4.1. Therapeutic indications

Children:

Growth failure due to growth hormone deficiency (GHD)

Growth failure in girls due to gonadal dysgenesis (Turner 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.

Growth failure due to Noonan syndrome.

Adults:

Childhood onset growth hormone deficiency:

Patients with childhood onset GHD should be re-evaluated for growth hormone secretory capacity after growth completion. Testing is not required for those with more than three pituitary hormone deficits, with severe GHD due to a defined genetic cause, due to structural hypothalamic pituitary abnormalities, due to central nervous system tumours or due to high-dose cranial irradiation, or with GHD secondary to a pituitary/hypothalamic disease or insult, if measurements of serum insulin-like growth factor 1 (IGF-1) is < -2 SDS after at least four weeks off growth hormone treatment.

In all other patients an IGF-1 measurement and one growth hormone stimulation test is required.

Adult onset growth hormone deficiency:

Pronounced GHD in known hypothalamic-pituitary disease, cranial irradiation and traumatic brain injury. GHD should be associated with one other deficient axis, other than prolactin. GHD should be demonstrated by one provocative test after institution of adequate replacement therapy for any other deficient axis.

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.

4.2. Posology and method of administration

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

Posology

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

Generally recommended dosages:

Paediatric population:

Growth hormone insufficiency

0.025-0.035 mg/kg/day or 0.7-1.0 mg/m2/day

When GHD persists after growth completion, growth hormone treatment should be continued to achieve full somatic adult development including lean body mass and bone mineral accrual (for guidance on dosing, see Replacement therapy in adults).

Turner syndrome

0.045-0.067 mg/kg/day or 1.3-2.0 mg/m2/day

Chronic renal disease

0.050 mg/kg/day or 1.4 mg/m2/day (see section 4.4)

Small for Gestational Age

0.035 mg/kg/day or 1.0 mg/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.

Noonan syndrome:

0.066 mg/kg/day is the recommended dose, however in some cases 0.033 mg/kg/day may be sufficient (see section 5.1).

Treatment should be discontinued at the time of epiphyseal closure (see section 4.4).

Adult population:

Replacement therapy in adults

The dosage must be adjusted to the need of the individual patient.

In patients with childhood onset GHD, the recommended dose to restart is 0.2-0.5 mg/day with subsequent dose adjustment on the basis of IGF-1 concentration determination.

In patients with adult onset GHD, it is recommended to start treatment with a low dose: 0.1-0.3 mg/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 IGF-1 can be used as guidance for the dose titration. Women may require higher doses than men, with men showing an increasing IGF-1 sensitivity over time. This means that there is a risk that women, especially those on oral oestrogen replacement are undertreated while men are overtreated.

Dose requirements decline with age. Maintenance dosages vary considerably from person to person, but seldom exceed 1.0 mg/day.

Method of administration

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

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting growth hormone (GH) therapy. Treatment should be discontinued if there is evidence of tumour growth.

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

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 somatropin (see section 4.4).

In children with chronic renal disease, treatment with Norditropin FlexPro should be discontinued at renal transplantation.

4.4. Special warnings and precautions for use

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.

Children treated with somatropin should be regularly assessed by a specialist in child growth. Somatropin 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 syndrome, chronic renal disease, SGA and Noonan syndrome. Data of final adult height following the use of Norditropin are limited for children with Noonan Syndrome and are not available for children with chronic renal disease.

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

The stimulation of longitudinal growth in children can only be expected until epiphyseal closure.

Children

Treatment of growth hormone deficiency in patients with Prader-Willi syndrome

There have been reports of sudden death after initiating somatropin therapy in 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.

Small for Gestational Age

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

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.

Turner syndrome

Monitoring of growth of hands and feet in Turner syndrome patients treated with somatropin is recommended, and a dose reduction to the lower part of the dose range should be considered if increased growth is observed.

Girls with Turner syndrome generally have an increased risk of otitis media, which is why otological evaluation is recommended on at least an annual basis.

Chronic renal disease

The dosage in children with chronic renal disease is individual and must be adjusted according to the individual response to therapy (see section 4.2). The growth disturbance should be clearly established before somatropin treatment by following growth on optimal treatment for renal disease over one year. Conservative management of uraemia with customary medicinal product and if needed dialysis should be maintained during somatropin 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 somatropin treatment, renal function should be monitored for an excessive decline or increase in the glomerular filtration rate (which could imply hyperfiltration).

Scoliosis

Scoliosis is known to be more frequent in some of the patient groups treated with somatropin for example Turner syndrome and Noonan syndrome. In addition, rapid growth in any child can cause progression of scoliosis. Somatropin has not been shown to increase the incidence or severity of scoliosis. Signs of scoliosis should be monitored during treatment.

Blood glucose and insulin

In Turner syndrome and SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk of 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, somatropin should not be administered.

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

IGF-1

In Turner syndrome and SGA children it is recommended to measure the IGF-1 level before start of treatment and twice a year thereafter. If on repeated measurements IGF-1 levels exceed +2 SD compared to references for age and pubertal status, the dose should be reduced to achieve an IGF-1 level within the normal range.

