Humatrope^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Lilly France (France)

ATC Code

H01AC01 (Somatropin)

Active Substance

Somatropin

Dosage Forms

	Humatrope®	Lyophilisate for preparation of solution for injection 6 mg: cartridges 3 ml 1 pc. in a set with solvent in a syringe
		Lyophilisate for preparation of solution for injection 12 mg: cartridges 3 ml 1 pc. in a set with solvent in a syringe

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for injection from white to almost white.

Excipients: glycine, mannitol, disodium phosphate, phosphoric acid (10% solution), sodium hydroxide solution 10%.

Solvent: m-cresol 3 mg/ml, glycerol, water for injection, phosphoric acid (10% solution) sodium hydroxide solution 10% (for pH adjustment).

Cartridges of 3 ml volume (1) in a set with solvent (syringe 3 ml) – cardboard packs.

Lyophilisate for preparation of solution for injection white to almost white.

Excipients: glycine, mannitol, disodium phosphate, phosphoric acid (10% solution), sodium hydroxide solution 10% (for pH adjustment).

Solvent: m-cresol 3 mg/ml, glycerol, water for injection, phosphoric acid (10% solution) sodium hydroxide solution 10% (for pH adjustment).

Cartridges of 3 ml volume (1) in a set with solvent (syringe 3 ml) – cardboard packs.

Clinical-Pharmacological Group

Recombinant somatropin

Pharmacotherapeutic Group

Somatotropic hormone

Pharmacological Action

Biosynthetic human DNA-recombinant growth hormone, which is a polypeptide hormone. Somatropin contains 191 amino acid residues and has a molecular weight of about 22,125 Da. The amino acid sequence of the drug is identical to the amino acid sequence of human growth hormone produced by the pituitary gland. Somatropin is synthesized by a strain of Escherichia coli that has been modified by the addition of the human growth hormone gene. It is a highly purified preparation.

Somatropin stimulates linear growth in children with endogenous growth hormone deficiency and in children with growth retardation due to Turner syndrome. A noticeable increase in linear body length after administration of somatropin occurs as a result of an effect on the growth plates of long bones. Treatment of growth hormone deficiency in children with somatropin causes an increase in growth rate and an increase in IGF-I (insulin-like growth factor/Somatomedin-C) concentrations. In addition, Somatropin enhances intracellular protein synthesis and causes nitrogen retention. Somatropin is equivalent in therapeutic effect to human pituitary growth hormone and has an equivalent pharmacokinetic profile in healthy adults.

Pharmacokinetics

Absorption

After administration of the drug to adult volunteers at a dose of 100 mcg/kg body weight, C_max is reached in 3-6 hours and is about 55 ng/ml. Absorption after subcutaneous or intramuscular administration is 63% and 75%, respectively.

Distribution and Metabolism

AUC is about 475 ng x h/ml. Somatropin penetrates into well-perfused organs, especially the liver and kidneys. It is metabolized in the kidneys and liver.

Elimination

T_1/2 is about 4 hours. It is excreted by the kidneys and with bile (including 0.1% unchanged).

Indications

For children

• Long-term treatment of children with growth retardation due to endogenous growth hormone deficiency;
• Treatment of short stature in children with Turner syndrome;
• Treatment of growth retardation in prepubertal children with chronic renal failure.

For adults

• Replacement therapy in adults with pronounced growth hormone deficiency. Patients must meet the following two criteria

1. In patients with growth hormone deficiency that occurred in childhood, stimulation tests should be repeated to confirm growth hormone deficiency before starting replacement therapy with somatropin.

2. In patients with growth hormone deficiency that occurred in adulthood (patients with both isolated growth hormone deficiency and deficiency of other pituitary hormones /hypopituitarism/, which developed as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma), biochemical confirmation of the diagnosis of growth hormone deficiency should also be performed based on an inappropriately reduced response to dynamic tests for stimulation of growth hormone secretion.

ICD codes

Dosage Regimen

The dosage regimen and administration of somatropin is established individually.

