Norditropin solution for subcutaneous injection 10mg/1.5ml 1.5ml syringe cartridges Nordiflex, 1pc

Composition

1 ml of the drug contains:

Active ingredient:

somatropin (genetically engineered human growth hormone) 6.7 mg (10 mg/1.5 ml);

excipients: mannitol, histidine, poloxamer 188, phenol, hydrochloric acid or sodium hydroxide (for pH correction), water for injection.

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

Pharmacological action

Pharmacotherapeutic group: somatotropic hormone.

ATX code: H 01 AC 01.

Pharmacological properties

Norditropin® contains somatropin, a human growth hormone (GH) produced by recombinant DNA (deoxyribonucleic acid) biotechnology.

Somatropin is an anabolic peptide consisting of 191 amino acids, stabilized by two disulfide bridges, with a molecular weight of approximately 22,000 Da.

Pharmacodynamics

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

Somatropin, replenishing the deficiency of endogenous GH, 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 1 (IGF-1), which is produced in all body tissues (mainly in the liver).

More than 90% of IGF-1 is associated with proteins (IGFBPs), of which IGFB-3 is the most important.

The lack of lipolytic and protein-sparing effects of the hormone becomes especially important during times of stress.

Somatropin also enhances bone remodeling, which is manifested by an increase in the activity of biochemical bone markers in plasma. In adults, in the first months of treatment, due to more pronounced bone resorption, there is a decrease in its mass, but with continued treatment, the mass of bone tissue increases.

Pharmacokinetics

Intravenous infusions of Norditropin® (33 ng / kg / min for 3 hours) 9 patients with GH deficiency were given the following results: the serum half-life was 21.1±1.7 min, the metabolic clearance rate was 2.33±0.58 ml / kg / min, and the volume of distribution was 67.6±14.6 ml/kg.

Indications

Children:

• growth retardation due to GH insufficiency;
• pronounced GH deficiency that persists in adolescents after the end of growth (transition period), confirmed as follows:
• If there is a high probability of persistent GH deficiency, i. e. a severe GH deficiency developed in childhood with or without two or three other hormone deficiencies, which may be due to genetic causes; if there is a severe GH deficiency associated with structural hypothalamic-pituitary disorders, central nervous system tumors, or in patients receiving cranial radiation therapy; the presence of certain genetic causes or a GH deficiency secondary to pituitary/hypothalamic disease or stroke, it is considered sufficient evidence of a deep If the standard deviation coefficient (CSR) of the IGF-1 level is equal to If the IGF-1 level is > -2 CSR, a provocative test with GR should be performed. >
• For all other patients (low probability, including idiopathic, isolated GH deficiency or deficiency of one additional hormone), quantitative determination of IGF-1 and one provocative test with GH are required. The diagnosis of GH deficiency is confirmed if the results obtained during quantitative determination and provocative testing were low.
• Low response (GH level) to stimulation (peak GH < 6 mcg / L during the insulin tolerance test (ITT), and peak GH + arginine) confirms the diagnosis of deficiency of G;
• growth retardation in girls with gonadal dysgenesis syndrome (Turner’s);
• growth retardation in children in the prepubertal period, due to chronic renal failure (CRF);
• short stature in children (CSR current growth < -2,5, CSR adjusted (depending on the height of the parents) growth < -1) had prenatal growth retardation and birth weight below -2 standard deviations (CO), and have not attained age rate of growth to 4 years or later (CSR growth rate (SR) < 0 in the past year).

Adults:

Confirmed GH insufficiency during the transition period, observed in childhood.

GH insufficiency and deficiency that developed in adulthood.

Pronounced GH deficiency in patients with an established hypothalamic-pituitary disease, radiation therapy of the cranial region, and craniocerebral trauma (insufficiency of another hormone other than prolactin), confirmed during one provocative test after starting adequate replacement therapy for a deficiency of any other hormone.

For adults, the provocative test of choice is ITT, the level of pathological values: peak GY If ITT is contraindicated, an alternative provocation test should be used. It is recommended to use a combined test using arginine and GR-RG. Arginine or glucagon tests may also be considered, but their diagnostic significance is lower than that of ITT.

