Norditropin^® SimpleXx® 5 mg/1.5 ml, solution for injection.

Norditropin^® SimpleXx® 10 mg/1.5 ml, solution for injection.

Norditropin^® SimpleXx® 15 mg/1.5 ml, solution for injection.

Norditropin SimpleXx:

Somatropin 5 mg/1.5 ml (3.3 mg/ml), 10 mg/1.5 ml (6.7 mg/ml) and 15 mg/1.5 ml (10 mg/ml).

Somatropin (epr).

1 mg of somatropin corresponds to 3 IU (International Unit) of somatropin.

Solution for injection.

Children:

Growth failure due to growth hormone insufficiency.

Growth failure in girls due to gonadal dysgenesis (Turner's Syndrome).

Growth retardation in prepubertal children due to chronic renal disease.

Growth disturbance (current height SDS < -2.5 and parental adjusted height SDS < -1) in short children born small for gestational age (SGA), with a birth weight and/or length below -2 SD, who failed to show catch-up growth (HV SDS <0 during the last year) by 4 years of age or later.

Adults:

Pronounced growth hormone deficiency in known hypothalamic-pituitary disease (one other deficient axis, other than prolactin), demonstrated by one provocative test after institution of adequate replacement therapy for any other deficient axis.

Childhood onset growth hormone insufficiency, reconfirmed by two provocative tests.

In adults, the insulin tolerance test is the provocative test of choice. When the insulin tolerance test is contraindicated, alternative provocative tests must be used. The combined arginine-growth hormone releasing hormone is recommended. An arginine or glucagon test may also be considered; however these tests have less established diagnostic value than the insulin tolerance test.

The dosage is individual and must always be adjusted in accordance with the individual's response to therapy.

Prescription only.

Norditropin should only be prescribed by doctors with special knowledge of the therapeutic indication of use.

Generally, daily subcutaneous administration in the evening is recommended. The injection site should be varied to prevent lipoatrophy.

Generally recommended dosages:

Children:

Growth hormone insufficiency

25-35 μg/kg/day or 0.7-1.0 mg/m²/day

Equal to: 0.07-0.1 IU/kg/day (2-3 IU/m²/day)

Turner's syndrome

45-67 μg/kg/day or 1.3-2.0 mg/m²/day

Equal to: 0.13-0.2 IU/kg/day (3.9-6 IU/m²/day)

Chronic Renal Disease

50 μg/kg/day or 1.4 mg/m²/day

Equal to: 0.14 IU/kg/day (4.3 IU/m²/day)

Small for Gestational Age

35 μg/kg/day or 1 mg/m²/day

Equal to: 0.1 IU/kg/day (3 IU/m²/day)

A dose of 0.035 mg/kg/day is usually recommended until final height is reached. (See section 5.1).

Treatment should be discontinued after the first year of treatment, if the height velocity SDS is below +1.

Treatment should be discontinued if height velocity is < 2 cm/year and, if confirmation is required, bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of the epiphyseal growth plates.

Adults:

Replacement therapy in adults

The dosage must be adjusted to the need of the individual patient. It is recommended to start treatment with a low dose 0.15-0.3 mg/day (equal to 0.45-0.9 IU/day). It is recommended to increase the dosage gradually at monthly intervals based on the clinical response and the patient's experience of adverse events. Serum insulin-like growth factor I (IGF-I) can be used as guidance for the dose titration.

Dose requirements decline with age. Maintenance dosage varies considerably from person to person, but seldom exceeds 1.0 mg/day (equal to 3 IU/day).

Any evidence of active malignant tumours.

Intracranial neoplasm must be inactive and anti-tumour therapy should be completed prior to institution of therapy.

Pregnancy and lactation. Please refer to Section 4.6.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with Norditropin.

Hypersensitivity to somatropin or to any of the excipients.

In the children with chronic renal disease treatment with Norditropin SimpleXx should be discontinued at renal transplantation.