Depending on the indications, the following schemes are recommended

For growth hormone deficiency in children the recommended dose is 0.18-0.3 mg (0.5-0.9 IU)/kg body weight per week. This weekly dose should be divided into 6-7 injections (0.07-0.1 IU/kg body weight/day), administered daily subcutaneously. Intramuscular administration is also allowed.

For Turner syndrome the recommended dose is 0.17-0.375 mg (0.5-1.125 IU)/kg body weight per week. This weekly dose should be divided into 6-7 injections. The drug is administered subcutaneously, in the evening.

For growth hormone deficiency in adults the recommended dose at the start of treatment is 0.04 mg (0.125 IU)/kg body weight per week, daily, subcutaneously. The maximum dose is 0.08 mg (0.25 IU)/kg body weight per week. The dose of the drug is selected gradually depending on efficacy, adverse reactions and the level of insulin-like growth factor (IGF-1). With increasing age of the patient, the recommended doses may be reduced.

For growth retardation inprepubertal childrenwith chronic renal failure the recommended dose at the start of treatment is 0.045-0.05 mg/kg (about 0.14 IU) body weight daily, subcutaneously.

Rules for solution preparation

The cartridge with somatropin can be supplied in 2 configurations.

1. Kit No. 1 – cartridge with somatropin, syringe with solvent and connecting block.

Each cartridge with somatropin should be diluted using the supplied syringe with solvent and connecting block. Attach the connecting block to the cartridge, and then inject the entire contents of the syringe (solvent) into the cartridge. The connecting block will automatically direct the fluid flow onto the glass wall of the cartridge. For complete dissolution of the contents, gently turn the cartridge up and down (about 10 times), do not shake. The resulting solution should be clear and free of suspended particles. If the solution is cloudy or contains suspended particles, the contents must not be administered.

2. Kit No. 2 – cartridge with somatropin and a modified syringe with solvent (without a connecting block).

Each cartridge with somatropin should be diluted using the supplied modified syringe with solvent. Connect the cartridge to the syringe with solvent and inject the entire contents of the syringe (solvent) into the cartridge, directing the fluid flow onto the glass wall of the cartridge. For complete dissolution of the contents, gently turn the cartridge up and down (about 10 times), do not shake. The resulting solution should be clear and free of suspended particles. If the solution is cloudy or contains suspended particles, the contents must not be administered.

Rules for using the drug

Cartridges with the prepared solution should only be used with the Humatrope^®en injector. For instructions on installing the cartridge, see the Humatrope^®en injector manual. A sterile needle must be used for each administration of somatropin. In case of hypersensitivity to m-cresol or glycerol, the somatropin solution should not be prepared using the supplied solvent; in this case, Somatropin can be dissolved in sterile water for injection. When preparing the somatropin solution in this way, the following should be observed

• Only one dose should be withdrawn from the cartridge with the prepared solution;
• If the prepared solution is not used immediately after preparation, it should be stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F);
• Use the prepared dose within 24 hours;
• Discard the unused portion of the prepared solution.

Adverse Reactions

From the CNS: headache, weakness, fatigue, increased intracranial pressure.

From the endocrine system: with long-term use of the drug in high doses – acromegaly, hypothyroidism, decreased serum cortisol levels.

From the musculoskeletal system: epiphysiolysis of the femoral head (limping, pain in the hip and knee), myalgia.

Allergic reactions: skin rash, itching.

Local reactions: soreness, numbness, redness, swelling, lipoatrophy, itching.

Other: gynecomastia, otitis media (in Turner syndrome), peripheral edema in the first weeks of treatment, pancreatitis; rarely – glucosuria.

There are reports that a small number of children treated with growth hormone, including both pituitary growth hormone and DNA-recombinant growth hormone, developed leukemia. The relationship between leukemia and growth hormone treatment remains unclear to date.

