Factor vii (coagulation factor vii). FS.3.2.0002.15 Human blood clotting factor VII

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Instructions for medical use

Factor VII (Blood Clotting Factor VII)
Instructions for medical use- RU No. P N016158/01

date last change: 10.05.2016

Dosage form

Lyophilisate for the preparation of solution for intravenous administration

Compound

Composition (per 1 bottle):

Active Ingredient:

Factor VII 600 IU

As protein contained in plasma 50-200 mg/vial

Auxiliary ingredients:

Sodium citrate dihydrate 40 mg

Sodium chloride 80 mg

Heparin sodium 250 ME

Solvent:

Water for injections 10 ml

Description of the dosage form

Lyophilisate: white or slightly colored powder or friable solid mass.

Solvent: transparent colorless liquid.

Reconstituted solution: clear or slightly opalescent, colorless to yellowish solution.

Pharmacological group

Hemostatic agent

Pharmacodynamics

Factor VII is one of the vitamin K-dependent factors of normal human plasma, a component of the extrinsic pathway of the blood coagulation system. It is a single chain glycoprotein with molecular weight about 50,000 Dalton. Factor VII is a zymogen of the serine protease factor Vila (an active serine protease), which initiates the extrinsic coagulation pathway. The tissue factor-factor VIIa complex activates coagulation factors IX and X, resulting in the formation of factors IXa and Xa. With further deployment of the coagulation cascade, thrombin is formed, fibrinogen is converted to fibrin, and a clot is formed. Normal thrombin generation is also extremely important for platelet function as part of the hemostatic system. Hereditary factor VII deficiency is an autosomal recessive disorder. The use of human factor VII increases plasma concentrations of factor VII and may temporarily correct the coagulation defect in patients with factor VII deficiency.

Pharmacokinetics

When factor VII is administered intravenously, its concentration in the patient's blood plasma increases to 60-100%.

The half-life is approximately 3-5 hours.

Indications

The drug Factor VII is indicated:

• in the treatment of blood coagulation disorders caused by isolated hereditary deficiency of factor VII;
• for the prevention of blood coagulation disorders caused by isolated hereditary deficiency of factor VII, with a history of bleeding and a residual concentration of factor VII below 25% (0.25 IU/ml).

The drug does not contain significant amounts of factor VIIa and should not be used in hemophilia patients with inhibitors.

Contraindications

• increased sensitivity to active substance or any component of the drug;
• high risk of thrombosis or disseminated intravascular coagulation (DIC);
• known allergy to heparin or history of heparin-induced thrombocytopenia;
• children under 6 years of age (currently available data are insufficient to recommend the use of medicinal product Factor VII for children under 6 years of age).

Use during pregnancy and breastfeeding

The effect of Factor VII on fertility has not been studied in controlled clinical trials.

Safety human factor coagulation VII for use during pregnancy has not been confirmed by controlled clinical studies.

Data obtained from animal experiments do not allow us to assess the safety of the drug for pregnant women, the effect on the development of the embryo and fetus, childbirth or postnatal development. The physician must carefully evaluate the expected benefit and possible risk and prescribe the drug Factor VII during pregnancy and during breastfeeding only under strict indications.

See section " special instructions", containing information about the risks associated with potential danger infection of pregnant women with parvovirus B19.

Directions for use and doses

Treatment with Factor VII should only be carried out by a physician experienced in its use. replacement therapy coagulation factors.

The drug Factor VII is administered intravenously in the form of intermittent injections or infusions.

Reconstitution of the Factor VII drug must be carried out immediately before use. When used as an infusion, use only the included infusion set.

Recovery of lyophilisate

1. Warm the unopened bottle of solvent to room temperature, but not more than 37°C.

2. Remove the protective discs from the bottles with lyophilisate and solvent (Fig. A) and wipe the stoppers of both bottles.

3. Remove, by rotating and peeling, the protective coating from one end of the supplied transfer needle (Figure B). Insert the open needle through the rubber stopper into the bottle with the solvent (Fig. B).

4. Remove the protective coating from the other end of the transfer needle without touching the surface of the needle.

5. Turn the bottle with the solvent vertically over the bottle with the concentrate and insert the free end of the needle to transfer it through the rubber stopper of the bottle with the concentrate (Fig. D). The solvent will flow into the concentrate vial under vacuum.

