Eutropin S Pen Injection

Dose-adjustable pen-type injection with a clear cartridge which contains colorless transparent solution.
Each pre-filled pen of Eutropin S Pen Inj. contains 36 IU of recombinant human somatropin (INN: somatropin).
Excipients/Inactive Ingredients: Poloxamer 188, L-Histidine, Histidine monohydrochloride monohydrate, D-Mannitol, L-Methionine, Phenol, Sodium hydroxide, Water for injection.

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and somatropin agonists. ATC code: H01AC01.
Recombinant Human Growth Hormone.
Pharmacology: Pharmacodynamics: Mechanism of action: Somatropin is a polypeptide hormone made up of 191 amino acids made by recombinant DNA technology, and promotes the growth of cells, particularly bones, synthesizes protein necessary for growth, and stimulates adipolysis.
Clinical efficacy and safety: A total of three clinical tests were conducted to verify the efficacy of this drug. This drug was administered to children with growth hormone deficiency, Turner's syndrome, as well as small for gestational age (SGA).
To evaluate its efficacy, 0.15 IU/kg of this drug was administered to children with growth hormone deficiency three times a week for 12 months. A total of 20 children (average age: 10.2), were evaluated for efficacy such as height velocity that was measured before treatment and every three months after treatment. Height velocity increased from an average of 3.20±1.21 cm/year before treatment to 9.60±2.85 cm/year, 8.55±2.28 cm/year, 7.48±1.32 cm/year, and 7.22±1.46 cm/year, at three, six, nine and 12 months after treatment, respectively. IGF-1 concentration rose from 18.6±5.5 nMol/L before treatment to 26.5±8.8 nMol/L and 35.8±12.7 nMol/L at six and 12 months after treatment, respectively.
After administering this drug to children with Turner's syndrome, an open-label, single -arm, clinical trial was conducted before and after administration to assess its efficacy. Sixty children with Turner's syndrome whose chronological age is under 14 and whose height is less than 1 SD than the average for the same age (average chronological age: about 10.8) received about 1 IU/kg per week six to seven times a week for one year. For 50 of these children, standard deviation scores (SDS) of height, height velocity, weight SDS for chronological age (CA), weight SDS for height, ratio of height age to bone age, and IGF-1 were measured to evaluate efficacy before and after treatment. The height curve and height velocity curve showed that height SDS rose by about 0.5 one year after treatment, height velocity for 88% of patients increased by more than 2 SD (standard deviation), and height velocity for 98% of patients rose by more than 1 SD. (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

An open-label, single-arm, phase III clinical trial was conducted to assess the efficacy of about 0.48 mg/kg/week of this drug administered to prepubertal SGA for six months. During the clinical trial of 30 patients, the difference in height velocity before and after six months of treatment was compared through four visits (screening, Day 0, 3 months, and 6 months). The difference in height velocity before and after treatment in the PP group analysis was statistically significant (5.30±1.84 cm/year, p<0.0001), and the lower limit of the 95% one-sided confidence interval was 4.55 cm, larger than the predetermined level of 2 cm. This showed that the administration of about 0.48 mg/kg/week of this drug to prepubertal SGA for six months led to the improvement of height velocity.
Pharmacokinetics: Intramuscular injection or subcutaneous injection of 0.1 IU of this drug per kg of body weight was applied to children with growth hormone deficiency.
T_max: 27±0.3 hours for intramuscular injection, and 5.3±0.3 hours for subcutaneous injection.
Clearance: 24.5 L/hr for intramuscular injection, and 27.2 L/hr for subcutaneous injection.
Half-life: 1.99 hours for intramuscular injection, and 2.39 hours for subcutaneous injection.
Absorption constant rate: 0.47/hr for intramuscular injection, and 0.40/hr for subcutaneous injection.
Elimination constant rate: 0.35/hr for intramuscular injection, and 0.29/hr for subcutaneous injection.
Toxicology: Preclinical Safety Data: Non-clinical data showed that this drug does not have a particular risk to people based on the results of traditional tests related to safety pharmacology, acute toxicity, repeated-dose toxicity, genotoxicity, local tolerance, immune toxicity and reproductive toxicity. A carcinogenicity test was not performed for this drug.
Subcutaneous injection of 40 IU/kg in mice did not have a neurological affect. Intravenous injection of 20 IU/kg in rabbits did not have cardiovascular or respiratory affects.
In acute toxicity studies where intramuscular injections of 40 IU/kg and subcutaneous injections of 80 IU/kg were made in rats and mice, toxicity due to the drug was not detected.
In repeated subcutaneous injections of up to 10 IU/kg/day in mice for 90 days, only the high-dose injection group (10 IU/kg/day, more than 60 times the clinical dose) showed various kinds of toxicity symptoms such as death, reduced activity, and dyspnea. The same trial for rats did not produce toxicity symptoms in all-dose groups.
Genotoxicity of this drug was not observed in a bacterial reverse mutation test, in vitro chromosomal aberration assay, and in vivo micronucleus assay for mice.
Local tolerance and immunogenicity test results showed that this drug does not cause particular hazards for people.
In a fertility and early embryonic development toxicity test, embryo-fetal developmental toxicity test and prenatal & postnatal toxicity test for rats with subcutaneous injections of up to 10 IU/kg/day, reproductive hazards were not observed. The embryo-fetal developmental toxicity test for rabbits with subcutaneous injection of the same dose also did not produce reproductive risks.