Children treated with Norditropin SimpleXx should be regularly assessed by a specialist in child growth. Norditropin SimpleXx treatment should always be instigated by a physician with special knowledge of growth hormone insufficiency and its treatment. This is true also for the management of Turner's syndrome and chronic renal disease and SGA. Data of final adult height following the use of Norditropin for children with chronic renal disease are not available.

The stimulation of skeletal growth in children can only be expected until the epiphyseal discs are closed.

The dosage in children with chronic renal disease is individual and must be adjusted according to the individual response to therapy. The growth disturbance should be clearly established before Norditropin SimpleXx treatment by following growth on optimal treatment for renal disease over one year. Conservative management of uraemia with customary medication and if needed dialysis should be maintained during Norditropin SimpleXx therapy.

Patients with chronic renal disease normally experience a decline in renal function as part of the natural course of their illness. However, as a precautionary measure during Norditropin SimpleXx treatment renal function should be monitored for an excessive decline, or increase in the glomerular filtration rate (which could imply hyperfiltration).

In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.

In SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.

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

Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty.

Experience with patients with Silver-Russell syndrome is limited.

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

Somatropin has been found to influence carbohydrate metabolism, therefore, patients should be observed for evidence of glucose intolerance.

Serum thyroxine levels may fall during treatment with Norditropin SimpleXx due to the increased peripheral deiodination of T4 to T3.

In patients with a pituitary disease in progression, hypothyroidism may develop.

Patients with Turner's syndrome have an increased risk of developing primary hypothyroidism associated with anti-thyroid antibodies.

As hypothyroidism interferes with the response to Norditropin SimpleXx therapy patients should have their thyroid function tested regularly, and should receive replacement therapy with thyroid hormone when indicated.

In insulin treated patients adjustment of insulin dose may be needed after initiation of Norditropin SimpleXx treatment.

Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process.

Leukaemia has been reported in a small number of growth hormone deficient patients some of whom have been treated with somatropin. Based on 10 years global assessment there is no increased risk of development of leukaemia during somatropin treatment. In patients in complete remission from tumours or malignant disease, growth hormone therapy has not been associated with an increased relapse rate. Nevertheless, patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of Norditropin SimpleXx therapy.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders and Legg-Calvé-Perthes disease may occur more frequently in patients with short stature. These diseases may present as the development of a limp or complaints of hip or knee pain and physicians and parents should be alerted to this possibility.

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.

In the event of severe or recurrent headache, visual problems, nausea, and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and if appropriate the growth hormone treatment should be discontinued.

At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Growth hormone deficiency in adults is a lifelong disease and needs to be treated accordingly, however, experience in patients older than 60 years and in patients with more than five years of treatment in adult growth hormone deficiency is still limited.

Two placebo-controlled clinical trials of patients in intensive care units have demonstrated an increased mortality among patients suffering from acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure, who were treated with somatropin in high doses (5.3 – 8 mg/day). The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illness should be weighed against the potential risk.

Concomitant glucocorticoid therapy may inhibit growth and thereby oppose the growth promoting effect of Norditropin SimpleXx. The effect of growth hormone on final height can also be influenced by additional therapy with other hormones, e.g. gonadotrophin, anabolic steroids, estrogen and thyroid hormone.

Currently there is insufficient evidence of safety of somatropin therapy during pregnancy. The possibility that somatropin is secreted in breast milk cannot be discounted.

No effects.

Growth hormone deficient patients are characterised by extracellular volume deficit. When treatment with somatropin is initiated, this deficit is corrected. Fluid retention with peripheral oedema may occur especially in adults. Carpal tunnel syndrome is uncommon, but may be seen in adults. The symptoms are usually transient dose dependent and may require dose reduction. Mild arthralgia, muscle pain and paresthesia may also occur, but is usually self-limiting.

Adverse reactions in children are uncommon or rare.

Clinical trial experience:

Nervous system disorders

Common (>1/100, <1/10): In adults headache and paraesthesia.

Uncommon (>1/1000, <1/100): In adults carpal tunnel syndrome. In children headache.

