Saizen^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Merck Serono, S.p.A. (Italy)

ATC Code

H01AC01 (Somatropin)

Active Substance

Somatropin (Rec.INN registered by WHO)

Dosage Form

Saizen®

Lyophilizate for the preparation of solution for subcutaneous administration 8 mg: fl. 1 or 5 pcs. in a set with solvent in a cartridge and a solution preparation device "Click. easy"

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for subcutaneous administration in the form of a powder or porous mass of white or almost white color.

Excipients: sucrose, phosphoric acid, sodium hydroxide.

Solvent 0.3% solution of metacresol in water for injections (1.37 ml).

Colorless glass vials with a volume of 3 ml (1) in a set with solvent (cartridges 1 pc.), solution preparation device "Click.easy" (body, sterile transitional cannula) (1 pc.) – plastic trays (1) – cardboard boxes.
Colorless glass vials with a volume of 3 ml (5) in a set with solvent (cartridges 5 pcs.), solution preparation device "Click.easy" (body, sterile transitional cannula) (5 pcs.) – plastic trays (1) – cardboard boxes.

* 1 mg corresponds to 3 IU.

Clinical-Pharmacological Group

Recombinant somatropin

Pharmacotherapeutic Group

Somatotropic hormone

Pharmacological Action

Recombinant somatotropic hormone, obtained by genetic engineering using a mammalian cell line. It is identical in its composition and action to the human pituitary growth hormone – somatropin (a single-chain polypeptide consisting of 191 amino acid residues). It has anabolic and anti-catabolic properties, affecting not only growth but also metabolic processes.

By acting on the epiphysis of tubular bones, it stimulates the growth of skeletal bones. It regulates protein metabolism, stimulates the transport of amino acids into the cell and protein synthesis.

Pharmacokinetics

Pharmacokinetics in doses not exceeding 2.67 mg (8 IU) is linear; at higher doses, linearity is disrupted without any clinical manifestations.

Absorption and Distribution

The absolute bioavailability after subcutaneous administration is 70-90%. C_max is observed after 4 hours and returns to the initial level 24 hours after administration. After intravenous administration, V_d is 7 l/kg, total clearance is 15 l/h.

No accumulation is observed.

Metabolism and Excretion

It is metabolized in the kidneys and liver. Excreted with bile. T_1/2 is 2-4 hours.

Indications

• Growth retardation in children due to growth hormone deficiency;
• Growth retardation in girls with gonadal dysgenesis (Turner syndrome);
• Growth retardation in prepubertal children caused by chronic renal failure;
• Growth retardation in children aged 4 years and older with a history of intrauterine growth retardation;
• Confirmed congenital or acquired growth hormone deficiency in adults (as replacement therapy).

ICD codes

Dosage Regimen

The drug should be used under the regular supervision of a physician with sufficient experience in diagnosing and treating patients with growth hormone deficiency or Turner syndrome.

The drug Saizen^® in vials containing 8 mg (24 IU) of somatropin is intended for multiple subcutaneous administration.

The dosing regimen is determined individually for each patient, taking into account the body surface area (m²) and body weight (kg).

Saizen^® is recommended to be administered in the evening.

For children with growth retardation caused by growth hormone secretion deficiency, the drug is prescribed subcutaneously at a dose of 0.7-1 mg/m²/day or 0.025-0.035 mg/kg/day.

For growth impairment in girls with gonadal dysgenesis (Turner syndrome), the drug is prescribed subcutaneously at a dose of 1.4 mg/m²/day or 0.045-0.05 mg/kg/day. If the girl is simultaneously taking non-androgenic anabolic steroids, the growth rate may be increased.

For growth retardation in prepubertal childrencaused by chronic renal failure, the drug is prescribed subcutaneously at a dose of 1.4 mg/m²/day or 0.045-0.05 mg/kg/day.

For growth retardation inchildren aged 4 years and olderwith a history of intrauterine growth retardation, the dose for subcutaneous administration is 1 mg/m²/day or 0.035 mg/kg/day.

Treatment is discontinued after the patient’s height reaches values corresponding to adult height or after closure of the epiphyseal growth zones.

For adults, therapy is recommended to start with subcutaneous administration of the drug at a low dose of 0.15-0.3 mg/day. Dose increases should be carried out strictly under medical supervision. The recommended final dose usually does not exceed 1 mg/day. Mostly, small doses are effective. In elderly patients, the dose should be reduced.

Rules for the preparation of the injection solution and administration of the drug

To prepare the injection solution, the contents of the vial are dissolved in the supplied bacteriostatic solvent, which contains a 0.3% solution of metacresol in water for injections, using the "Click.easy" device. The prepared solution intended for subcutaneous injections must be clear and free of visible particles. If visible particles are present in the solution, its use is not allowed. The prepared solution contains 8 mg of the drug Saizen^® (5.83 mg/ml).

