Ivisel - instructions for use, dose, side effects, contraindications

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Dosage form: & nbspsolutions for preparation of surgical glue

Composition:

SOLUTION OF FIBRINOGEN

Active substance: human coagulating protein, consisting mainly of fibrinogen and fibronectin * - 70 mg;

Excipients: arginine hydrochloride 20.5 mg, glycine 8.0 mg, sodium citrate 2.65 mg, sodium chloride 7.0 mg, calcium chloride 0.15 mg, water for injection up to 1.0 ml

* total amount of protein from 80 to 120 mg / ml

THROMBIN SOLUTION

Active substance: human thrombin 1000 ME;

Excipients: calcium chloride 5.9 mg, human serum albumin 5.75 mg, mannitol 19.5 mg, sodium acetate 2.6 mg, water for injection up to 1.0 ml

Description:

SOLUTION OF FIBRINOGEN

Opaque from white to slightly yellowish color, frozen mass. After thawing, a slightly yellowish opalescent solution without visible fibers or foreign particles

THROMBIN SOLUTION

Opaque from white to slightly yellowish color, frozen mass. After thawing, a clear, colorless solution without visible fibers or foreign particles

Pharmacotherapeutic group:Hemostatics are local in combination

ATX: & nbsp

Hemostatic preparations for topical application

Pharmacodynamics:

The conversion of fibrinogen to fibrin occurs by splitting fibrinogen into fibrin monomers and fibrinopeptides.Adhesive system of fibrin initiates the last stage of physiological clotting of blood. Aggregation of fibrin monomers leads to the formation of a fibrin clot. The factor is HHS. activated iodine by the action of thrombin form factor XIII. binds together the threads of fibrin. Calcium ions are necessary for both the conversion of fibrinogen and cross-linking fibrin. As the wound heals, plasmin induces an increased fibrinolytic activity of the plasma, which results in the decomposition of fibrin to fibrin degradation products.

The results of clinical studies confirming the efficacy of the preparation of I Visel® as an aid for the provision of hemostasis during the application of sutures were obtained in 147 patients (75 patients were using I-veel®, 72 patients were included in the control group) who were used to install the non-etetrafluoroethylene vascular stents , as well as in 135 patients who underwent retroperitoneal and intra-abdominal surgery (66 patients used Evisel®, 69 patients were included in the control group).

The clinical experience of using the drug Avicel in children is very limited.Of the 135 patients who underwent retroperitoneal and intra-abdominal surgery, only 4 patients who had Avicel® were aged 16 years and under, namely 2 children aged 16 years and 2 children aged 2 and 5 years. Until now, no data on the use of Avicel in children younger than 2 years of age have been obtained.

Preclinical safety data

In the bacterial mutagenicity test, negative results were obtained for thrombin itself, a biologically active component (containing fibrinogen, citrate, glycine, tranexamic acid and arginine hydrochloride), separately for tri-n-butyl phosphate (TNB) and separately for Triton X-100 in all concentrations studied. All tested concentrations of the combination of TNBP and Triton X-100 also gave a negative response in the study of mutagenicity in mammalian cells and in tests on the incorporation of chromosomal aberrations and micro-nuclear induction.

With topical application, the absorption of thrombin occurs slowly and reduces, mainly, to the appearance in the plasma of the products of its decomposition, which are excreted from the body. The likelihood of toxic effects of solvent-detergents (TNB and Triton X-100), which are used to inactivate viruses, is negligible,since their residual content does not exceed 5 μg / ml.

With subdural administration to rabbits, the absence of neurotic toxicity was demonstrated in the drug. During the entire follow-up period (14 ± 1 days), neuroscientific abnormalities were noted in animals with ns. There were also no visible signs of local intolerance and macroscopic changes associated with the administration of the drug. When analyzing the cerebrospinal fluid, signs of inflammation were absent.

Pharmacokinetics:

IVISEL® is intended only for direct application to tissues during surgery and is contraindicated for intravascular administration, so no pharmacokinetic studies of the drug have been conducted in humans.

In preclinical studies on rabbits, an evaluation was made of the absorption and elimination of thrombin when applied to the surface of the liver incision after partial hepatectomy. Using thrombin labeled I¹²⁵, a slow absorption of biologically inactive peptides formed as a result of thrombin decomposition was demonstrated. Their maximum concentration (Сmах) in blood plasma was achieved in 6-8 hours and was only 1-2% of the used dose.

Fibrin glue / hemostatic agent is metabolized as well as endogenous fibrin, due to fibrinolysis and phagocytosis.

Indications:

As an auxiliary means to maintain hemostasis in surgical operations in cases when standard surgical methods are not effective enough, including to maintain hemostasis when applying sutures during surgical operations on vessels.

