Instruction for use: Norditropin NordiLet

ATX Code H01AC01 Somatropin

Active substance: Somatropin

Pharmacological group

Growth hormone [Hormones of the hypothalamus, pituitary gland, gonadotropins and their antagonists]

Nosological classification (ICD-10)

E22.0 Acromegaly and pituitary gigantism

Pituitary gigantism, Acromegaly, Dysfunction of growth hormone secretion

E34.3 Low-growth [dwarfism], not elsewhere classified

Growth retardation, Growth retardation in children, Dwarfism, Nanism hypophyseal, Inadequate endogenous growth hormone, Growth Hormone Deficiency, Pituitary Nanism, Low height, Growth disorder, Disturbance of the growth process, Pituitary dwarfism, Disruption of endogenous hormone secretion with growth retardation, Growth disorders, Naniz disproportionate, Nanism associated with external factors

Q96 Turner Syndrome

Turner syndrome, Gonadal Dysgenesis, Mixed gonadal dysgenesis, Shereshevsky-Turner Syndrome

R62 Lack of expected normal physiological development

Genetic Disease, Delay in the child's physical development, Insufficient growth intensity, Growth lag

Composition

Solution for subcutaneous administration 1 ml

active substance:

Somatropin (genetically engineered human growth hormone) 3.3 mg

(Corresponding to 5 mg / 1.5 ml)- 6.7 mg

(Corresponding to 10 mg / 1.5 ml) - 10 mg

(Corresponding to 15 mg / 1.5 ml)

Auxiliary substances: mannitol - 40/40/39 mg; Histidine - 0.68 / 0.68 / 1.1 mg; Poloxamer 188 - 3/3/3 mg; Phenol - 3/3/3 mg; Hydrochloric acid or sodium hydroxide - q.s. For pH correction; Water for injection - up to 1/1/1 ml

Description of dosage form

Colorless transparent solution.

pharmachologic effect

Pharmacological action - somatotropic.

Pharmacodynamics

Norditropin® NordiLet® stimulates skeletal and somatic growth, and also has a pronounced effect on metabolic processes.

Somatropin, replenishing the deficiency of endogenous growth hormone, contributes to the normalization of body structure by increasing muscle mass and reducing body fat.

Most of the effects of somatropin are realized through insulin-like growth factor-I (IGF-I), which is produced in all cells of the body (mainly by liver cells). More than 90% of IGF-I is associated with proteins (IGFBP), of which IFDB-3 is the most important.

Somatropin enhances the restructuring of bone tissue, which is manifested by an increase in the activity of biochemical bone markers in plasma. In adults, during the first months of treatment, due to more pronounced bone resorption, a decrease in its mass is observed, however, when the treatment continues, the mass of bone tissue increases.

Pharmacokinetics

In / in the infusion of somatropin (33 ng / kg / min for 3 hours), 9 patients with growth hormone deficiency gave the following results: T1 / 2 from serum (21.1 ± 1.7) min, metabolic clearance rate - ( 2.33 ± 0.58) ml / kg / min, the volume of distribution - (67.6 ± 14.6) ml / kg.

Indications

Children:

- growth retardation due to insufficiency of growth hormone;

- a pronounced growth hormone (GHD) deficiency that persists in adolescents after the end of growth (transitional period), confirmed as follows: with a high probability of persistent GDR, i.e. Severe DGR, developed in childhood with or without two or three deficiencies of other hormones, which may be due to genetic causes; In severe DGD associated with structural hypothalamic-pituitary disorders, tumors of the central nervous system or in patients receiving radiotherapy of the skull region, the presence of certain genetic causes or DGR secondary to pituitary / hypothalamic disease or stroke is considered sufficient evidence of deep GDR, If the CSR level of IGF-I is <-2 when treated with growth hormone for at least 4 weeks. If IGF-I is> -2 CSR, it is necessary to perform a provocative test with a growth hormone.