For the treatment of: Short stature in children due to an inadequate secretion of endogenous growth hormone (Growth hormone deficiency, GHD).
Short stature in children who have Turner syndrome.
Short stature in children born Small for Gestational Age (SGA).

In subcutaneous injection, the injection site of Eutropin S Pen Inj. should be varied through brachium, femoral region, abdomen and not be repeated on the same site in short-term. After first opening, Eutropin S Pen Inj. should be used within 42 days.
The dosage and administration schedule for Eutropin S Pen Inj. should be individualized for each patient.
Short stature in children due to GHD: Generally, a dosage of 0.5-0.6 IU (0.17-0.21 mg) per kg of body weight per week or 12 IU (4 mg)/m² of body surface area per week is recommended. The weekly dose should be divided into 3-6 subcutaneous injections.
Short stature in children who have Turner syndrome: 1 IU (0.33 mg)/kg/week of Eutropin S Pen Inj. is recommended. The weekly dosage should be divided into 6-7 injections.
Short stature in children born Small for Gestational Age (SGA): A dosage of 1.44 IU (0.48 mg)/kg/week is given divided into 6-7 subcutaneous injections.

Short-Term: Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention.
Long-Term: Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone.
Treatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.

Eutropin S Pen Inj. should not be used in subjects with following diseases.
Diabetes mellitus; Malignant tumor; Closed epiphyses; Short stature due to brain tumor which induce hypopituitarism and hyposecretion of growth hormone; Hypersensitivity to somatropin or any of the product excipients; Acute critical illness with complications following open heart surgery, abdominal surgery, multiple accidental trauma; Acute respiratory failure.

Eutropin S Pen Inj. should be carefully administered in following cases.
Because transient undesirable side effect may be induced by Eutropin S Pen Inj., patients with heart and kidney disease should be carefully monitored.
Patients with familial history of diabetes mellitus.
Treatment of GHD with Eutropin S Pen Inj. should be initiated by a paediatrician who specializes in treating disorders of the endocrine system.
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.
In SGA children, it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered. In SGA children, it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account to consider dose adjustment.
Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before final height is reached.
Neoplasms: Patients with signs of developing malignancies and patients with growth hormone deficiency secondary to an intracranial lesion should be regularly examined for progression or recurrence of the underlying disease prior to the therapy and Eutropin S Pen Inj. should be carefully administered in this case. In pediatric patients, clinical literature has demonstrated no relationship between somatropin therapy and central nervous system (CNS) tumour recurrence or new intracranial tumors. However, in childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. If the lesion is on the skin, it should be carefully monitored for increased growth, or potential malignant changes.
Impaired Glucose Tolerance and Diabetes Mellitus: Because of the diabetogenic action of growth hormone, hyperglycemia and ketosis may occur and a state of insulin resistance may be induced, patients should be closed monitored for evidence of glucose intolerance. New-onset Type 2 diabetes mellitus has been occasionally reported. In most of these cases, there were risk factors such as obesity, family history of diabetes mellitus, steroid treatment, or previously impaired glucose tolerance. In patients with previously diagnosed diabetes, the dosage of antidiabetic agents in somatropin therapy may need to be adjusted. Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus.
Patients with pre-existing type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral/injectable agents) may require adjustment when somatropin therapy is instituted in these patients.
Insulin resistance induced by somatropin may lead to increased blood sugar and urine glucose, and it is advisable that urine glucose test is conducted periodically.
Intracranial Hypertension: Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude pre-existing papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH.
Fluid Retention: Eutropin S Pen Inj. may induce overfiltration with increasing renal plasma flow and glomerular filtration rate, patients should be carefully monitored in long-term.
Hypoglycemia: Hypoglycemia may occur in the rare case of intermittent administration and the switch to daily administration is recommended.
Thyroid Function: Growth hormone increases the extrathyroidal conversion of T4 to T3 which may result in a reduction in serum T4 and an increase in serum T3 concentrations. Whereas the peripheral thyroid hormone levels have remained within the reference ranges in the majority of healthy subjects, hypothyroidism theoretically may develop in subjects with subclinical hypothyroidism. Consequently, monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism on standard replacement therapy, the potential effect of growth hormone treatment on thyroid function must be closely monitored.
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with hypothyroidism should be examined periodically and treated with thyroid hormone, if necessary.
Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
Patients with hypothyroidism (lacking in multiple pituitary hormones) should be closely monitored for hormone replacement therapy during treatment with somatropin.
Slipped Capital Femoral Epiphyses in Pediatric Patients: Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.
Progression of Preexisting Scoliosis in Pediatric Patients: Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
Otitis Media and Cardiovascular Disorders in Turner Syndrome: Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
Lipoatrophy: When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site.
Allergic Reactions: As with other proteins, local or systemic allergic reactions may occur, and patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.
Laboratory Tests: Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.
Anti-hGH Antibodies: Because antibody to human growth hormone may be formed, antibodies to growth hormone should be determined periodically.
In successive treatment of Eutropin S Pen Inj., antibody to human growth hormone may be formed and the effect of growth hormone may also be decreased, so Eutropin S Pen Inj. should be discontinued in those cases and appropriate medical therapy should be instituted.
Others: Therapy with somatropin should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure associated with growth hormone deficiency (GHD).
If growth hormone therapy is used in patients with panhypopituitarism, standard hormone replacement therapy should be carefully monitored.
Effects on Ability to Drive and Use Machines: It is not known whether somatropin affects the ability to drive and use machines.