Contraindications:

Intravascular administration of IVISEL® is prohibited.

Hypersensitivity to the active components or any auxiliary substance.

In endoscopic procedures, Avicel® should not be applied with a spray device.

The use of Avicel® with laparoscopy is discussed in the section "Special instructions".

Carefully:

Pregnancy and lactation:

Controlled clinical studies on the safety of fibrin glue / hemostatic agents during pregnancy or lactation were not conducted. Experimental data are not sufficient to assess the reproductive safety of the drug Avicel®, the effect of the drug on the embryonic development and fetal status of the fetus, the course of pregnancy and the peri- and postnatal period.

Therefore, in pregnant and lactating women, the drug can be used only in case of emergency.

Dosing and Administration:

Only for application to the wound surface.

In order to reduce the risk of life-threatening gas embolism, only compressed CO2 gas can be used to spray the Avicel® preparation.

Before application of the preparation, Avicel®, it is necessary to dry the surface of the wound with the help of conventional methods (for example, by repeated application of compresses, the use of tampons or suction).

IVISEL® can only be used by experienced surgeons who are trained in the use of the drug. Preparation of IVISEL® and its use should be carried out strictly in accordance with the instructions for use and with a special device recommended for application.

Avicel® is applied only with the use of a special device supplied separately, and if necessary - with a special tip. The device is accompanied by an instruction containing a detailed description of the device and the tip, as well as a diagram of its use in conjunction with solutions.A special tip can only be used by specially trained personnel with experience in performing laparoscopic, auxiliary laparoscopic procedures or open surgical procedures.

The amount of Avicel® and the frequency of its application depends on the specific clinical needs of the patient.

The dose of the drug is determined, but not limited to, by the following circumstances: the type of surgery, the size of the application, the type of application and the number of applications. In clinical trials in vascular surgery, the individual dose of the drug reached 4 ml, whereas in retroperitoneal or intraperitoneal surgeries the individual maximum dose was 10 ml. However, for some procedures (for example, with a liver injury), a larger volume of the drug may be required.

The individual volume of the drug should be determined by the attending physician. The initial volume of the drug that must be applied to the selected anatomical site or surface should completely cover the area to be treated. If necessary, repeat the application of the drug.

Preparation

The contents of the vials are thawed using any of the following methods: at 2-8 ° C (in the refrigerator): the contents of the vials are thawed for 1 days, or at 20-25 ° C (room temperature): the contents of the vials are thawed for 1 hours, or at 37 ° C (in a water bath with the observance of aseptic rules or heating the bottle in hand): the contents of the vials are defrosted for no more than 10 minutes. Do not keep bottles at this temperature for more than 10 minutes or after a complete defrost.

The temperature should not exceed 37 ° C.

Before use, the temperature of the drug should reach 20-30 ° C.

Solutions should be clear or slightly opalescent. Do not use turbid or precipitate-containing solutions.

The contents of the two vials are placed in the application device according to the instructions for use enclosed in the package with this device. Both syringes of the device must be filled with equal volumes of solutions and do not contain air bubbles. During preparation of the drug, Avicel® is not used.

Drip application drip

During the use of the drug should keep the tip of the device as close to the wound surface,but do not touch the fabric and apply Evisel one drop on the surface being treated.

If the tip of the tip is clogged, it can be cut off about 0.5 cm each time.

Spray application

In order to reduce the risk of life-threatening gas embolism, Avicel should be sprayed only with compressed CO2 gas.

Connect the short tube of the applicator to the "male" end of the luer lock of the long gas tube. Connect the "female" end of the luer lock of the gas tube (equipped with a 0.2 micron bacteriostatic filter) with a pressure regulator. The pressure regulator must be used in accordance with the manufacturer's instructions.

When applying Avicel® by spraying, make sure that the pressure and distance between the nozzle and the surface of the tissue are within the limits recommended by the manufacturer.

Surgical interventions

Device

for spraying

A type

handpiece for the device

Regulator

pressures

Recommended

distance to

fabrics

Recommended

pressure for

spraying

Open

operations

Applicator

preparation

Avicel®

Yellow

flexible

tip

6 cm in length

Regulator

pressures

Omriks

10-15 cm

20-25 psi (1.4-1.7 bar)

Black hard tip length 35 cm

Laparoscopic

procedures

Yellow flexible tip length 45 cm

4 - 10 cm

15-20 psi

(1.0-1.4 bar)

The black

hard

tip length 35 cm

Yellow flexible tip length 45 cm

20 - 25 psi (1.4-1.7 bar)

The drug should be sprayed with short jets (0.1-0.2 ml) to form a thin, even layer. Avicel® forms a transparent film on the surface to be treated. When spraying the drug, Avicel®, it is necessary to monitor changes in blood pressure, pulse, oxygen saturation and the final CO2 content, considering the possibility of developing air or gas embolism.