For all other patients (low probability, including idiopathic, isolated DGR or deficiency of one additional hormone), quantitative determination of IGF-I and carrying out one provocative test with growth hormone is required. Diagnosis of GDR is confirmed if the results obtained in the quantification and provocation test were low.

The low response (the level of growth hormone) to stimulation (peak GR <6 μg / L for the insulin tolerance test (ITT) and peak GR <16.5 μg / L for the test with GR-RH + arginine) confirms the diagnosis of GDR.

- growth retardation in girls with gonadal dysgenesis (Shereshevsky-Turner syndrome);

- growth retardation in children in the prepubertal period, caused by chronic renal failure (CRF);

- short stature in children (coefficient of standard deviation (CSR) of current growth <-2.5, CSR of corrected (depending on growth of parents) growth <-1), who had prenatal growth retardation and birth weight below -2 ° C, and who did not reach Age growth rate to 4 years or later (CSR growth rate (CP) <0 during the last year).

Adults:

Insufficiency of growth hormone confirmed during the transition period, observed in childhood.

Insufficiency and deficiency of growth hormone developed in adulthood.

The pronounced deficiency of growth hormone in the established disease of the hypothalamic-pituitary region, with radiation therapy of the skull and craniocerebral trauma (the insufficiency of yet another hormone other than prolactin), confirmed during one provocative test after the initiation of adequate replacement therapy for the deficiency of any other hormone.

For adults, a provocation test is a test for tolerance to insulin, a level of pathological values: a peak of growth hormone <3 mcg / l. If the test for tolerance to insulin is contraindicated, an alternative provocation test should be used. It is recommended to use a combined test using arginine and somatocrinine (GR-RG). You can also consider the use of arginine or glucagon tests, but their diagnostic significance is lower than that of the test for tolerance to insulin.

Contraindications

Hypersensitivity to any of the components of the drug.

Signs of active malignant neoplasm (at the beginning of treatment, the intracranial tumor should be inactive and antitumor therapy completed). Treatment should be discontinued if signs of tumor growth appear.

Urgent conditions (including conditions after surgical interventions on the heart, abdominal cavity, acute respiratory failure, multiple injuries as a result of accidents).

Willy-Prader syndrome in case of severe obesity and respiratory disorders.

Stimulation of longitudinal growth in children with closed epiphyseal growth zones.

In children with chronic renal failure, treatment with Norditropin® NordiLet® should be interrupted during kidney transplantation.

With caution: hypothyroidism, diabetes, the period of breastfeeding.

pregnancy and lactation

At present, there is limited experience with the use of somatropin in pregnancy. Possible secretion of somatropin with breast milk is not excluded. It is not recommended to use the drug during pregnancy. During the period of breastfeeding, the drug should be used with caution.

Side effects

In patients with growth hormone deficiency, there is often a deficiency in the intercellular volume. With the start of treatment with somatropin, this deficit is corrected. More often fluid retention in the form of peripheral edema occurs in adults. Also, non-severe arthralgia, myalgia and paresthesia may occur, which usually do not require additional treatment. Symptoms are transient, dose-dependent and may require a temporary dose reduction.

Adverse reactions in children are rare or infrequent.

Pancreatitis

There have been reports of rare cases of pancreatitis in adults and children receiving somatropin treatment; Some data confirm that children are at greater risk of developing this adverse reaction than adults. Published literature data suggest that girls with Shereshevsky-Turner syndrome are at greater risk of developing this adverse reaction compared to other children receiving somatropin treatment. It is necessary to take into account the possibility of developing pancreatitis in all patients receiving somatropin treatment, especially in children with complaints of persistent severe pain in the abdominal area.

An increase in the size of the upper and lower extremities in children with Shereshevsky-Turner syndrome during treatment with growth hormone has been reported.

In two clinical studies, there was a tendency to develop otitis media of the middle ear and external ear in patients with the Shereshevsky-Turner syndrome who received high doses of the drug Norditropin®. However, inflammatory diseases of the ear did not lead to more medical manipulations, compared to the group of patients receiving lower doses of the drug.