Patients should receive detailed instructions on how to properly perform the drug dilution procedure. The instructions for using the "Click.easy" device should be carefully read. If necessary, patients should consult a doctor, nurse, or pharmacist.

Ensure that the "Click.easy" solution preparation device is assembled, check for the presence of the vial with Saizen^®, the sterile transitional cannula, and the cartridge with solvent. Check the presence and integrity of the control visible marks on the "Click.easy" and on the cap. If they are broken, the device must not be used, and the patient should return it to the pharmacist or treating physician.

Preparation of the solution and subcutaneous administration are carried out under conditions of asepsis and antisepsis.

To prepare the drug solution, one should be guided by the color insert with pictures included in the package, illustrating the procedure for preparing the solution using the "Click.easy" device.

1. Place the "Click.easy" mixing device vertically on a flat surface with the vial down and the cap up.
2. Press the cap all the way down (the control visible mark on the "Click.easy" will now be broken).
3. Slowly turn the cap clockwise until the green indicator moves into the vertical window.
4. Continue to press slowly on the cap until all the solvent has transferred from the cartridge into the vial (the control visible mark on the cap will now be broken). It is very important to press the cap slowly to prevent bubble formation. Ensure that all the solvent has transferred into the vial.
5. The powder should be dissolved in the solvent with gentle circular motions. Do not shake the "Click.easy" sharply, as foam or bubbles may form. Allow the solution to stand until the powder is completely dissolved.
6. Turn the "Click.easy" over (vial up). Pull the cap down all the way and then pull slowly until the solution has completely transferred back into the cartridge. Ensure that no more than 1-2 drops of solution remain in the vial.

If more than 1-2 drops of solution remain in the vial, then slowly press the cap again until the solution transfers back into the vial. Then transfer the solution into the cartridge again as described above.

Remove any air that has entered the cartridge by slowly pressing on the cap.

Do not pull the cap too quickly, as air may enter the cartridge.

1. Holding the "Click.easy" with the vial up, unscrew the cap and remove it. Holding the "Click.easy" in the same position, remove the cartridge with the prepared solution from the "Click.easy".
2. Carefully remove the outer label from the cartridge. Write the date of solution preparation on the inner label of the cartridge.

The "Click.easy" should be disposed of in accordance with accepted rules.

The cartridge containing the prepared solution of Saizen^® is ready for use with injectors used for drug injection. The injectors are supplied separately and come with separate instructions.

Injections should be made into different areas of the body. Do not administer the drug into areas where swelling, hard nodules, indentations have formed, or where pain is noted; the patient should report all symptoms to the doctor or other healthcare professional. The skin at the injection site should be washed with soap.

If a scheduled dose is missed or an excessive dose of Saizen^® is administered, the patient should inform the doctor, as minor adjustments to the recommended dose may be needed to compensate for the deviation. Administration of an excessive dose will lead to changes in blood glucose levels, which may be accompanied by tremors and dizziness. If the patient receives a very high dose for some time, it will cause excessive bone growth, mainly in the bones of the hands, feet, and jaws.

Adverse Reactions

Local reactions sometimes – soreness, redness, swelling, itching.

Very rarely formation of antibodies to somatropin.

Rarely benign intracranial hypertension (severe headache, nausea, vomiting).

Possibly epiphysiolysis of the femoral head. In adult patients on replacement hormone therapy in 10% – fluid retention in the body with the development of peripheral edema, joint pain, muscle pain, paresthesia (appeared at the beginning of therapy and usually disappeared during treatment). Adults with growth hormone deficiency diagnosed in childhood have fewer side effects compared to those whose deficiency occurred in adulthood.

The following side effects have been described in the literature with the use of somatropin (however, they have not been noted to date with the use of Saizen^®): weakness, fatigue, gynecomastia, optic disc edema (usually observed within the first 8 weeks of treatment, most common in patients with Turner syndrome); pancreatitis (abdominal pain, nausea, vomiting); otitis media and hearing impairment (in patients with Turner syndrome); hip subluxation in children (limping, pain in the hip and knee); leukemoid reactions, acceleration of growth of a pre-existing nevus (possible malignancy); progression of scoliosis (in patients with excessively rapid growth).

Regarding laboratory parameters increase in the blood levels of inorganic phosphate, parathyroid hormone and alkaline phosphatase activity.

Allergic reactions skin rash, itching.

Most patients tolerate therapy with the drug well. Patients or the child’s parents should inform the doctor about the occurrence of the above or any other side effects.

Contraindications

• Signs of active malignant neoplasm (antitumor therapy should be completed before starting use);
• Pregnancy;
• Lactation (breastfeeding);
• Hypersensitivity to somatropin, to any other component of the drug, or to metacresol (part of the solvent).

Use with caution in diabetes mellitus, intracranial hypertension, hypothyroidism.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy, as there is currently insufficient data on the safety of growth hormone use during this period.