When using tips, follow the instructions for using tips.

Recycling

Any unused product or waste when it is used must be disposed of in accordance with local regulations.

Side effects:

Life-threatening gas or air embolism developed with the use of nebulizers having pressure regulators for the application of Avicel®. This undesirable phenomenon (AE), most likely,was caused by spraying the drug under more than recommended pressure, or by reducing the distance to the treated surface, which was recommended to comply.

The following AEs that were recorded during clinical trials had a possible causal relationship with the use of the Avicel® preparation.

The frequency of development of all the AEs listed below was estimated as often (> 1/100, < 1/10).

Adverse events in retroperitoneal or intraperitoneal surgeries

Infectious and parasitic diseases: abdominal abscess.

Undesirable effects in the study of the drug in vascular surgery

Infectious and parasitic diseases: transplant infection, staphylococcal infection;

Vascular disorders: hematoma;

General disorders and complications at the site of administration: peripheral edema; Laboratory and instrumental data: reduction of hemoglobin concentration;Injuries, intoxications and complications associated with various manipulations: bleeding at the incision site, occlusion of the vascular graft, wound, hematoma after the procedure, postoperative wound complication.

Additional Information

AEs that can develop with the use of fibrin glue are described below. Since these AEs were not observed during the clinical trials of Avicel®, the incidence of these AEs was not established with the use of the Avicel® preparation. In rare cases, fibrin glue / haemostatic agents may develop hypersensitivity reactions or allergic reactions (angioedema, burning and pain at the site of application, bronchospasm, chills, blood flushes to the skin, generalized urticaria, headache, allergic rash, decrease in arterial pressure, lethargy, nausea, agitation, tachycardia, chest tightness, wheezing, vomiting, tingling). In some cases, these reactions can progress to severe anaphylaxis. Such reactions, mainly, can be observed in the case of repeated use of the drug or if the patient has an increased sensitivity to any component of the drug.

In very rare cases, antibodies can develop into the components of the fibrin glue / hemostatic agent.

With occasional intravascular administration of the drug, development of thromboembolic complications or disseminated intravascular coagulation syndrome is possible, and there is a risk of developing an anaphylactic reaction.

Adverse events in the study of the drug in retroperitoneal or intraperitoneal surgeries

According to the researchers' estimates, none of the AEs in 135 patients who underwent retroperitoneal and intraperitoneal surgical interventions (67 patients were treated with Avicel® and 68 patients were included in the control group) had no causal relationship with the study therapy. However, according to the sponsor's assessment, 3 serious AEs (one abdominal abscess in the therapy group with Avicel®, one abdominal abscess and one pelvic abscess in the control group) were probably related to the study therapy.

Undesirable effects - in vascular surgery

In a controlled study of 147 patients who underwent vascular transplantation (75 patients in the IVISEL® group, 72 patients in the control group), 16 patients developed transplant thrombosis / occlusion

during the study period.These AEs were evenly distributed among groups of patients, with 8 events in each group.

Safety data regarding the transmission of pathogens with blood products are indicated in the section "Special instructions".

Light reactions can be quenched by prescribing antihistamines, severe hypotensive reactions require immediate use of anti-shock therapy.

Overdose:

No cases of an overdose of Avicel® have been reported.

Interaction:

There were no special studies of the interaction of the drug with Avicel® with other drugs. Nevertheless, by analogy with preparations or solutions containing thrombin, the components of the preparation of Avicel® can be denatured by interaction with alcohol solutions, solutions containing iodine or heavy metals (for example, antiseptic solutions). Such substances must be completely removed before applying the drug Avicel®.

Avicel® should not be mixed with other medications.

Special instructions:

Only for application to the wound surface. Intravascular administration is prohibited.
There are no statistically significant results of studies supporting the use of this drug for tissue connectivity in neurosurgery when administered through a flexible endoscope to stop bleeding or with gastrointestinal anastomoses.
With intravascular administration of the drug, development of thromboembolic complications threatening the patient's life is possible.

The preparation of Avicel® should be applied in a thin layer. Excessive thickening of the clot can adversely affect the haemostatic efficacy of the drug and the healing process of the wound surface.

Life-threatening gas or air embolism can develop with the use of nebulizers having pressure regulators for the application of Avicel®. This complication is most likely due to the use in the device of a higher spray pressure of the drug and / or a closer distance from the tip of the nebulizer to the wound surface.