Data received in the postmarketing period:

Rarely (less than 1 per 1000) was reported on the reactions of generalized hypersensitivity (including anaphylactic reactions). See section "Contraindications".

In addition to the above listed adverse reactions, spontaneously reported adverse reactions are listed below, which are considered to be possibly relevant to the use of Norditropin®.

Disorders from the immune system: hypersensitivity, see the section "Contraindications."

During treatment with the drug Norditropin®, the formation of antibodies to somatropin was rarely observed. The titers and binding capacity of these antibodies were very low and did not affect the growth response when Norditropin® was used.

Disorders from the endocrine system: hypothyroidism. Reduction of thyroxine (T4) concentration in serum, see section "Special instructions".

Very rarely reported decrease in the concentration of thyroxine (T4) in the blood serum during treatment with the drug Norditropin®.

Disorders from the metabolism and nutrition: hyperglycemia, see section "Special instructions".

Violations from the nervous system: benign intracranial hypertension, see section "Special instructions"

Hearing disorders and labyrinthine disturbances: otitis media, see section "Special instructions".

Disturbances from the musculoskeletal and connective tissue: epiphysis of the femoral head, see section "Special instructions". Legg-Calvet-Perthes disease, see section "Special instructions".

Research: increasing the concentration of alkaline phosphor in the blood.

Interaction

Concomitant glucocorticosteroid therapy can suppress growth and, thus, inhibit the growth effect of somatropin drugs. A careful selection of glucocorticosteroid substitution therapy for patients with ACTH deficiency is necessary in order to avoid the neutralization of the action of somatropin.

Data from an interaction study conducted in adult patients with growth hormone deficiency showed that the use of somatropin can increase the clearance of compounds metabolized by cytochrome P450 isoenzymes. The clearance of compounds that are able to be metabolized by cytochrome P450 3A4 (including sex steroid hormones, GCS, anticonvulsant drugs and cyclosporine) can greatly increase, leading to a decrease in the concentration of these compounds in the plasma. The clinical significance of this interaction has not been studied.

Patients receiving insulin may require a dose adjustment after commencement of treatment with somatropin (see section "Special instructions").

The effectiveness of the drug (with respect to final growth) may also be influenced by concomitant therapy with other hormones, for example gonadotropin, anabolic steroids, estrogens and thyroid hormones.

Incompatibility. Compatibility studies have not been carried out, therefore, Norditropin® NordiLet® should not be mixed with other drugs.

Dosing and Administration

Somatropin can be prescribed only by a doctor who has special knowledge in the field of indications for the use of the drug.

The dose is selected individually on the basis of an individual clinical and biochemical response to therapy.

It is usually recommended to do one subcutaneous injection of the drug at night. To prevent the development of lipoatrophy, it is necessary to change the injection site.

Children

Insufficient growth hormone: 25-35 mcg / kg / day or 0.7-1 mg / m 2 / day. Meets: 0.07-0.1 IU / kg / day (2-3 IU / m2 / day).

Expressed growth hormone deficiency persisting in adolescents after growth (transition): If there is a growth hormone deficiency after cessation of growth in patients, growth hormone therapy should continue until a complete somatic adult development, including lean body mass and bone mineral growth (cm , "Method of administration and dose", substitution therapy in adults).

Patients in whom growth hormone deficiency arose in childhood, the recommended dose for the resumption of therapy is 0.2-0.5 mg / day, followed by a dose selection based on the determination of IGF-I concentration.

Syndrome Shereshevsky-Turner: up to 67 mcg / kg / day or 2 mg / m 2 / day. Meets: 0.2 IU / kg / day and (6 IU / m2 / day).

Chronic renal failure: 50 mcg / kg / day or 1.4 mg / m 2 / day. Meets: 0.14 IU / kg / day (4.3 IU / m2 / day).

Low growth in children who had prenatal growth retardation: 33-67 μg / kg / day or 1-2 mg / m2 / day. Meets: 0.1-0.2 IU / kg / day (3-6 IU / m2 / day).

