Heberprot-P^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Irvin 2, LLC (Russia)

Manufactured By

Center For Genetic Engineering And Biotechnology (Cuba)

Or

Praxis Pharmaceutical, S.A. (Spain)

Quality Control Release

CENTER FOR GENETIC ENGINEERING AND BIOTECHNOLOGY (Cuba)

Or

DOBROLEK, LLC (Russia)

ATC Code

D03AX (Other drugs that promote normal scarring)

Dosage Form

Heberprot-P®

Lyophilizate for preparation of solution for injection 0.075 mg: fl. 1 or 6 pcs.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for injection in the form of a white lyophilized mass; reconstituted solution – a clear, colorless, homogeneous liquid without suspended particles.

Excipients: sucrose 15 mg, dextran 40 5 mg, sodium dihydrogen phosphate dihydrate 1.061 mg, disodium hydrogen phosphate 0.454 mg.

0.075 mg – glass vials (1) – cardboard packs.
0.075 mg – glass vials (6) – cardboard packs.

Clinical-Pharmacological Group

Drug promoting epithelialization and scarring of tissues

Pharmacotherapeutic Group

Other agents promoting scarring

Pharmacological Action

Recombinant human epidermal growth factor (rhEGF) is a highly purified peptide consisting of 53 amino acids with a molecular weight of 6054 daltons and an isoelectric point of 4.6.

RhEGF is produced by a strain of Saccharomyces cerevisiae yeast, into whose genome the rhEGF gene has been introduced by genetic engineering methods. rhEGF, obtained using recombinant DNA technology, is identical in its mechanism of action to the endogenous epidermal growth factor produced in the body.

RhEGF stimulates the proliferation of fibroblasts, keratinocytes, endothelial and other cells involved in wound healing, promoting epithelialization, scarring, and restoration of tissue elasticity.

Pharmacokinetics

RhEGF is not detected in plasma but is determined in platelets (approximately 500 mmol/10¹² platelets).

In most patients, the time to reach T_max after injection into the affected area ranged from 5 to 15 minutes. The mean value of the area under the pharmacokinetic curve (AUC) after the first administration of the drug at a dose of 75 mcg and after 27 days of administration was 198 and 243 pg×h/ml, respectively, and the mean C_max was 1040 pg/ml. T_1/2 and the mean residence time (MRT) of the drug in the body were close to 1 hour. Complete clearance occurs in approximately 2 hours.

Indications

• As part of complex therapy for diabetic foot syndrome with deep, non-healing for 4 weeks or more neuropathic or neuroischemic wounds with an area of more than 1 cm², reaching the tendon, ligament, joint, or bone.

ICD codes

Dosage Regimen

For use only in a specialized medical institution, taking into account inpatient and outpatient stages.

Before administering Heberprot-P^®, personnel working with it should properly wash their hands and wear sterile gloves. Heberprot-P^® is used at the rate of one vial per patient. The wound surface should be cleaned using sterile saline and dry sterile gauze pads. The area of the lesion should be measured (in cm²).

Heberprot-P^® vials contain a white lyophilized powder. Before use, add five milliliters of water for injections to the vial, then gently mix for a few seconds. The solution prepared in this way should be clear and colorless, without visible particles. The resulting solution should be used immediately after preparation. If the solution shows the presence of any solid particles or if the appearance of the solution differs from that described, the reconstituted drug should not be used; it must be properly disposed of.

The contents of each vial of Heberprot-P^® are reconstituted by adding 5 ml of water for injection; using the resulting solution, up to ten injections containing 0.5 ml of solution each can be performed. The syringe should be equipped with a 26Gx ¹/₂" needle or a 24Gx1 ¹/₂" needle for superficial or deep injections, respectively.

For the treatment of ulcers with an area of more than 10 cm², ten injections of 0.5 ml each should be made. Injections should be made into the soft tissues with uniform distribution of the drug administration sites, primarily injecting the edges of the wound, and then the wound bed. The depth of needle insertion during injections should be about 0.5 cm.

For the treatment of wounds with an area of less than 10 cm², only one injection with a volume of 0.5 ml of Heberprot-P^® should be used per cm² of the lesion area. For example, for the treatment of a wound with an area of 4 cm², only four injections of 1.25 ml of the drug should be performed.

To reduce the risk of infection, each injection should be performed with a new sterile needle.

After completing the injections, the ulcer should be covered with gauze moistened with saline, or a wet dressing should be applied to create a moist and clean environment.