6. Separate the two bottles by removing the needle from the stopper of the bottle with the concentrate (Fig. D). Gently shake and rotate the bottle of concentrate to speed up dissolution.

7. Once the product has been reconstituted, insert the supplied aeration needle (Fig. E) and allow the foam to settle completely. Remove the aeration needle.

8. Before administration, the resulting concentrate should be carefully examined for the presence of foreign particles and color changes (the concentrate may be colorless or yellowish).

If foreign particles, color changes or turbidity are detected, the drug should not be administered!

The drug must be used immediately after recovery.

Method of administration

1.Remove, by rotating and peeling, the protective coating from one end of the supplied filter needle, and attach it to a sterile disposable syringe. Draw the solution into a syringe (Fig. G).

2.Disconnect the filter needle from the syringe and perform a slow intravenous administration solution using the transfusion system (or the disposable needle provided).

Do not exceed the injection rate of 2 ml/min!

The dose and duration of replacement therapy depend on the severity of factor VII deficiency, the location and severity of bleeding episodes, and clinical condition sick. The relationship between residual factor VII concentrations and bleeding tendency is less clear in some patients than in classical hemophilia.

The number of Factor VII units administered is expressed in International Units (IU), corresponding to the existing WHO standard for Factor VII preparations. Factor VII activity in plasma is expressed either as a percentage (relative to normal plasma) or in International Units (relative to the International Standard for Factor VII plasma).

One International Unit (IU) of factor VII activity is equivalent to the amount of factor VII activity in 1 ml of normal human plasma.

Calculation of the required dose is based on the empirical observation that 1 International Unit (IU) of factor VII per kilogram of body weight increases factor VII activity in plasma by approximately 1.9% (0.019 IU/ml) relative to normal level activity.

The required dose is determined using the following formula:

Required dose (IU) = body weight (kg) × desired increase in factor VII activity (IU/ml) × 53* (unit divided by observed recovery (ml/kg))

*(since 1: 0.019 = 52.6)

In each individual case, the amount of drug to be administered and the frequency of application should always be related to clinical effectiveness. This is especially important in the treatment of factor VII deficiency, since individual bleeding susceptibility is not strictly dependent on plasma factor VII activity measured using laboratory tests. Individual dosing recommendations for Factor VII should be made based on regular measurements of factor VII plasma concentrations and long-term monitoring of the patient's clinical condition. Intervals between doses should take into account the short half-life of factor VII from the circulation, ranging from 3 to 5 hours.

When using Factor VII in the form of intermittent injections/infusions, it is advisable to interval between doses from 6 to 8 hours. Typically, treatment of factor VII deficiency requires (depending on activity in normal plasma) lower doses of the deficient factor compared to classical hemophilia (hemophilia A and B). The table below shows sample recommendations on the use of intermittent injections/infusions, developed based on the limited clinical experience available.

* 1 IU/ml=100 IU/dl=100% normal plasma. Factor VII activity in plasma is expressed either as a percentage (relative to the normal plasma content, taken as 100%) or in International Units (relative to the international standard for factor VII in plasma).

** Based clinical assessment in each case, provided that adequate hemostasis is achieved towards the end of treatment, lower doses may be sufficient. Intervals between doses should be adjusted taking into account short period the half-life of factor VII from the circulation is approximately 3 to 5 hours. If necessary, maintain high concentrations of factor VII for a period of time. long period Doses should be administered at intervals of 8-12 hours.

Unused drug and waste material must be destroyed in accordance with local requirements.

Side effects

Adverse effects observed in clinical studies

Adverse reactions encountered during the procedure clinical trials, are listed according to the following gradation: according to the following gradation: very often (> 1/10); often (> 1/100<1/10); нечасто (>1/1000<1/100); редко (> 1/10 000<1/1000); очень редко (<1/10 000, включая единичные сообщения).

The table below summarizes the adverse reactions observed in a clinical study of 57 adult and pediatric patients with hereditary factor VII deficiency who were administered Factor VII for the control of acute bleeding events, as part of surgery, and for long-term bleeding prophylaxis. In this study, Factor VII was administered for 8,234 days.

a - The rate per patient was determined based on the number of patients who experienced a given adverse event assessed by the investigator as at least possibly related to the administration of the drug, and assessed in the same way by Baxter Healthcare Corporation.

b - Frequency per day of administration was determined based on the total number of observations of a given adverse event assessed by the investigator as at least possibly related to the administration of the drug, and thus assessed by Baxter Healthcare Corporation.

c - “Impaired state of health” is the term used, implying unclear perception.