Adults

Substitution therapy

The dose is prescribed based on the individual needs of the patient.

Adult patients with growth hormone deficiency are advised to begin treatment with low doses of the drug: 0.1-0.3 mg / day (0.3-0.9 IU / day) and gradually increase the dose every month on the basis of the clinical response and drug tolerance . As a control parameter for titrating the dose, IGF-I concentration in serum can be used. Women may need a larger dose of the drug than men, since men will eventually become more sensitive to IGF-I. This means that in women (especially those receiving oral estrogen replacement therapy) there is a risk of using underestimated doses of the drug, and in men - too high.

As the patient's age increases, the need for growth hormone decreases. The maintenance dose of the drug is selected individually, but rarely exceeds 1 mg / day (corresponding to 3 IU / day).

Overdose

Symptoms of acute overdose: first hypoglycemia, followed by hyperglycemia. Such reduced levels of glucose were determined only biochemically without the clinical symptoms of hypoglycemia. With prolonged overdose, signs and symptoms characteristic of excess human growth hormone (acromegaly and / or gigantism) may appear, and hypothyroidism and a decrease in serum cortisol levels may occur.

Treatment: withdrawal of the drug, symptomatic therapy.

special instructions

A specialist in pathology of growth should regularly monitor the condition of children receiving Norditropin® NordiLet®. The treatment with Norditropin® NordiLet® should always be started by a doctor who has special knowledge in the field of growth hormone deficiency and its treatment. This also applies to the treatment of growth retardation in the Shereshevsky-Turner syndrome, CRF, and stunting in children with prenatal growth retardation in the history.

Do not exceed the maximum recommended daily dose (see section "Method of administration and dose").

Stimulation of longitudinal growth can be carried out in children before the closure of epiphyseal growth zones.

Adult growth hormone deficiency persists throughout life and requires appropriate treatment, but currently experience in treating patients older than 60 years, as well as the results of therapy lasting more than 10 years, are limited.

Shereshevsky-Turner Syndrome

In patients with the syndrome of Shereshevsky-Turner during treatment with somatropin, it is recommended to monitor the proportional growth of the upper and lower extremities, and when detecting increased growth, the dose of the drug should be reduced to the lower limit of the dose range.

Girls with Shereshevsky-Turner syndrome usually have an increased risk of developing otitis media, and therefore an otorhinolaryngologist should be monitored.

Chronic Renal Failure

Dysplasia in children with CRF should be accurately established before treatment with Norditropin® NordiLet® is started by monitoring the growth in optimal CRF therapy for one year. During therapy with Norditropin® NordiLet®, conservative treatment of uremia with traditional medicines and, if necessary, with dialysis, should be continued.

In patients with CRF, there is usually a decrease in kidney function, which is a natural manifestation of this disease. Therefore, as a precautionary measure, in patients with CRF during treatment with the drug Norditropin® NordiLet®, renal function should be monitored for its pronounced decrease or increase in the glomerular filtration rate (which may indicate hyperfiltration).

Tumors

There is no evidence of an increased risk of malignant tumors in children or adults treated with somatropin.

There is no evidence of an increased risk of recurrent malignant tumors in children or adults receiving somatropin treatment. Overall, a small increase in secondary tumors was found in children receiving somatropin treatment, the most frequent were intracranial tumors. The main risk factor for the development of secondary tumors is, most likely, the previous radiation therapy.

Patients with a history of malignant neoplasms should be carefully examined for their relapse. In case of occurrence or relapse of a malignant neoplasm, treatment with somatropin should be discontinued.

Benign intracranial hypertension

Very rarely reported cases of the occurrence of benign intracranial hypertension.

In the presence of severe or recurring headaches, visual impairment, nausea and / or vomiting, it is recommended that the fundus examination (fundoscopy) be performed to detect edema of the optic nerve disc. If the edema is confirmed, the presence of benign intracranial hypertension should be assumed and, with confirmation of the diagnosis, treatment with somatropin should be discontinued.