Use during pregnancy and lactation

The use of somatropin during pregnancy is contraindicated. Clinical experience with somatropin in pregnant women is limited. In the normal course of pregnancy, the concentration of pituitary GH decreases markedly after 20 weeks, being replaced almost completely by placental GH by 30 weeks of pregnancy. In this regard, the need to continue somatropin replacement therapy in the third trimester of pregnancy seems unlikely.

Reliable data on the possibility of somatropin penetration into breast milk are not available, however, in any case, the absorption of intact protein in the gastrointestinal tract of the child is extremely unlikely. However, somatropin should be used with caution during breastfeeding.

Recommendations for use

Norditropin®Pre-filled Syringe Pen Nordiflex® is designed for use with NovoFine ® disposable needles. Norditropin®Syringe Pen Nordiflex ® 10 mg / 1.5 ml delivers a maximum of 3 mg of somatropin in a single dose in increments of 0.05 mg of somatropin. Before the first injection, it is necessary to check that the pen is ready for use (remove air) in order to ensure proper dosing and avoid introducing air during the injection. The dose is selected by turning the dose selector until the required dose appears in the dose indicator window. If the dose has been set incorrectly, turn the dose selector forward or backward until the correct dose is set. To administer the dose, press the start button. Patients should be reminded to wash their hands thoroughly with soap and/or disinfectant before any contact with the Norditropin ® pen. Nordiflex®. Norditropin®Syringe Pen Nordiflex® should not be shaken vigorously. Guidelines for the use of Norditropin® Nordiflex® is included. Patients should be advised to study it carefully. The drug Norditropin® Nordiflex® should not be used if it is cloudy, i. e. it has ceased to be transparent and colorless. You can check this by turning the pen up and down once or twice. The drug Norditropin® Nordiflex® should not be used if a drop of growth hormone solution does not appear at the end of the needle.

Contraindications

-Hypersensitivity to somatropin or any of the excipients of the drug.

– Signs of an active malignant neoplasm (by the beginning of treatment, the intracranial tumor should be in an inactive state and the antitumor therapy is completed). Treatment should be discontinued if there are signs of tumor growth.

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

– Urgent conditions (including conditions after surgery on the heart, abdomen, multiple injuries in accidents, acute respiratory failure);

– the Prader-Willi Syndrome in the presence of one or more risk factors: severe obesity, the upper airway obstruction or sleep apnea in history, or unidentified respiratory infection.

– Pregnancy.

In children with CRF, treatment with Norditropin should be discontinued during kidney transplantation.

With caution

Caution should be exercised when using the drug in the following groups of patients and in the following conditions/diseases: – hypothyroidism;- diabetes mellitus( DM); – breast-feeding period; – Prader-Willi syndrome; – concomitant therapy with glucocorticosteroids (corticosteroids);- intracranial hypertension in the compensation stage.

Side effects

Patients with GH insufficiency often have a lack of intercellular volume. With the start of somatropin treatment, this deficiency is corrected. More often, fluid retention in the form of peripheral edema occurs in adults. Mild arthralgia, myalgia, and paresthesia may also 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.

Data from clinical trials:

Metabolic and nutritional disorders: Adults have type 2 diabetes mellitus (seedata obtained in the post-marketing period).

Nervous system disorders: In adults-headache and paresthesia, tunnel syndrome. Children have headaches.

Skin and subcutaneous tissue disorders In adults-pruritus In children-unspecified rash

Musculoskeletal and connective tissue disorders: In adults-arthralgia, joint stiffness and myalgia, muscle rigidity. Children have arthralgia and myalgia.

General disorders and disorders at the injection site: In adults-peripheral edema. In adults and children-pain at the injection site. In children – unspecified reaction at the injection site In children – peripheral edema.

Pancreatitis

Rare cases of pancreatitis have been reported in adults and children treated with somatropin; some data suggest 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 treated with somatropin. It is necessary to take into account the possibility of developing pancreatitis in all patients receiving somatropin treatment, especially in children with persistent severe abdominal pain.