Adverse effects observed during post-registration use

During post-marketing use, the following adverse effects were observed, listed according to the MedDRA organ system classification in order of increasing severity, where applicable.

Blood and lymphatic system disorders: Factor VII inhibition*.

*-Coded under the MedDRA preferred term for the presence of antibodies to factor VII.

Immune system disorders: hypersensitivity reactions.

Mental disorders: confusion, insomnia, restlessness.

Nervous system disorders: cerebral vein thrombosis, dizziness, sensory disturbance, headache.

Cardiovascular system disorders: arrhythmia, hypotension, deep vein thrombosis, superficial vein thrombosis, flushing of the facial skin.

Disorders of the respiratory system, chest and mediastinal organs: bronchospasm, shortness of breath.

Gastrointestinal disorders: diarrhea, nausea.

Skin and subcutaneous tissue disorders: itching.

General disorders and reactions at the injection site: chest discomfort.

Class-specific reactions

When using factor VII preparations and prothrombin complex preparations containing factor VII, the following adverse events were observed: stroke, myocardial infarction, arterial thrombosis, pulmonary embolism, disseminated intravascular coagulation, allergic or anaphylactic reactions, urticaria, vomiting, increased body temperature.

Precautionary measures

When performing heparin-sensitive clotting tests in patients receiving high doses of Factor VII, the presence of heparin in the drug should be taken into account.

special instructions

When using drugs containing factor VII, the development of hypersensitivity reactions, including anaphylactic reactions, was observed. Patients and their loved ones should be informed about the early signs of hypersensitivity reactions. If such symptoms occur, patients should be advised to immediately stop using the drug and contact their doctor.

If allergic and/or anaphylactic reactions occur, administration should be stopped immediately. In case of shock, standard medical measures should be taken.

Standard interventions to prevent infections resulting from the use of medicinal products derived from human blood or plasma include donor selection, screening of individual donors and plasma pools for specific markers of infection, and implementation of effective virus inactivation/removal steps into production. . Despite this, when using medicinal products prepared from human blood or plasma, the risk of transmitting infectious diseases, including those caused by unknown viruses or other pathogens, cannot be completely eliminated.

The technologies used to remove and inactivate pathogens may have limited effectiveness against some non-enveloped viruses, in particular parvovirus B19. Parvovirus B19 infection can be dangerous for pregnant women (infection of the fetus) and patients with immunodeficiency or increased breakdown of red blood cells (particularly hemolytic anemia).

Appropriate vaccination (against hepatitis A and B) may be recommended for patients regularly receiving plasma-derived Factor VII therapy.

Each time Factor VII is administered, it is strongly recommended that the name and batch number of the drug be recorded to ensure that the relationship between the drug administration and the patient's condition can be traced.

When treated with drugs containing factor VII, there is a risk of developing thromboembolic complications and disseminated intravascular coagulation. Thrombosis, including deep vein thrombosis, and thrombophlebitis have been observed during treatment with Factor VII. Patients receiving Factor VII therapy should be closely monitored due to the possibility of developing signs and symptoms of thromboembolic complications and disseminated intravascular coagulation.

Due to the risk of thromboembolic complications and disseminated intravascular coagulation, particularly strict monitoring should be carried out when administering human coagulation factor VII to patients with coronary heart disease, liver disease, before surgery, neonates or other patients.

Human factor VII replacement therapy may result in the formation of circulating antibodies that inhibit factor VII. If such inhibitors appear, this condition manifests itself as an insufficient clinical response.

Impact on the ability to drive vehicles and other mechanisms

There is no information on the effect of Factor VII on the ability to drive a car and use complex equipment that requires increased attention.

Release form

Lyophilisate for the preparation of solution for intravenous administration 600 ME

600 IU of the drug in a glass vial (type II, EP) and 10 ml of solvent in a glass vial (type I, EP) in a cardboard box along with a dissolution and administration kit (disposable syringe, disposable needle, transfer needle, filter needle , aeration needle, transfusion system) and instructions for use

Storage conditions

At temperatures from 2 to 8°C.

Keep out of the reach of children.

Best before date

Do not use after the expiration date stated on the package.

Conditions for dispensing from pharmacies

By doctor's prescription.

Factor VII (Blood Clotting Factor VII) - instructions for medical use - RU No. P N016158/01 dated 2009-12-15

Synonyms of nosological groups

Most plasma clotting factors are produced in the liver. The synthesis of some of them (II, VII, IX, X) requires vitamin K, contained in plant foods and synthesized by intestinal microflora. With a lack or decrease in the activity of blood clotting factors, pathological bleeding may occur. This can occur with severe and degenerative liver diseases, with vitamin K deficiency. Vitamin K is a fat-soluble vitamin, so its deficiency can be detected when the absorption of fats in the intestines is inhibited, for example, when bile formation is reduced. Endogenous vitamin K deficiency is also observed when intestinal microflora is suppressed by antibiotics. A number of diseases in which there is a deficiency of plasma factors are hereditary. An example is the various forms of hemophilia, which only affect men but are transmitted by women.

Substances found in platelets are called platelet, or platelet, blood clotting factors. They are designated by Arabic numerals. The most important platelet factors include: PF-3 (platelet thromboplastin) - a lipid-protein complex on which hemocoagulation occurs, like a matrix, PF-4 - antiheparin factor, PF-5 - thanks to which platelets are capable of adhesion and aggregation, PF- 6 (thrombostenin) is an actinomyosin complex that ensures thrombus retraction, PF-10 is serotonin, PF-11 is an aggregation factor representing a complex of ATP and thromboxane.

Similar substances have been discovered in both erythrocytes and leukocytes. When transfusion of incompatible blood, Rh conflict between mother and fetus, massive destruction of red blood cells occurs and these factors are released into the plasma, which causes intense intravascular coagulation. In many inflammatory and infectious diseases, disseminated (widespread) intravascular coagulation (DIC) also occurs. , which is caused by leukocyte clotting factors.

According to modern concepts, two mechanisms are involved in stopping bleeding: vascular-platelet and coagulation.

Vascular-platelet hemostasis

Thanks to this mechanism, bleeding from small vessels with low blood pressure stops. In case of injury, a reflex spasm of damaged blood vessels is observed, which is further supported by vasoconstrictor substances (serotonin, norepinephrine, adrenaline) released from platelets and damaged tissue cells. The inner wall of blood vessels at the site of damage changes its charge from negative to positive. Due to the ability of adhesion under the influence of von Willebrand factor contained in the subendothelium and blood platelets, negatively charged platelets adhere to the positively charged wound surface. Almost simultaneously, aggregation occurs—clumping and sticking together of platelets with the formation of a platelet plug, or thrombus. First, under the influence of ATP, ADP and adrenaline of platelets and erythrocytes, a loose platelet plug is formed, through which plasma passes (reversible aggregation). Then the platelets lose their structure and merge into a uniform mass, forming a plug impenetrable to plasma (irreversible aggregation). This reaction occurs under the influence of thrombin, which is formed in small quantities under the influence of tissue thromboplastin. Thrombin destroys the platelet membrane, which leads to the release of serotonin, histamine, enzymes, and blood clotting factors. Lamellar factor 3 gives rise to the formation of platelet prothrombinase, which leads to the formation of a small number of fibrin strands on platelet aggregates, among which red blood cells and leukocytes are retained. After the formation of a platelet thrombus, it becomes compacted and secured in the damaged vessel due to retraction of the blood clot. Retraction is carried out under the influence of platelet thrombostenin due to contraction of the actin-myosin complex of platelets. A platelet plug generally forms within 1 to 3 minutes from the moment of injury, and bleeding from small vessels stops.

In large vessels, the platelet thrombus cannot withstand high pressure and is washed out. Therefore, in large vessels, hemostasis can be achieved by forming a more durable fibrin thrombus, the formation of which requires enzymatic coagulation

mechanism.

The main stages of vascular-platelet hemostasis.

The first stage is adhesion (sticking of platelets to the site of damage, for example to the subendothelial layer). After this, platelet activation and degranulation occurs (some of the substances secreted by platelets are shown). At the last stage, platelet aggregation occurs (binding of activated platelets with platelets adhering to the site of damage).