Contraindications

• Brain tumors, malignant neoplasms of any location;
• Stimulation of growth in children with closed growth zones;
• Acute critical conditions associated with complications after open heart surgery or abdominal surgery, multiple trauma, or acute respiratory failure;
• Established hypersensitivity to any of the components of the drug or solvent.

With caution the drug should be prescribed for diabetes mellitus, intracranial hypertension, hypothyroidism.

Use in Pregnancy and Lactation

It is not known whether Somatropin affects reproductive function or causes fetal damage when administered to pregnant women. Therefore, Somatropin should not be prescribed during pregnancy.

It is not known whether this drug is excreted in breast milk. Since many drugs can be excreted in breast milk, if it is necessary to prescribe somatropin during lactation, breastfeeding should be discontinued.

Special Precautions

Treatment with somatropin should be carried out by physicians experienced in the diagnosis and treatment of patients with growth hormone deficiency or Turner syndrome.

Patients who were treated with growth hormone in childhood until growth was completed, before resuming replacement therapy with somatropin in doses recommended for adults after closure of the growth zones, should be re-examined to identify growth hormone deficiency.

Patients with growth hormone deficiency that occurred secondary to the presence of brain neoplasms should be examined more frequently to exclude progression and recurrence of the underlying disease. Somatropin should not be prescribed if any signs of active tumor growth are detected. Before prescribing growth hormone, the tumor process must be in an inactive phase and antitumor therapy must be completed. If signs of tumor growth resumption appear, administration of the drug should be discontinued.

In case of severe or recurrent headaches, visual disturbances, nausea and/or vomiting, examination of the fundus (fundoscopy) is recommended to detect papilledema, the presence of which suggests the possibility of intracranial hypertension. In this case, it is necessary to stop treatment with growth hormone.

In patients with endocrine disorders, including growth hormone deficiency, epiphysiolysis of the heads of long bones may be observed more frequently. A thorough examination should be carried out if a child develops a limp during treatment with growth hormone.

Patients with hypopituitarism, in case of standard hormonal replacement therapy, should be under strict supervision when somatropin is administered.

During treatment with somatropin, hypothyroidism may develop, and the lack of adequate therapy for hypothyroidism may prevent optimal results of treatment with somatropin.

Formation of antibodies to the drug and to Escherichia coli proteins is possible.

Testing for the titer of antibodies to somatropin should be carried out in cases where the patient does not respond to the therapy.

Since human growth hormone can cause the development of insulin resistance, it is necessary to monitor patients for signs of impaired glucose tolerance.

Patients with diabetes mellitus should be under constant medical supervision during treatment with somatropin. Against the background of somatropin administration, patients with diabetes mellitus may require adjustment of the insulin dose.

Before prescribing treatment with somatropin for growth retardation due to chronic renal failure, patients should be preliminarily observed for one year to confirm growth impairment. Conservative treatment of renal failure should be initiated and should be continued during treatment with somatropin. During kidney transplantation, treatment with somatropin should be discontinued.

Experience with treatment with somatropin in patients over 60 years of age is lacking.

Experience with long-term treatment of adults is lacking.

Overdose

Acute overdose may initially lead to hypoglycemia and then to hyperglycemia. Chronic overdose may cause signs and symptoms of gigantism/acromegaly, consistent with the known effects of excess amounts of human growth hormone.

Drug Interactions

With simultaneous administration of glucocorticoids, suppression of the growth-stimulating effect of somatropin is observed. If it is necessary to carry out replacement therapy with glucocorticoids, adequate doses of glucocorticoids should be carefully selected to prevent the development of adrenal insufficiency or growth suppression.

It has not been established that somatropin is incompatible with other drugs.

Storage Conditions

Before dilution (in the cartridge), the drug should be stored in the refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 3 years.

The prepared solution should be stored in the refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for no more than 28 days; do not freeze. Shelf life 28 days. The prepared solution of the drug can be stored at room temperature for no more than 30 minutes.

List B. The solvent in the syringe should be stored in the refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F). Shelf life – 3 years.

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.