If it is necessary to use Saizen^® during lactation, breastfeeding should be discontinued. There is evidence of possible excretion of somatropin in breast milk.

Use in Renal Impairment

Femoral bone lesions occur more often in children with endocrine or kidney disorders. In chronic renal failure, the child should be regularly examined for bone lesions. Before starting treatment, an X-ray of the femur should be taken. Patients should be warned that if limping or pain in the hip or knee joints appears during treatment with Saizen^®, they should immediately consult a doctor.

In children with chronic renal failure, treatment should be discontinued during kidney transplantation.

For growth retardation in prepubertal children, caused by chronic renal failure, the recommended dose for subcutaneous administration is 1.4 mg/ m²/day or 0.045-0.05 mg/kg/day.

Pediatric Use

Used in children according to indications in accordance with the dosage regimen.

Geriatric Use

Patients over 60 years of age receiving long-term therapy with Saizen^® should be under careful supervision, as experience with the drug in elderly patients is insufficient.

Special Precautions

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

Some time after administration of Saizen^®, a decrease in blood glucose concentration may occur, which may be accompanied by short-term tremors or dizziness. Within the next 2-4 hours, the blood glucose concentration may increase. Since growth hormone treatment may cause impaired glucose tolerance, blood glucose levels should be monitored regularly. In diabetes mellitus or a hereditary predisposition to this disease, careful medical supervision is necessary during the use of Saizen^® and, if necessary, adjustment of hypoglycemic therapy.

During treatment with Saizen^®, hypothyroidism may develop, so thyroid function tests should be performed periodically. If hypothyroidism develops during the course of growth hormone treatment, replacement therapy with thyroid hormone preparations should be prescribed.

If the child has a history of a brain tumor, regular examination for recurrence is necessary. Currently, there are no data on an increased likelihood of tumor recurrence during treatment with Saizen^®.

Some children with growth hormone deficiency developed leukemia (regardless of whether they received growth hormone or not), i.e., this disease is associated with an increased risk of developing leukemia compared to children without growth hormone deficiency. A causal relationship between the use of growth hormone and these phenomena has not been established.

If severe or recurrent headache, visual disturbances, nausea and/or vomiting occur during the use of the drug, an examination of the fundus (fundoscopy) should be performed to detect optic disc edema. If edema is confirmed, the presence of benign intracranial hypertension should be assumed. In this case, the use of growth hormone should be discontinued; later, resumption of the drug use may be possible. If symptoms of intracranial hypertension recur, Saizen^® should be discontinued.

Femoral bone lesions occur more often in children with endocrine or kidney disorders. In chronic renal failure, the child should be regularly examined for bone lesions. Before starting treatment, an X-ray of the femur should be taken. Patients should be warned that if limping or pain in the hip or knee joints appears during treatment with Saizen^®, they should immediately consult a doctor.

In children with chronic renal failure, treatment should be discontinued during kidney transplantation.

In children diagnosed with growth retardation as a result of intrauterine growth retardation, other causes of growth delay should be excluded before starting treatment. In this category of patients, fasting serum insulin and glucose levels should be determined before starting treatment and these tests should be performed annually. If diabetes mellitus is present, treatment with Saizen^® is not recommended.

In children diagnosed with growth retardation as a result of intrauterine growth retardation, it is recommended to determine the level of insulin-like growth factor I before starting treatment and then twice a year. The final height of children with this diagnosis will not be achieved if treatment with Saizen^® is discontinued before the final height is reached.

Administering the drug to the same site for a long time may cause damage to that area of the skin. It is important to constantly change the injection site. Growth hormone should not be used in case of emergency conditions.

Patients over 60 years of age receiving long-term therapy with Saizen^® should be under careful supervision, as experience with the drug in elderly patients is insufficient.

Effect on the ability to drive vehicles and operate machinery

Saizen^® does not affect the ability to drive vehicles and operate machinery.

Overdose

Reports of cases of acute overdose are absent.

Symptoms when using a dose exceeding the recommended one, hypoglycemia is possible. With prolonged overdose, signs and symptoms characteristic of growth hormone excess may appear – active growth of bone tissue, especially of the hands, feet, and jaws, as well as the development of hypothyroidism, and a decrease in blood cortisol.

Treatment withdrawal of the drug, symptomatic therapy.

Drug Interactions

Concomitant use of glucocorticosteroids may suppress growth and thus inhibit the effect of Saizen^®. The effectiveness of the drug (regarding final height) can also be influenced by concomitant therapy with other hormonal drugs (for example, gonadotropin, anabolic steroids, estrogens, and thyroid hormones).

Currently, medicines incompatible with Saizen^® are not known.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F) in the original packaging.

Shelf Life

The shelf life is 3 years.

The reconstituted solution should be stored at a temperature between 2°C (35.6°F) and 8°C (46.4°F) for no more than 28 days; do not freeze.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.