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

Adults

Growth hormone deficiency in adults

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.

Adults and Children

Pancreatitis

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

General

Neoplasms

There is no evidence for increased risk of new primary cancers in children or in adults treated with somatropin.

In patients in complete remission from tumours or malignant disease, somatropin therapy has not been associated with an increased relapse rate.

An overall slight increase in second neoplasms has been observed in childhood cancer survivors treated with growth hormone, with the most frequent being intracranial tumours. The dominant risk factor for second neoplasms seems to be prior exposure to radiation.

Patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of somatropin therapy.

Leukaemia

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

Benign intracranial hypertension

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 somatropin treatment should be discontinued.

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

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

Thyroid function

Somatropin increases the extrathyroidal conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.

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

Patients with Turner syndrome have an increased risk of developing primary hypothyroidism associated with anti-thyroid antibodies. As hypothyroidism interferes with the response to somatropin therapy patients should have their thyroid function tested regularly and should receive replacement therapy with thyroid hormone when indicated.

Insulin sensitivity

Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance (see section 4.5). For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin containing product therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.

Antibodies

As with all somatropin containing products, a small percentage of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low, and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Acute adrenal insufficiency

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

Use with oral oestrogen therapy

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

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.

Clinical trial experience

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 somatropin 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 somatropin in patients having acute critical illnesses should be weighed against the potential risk.

One open-label, randomised clinical trial (dose range 0.045-0.090 mg/kg/day) with patients with Turner syndrome indicated a tendency for a dose-dependent risk of otitis externa and otitis media. The increase in ear infections did not result in more ear operations/tube insertions compared to the lower dose group in the trial.

Excipients

Norditropin contains less than 1 mmol sodium (23 mg) per 1.5 ml, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant treatment with glucocorticoids inhibits the growth-promoting effect of Norditropin. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth.

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

Data from an interaction study performed in growth hormone deficient adults suggest that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

The effect of somatropin on final height can also be influenced by additional therapy with other hormones, e.g. gonadotropin, anabolic steroids, oestrogen and thyroid hormone.

In insulin treated patients adjustment of insulin dose may be needed after initiation of somatropin treatment (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal studies are insufficient with regard to effects on pregnancy, embryo-foetal development, parturition or postnatal development. No clinical data on exposed pregnancies are available.

Therefore, somatropin containing products are not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There have been no clinical studies conducted with somatropin containing products in breast-feeding women. It is not known whether somatropin is excreted in human milk. Therefore caution should be exercised when somatropin containing products are administered to breast-feeding women.

Fertility

Fertility studies with Norditropin have not been performed.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable 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 transient dose reduction.

Mild arthralgia, muscle pain and paresthesia may also occur but are usually self-limiting.

Adverse reactions in children are uncommon or rare.

Clinical trial experience:

System organ classes

Very common(≥ 1/10)

Common(≥ 1/100 to < 1/10)

Uncommon(≥ 1/1,000 to < 1/100)

Rare(≥ 1/10,000 to < 1/1,000)

Metabolism and nutrition disorders

In adults Diabetes mellitus type 2

Nervous system disorders

In adults headache and paraesthesia

In adults carpal tunnel syndrome. In children headache

Skin and subcutaneous tissue disorders

In adults pruritus

In children rash

Musculoskeletal, connective tissue disorders

In adults arthralgia, joint stiffness and myalgia

In adults muscle stiffness

In children arthralgia and myalgia

Reproductive system and breast disorders

In adults and children Gynaecomastia

General disorders and administration site conditions

In adults peripheral oedema (see text above)

In adults and children injection site pain. In children injection site reaction

In children peripheral oedema

In children with Turner syndrome increased growth of hands and feet has been reported during somatropin therapy.

A tendency for increased incidence of otitis media in Turner syndrome patients treated with high doses of Norditropin has been observed in one open-label randomised clinical trial. However, the increase in ear infections did not result in more ear operations/tube insertions compared to the lower dose group in the trial.

Post-marketing experience:

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported and are by an overall judgement considered possibly related to Norditropin treatment. Frequencies of these adverse events cannot be estimated from the available data:

- Neoplasms benign and malignant (including cysts and polyps): Leukaemia has been reported in a small number of growth hormone deficiency patients (see section 4.4)

- Immune system disorders: Hypersensitivity (see section 4.3). Formation of antibodies directed against somatropin. The titres and binding capacities of these antibodies have been very low and have not interfered with the growth response to Norditropin administration

- Endocrine disorders: Hypothyroidism. Decrease in serum thyroxin levels (see section 4.4)

- Metabolism and nutrition disorders: Hyperglycaemia (see section 4.4)

- Nervous system disorders: Benign intracranial hypertension (see section 4.4)

- Musculoskeletal and connective tissue disorders: Legg-Calvé -Perthes disease. Legg-Calvé -Perthes disease may occur more frequently in patients with short stature

- Investigations: Increase in blood alkaline phosphatase level.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 Yellow Card Scheme

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

4.9. Overdose

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.