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

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

Data obtained in the post-marketing period:

Rarely (less than 1 in 1000), generalized hypersensitivity reactions (including anaphylactic reactions) have been reported. In addition to the adverse reactions listed above, the following are adverse reactions based on spontaneous reports that are considered as possibly related to the use of Norditropin®.

Immune system disorders

Hypersensitivity.

When treated with Norditropin, the formation of antibodies to somatropin was rarely observed. Titers and binding capacity of these antibodies were very low and did not affect the growth response when using Norditropin®.

Endocrine system disorders

Hypothyroidism. Decrease in the concentration of thyroxine (T4) in the blood serum.

Very rarely, a decrease in serum thyroxine (T4) concentrations has been reported during treatment with Norditropin®.

Metabolic and nutritional disorders

Hyperglycemia.

Nervous system disorders

Benign intracranial hypertension.

Hearing disorders and labyrinth disorders

Otitis media.

Musculoskeletal and connective tissue disorders

Epiphysis of the femoral head.

Legg-Calve-Perthes disease.

Laboratory and instrumental data

An increase in the concentration of alkaline phosphatase in blood plasma.

Interaction

Concomitant corticosteroid therapy may inhibit growth and thus inhibit the growth effect of somatropin preparations. Careful selection of corticosteroid replacement therapy in patients with adrenocorticotropic hormone (ACTH) deficiency is necessary to avoid neutralizing the effect of somatropin.

Data obtained in an interaction study conducted in adult patients with GH insufficiency showed that the use of somatropin can increase the clearance of compounds metabolized by cytochrome P450 isoenzymes. Clearance of compounds that can be metabolized by cytochrome P4503A4 (including sex steroid hormones, corticosteroids, anticonvulsants and cyclosporine) it can greatly increase, leading to a decrease in the concentration of these compounds in plasma. The clinical significance of this interaction has not been studied.

Patients receiving insulin may need to adjust the dose after starting somatropin treatment (see section “Special instructions”).

Concomitant therapy with other hormones, such as gonadotropin, anabolic steroids, estrogens, and thyroid hormones, may also affect the effectiveness of the drug (with respect to final growth).

Incompatibility

Compatibility studies have not been conducted, so the drug Norditropin® should not be mixed with other drugs.

How to take, course of use and dosage

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

The dose is selected individually based on the individual clinical and biochemical response to therapy.

It is usually recommended to make one subcutaneous injection of the drug at night. To prevent the development of lipoatrophy, it is necessary to change the injection sites. For the injection procedure, see the “Instructions for use of the drug”.

General recommendations for dosage of the drug are presented below.

Children:

GY insufficiency:

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

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

Pronounced GH deficiency that persists in adolescents after the end of growth (transition period):

If there is a GH deficiency after patients stop growing, GH therapy should be continued until full somatic adult development is achieved, including lean body weight and bone mineral gain (see the subsection ” Adult replacement therapy:»).

In patients who develop GH insufficiency in childhood, the recommended dose for resuming therapy is 0.2-0.5 mg / day, followed by dose selection based on the determination of IGF-1 concentration.

Shereshevsky-Turner syndrome:

up to 0.067 mg / kg / day or 2.0 mg / m2 / day.

Corresponds to: 0.2 IU / kg / day (6 IU / m2 / day)

CRF:

0.050 mg / kg / day or 1.4 mg / m2 / day.

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

Short stature in children with prenatal growth retardation:

0.033-0.067 mg / kg / day or 1-2 mg / m2 / day.

Corresponds to: 0.1-0.2 IU / kg / day (3-6 IU / m2 / day)

Treatment should be discontinued after the first year of therapy if the CSR of the growth rate is less than +1.

Adults:

Substitution therapy:

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

Adult patients with GH insufficiency are recommended to start treatment with low doses of the drug: 0.1-0.3 mg / day (0.3 – 0.9 IU/day) and gradually increase the dose each month based on the clinical response and tolerability of the drug. The concentration of IGF-1 in the blood serum can be used as a control indicator when titrating the dose. Women may need a higher dose of the drug than men, since men have an increased sensitivity to IGF-1 over time. This means that women (especially those who receive oral hormone replacement therapy with estrogen preparations) are at risk of using low doses of the drug, and men – overestimated.