Coagulation hemostasis

Blood coagulation is a chain enzymatic process in which the activation of coagulation factors and the formation of their complexes sequentially occur. The essence of blood clotting is the transition of the soluble blood protein fibrinogen into insoluble fibrin, resulting in the formation of a durable fibrin thrombus.

Blood coagulation diagram.

Clotting factors are traditionally designated by Roman numerals and their active forms by the letter "a".

There are two independent coagulation mechanisms - internal, or contact, and external, dependent on tissue factor. They converge at the stage of factor X activation and lead to the formation of thrombin, which converts fibrinogen into fibrin. These reactions are inhibited by antithrombin III, which binds all coagulation factors related to serine proteases (with the exception of factor VII), as well as by the protein C-protein S system, which inactivates factors V and VIII.

HMK - high molecular weight kininogen;

TM - thrombomodulin;

PC - prekallikrein;

PL - phospholipids.

The blood clotting process occurs in 3 successive phases.

First phase is the most difficult and lengthy. During this phase, an active enzymatic complex, prothrombinase, is formed, which is an activator of prothrombin. Tissue and blood factors take part in the formation of this complex. As a result, tissue and blood prothrombinases are formed. The formation of tissue prothrombinase begins with the activation of tissue thromboplastin, which is formed when the walls of the vessel and surrounding tissues are damaged. Together with factor VII and calcium ions, it activates factor X. As a result of the interaction of activated X factor with V factor and with phospholipids of tissues or plasma, tissue prothrombinase is formed. This process lasts 5 – 10 seconds.

The formation of blood prothrombinase begins with the activation of factor XII upon its contact with collagen fibers of damaged vessels. High molecular weight kininogen (f XV) and kallikrein (f XIV) are also involved in the activation and action of factor XII. Factor XII then activates factor XI, forming a complex with it. Active factor XI, together with factor IV, activates factor IX, which, in turn, activates factor VIII. Then factor X is activated, which forms a complex with factor V and calcium ions, which ends the formation of blood prothrombinase. Platelet factor 3 is also involved in this. This process lasts 5-10 minutes.

Second phase. The resulting prothrombinase adsorbs the inactive plasma enzyme prothrombin (II factor) and converts it on its surface into the active enzyme thrombin. Factors IV, V, X and platelet factors 1 and 2 take part in this process. The second phase - the formation of thrombin - occurs in 2 - 5 s.

Third phase. During this phase, the soluble blood protein fibrinogen is converted into insoluble fibrin, which forms the basis of the blood clot. First, under the influence of thrombin, fibrin monomer is formed. Then, with the participation of calcium ions, a soluble fibrin polymer is formed (fibrin “S”, soluble). Under the influence of fibrin-stabilizing factor XIII, the formation of an insoluble fibrin polymer (fibrin “I”, insoluble), resistant to fibrinolysis, occurs. Formed elements of blood, in particular red blood cells, settle in fibrin threads, and a blood clot or thrombus is formed, which clogs the wound.

After the formation of a clot, the retraction process begins, i.e. compaction and fixation of a blood clot in a damaged vessel. This occurs with the help of the contractile platelet protein thrombostenin and calcium ions. After 2–3 hours, the clot shrinks to 25–50% of its original volume and the whey is squeezed out, i.e. plasma devoid of fibrinogen. Due to retraction, the thrombus becomes denser and tightens the edges of the wound.

Fibrinolysis

Fibrinolysis is the process of splitting a fibrin clot, which results in the restoration of the lumen of the vessel. Fibrinolysis begins simultaneously with clot retraction, but proceeds more slowly. This is also an enzymatic process, which is carried out under the influence of plasmin (fibrinolysin). Plasmin is found in the blood plasma in an inactive state in the form of plasminogen. Under the influence of blood and tissue plasminogen activators, its activation occurs. A highly active tissue activator is urokinase. Blood activators are in an inactive state in the blood and are activated by adrenaline and lysokinases. Plasmin breaks down fibrin into individual polypeptide chains, resulting in lysis (dissolution) of the fibrin clot,

If there are no conditions for fibrinolysis, then the formation of a blood clot is possible, i.e. replacing it with connective tissue. Sometimes a blood clot can break away from the site of its formation and cause a blockage of a vessel in another location (embolism).

B.02.B.D.05 Blood clotting factor VII