Injections are performed 3 times a week. Injections of Heberprot-P^® should be continued until granulation tissue forms, covering the entire wound surface, or for up to 8 weeks (maximum duration of treatment).

The wound surface must be covered with a neutral non-traumatic dressing.

If after three weeks of treatment with Heberprot-P^® granulation tissue has not begun to form in the wound, the presence of a local infection or osteomyelitis should be ruled out.

Adverse Reactions

The frequency of side effects (taking into account the number of all patients treated with Heberprot-P^® in clinical trials, including in the Russian Federation): headache was noted in 1.2% of patients, tremor in 24.3%, pain at the injection site in 24.0%, burning sensation at the injection site in 17.8%, chills in 11.3%, increased body temperature in 2.8%, infection at the injection site in 4.4%.

Pain or burning at the injection site was observed with similar frequency in patients who received Heberprot-P^® and placebo. These adverse events are most likely related to the injection procedure itself.

Chills and shivering were observed in approximately 10-30% of patients in all studies. These phenomena were often observed shortly after the injection and were transient. They were never severe and did not lead to treatment discontinuation. In most cases, their relationship with the treatment was considered definite or probable.

Moderate or severe wound infections at the injection site were recorded in 15-18% of patients, both in the group receiving Heberprot-P^® and in the placebo group, therefore, these adverse events were probably not related to the use of the drug, but could be related to the injection procedure. All other adverse events were observed with low frequency in the Heberprot-P^® group and the placebo group, so their relationship with the treatment is unlikely.

Contraindications

• Hypersensitivity to the components of the drug;
• Diabetic coma or diabetic ketoacidosis;
• Chronic heart failure NYHA class III-IV;
• Episodes of acute cardiovascular pathology (severe acute cardiovascular condition) within the last 3 months, such as acute myocardial infarction, severe angina, acute stroke or transient ischemic attack and/or thromboembolic events (deep vein thrombosis, pulmonary embolism);
• Severe atrioventricular block (III degree), atrial fibrillation with uncontrolled rhythm;
• Malignant neoplasms;
• Pregnancy, breastfeeding period;
• Children under 18 years of age;
• Renal failure (glomerular filtration rate <30 ml/min);
• Presence of wound necrosis (surgical debridement of the wound is required before administration of the drug);
• Presence of an infectious process, including osteomyelitis (the drug is used after its complete resolution);
• Presence of signs of critical limb ischemia (ankle-brachial index (ABI) value ≥0.6 but ≤1.3 and/or toe-brachial index value ≥0.5, and/or TcPO₂ < 30 mm Hg) (use of the drug is possible only after revascularization.)

With caution

Heberprot-P^® should be used with caution in patients with heart valve damage (e.g., aortic valve calcification), severe carotid artery stenosis (< 70% NACET), severe uncontrolled arterial hypertension.

Use in Pregnancy and Lactation

The use of Heberprot-P^® during pregnancy is contraindicated (due to the lack of safety data).

When prescribing the drug during breastfeeding, breastfeeding should be discontinued.

Use in Renal Impairment

The drug is contraindicated in patients with renal failure (glomerular filtration rate <30 ml/min.)

Pediatric Use

The drug is contraindicated in children under 18 years of age.

Special Precautions

Heberprot-P^® is used as part of complex therapy (antibacterial therapy, surgical wound debridement) for diabetic foot syndrome.

Before administering the drug, surgical debridement of the wound is performed in compliance with all conditions of asepsis and antisepsis.

Before starting treatment with Heberprot-P^®, a malignant etiology of the ulcer must be ruled out.

The contents of the Heberprot-P^® vial are used for only one patient. Care should be taken to avoid damage and bacterial contamination of the vials.

It is strongly recommended to use a new sterile needle for each injection to avoid any potential introduction of pathogens into the lesion.

Unused drug or its residues that are not used in a timely manner must be properly disposed of.

The needle must be changed for each injection.

Effect on ability to drive vehicles and operate machinery

There are no data on the negative effect of Heberprot-P^® on the ability to drive vehicles or operate machinery.

Overdose

There is no information on overdose of Heberprot-P^®.

Drug Interactions

During the course of treatment with Heberprot-P^®, the local use of other medicinal products is not recommended.

Storage Conditions

Store at a temperature of 2 to 8°C (46.4°F). Do not freeze. Keep out of reach of children.

Shelf Life

Shelf life – 2 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.