As the patient ages, the need for GH decreases. The maintenance dose of the drug is selected individually, but rarely exceeds 1.0 mg / day (which corresponds to 3 IU/day).

Overdose

Acute overdose of somatropin can lead to hypoglycemia and then to hyperglycemia. Prolonged overdose can lead to the development of signs and symptoms of gigantism and / or acromegaly, which corresponds to the known effects of excess GH.

Treatment: withdrawal of somatropin, symptomatic therapy.

Next, it is recommended to monitor the function of the thyroid gland.

Description

Colorless transparent or slightly opalescent solution.

Special instructions

A specialist in the field of growth pathology should regularly monitor the condition of children receiving somatropin. Initiation of treatment with Norditropin® should always be carried out by a doctor who has special knowledge in the field of GH insufficiency and its treatment. This also applies to the treatment of growth retardation in patients with Shereshevsky-Turner syndrome, CRF, and short stature in children with a history of prenatal growth retardation.

Do not exceed the maximum recommended daily dose (see section “Dosage and use”).

Longitudinal growth stimulation can be performed in children before epiphyseal growth zones are closed.

GH deficiency in adults

GH insufficiency in adults persists throughout life and requires appropriate treatment, but currently the experience of treating patients over 60 years of age, as well as the results of therapy lasting more than 5 years, is limited.

Shereshevsky-Turner syndrome

In patients with Shereshevsky-Turner syndrome, monitoring of proportional growth of the upper and lower extremities is recommended during somatropin treatment, and if increased growth is detected, 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 should be monitored by an otorhinolaryngologist. Examination by an otorhinolaryngologist should be carried out at least once a year.

CRF

Growth disorders in children with CRF should be accurately identified before starting somatropin treatment by monitoring growth on optimal CRF therapy for one year. During somatropin therapy, conservative treatment of uremia with traditional medications and, if necessary, dialysis should be continued.

Patients with CRF usually experience a decrease in renal function, which is a natural manifestation of this disease. Therefore, as a precautionary measure, in patients with CRF during somatropin treatment, renal function should be monitored for a marked decrease or increase in glomerular filtration rate (which may indicate hyperfiltration).

Tumors

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

In patients with complete remission of malignancies, somatropin treatment was not associated with an increased relapse rate.

Overall, a slight increase in secondary tumors was found in patients who had had childhood cancer and were receiving growth hormone treatment, with intracranial tumors being the most common. The main risk factor for developing secondary tumors is most likely previous radiation therapy.

After starting somatropin treatment, patients who have achieved complete remission should be closely monitored for relapse of malignancies.

If a malignant neoplasm occurs or recurs, somatropin treatment should be discontinued.

Leukemia

Few cases of leukemia have been reported in patients with GH deficiency, and some of them were treated with somatropin. However, it is not proven that the incidence of leukemia in patients without predisposing factors increases with somatropin treatment.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been reported very rarely.

In the presence of severe or recurrent headaches, visual disturbances, nausea and/or vomiting, it is recommended to conduct a fundus examination (fundoscopy) to detect edema of the optic nerve disc. If the edema is confirmed, the presence of benign intracranial hypertension should be assumed and, if the diagnosis is confirmed, somatropin treatment should be discontinued.

Currently, there are insufficient data for clinical decision-making in patients with intracranial hypertension in the resolution stage. When resuming treatment for GH, careful monitoring of the symptoms of intracranial hypertension is necessary.

If secondary GH insufficiency is caused by the presence of intracranial damage, patients should be regularly examined for signs of progression or relapse of the primary disease.

Thyroid function

As a result of somatropin treatment, the transition of the hormone T4 (thyroxine) to T3 (triiodothyronine) is activated, which can be used to detect hypothyroidism in the initial stage. Since hypothyroidism prevents an adequate growth effect during somatropin treatment, patients receiving this therapy should regularly examine thyroid function and conduct thyroid hormone replacement therapy if it is detected to decrease. Patients with Shereshevsky-Turner syndrome have an increased risk of developing primary hypothyroidism associated with antithyroid antibodies.