Currently, there is insufficient data to make clinical decisions in patients with intracranial hypertension in the resolution stage. When resuming treatment with somatropin, careful monitoring of symptoms of intracranial hypertension is necessary.

In secondary insufficiency of growth hormone due to the presence of intracranial lesion, regular patient examinations should be performed to identify signs of progression or relapse of the primary disease.

Thyroid function

As a result of the treatment with somatropin, the transition of the hormone T4 (thyroxine) to T3 (triiodothyronine) is activated, with the help of which it is possible to detect hypothyroidism in the initial stage. Since hypothyroidism interferes with the adequate growth effect when treated with Norditropin® NordiLet®, patients who receive this therapy should regularly examine the thyroid function and conduct replacement therapy with thyroid hormones when it is detected. Patients with Shereshevsky-Turner syndrome have an increased risk of developing primary hypothyroidism associated with antithyroid antibodies.

Scoliosis

Some children in the period of excessively rapid growth (especially often in children with Prader-Willi syndrome) may experience a progression of scoliosis. During the entire treatment period, somatropin should be monitored to identify signs of scoliosis. However, the available data suggest that treatment with somatropin does not affect the frequency or severity of scoliosis.

In patients with endocrine diseases, subluxation of the femur may be more common, and in patients of low growth, Legg-Calve-Perthes disease may be more likely.

Carbohydrate metabolism

Somatropin decreases sensitivity to insulin, especially in high doses in patients with high sensitivity, which can cause the development of hyperglycemia in patients with inadequate insulin secretion.

Thus, previously not diagnosed impaired glucose tolerance and diabetes mellitus can be detected.

All patients receiving somatropin require periodic monitoring of glucose levels; Especially in patients with a high risk of diabetes: in patients with obesity, Shereshevsky-Turner syndrome or with diabetes in a family history. In the course of treatment with somatropin, more careful monitoring is needed for patients with diagnosed type 1 or 2 diabetes mellitus or with impaired glucose tolerance (see section "Interaction"). Such patients should assess the need for correcting the dose of hypoglycemic drugs in the appointment of somatropin.

IGF-I

It is recommended to measure the serum IGF-I concentration before starting therapy with somatropin and then regularly.

There have been reports of deaths during treatment with somatropin in children with Prader-Willi syndrome that are not included in the approved indications for Norditropin® NordiLet®. These cases were observed in patients who had one or more risk factors, such as severe form of obesity, family history of upper respiratory tract obstruction or sleep apnea, or unidentified respiratory infections.

Data from clinical trials

Two placebo-controlled clinical trials, including patients in intensive care units, showed an increase in mortality among acute patients after open-heart surgery, abdominal cavity with acute respiratory failure, multiple injuries from accidents and those receiving somatropin treatment in high Doses (5.3-8 mg / day). The safety of continuation of treatment with somatropin in replacement doses within the limits of the registered indications in patients with the listed diseases has not been studied. Accordingly, the ratio of potential risk and the benefit of continuing treatment with somatropin in patients in the urgent state should be carefully evaluated.

Impact on the ability to drive vehicles and work with mechanisms. The drug does not affect the ability to drive vehicles and work with mechanisms.

Form of issue

Solution for subcutaneous administration, 5 mg / 1.5 ml, 10 mg / 1.5 ml, 15 mg / 1.5 ml. In glass cartridges installed in plastic multi-dose disposable syringe-pens for multiple injections, sealed on one side with rubber pistons, on the other hand - laminated rubber disks, under aluminum rolls, 1.5 ml each; In a pack of cardboard 1 syringe-pen.

Terms of leave from pharmacies

On prescription.

Storage conditions

At a temperature of 2 ° C to 8 ° C (in the refrigerator) in a cardboard bundle. For the syringe pen in use: store for 4 weeks at a temperature of 2 ° C to 8 ° C (in the refrigerator). Do not freeze.

Keep out of the reach of children.

shelf life

2 years.

Do not use after the expiry date printed on the package.