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Brand name: Heberprot-P®

Pharmaceutical activity: stimulate tissue healing and citoprotection.

Pharmaceutical form: injectable, lyophilized distributed in glass bulb.

Application route: Parenteral administration, through intralesional and perilesional route.

Package: Box containing:Glass bulb 6R made of neutral borosilicate light with hydrolytic quality class I­, a capacity of 5 ml, containing hr-EGF as active ingredient; bromobutile buffer, and a flip-top cap.

Product composition: depending on the dose, each bulb of 5 ml contains:

 Substance  mg / 5 ml of water
 Human recombinant epithermal growth factor  0,075 or 0.025
 Sucrose  15 000
 Dextran 40  5 000
 di-sodium hydrogen phosphate  0,454
 di-hydrated sodium di-hydrogen phosphate  1,061
 Water for injection  5 ml

The hr-EGF is a peptide that stimulates cell proliferation and tissue healing. 

Manufacturer Center for Genetic Engineering and Biotechnology

Ave. 31 e/ 158 y 190, Cubanacán, Playa La Habana, Cuba

C.P. 11600Phone: 271-6022; 271-8466; 271-6644

Fax: 273-6008; 271-8070

The CIGB is in charge of the hr-EGF production, filling and packaging of the final product. 

PHARMACOLOGY

PHARMACOKINETICS  

The biological activity of the EGF as a healing agent has been widely studied and documented in the literature. The EGF is a 53 amino acids single protein with a molecular weight of 6045 Dalton, and isoelectric point of 4,60. This molecule stimulates fibroblast and epithelial cell proliferation with a potent in vivo mitogenic activity on ectodermic and mesoderm cell, smooth muscle cell of blood vessels, fibroblast, and cheratinocytes. 

The first biological effects of the EGF found were early eye opening and dental eruption in newborn mouse, when administered through parenteral route. Later, the molecule was isolated from humans. The EGF concentration is not detectable in blood, but blood-plaque contain high levels (≈ 500 pmol/1012 blood-plaque). 

After coagulation, EGF concentration grown to 130 pmol/l, which is enough for inducing mitosis and cell migration.

This molecule regulates growing, differentiation and metabolism of different cell, acting as mitogen and chemo-tactic substance on neutrophils and monocytes, stimulating fibroblasts migration and proliferation that syntheses and deposits collagen, and on epithelial and endothelial cell. The profiles of pharmacokinetic EGF deposition and distribution in organs and wasting route have also been studied. Studies in animal model (mice and dog) have included EGF topic application and injection with a unique dose. The higher EGF concentrations were found in kidney, liver, skin and stomach. According to radioactivity data, 78% of EGF elimination was detected in urine, after 96 hours. The kinetics of EGF distribution, after administration, includes a high rate step followed by a slower removal from blood and plasma.

The importance of kidney and liver in the high rate step has been demonstrated.  The EGF concentration in blood was lower than in plasma. This protein is not distributed in the blood cell fraction, which is predictable since the lack of receptors in this stem cell. The EGF is rapidly degraded before being excreted through urine, which is the main route of removal from the organism. It has been argued that the kidney is the most important organ in the assimilation and metabolism of the EGF. A scarce amount of EGF passes to the blood circulation, when it is administered topically, in animal model with and without lesions. Subcutaneous application of 5,5 µg 125l radio-labeled EGF in Balb-c mouse, gave rise to high plasmatic concentration in 30 minutes, which diminished to be undetectable 2 hours later. Measurements of EGF concentrations using ELISA and radioactivity methods revealed similar pharmacokinetic profiles, which suggested that EGF total degradation toke place after 2 hours. The higher accumulation rates were found in skin, kidney, liver and bladder, and removal was through urine.    

The intralesional application of 25 or 75 µg of rh-EGF in humans was followed by the absorption of the molecule up to a maximum level between 5 and 15 minutes and a rapid diminishing to reach basal levels after 2 hours. These results were not observed in patients that received a placebo, which was an evidence supporting that the measured EGF corresponds to that administered and not to the endogenous wound EGF.  The amount of pharmaceutical that was absorbed was dose-dependent.  

PHARMACODYNAMICS  

The major therapeutic effect of the rhEGF pharmacodynamics has been reported in two peer-reviewed papers. The first one deal with the effect of different rhEGF concentrations on the wound healing in mice. A second study evaluated wound healing in pigs. In this dose study, restoration of dermal tissue and epithelization of wounds were demonstrated when rhEGF concentrations between 5 and 10 µg/g of cream were applied. It was interesting to note the higher relative sensibility of the epidermis to higher dose tested.  

USES: For use only under medical prescription.

Heberprot-P® is indicated, alone with conventional therapies, for diabetic foot ulcers treatment in patients with naturopathic and ischemic ulcers grade 3 and 4, according to Wagner’s scale, and with a wound area higher than 1 cm2. It is also indicated to stimulate tissue granulation useful to allow healing as second intention or by skin self-grafting.  

CONTRA-INDICATIONS

Heberprot-P® is contra-indicated in:

§     Patients with antecedents of hyper-sensitivity to the product or any of its inactive ingredients.

§     Patients with any current diagnosis of cancer pathology, and antecedents or suspect of any neoplasia. 

§     Patients with decompensate, diabetic coma or keto-acidosis.

PRECAUTIONS  

There is not previous knowledge on the transfer of Heberprot-P® to maternal milk, therefore, this product is not recommended for nursing mothers. At present, enough data is not available to validate the use of Heberprot-P® in pregnant and pediatric patients; therefore, medical doctors should perform a customized risk-benefit assessment case-by-case. Heberprot-P® should be applied with precaution in patients with antecedents of ischemic cardiopathy and kidney insufficiency with creatine levels higher than 200 mmol/l.  A suitable and preventive treatment of the wound sepsis should be performed before using Heberprot-P®. In case of local infection during treatment with Heberprot-P® this should be renewed after completing infection treatment, taking care not to apply more than 24 doses.

 WARNINGS

 

  • The treatment with Heberprot-P® should be performed by specialized doctors with suitable diagnosis facilities, and enough expertise in the treatment of DFU patients.
  •  This medicine can only used until the expiring date specified in the bulb.
  •  Dissolved solutions of Heberprot-P® should be applied immediately after preparation.
  • The product should be use during the before 24 hours after opening the bulb. 

 

 

 

ADVERSE EVENTS

 The most frequent clinical adverse events reported alter using Heberprot-P® have been ardor and pain in the injection site. Cases of fever and local infection have also been reported.  

INTERACTIONS

There is not previous knowledge on the interactions of Heberprot-P® with other medicine for topic uses; therefore, it is not recommended to apply Heberprot-P® alone with other products indicated for topic uses.

OVERDOSE

For use only under medical prescription.

There have not been reported overdose cases and there is not previous knowledge on antidotes for this product. There is a low probability of systemic effects since the application of the product is local and circulatory system is seriously compromised in diabetic patients with advance lesions.

 

DIRECTIONS

The study medication was administered. Ulcers were sharply debrided, gangrenous and necrotic tissue removed whenever necessary, saline-moistened gauze dressing was used, and the affected area was pressure off-loaded. Broad-spectrum antibiotics were used to manage infections and metabolic control was strictly followed.

Heberprot-P® should be used together with a standardized good wound care regimen, including sharply debridements, gangrenous and necrotic tissue removal whenever necessary, as such as saline-moistened gauze dressing, and pressure off-loaded of the affected area. Previous diagnosis and suitable treatment of infections should be performed before Heberprot-P® application.

Heberprot-P® should be applied in doses of 75 µg, dissolved in 5 ml of water for injection, thrice weekly on alternate days, through perilesional and intralesional route. Applications of the product should be kept until complete wound granulation, lesion closing by grafting or until a maximum time of 8 weeks of treatment being reached. The treatment should be discontinued when useful tissue granulation spread over all the lesion area appears or a reduction of the wound area to less than 1 cm2 takes place.

Infiltration should be performed  The EGF solution should be injected using standard disposable syringe with a 26 G x ½” needle, first into the dermo-epidermal junction at equidistant points all over the lesion contours, and then deeply downward into the wound bottom in circles and centripetally to ensure a uniform distribution. In case of deep lesions, 24Gx1½” needles should be used.  

Product injections should be performed first in the cleaner areas, and the needle should be changed at different sites of injection to avoid sepsis transmission from a site to another.  Later, the lesion should be covered with saline-moistened gauze dressing to keep wet and cleaned environment.  

 

 EsquemaGuia

The treatment should be re-evaluated if after 3 week useful tissue granulation is not observed in the ulcer, looking for factors that affect wound healing, such as osteomyelitis, local infection or metabolism out of control.

PRODUCT PRESENTATIONS

Box containing 1 bulb of Heberprot-P®, dose of 75 µg.

Box containing 6 bulb of Heberprot-P®,dose of 75 µg

Prospectus.

 

DIRECTIONS FOR USING, HANDLING AND DISCARDING THE PRODUCT  

  • Care should be taken to avoid deterioration and bacterial contamination of bulbs.
  • The personal that use the product should wash their hands and use globes before performing Heberprot-P® applications.
  • Care should be taken to avoid extending infection in ulcers. Changes of needles are recommended for applications in different parts of the lesion.
  • Once the treatment has been finished the remaining product should be discarded.
  • Use each bulb of Heberprot-P® for only one patient.

     

STORAGE CONDITIONS

  • Heberprot-P® should be stored at temperature between 2 and 8ºC, far from heat sources. This product is stable at this temperature range during 36 months.
  • Accidental exposure of the product to a different temperature could affect its stability. In case of exposure to higher temperatures, it is recommended to contact the manufacturer before making any decision on the use or discard of the product.
  • Keep this medicine always in the original sealed bulb.
  • Keep out of children’s reach.

Testimonio de paciente tratado con Heberprot-P

Programa Nacional Heberprot-P

Patients treated

225 000

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Premios Obtenidos

World Intellectual Property Organizational
Premio Nacional a la Innovación Tecnológica
Mejor invención joven otorgada por la Oficina Mundial de Propiedad Intelectual en la 39 International Exhibition of Inventions of Geneva