Antibodies

When treated with somatropin-containing drugs, a small proportion of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low, and they do not affect the growth rate. Patients who do not respond to therapy should be screened for somatropin antibodies.

Scoliosis

Some children may develop scoliosis during the period of excessively rapid growth (especially often in children with Prader-Willi syndrome). During the entire period of somatropin treatment, monitoring should be performed to detect signs of scoliosis. However, available evidence suggests that somatropin treatment does not affect the frequency or severity of scoliosis.

Patients with endocrine disorders may experience hip subluxation more frequently, and short patients may develop Legg-Calve-Perthes disease more frequently. These conditions may manifest as lameness or complaints of hip or knee pain; doctors and parents of patients should be warned about this possibility.

Carbohydrate metabolism

Somatropin reduces insulin sensitivity, especially in high doses in patients with high sensitivity, which can cause hyperglycemia in patients with inadequate insulin secretion.

As a result, previously undiagnosed glucose tolerance disorders and diabetes may be detected during somatropin therapy.

Therefore, all patients receiving somatropin should be regularly monitored for glucose levels, especially in patients at high risk of diabetes, such as those with obesity, Shereshevsky-Turner syndrome, or a family history of diabetes. Patients diagnosed with type 1 or 2 diabetes or with impaired glucose tolerance should be monitored more closely during somatropin treatment (see section “Interactions with other medications”). In such patients, the need for dose adjustment of hypoglycemic drugs (insulin and/or oral hypoglycemic drugs) should be evaluated when prescribing somatropin.

IGF-1

In patients with Shereshevsky-Turner syndrome and children with prenatal growth retardation, it is recommended to measure the concentration of serum IGF-1 before starting somatropin therapy and then 2 times a year. If repeated measurements confirm that the serum IGF-1 concentration exceeds the standard for age and puberty status by +2 CO, a reduction in the dose of the drug is required to achieve the IGF-1 concentration within the range of normal values.

Some of the growth gains achieved with somatropin treatment in children with prenatal growth retardation may be lost if treatment is discontinued before the final growth is achieved.

Fatal cases have been reported during somatropin treatment in children with Prader-Willi syndrome, which is not included in the approved indications for Norditropin®. These cases were observed in patients who had one or more risk factors, such as severe obesity, a history of upper airway obstruction or sleep apnea, or unidentified respiratory infections.

Replacement therapy with Norditropin® for GH deficiency in adults should be carried out under the supervision of an endocrinologist with extensive experience in the treatment of pituitary gland disease.

Data from clinical trials

Two placebo-controlled clinical trials involving patients in intensive care units showed an increase in mortality among patients who were in an acute condition after open-heart surgery, abdominal surgery, who had acute respiratory failure, multiple injuries as a result of accidents, and who received high-dose somatropin treatment (5.3-8 mg / day). The safety of continuing somatropin replacement therapy within the registered indications in patients with these diseases has not been studied. Accordingly, the ratio of the potential risk and benefit of continuing somatropin treatment in patients in an urgent condition should be carefully evaluated.

Influence on the ability to drive vehicles and mechanisms

The drug does not affect the ability to drive vehicles and mechanisms.

Form of production

Solution for subcutaneous use of 10 mg / 1.5 ml.

1.5 ml each in hydrolytic class 1 glass cartridges, capped with brombutyl rubber/polyisoprene discs on one side and brombutyl rubber pistons on the other.

The cartridge is sealed in a plastic multi-dose disposable syringe pen for multiple injections (pre-filled syringe pen) Nordiflex®.1 pre-filled syringe pen together with instructions for use in a cardboard box.

Storage conditions

Keep out of reach of children

Store at a temperature of 2°C to 8°C (in the refrigerator) in a cardboard box.

For the syringe pen in use: store for 4 weeks at a temperature of 2°C to 8°C (in the refrigerator) or for 3 weeks at a temperature not exceeding 25°C.

Do not freeze it.

Shelf

life is 2 years. Do not use after the expiration date indicated on the label of the syringe pen and packaging.

Active ingredient

Somatropin

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection