INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GROWTROPIN (GROWTROPIN)

Composition:

Active substance: somatropin;

1 ml of injection solution contains 8 IU of recombinant somatropin;

Excipients: sodium acetate, hydrochloric acid, sodium chloride, polysorbate 20, benzyl alcohol, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear or slightly opalescent, colorless solution.

Pharmacotherapeutic group. Anterior pituitary hormones and their analogues. Somatotropin. ATC code H01AC01.

Pharmacological properties.

Pharmacodynamics.

The medicinal product Grothropin contains recombinant human growth hormone (somatropin), produced by genetic engineering using mammalian cells. Somatropin is a peptide consisting of 191 amino acids and is identical to human pituitary growth hormone in amino acid sequence and composition, as well as in peptide map, isoelectric point, molecular mass, isomeric structure, and biological activity.

Somatropin possesses anabolic and anticatabolic properties; that is, it affects not only growth but also body composition and metabolism. Somatropin interacts with specific receptors on various cell types, including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some of these effects are mediated by another class of hormones known as somatomedins (IGF-1 and IGF-2).

Depending on the administered dose, the drug increases serum levels of IGF-1, IGFBP-3, and non-esterified fatty acids and glycerol, while decreasing blood urea levels and reducing urinary excretion of nitrogen, sodium, and potassium. The duration of elevated growth hormone levels may play an important role in determining the extent of its efficacy. For high doses of somatropin, a phenomenon of relative saturation is likely; however, this does not apply to glycemia and urinary C-peptide excretion, which increase significantly only after administration of high doses of the drug (20 mg).

Pharmacokinetics.

The pharmacokinetics of the medicinal product are linear at least when doses up to 8 IU (2.67 mg) are administered. When higher doses (60 IU/20 mg) are used, some non-linearity of response cannot be excluded, although it lacks clinical significance.

After intravenous administration of the drug to healthy volunteers, the volume of distribution at steady state is approximately 7 L, total metabolic clearance is about 15 L/hour, while renal clearance is negligible. The elimination half-life of the drug is 20–35 minutes.

After single subcutaneous or intramuscular administration, the apparent terminal half-life is longer, approximately 2 to 4 hours, due to the absorption process limiting the elimination rate.

Maximum serum concentration of somatropin is reached approximately 4 hours after administration, after which serum growth hormone levels return to baseline within 24 hours, indicating absence of somatropin accumulation with repeated dosing.

Absolute bioavailability of somatropin following intramuscular or subcutaneous administration is 70–90%.

Clinical characteristics.

Indications.

Children.

Growth failure in children due to decreased or absent endogenous growth hormone secretion.
Growth failure in girls with gonadal dysgenesis (Turner syndrome), confirmed by chromosomal analysis.
Growth failure in prepubertal children due to chronic renal insufficiency.
Growth disturbance in short children aged 4 years and older (current height standard deviation score (SDS) < -2.5 and parental height SDS < -1), who were born small for gestational age with birth weight and/or length below -2 SD (standard deviation), and who have failed to catch up in growth (growth velocity SDS < 0 during the past year).

Adults.

Replacement therapy in adults with severe growth hormone deficiency diagnosed by one dynamic growth hormone deficiency test.

Growth hormone deficiency diagnosed in childhood.

Patients in whom growth hormone deficiency was diagnosed during childhood must undergo re-evaluation before initiating hormone replacement therapy with the medicinal product Grotrupin to confirm persistent growth hormone deficiency.

Growth hormone deficiency diagnosed in adulthood.

Patients must have a diagnosis of growth hormone deficiency due to hypothalamic or pituitary disease and deficiency of at least one additional hormone (except prolactin). In addition, appropriate hormone replacement therapy with other hormones should be initiated prior to starting somatropin treatment.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
Closed epiphyseal growth plates in children;
Presence of active neoplasms; prior to initiation of treatment, it must be ensured that any existing neoplasms are inactive and that any antineoplastic therapy has been completed; treatment should be discontinued if there is evidence of tumor growth;
Confirmed progression or recurrence of the primary intracranial space-occupying lesion;
Acute critical conditions resulting from complications following open heart surgery, abdominal surgery, multiple traumas, acute respiratory failure, or similar pathologies;
Kidney transplantation in children with chronic renal insufficiency; somatropin treatment must be discontinued during kidney transplantation;
Proliferative or preproliferative diabetic retinopathy.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of corticosteroids inhibits the growth-promoting effect induced by medicinal products containing somatropin. To prevent any inhibitory effect of corticosteroids on growth hormone action, careful adjustment of replacement therapy is required in patients with adrenocorticotropic hormone deficiency.

Furthermore, in some patients, initiation of hormone replacement therapy may unmask latent secondary adrenal insufficiency due to reduced activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) – an enzyme that converts inactive cortisone into cortisol, potentially leading to manifestation of previously masked central hypoadrenalism or reduced efficacy of low-dose corticosteroid replacement therapy.

Initiation of somatropin in patients receiving corticosteroid replacement therapy may lead to cortisol deficiency. In such cases, adjustment of corticosteroid dosage may be required.

Since oral estrogen preparations may reduce the response to somatropin treatment, as evidenced by decreased serum IGF-1 levels, patients receiving concomitant oral estrogen therapy may require an increased somatropin dose.

Data from drug interaction studies in adult patients with growth hormone deficiency suggest that somatropin administration may increase the clearance of compounds metabolized by cytochrome P450 isoenzymes. Clearance of compounds metabolized by cytochrome P450 3A4 (e.g., sex hormones, corticosteroids, anticonvulsants, and cyclosporine) may increase significantly, leading to reduced plasma concentrations of these compounds. The clinical significance of this phenomenon is unknown.

Special precautions for use.

Treatment with Gropropin should be carried out under the constant supervision of a physician experienced in the diagnosis and treatment of patients with growth hormone deficiency.

Prior to initiating treatment, a definitive diagnosis should be established and a functional assessment of the pituitary gland performed.

Gropropin should not be prescribed to patients with Down syndrome, Bloom syndrome, or Fanconi anemia.

Experience in treating patients with Silver-Russell syndrome is limited.

During treatment with Gropropin, bone age should be monitored periodically, especially in patients at pubertal age and in those receiving thyroid hormone medications, as epiphyseal growth plate closure may occur more rapidly in such patients. Prior to continuing therapy after epiphyseal plate closure, the diagnosis of growth hormone deficiency should be reconfirmed with hormonal profile assessment. If continuation of somatropin replacement therapy is necessary, lower doses recommended for adults should be used.

In the event of an acute severe condition in a patient, the potential benefits of somatropin treatment should be carefully weighed against possible risks.

Treatment of patients with tumors

Since growth hormone deficiency may rarely be an early sign of brain tumor development, the presence of such tumors should be excluded before initiating the medication. Prior to starting Gropropin therapy, any pre-existing neoplasm should be confirmed to be in an inactive state and its treatment completed.

In cases of growth hormone deficiency resulting from prior anti-tumor therapy, the patient should remain under close medical supervision to detect possible disease progression or recurrence. In the event of tumor recurrence, treatment with Gropropin should be discontinued.

Due to limited data on the risk of neoplasm development during somatropin therapy, such patients require careful medical monitoring during treatment.

Cases of increased risk of secondary neoplasms have been reported in children treated with somatropin after cured cancer. Among these secondary neoplasms, intracranial tumors—particularly meningiomas—were most common, observed in patients previously treated with radiation therapy for primary head tumors.

Leukemia

Cases of leukemia have been reported in a small number of patients with growth hormone deficiency (including those treated with somatropin). However, the frequency of such cases is similar to that observed in children without growth hormone deficiency.

Benign intracranial hypertension

Ophthalmoscopy should be performed before initiating treatment and repeated if clinical symptoms such as severe or periodic headache, visual disturbances, nausea, and/or vomiting—suggestive of papilledema—develop. If papilledema is confirmed, benign intracranial hypertension (or pseudotumor cerebri) should be considered, and treatment with Gropropin may need to be discontinued. Idiopathic intracranial hypertension usually resolves rapidly after discontinuation of therapy.

Currently, experience with treatment after normalization of intracranial pressure is limited. Therefore, if somatropin therapy is resumed, the patient should remain under close medical supervision for possible symptoms of intracranial hypertension.

Insulin resistance

Somatropin administration causes a transient phase of hypoglycemia lasting approximately 2 hours. Within 2–4 hours, blood glucose levels rise despite high insulin concentrations. Somatropin may induce insulin resistance, potentially leading to hyperinsulinemia and, rarely, hyperglycemia. Regular monitoring of blood glucose levels is recommended to detect insulin resistance. Risk factors for developing diabetes during somatropin therapy include obesity, genetic predisposition to diabetes, use of steroid hormones, or pre-existing impaired glucose tolerance. Patients with one or more of these risk factors should be under close medical supervision during Gropropin treatment.

The medicinal product should be prescribed with caution in patients with diabetes mellitus or a family history of diabetes. During somatropin therapy, patients with diabetes may require appropriate adjustments in their antidiabetic treatment.

Retinopathy

Replacement therapy with somatropin should be discontinued in cases of pre-proliferative retinal changes or proliferative retinopathy occurring during treatment. However, the presence of stable background retinopathy is not a reason to discontinue somatropin replacement therapy.

Pancreatitis

Cases of pancreatitis have been reported during somatropin therapy, particularly in children. Published data suggest that the risk of pancreatitis may increase during somatropin treatment, especially in girls with Turner syndrome. Acute epigastric pain in patients receiving Gropropin may indicate the development of pancreatitis.

Fluid retention

Growth hormone deficiency is associated with reduced extracellular fluid volume, which is rapidly corrected after initiating somatropin therapy.

In adults, fluid retention during somatropin replacement therapy may manifest as edema, joint swelling, arthralgia, myalgia, and paresthesia. These symptoms are dose-dependent and usually transient. In cases of persistent edema or severe paresthesia, the drug dose should be reduced to prevent the development of carpal tunnel syndrome.

Bone disorders

Slipped capital femoral epiphysis is often associated with endocrine disorders such as growth hormone deficiency or hypothyroidism, or with rapid growth. In children treated with somatropin, slipped capital femoral epiphysis may result from the underlying endocrine disorder or from accelerated growth due to treatment. Any occurrence of limping or complaints of hip or knee pain during Gropropin therapy requires appropriate clinical evaluation. Parents should be advised to monitor for these symptoms and report them to the physician immediately.

Patients with growth failure due to chronic renal insufficiency should be periodically evaluated for signs of possible progression of renal osteodystrophy. Cases of slipped capital femoral epiphysis or avascular necrosis of the femoral head have been observed in children with advanced renal osteodystrophy, although a causal relationship with somatropin therapy has not been established. Therefore, radiographic examination of the hip joint should be performed before initiating therapy in such patients.

Scoliosis

Scoliosis may develop or progress during periods of rapid growth in children. Scoliosis is more common in certain patient groups (e.g., patients with Turner syndrome or Prader-Willi syndrome). Since somatropin increases growth velocity, patients should be monitored for the development or progression of scoliosis. However, there is no evidence that somatropin increases the frequency or severity of scoliosis.

Hypothyroidism

During Gropropin therapy, serum thyroid hormone levels may decrease due to increased peripheral deiodination and conversion of T4 to T3. Hypothyroidism may develop, which, if untreated, may negatively affect the drug's efficacy. Therefore, thyroid function should be regularly monitored before and during Gropropin therapy. In cases of hypothyroidism developing during somatropin treatment, replacement therapy with thyroid hormones should be initiated to achieve the desired therapeutic effect.

Interaction with exogenous estrogens

Exogenous estrogens, particularly when administered orally, may reduce serum IGF-1 concentrations and thus the effectiveness of somatropin. Therefore, women undergoing estrogen therapy may require higher doses of somatropin to achieve age-appropriate IGF-1 levels. This should be considered when initiating estrogen therapy in patients receiving somatropin replacement therapy. In such cases, non-hormonal contraceptive methods should be used.

Conversely, in patients discontinuing estrogen therapy, IGF-1 levels may increase, leading to enhanced desired and adverse effects of somatropin. Therefore, somatropin dose reduction may be necessary in such cases. Evidence suggests that these changes are less pronounced with transdermal estrogen administration.

Prader-Willi syndrome

Gropropin is not indicated for long-term treatment of pediatric patients with growth failure due to genetically confirmed Prader-Willi syndrome unless they also have diagnosed growth hormone deficiency. Cases of nocturnal apnea or sudden cardiac arrest have been reported in pediatric patients with Prader-Willi syndrome after initiating somatropin therapy, particularly in those with one or more risk factors: severe obesity, upper airway obstruction, history of sleep apnea, or unexplained respiratory infections. Before initiating somatropin therapy, patients with Prader-Willi syndrome should be evaluated for sleep apnea and upper airway obstruction.

Short stature in children due to intrauterine growth retardation

In children with short stature due to intrauterine growth retardation (IUGR), other medical causes and treatment options explaining the growth impairment should be excluded before initiating Gropropin therapy.

In patients with IUGR, IGF-1 levels should be measured before starting treatment and subsequently twice a year. If repeated measurements show IGF-1 levels exceeding +2 SD compared to age- and pubertal stage-appropriate values, the drug dose should be adjusted considering the IGF-1/IGFBP-3 ratio (insulin-like growth factor binding protein 3).

Experience with somatropin therapy initiated close to the onset of puberty in patients with IUGR is limited; therefore, initiating treatment shortly before puberty is not recommended.

In children with IUGR, insulin and blood glucose levels should be measured before treatment initiation and annually thereafter. Oral glucose tolerance testing should be performed in patients at increased risk of diabetes (e.g., family history of diabetes, obesity, high body mass index, severe insulin resistance, acanthosis nigricans). Somatropin should not be prescribed in cases of overt diabetes mellitus.

The growth improvement achieved with somatropin in short children with IUGR may be partially lost if treatment is discontinued before the patient reaches final height.

Pediatric patients with chronic renal insufficiency

Treatment of children with chronic renal insufficiency should only be initiated when renal function is reduced by more than 50% of normal. To confirm growth impairment, the patient's growth velocity should be monitored for one year prior to therapy initiation. Treatment of chronic renal insufficiency should continue according to standard protocols during somatropin therapy.

Somatropin therapy should be discontinued during kidney transplantation.

Antibodies

As with other somatropin preparations, a small percentage of patients may develop antibodies to somatropin during Gropropin therapy. Generally, these antibodies have low binding affinity and do not usually affect growth rate.

However, in very rare cases, high antibody titers—particularly in patients with growth failure due to deletion of the growth hormone gene complex—may reduce clinical response to treatment.

Therefore, in patients with confirmed growth hormone deficiency who show no response to Gropropin therapy, testing for antibodies to human growth hormone should be performed, along with assessment of thyroid function.

Other warnings

Patients with Turner syndrome should be regularly examined during therapy for possible signs of Scheuermann-Mau disease, particularly if bone pain develops. In cases of complete or partial anterior pituitary insufficiency, replacement therapy with additional hormones (e.g., corticosteroids) may be required. In such cases, careful dose adjustment of the additional hormone should be performed to prevent growth inhibition.

Treatment with medicinal products containing human proteins may lead to hypersensitivity reactions (e.g., redness and itching at the injection site).

To prevent local lipoatrophy, particularly with prolonged use of the drug, the injection site should be rotated regularly.

Growth hormone deficiency in adults is a lifelong condition requiring appropriate treatment. However, experience with treatment in patients over 60 years of age and long-term use in adult patients is generally limited.

Important information on excipients.

This medicinal product contains less than 1 mmol sodium (23 mg)/dose, i.e., essentially "sodium-free".

This medicinal product contains benzyl alcohol; its content per dose is less than 90 mg/kg/day. Parenteral administration may cause toxic and allergic reactions in infants and children under 3 years of age; therefore, the product should not be used in premature and newborn infants.

Use during pregnancy or breastfeeding.

Pregnancy.

Clinical data on the use of the medicinal product during pregnancy are lacking. Therefore, somatropin preparations are not recommended during pregnancy or in women of reproductive potential who are not using appropriate contraceptive measures.

Breastfeeding.

Clinical studies on the use of somatropin in breastfeeding women have not been conducted. It is unknown whether somatropin is excreted in human breast milk. Therefore, somatropin preparations should be used with caution in breastfeeding women.

Ability to affect reaction speed when driving or operating machinery.

Somatropin preparations do not affect the patient's ability to drive or operate machinery.

Administration and Dosage.

The medicinal product Groptropin is intended for multiple use. The dosage of Groptropin should be individually adjusted for each patient depending on body surface area or body weight.

Treatment of children.

Groptropin is recommended to be administered subcutaneously before bedtime in the following doses:

Growth failure due to endogenous growth hormone deficiency: administer subcutaneously 0.7–1.0 mg/m² body surface area per day or 0.025–0.035 mg/kg body weight per day.

Growth failure in girls due to gonadal dysgenesis (Turner syndrome): administer subcutaneously 1.4 mg/m² body surface area per day or 0.045–0.050 mg/kg body weight per day.

Concurrent therapy with non-androgenic anabolic steroids in patients with Turner syndrome may enhance the response to growth hormone administration.

Growth failure in prepubertal children due to chronic renal insufficiency: administer subcutaneously 1.4 mg/m² body surface area per day, approximately equivalent to 0.045–0.050 mg/kg body weight per day.

Growth disturbances in short-stature children born small for gestational age (SGA): it is recommended to administer subcutaneously 0.035 mg/kg body weight daily (or 1 mg/m² body surface area per day, equivalent to 0.1 IU/kg/day or 3 IU/m²/day).

Treatment duration.

Treatment should be discontinued when the patient reaches adult height or when epiphyseal growth plates are closed.

Treatment of growth disturbances in short-stature children born SGA is generally recommended to continue until final height is achieved. Treatment should be discontinued after the first year of therapy if the growth velocity SDS is less than +1. Treatment should be stopped when the patient reaches final height (defined as growth velocity < 2 cm/year). Confirmation of the need for continued treatment is required if bone age exceeds 14 years (in girls) or 16 years (in boys), corresponding to closure of epiphyseal growth plates.

Growth hormone deficiency in adults.

At the beginning of therapy, low doses of the medicinal product are recommended: 0.15–0.3 mg of somatropin per day administered subcutaneously. The dose should be gradually adjusted and monitored based on insulin-like growth factor-1 (IGF-1) levels. The recommended final dose of growth hormone rarely exceeds 1.0 mg/day. In general, the lowest effective dose should be administered.

Women may require higher doses of the medicinal product than men, while men show increased sensitivity to IGF-1 over time. This implies a risk that women, especially those receiving estrogen therapy, may be underdosed, whereas men may be overdosed. Dose reduction may be necessary for elderly patients or patients with excess body weight. Growth hormone deficiency in adults is a lifelong condition requiring appropriate treatment. However, experience with treatment in patients aged 60 years and older, as well as long-term use of the medicinal product, is limited.

Administration method.

Subcutaneous administration is recommended, as this route provides stable serum concentrations of growth hormone close to physiological levels compared to intramuscular injection. Furthermore, subcutaneous administration allows caregivers of children or adult patients to self-administer injections after appropriate training. It should be noted that prolonged subcutaneous administration at the same site may lead to lipodystrophy; therefore, the injection site should be rotated regularly when administering Groptropin.

Children.

The medicinal product Groptropipin is used in pediatric practice.

Overdose.

There have been no reports of acute overdose. However, exceeding the recommended doses may cause adverse effects. Overdose may lead to hypoglycemia followed by hyperglycemia. In addition, somatropin overdose may likely result in fluid retention.

Side effects

Up to 10% of patients may experience redness and itching at the injection site. When growth hormone replacement therapy is administered to adults, fluid retention is expected. Clinically, fluid retention may manifest as peripheral edema, joint swelling, arthralgia, myalgia, and paresthesia. However, these symptoms and signs are usually transient and dose-dependent. In adult patients treated for growth hormone deficiency diagnosed in childhood, a lower incidence of adverse reactions has been reported compared to those in whom growth hormone deficiency began in adulthood. In a small percentage of patients, antibodies to somatropin may develop. To date, these antibodies have demonstrated low binding affinity, and their formation has not led to growth attenuation, except in patients with gene deletions. In extremely rare cases, when short stature is associated with deletion of the growth hormone gene complex, treatment with somatropin may induce the development of antibodies that attenuate growth. In a small number of patients with growth hormone deficiency, some of whom were treated with somatropin, leukemia has been diagnosed. However, there is no evidence that treatment with somatropin increases the incidence of leukemia in patients without predisposing risk factors.

Adverse reactions reported in association with the use of the medicinal product and listed below are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from the available data).

Immune system disorders:

Frequency not known: formation of antibodies (see section "Special instructions"). Localized and generalized hypersensitivity reactions.

Endocrine system disorders:

Rare: hypothyroidism.

Metabolism and nutrition disorders:

Frequency not known: hyperinsulinism, insulin resistance, hyperglycemia (see section "Special instructions").

Nervous system disorders:

Common: hypesthesia, paresthesia, carpal tunnel syndrome, headache.

Uncommon: idiopathic intracranial hypertension (pseudotumor cerebri).

Gastrointestinal disorders:

Frequency not known: pancreatitis.

Musculoskeletal and connective tissue disorders:

Very common: arthralgia.

Common: myalgia, bone pain, muscle stiffness.

Frequency not known: joint swelling.

Reproductive system and breast disorders:

Uncommon: gynecomastia.

General disorders and administration site conditions:

Very common: edema.

Common: injection site reactions such as redness, itching, rash, inflammation, hematoma, swelling, or pain. Localized lipodystrophy.

Side effects in children:

In children, the same types of adverse reactions are predominantly observed as in adults, although some occur at different frequencies, as indicated below.

Nervous system disorders:

Uncommon: paresthesia, carpal tunnel syndrome.

Musculoskeletal and connective tissue disorders:

Uncommon: arthralgia, myalgia, muscle stiffness, bone pain.

Rare: slipped capital femoral epiphysis, avascular necrosis of the femoral head.

General disorders and administration site conditions:

Uncommon: edema.

In adult patients with growth hormone deficiency diagnosed in childhood, fewer adverse reactions are observed compared to those in whom the diagnosis was made in adulthood.

Adverse reactions observed with other products in this therapeutic class:
Hyperthyroidism, fluid balance disorders, insomnia, seizures, sleep apnea (particularly in patients with Prader-Willi syndrome), arterial hypertension, increased frequency of pigmented nevi, worsening of pre-existing psoriasis, gynecomastia, premature thelarche.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store at 2–8°C in the original packaging, out of reach of children. Do not freeze!

After first opening of the vial, store for no more than 28 days at 2–8°C.

Do not use after the expiry date stated on the packaging.

Incompatibilities.

Since specific compatibility studies have not been conducted, Grothropin must not be mixed with other medicinal products.

Packaging.

0.5 ml or 2.0 ml of solution for injection in glass vials. 1 or 10 vials per cardboard box.

Prescription status. By prescription only.

Manufacturer.

Dong-A ST Co., Ltd, Korea.

Manufacturer's address and place of business.

493, Nongong-ro, Nongon-ap, Dalseong-gun, Daegu (N-dong, B-dong Section 2), Korea.

Growtropin