Pregnancy: Safe use in human pregnancy has not been established. Therefore, Eutropin S Pen Inj. should not be used in pregnant women or women of childbearing potential.
Lactation: There have been no studies conducted with somatropin in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when somatropin is administered to a nursing woman.

Summary of the safety profile: The relatively frequently reported adverse reactions include gastrointestinal disorders (nausea, vomiting, etc.), general disorders and administration site conditions (injection site reactions, etc.), musculoskeletal and connective tissue disorders (arthralgia, etc.), nervous system disorders (headache, etc.) and skin and subcutaneous tissue disorders (pruritus, rash and urticaria, etc.).
Tabulated list of adverse reactions: see Table 3.

Click on icon to see table/diagram/image

Description of selected adverse reactions: Hypersensitivity: Occasionally skin rashes (urticarial or erythema), generalized pruritus, or redness, pain or burning at injection site may occur uncommonly. In these cases, Eutropin S Pen Inj. should be discontinued.
Endocrine system disorders: A state of hypothyroidism may be developed or exacerbated during Eutropin S Pen Inj. treatment. Since untreated hypothyroidism may interfere with the response to Eutropin S Pen Inj., the patients should have a periodic thyroid test and should be treated with thyroid hormone when indicated.
Skin: Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi.
Immunogenicity: Eutropin has given rise to the formation of antibodies to growth hormone in approximately 3.3% (2 out of 60 patients) in Turner syndrome patients.
Other adverse reactions: Occasionally, edema, headache, loss of subcutaneous fat, microscopic hematuria may occur. Rarely, proteinuria, increase of CPK, myoglobin may occur. And papilloedema, dysopia, headache, nausea, and vomiting accompanied by intracranial hypertension were reported. When these symptoms occur, Eutropin S Pen Inj. should be discontinued or lowered dosage.

Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: An excessive treatment with glucocorticoids can inhibit the expected effect of somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage and compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of growth promoting effects.
Cytochrome P450-Metabolized Drugs: Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes.
11 β-Hydroxysteroid Dehydrogenase Type 1: Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Oral Estrogen: In patients on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal.
Insulin and/or Oral/Injectable Hypoglycemic Agents: In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated.

Incompatibilities: In the absence of compatibility studies, the medicinal product must not be mixed with other medicinal products.
Special Precautions for Disposal: Detailed instructions for the handling of the medicinal product are given at the end of the package leaflet.
Instruction for Use: A needle for injection is not provided with this product. You can use disposal sterile needle (length 4-6 mm, 32-34 gauge) authorized as a medical device.
Eutropin S Pen Inj. must be administered by subcutaneous injection to the back of the upper arm, abdomen, buttocks, or thigh with regular rotation of injection sites to avoid lipoatrophy. Inspect visually for particulate matter and discoloration. Eutropin S Pen Inj. should be clear and colorless. If the solution is cloudy or contains particulate matter do not use.
Instructions for delivering the dosage are provided in INSTRUCTIONS FOR USE leaflets enclosed with the Eutropin S Pen Injection.

Eutropin S Pen Inj. in pre-filled pen are stable when stored at 2-8°C in hermetic container. Protect from light. Avoid freezing.
For in-use storage conditions of the medicinal product, see Shelf-life as follows.
Shelf-life: 24 months.
After first opening: Store for a maximum of 42 days in a refrigerator (2-8°C).
Alternatively, the medicinal product may be stored for a maximum of 14 days below 25°C.

Trophic Hormones & Related Synthetic Drugs

H01AC01 - somatropin ; Belongs to the class of somatropin and somatropin agonists. Used in anterior pituitary lobe hormone and analogue preparations.

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