Applying Avicel® by spraying should only be done in cases where it is possible to accurately control the distance from which the spray is carried out, especially during laparoscopy.The distance from the tip of the sprayer to the wound surface and the pressure should correspond to the norms recommended by the manufacturer (see Table in the section "Method of administration and dose").

During the spraying of the drug, Avicel®, it is necessary to monitor changes in blood pressure, pulse, oxygen saturation and partial pressure of CO2 in the exhaled air due to the possible development of air or gas embolism. When using nozzle tips for applying the drug, follow the instructions for using the tips. Device for applying the drug and special tips are supplied separately.

Before using Avicel®, precautions should be taken to protect areas that should not be treated with the drug, in order to prevent unwanted tissue adhesion in these areas.

As with any protein containing preparation, hypersensitivity reactions or allergic reactions may occur, including: urticaria, generalized skin rashes, chest tightness, wheezing, lowering of blood pressure and anaphylaxis.When these symptoms appear, the drug should be discontinued immediately. In the case of shock development, standard anti-shock therapy should be prescribed.

To prevent the transmission of infection due to the use of drugs derived from human blood or plasma, standard measures have been taken, namely: selection of donors, screening of harvested blood plasma for specific infection markers, and the introduction of effective inactivation / removal stages in production. However, when using drugs from blood or blood plasma, you can not completely exclude probability of transfer of infection. This applies to both unknown and known viruses and other pathogens. The measures taken during the production of the drug IVISEL® are effective against envelope viruses such as HIV, hepatitis C virus and hepatitis B virus, and also the non-enveloped hepatitis A virus. At the same time, standard measures may not be sufficient to prevent the transmission of non-enveloped viruses, such as parvovirus B19, which may pose a risk to pregnant women (fetal infection) and patients with immunodeficiency or elevated erythropoiesis (eg, hemolytic anemia).

With each use of the drug, Avicel®, it is strongly recommended that you record the patient's name and series of medication to maintain the relationship between the patient and the serial number of the drug.

Special instructions for storage of the drug

Keep the vials in an upright position.

In the frozen state, store the product at a temperature not higher than -18 ° C. Keep vials in a pack to protect from light. Do not re-freeze.

After thawing, the closed vials should be stored at a temperature of 2 to 8 ° C in the dark place for not more than 30 days without re-freezing during this period. Immediately after thawing, the defrosting date and information about the new shelf life at a temperature of 2 to 8 ° C should be applied to the vial. The product must be used or disposed of within 30 days.

The solutions of thrombin and fibrinogen, which are part of the preparation of IVISEL®, are stable at room temperature for 24 hours, however, once the solutions are transferred to the drug application device, they must be used immediately.

Form release / dosage:

A solution for preparation of surgical glue.

Packaging:

Fibrinogen solution: 1, 2 or 5 ml of a solution of fibrinogen in a vial of transparent colorless glass type 1 (Hebrew F) with a capacity of 7 ml (for 1 and 2 ml) and 10 ml (for 5 ml) with bromobutyl plug (HeF.F.) and an aluminum cap for running in with a detachable plastic lid of the type "flip-off".

Thrombin solution: 1, 2 or 5 ml of a solution of thrombin in a vial of transparent colorless glass type 1 (HeF) with a capacity of 7 ml (for 1 and 2 ml) and 10 ml (for 5 ml) with bromobutyl stopper (Fkirotcc®) (Hev.F.) and an aluminum cap under the break-in with a detachable plastic lid type "flip-off".

1 bottle with a frozen solution of thrombin and 1 bottle with a frozen solution of fibrinogen with instructions for use in a pack of cardboard.

Storage conditions:

Keep the vials in an upright position.

In a frozen condition, store at a temperature not higher than -18 ° C.

Do not use Avicel® after the expiration date. The expiry date should be considered the last day of the month indicated on the package. Keep vials in a pack to protect from light. Do not re-freeze.

After thawing, the closed vials should be stored at a temperature of 2 to 8 ° C in the dark place for not more than 30 days.

The solutions of thrombin and fibrinogen, which are part of the preparation of IVISEL® after thawing, are stable at room temperature for 24 hours, however, once the solutions are transferred to the device for applying the drug, they must be used immediately.

Keep out of the reach of children.

Shelf life:

2 years at a temperature not higher than minus 18 ° С.

After thawing, the closed vials should be stored at a temperature of 2 to 8 ° C in the dark place for not more than 30 days.

After thawing, the solutions of thrombin and fibrinogen, which are part of the preparation of IVISEL®, are stable at room temperature for 24 hours.

Terms of leave from pharmacies:On prescription

Registration number:LP-000442

Date of registration:01.03.2011 / 10.05.2016

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

Omrix Biopharmaceuticals, Ltd Israel

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp03.02.2016

Illustrated instructions

Instructions

Ibisel (Evicel)