Musculoskeletal, connective tissue and bone disorders

Common (>1/100, <1/10): In adults arthralgia, joint stiffness and myalgia.

Uncommon (>1/1000, <1/100): In adults muscle stiffness.

Rare (>1/10000, <1/1000): In children arthralgia and myalgia.

General disorders and administration site conditions

Very common (>1/10): In adults peripheral oedema

Uncommon (>1/1000, <1/100): In adults and children injection site pain. In children injection site reaction NOS.

Rare (>1/10000, <1/1000): In children peripheral oedema.

Skin and subcutaneous tissue disorders

Uncommon (>1/1000, <1/100): In adults pruritus.

Rare (>1/10000, <1/1000): In children rash NOS.

Metabolism and nutrition disorders

Uncommon (>1/1000, <1/100): In adults Diabetes mellitus type 2 (See Post marketing experience)

Post marketing experience:

Very rare cases of hypersensitivity reactions have been reported (please refer to section 4.3).

Formation of antibodies directed against somatropin has rarely been observed during Norditropin therapy. The titres and binding capacities of these antibodies have been very low and have not interfered with the growth response to Norditropin administration.

Very rare cases of decrease in serum thyroxin levels have been reported during treatment with Norditropin (see under 4.4.). Increase in blood alkaline phosphatase level may be seen during the treatment with Norditropin.

Very rare cases of benign intracranial hypertension have been reported.

Very rare cases of diabetes mellitus type 2 have been reported, but most of the available literature does not demonstrate an increased incidence of diabetes associated with somatropin treatment.

Information on overdose and poisoning is lacking.

Acute overdosage can lead to low blood glucose levels initially, followed by high blood glucose levels. These decreased glucose levels have been detected biochemically, but without clinical signs of hypoglycaemia. Long-term overdosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.

ATC:H 01 AC 01.

Norditropin SimpleXx contains somatropin, which is human growth hormone produced by recombinant DNA-technology. It is an anabolic peptide of 191 amino acids stabilised by two disulphide bridges with a molecular weight of approximately 22,000 Daltons.

The major effects of Norditropin SimpleXx are stimulation of skeletal and somatic growth and pronounced influence on the body's metabolic processes.

When growth hormone deficiency is treated a normalisation of body composition takes place resulting in an increase in lean body mass and a decrease in fat mass. Somatropin exerts most of its actions through insulin-like growth factor I (IGF-I), which are produced in tissues throughout the body, but predominantly by the liver.

More than 90% of IGF-I is bound to binding proteins (IGFBPs) of which IGFBP-3 is the most important.

A lipolytic and protein sparing effect of the hormone becomes of particular importance during stress.

Somatropin also increases bone turnover indicated by an increase in plasma levels of biochemical bone markers. In adults bone mass is slightly decreased during the initial months of treatment due to more pronounced bone resorption, however, bone mass increases with prolonged treatment.

In clinical trials in short children born SGA doses of 0.033 and 0.067 mg/kg/day have been used for treatment until final height. In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at start of treatment was +1.90 SDS (0.033 mg/kg/day) and +2.19 SDS (0.067 mg/kg/day). Literature data from untreated SGA children without early spontaneous catch-up suggest a late growth of 0.5 SDS. Long-term safety data are still limited.

I.v. infusion of Norditropin (33 ng/kg/min for 3 hours) to nine growth hormone deficient patients, gave the following results: serum half-time of 21.1 ± 1.7 min., metabolic clearance rate of 2.33 ± 0.58 ml/kg/min. and a distribution space of 67.6 ± 14.6 ml/kg.

S.c. injection of Norditropin SimpleXx (2.5 mg/m²) to 31 healthy subjects (with endogenous somatropin suppressed by continuous infusion of somatostatin) gave the following results:

Maximal concentration of human growth hormone (42-46 ng/ml) after approximately 4 hours. Thereafter human growth hormone declined with a half life of approximately 2.6 hours.

In addition the different strengths of Norditropin SimpleXx were demonstrated to be bioequivalent to each other and to conventional Norditropin after subcutaneous injection to healthy subjects.

The general pharmacological effects on the CNS, cardiovascular and respiratory systems following administration of Norditropin SimpleXx with and without forced degradation were investigated in mice and rats; renal function was also evaluated. The degraded product showed no difference in effect when compared with Norditropin SimpleXx and Norditropin. All three preparations showed the expected dose dependent decrease in urine volume and retention of sodium and chloride ions.

In rats, similar pharmacokinetics has been demonstrated between Norditropin SimpleXx and Norditropin. Degraded Norditropin SimpleXx has also been demonstrated to be bioequivalent with Norditropin SimpleXx.

Single and repeated dose toxicity and local tolerance studies of Norditropin SimpleXx or the degraded product did not reveal any toxic effect or damage to the muscle tissue.

The toxicity of Poloxamer 188 has been tested in mice, rats, rabbits and dogs and no findings of toxicological relevance were revealed.

Poloxamer 188 was rapidly absorbed from the injection site with no significant retention of the dose at the site of injection. Poloxamer 188 was excreted primarily via the urine.

Mannitol, Histidine, Poloxamer 188, Phenol, Water for Injections.

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

Norditropin SimpleXx 5 mg/1.5 ml and 10 mg/1.5 ml:

The shelf life is 2 years.

After first opening: store for a maximum of 28 days at + 2°C - + 8°C.

Alternatively, the medicinal product may be stored for a maximum of 21 days not above +25°C.

Norditropin SimpleXx 15 mg/1.5 ml

The shelf life is 2 years.

After first opening: store for a maximum of 28 days at + 2°C - + 8°C.

Norditropin SimpleXx 5 mg/1.5 ml and 10 mg/1.5 ml:

Before use: Store at + 2°C - + 8°C in the outer carton. Do not freeze.

Once opened, the product may be stored for a maximum of 28 days at + 2°C - + 8°C, alternatively stored not above + 25°C for a maximum of 21 days. Store in the pen (NordiPen®) during use. Do not freeze.

Norditropin SimpleXx 15 mg/1.5 ml

Before use: Store at + 2°C - + 8°C in the outer carton. Do not freeze.

Once opened, the product may be stored for a maximum of 28 days at + 2°C - + 8°C. Store in the pen (NordiPen®) during use. Do not freeze.

Norditropin SimpleXx is contained in a colourless cartridge made of type I glass. The cartridge is closed at the bottom with a rubber stopper shaped as a plunger and at the top with a laminated rubber stopper shaped as a disc and sealed with an aluminium cap. The aluminium cap is finally sealed with a coloured cap (5 mg/1.5 ml (yellow), 10 mg/1.5 ml (blue), 15 mg/1.5 ml (green)).

The cartridge is contained in a blister packed in a carton.

Pack sizes: Norditropin SimpleXx 1 x 5mg/1.5ml

Norditropin SimpleXx 1 x 10mg/1.5ml

Norditropin SimpleXx 1 x 15 mg/1.5ml

Patients should be reminded to wash their hands thoroughly with soap and water and/or disinfectant prior to any contact with Norditropin. Norditropin should not be shaken vigorously at any time.

Norditropin SimpleXx 5 mg/1.5 ml, 10 mg/1.5 ml and 15 mg/1.5 ml should only be prescribed for use with the matching NordiPen® (NordiPen® 5, 10 and 15 respectively). Instructions for use of Norditropin SimpleXx in NordiPen® are provided within the respective packs. Patients should be advised to read these instructions very carefully.

Do not use Norditropin SimpleXx if it does not appear water clear and colourless.

Novo Nordisk Limited

BroadfieldPark, Brighton Road

Crawley, West Sussex

RH11 9RT

Norditropin^® SimpleXx® 5 mg/1.5 ml - PL 03132/0131

Norditropin^® SimpleXx® 10 mg/1.5 ml - PL 03132/0132

Norditropin^® SimpleXx® 15 mg/1.5 ml - PL 03132/0133

October 1999/31 December 2003

January 2009

POM (Prescription Only Medicine), CD (Sch. 4).