancy, maternal somatropin will largely be replaced by placental growth hormone.

It is not known whether somatropin is excreted in human milk, however, absorption of intact protein from the gastrointestinal tract of the infant is unlikely.

No studies on the effects of NutropinAq on the ability to drive and use machines have been performed.

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 or NutropinAq are listed in the table below, based on experience from clinical trials all approved indications (642 patients) and a post-marketing 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, with most of these adverse reactions being reported in the “general disorders and administration site conditions” system organ class.

In addition, indication-specific adverse reactions from the same clinical trials are listed in the text below the table.

Within the system organ classes, adverse reactions are listed under headings of frequency using the following categories: very common ( 1/10), common ( 1/100, < 1/10); uncommon ( 1/1000, < 1/100); rare ( 1/10,000, < 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

As with all recombinant proteins, 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.

Patients with endocrinological disorders are more prone to develop an epiphysiolysis.

Indication-specific adverse drug reactions from clinical trials

Paediatric patients:

Patients 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.

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

Common: menorrhagia.

Patients 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 patients:

Adults with growth hormone deficiency (n=127)

Very common: paraesthesia.

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

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.

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

Somatropin stimulates growth rate and increases adult height in children who lack endogenous growth hormone. 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-1 serum levels.

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-1 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.

General characteristics

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

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.

Metabolism: 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 t_½ of somatropin is about 2.3 hours. After intravenous bolus administration of somatropin, the mean terminal half-life t_½β or t_½γ 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.

Characteristics in patients

Clearance and mean terminal half-life t_½ of somatropin in adult and paediatric growth hormone deficient patients are similar to those observed in healthy subjects.

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.

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

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

The toxicity of NutropinAq has been tested in rats and monkeys and no findings of toxicological relevance were revealed. Carcinogenecity, mutagenicity and reproduction studies have not been conducted with NutropinAq.

Due to its hormonal activity, somatropin may exert a promotional effect on tumour growth in tumour-bearing subjects. To date, this has not been confirmed in patients.

Local tolerance studies with NutropinAq showed no substantial adverse local reactions.

Studies in transgenic mice suggest a low antibody provoking potential of (aged) liquid Nutropin.

No common reproduction studies were performed. However, 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.

Sodium chloride

Phenol

Polysorbate 20

Sodium citrate and 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.

Instructions for use and handling

NutropinAq is supplied as a sterile solution with preservative for multiple use. The solution should be clear immediately after removal from the refrigerator. If the solution is cloudy, the content must not be injected. Gently swirl. Do not shake vigorously in order not to 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.

Ipsen Pharma

65 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 last renewal: 16 February 2006

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.eu.int/