Uman complex 500 iu/20ml

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT UMAN COMPLEX 500 IU/20 ml

Composition:

1 vial contains:

Active substances: human prothrombin complex:

human blood coagulation factor IX – 500 IU;
human blood coagulation factor II – 500 IU;
human blood coagulation factor X – 400 IU;

Excipients: sodium chloride, sodium citrate, glycine, heparin, antithrombin III;
Solvent: water for injections – 20 ml.

Factor IX is calibrated according to the international standard.
The total protein content per vial does not exceed 300 mg. The specific activity of the medicinal product is more than 0.6 IU/mg, expressed as factor IX activity.

Excipients with known effect: the medicinal product contains up to 92 mg of sodium per vial (20 ml).

Pharmaceutical form. Powder and solvent for solution for infusion.

Main physicochemical properties: the product is a white or slightly coloured, highly hygroscopic powder or brittle solid.

Pharmacotherapeutic group. Antihemorrhagics. Combination of blood coagulation factors IX, II, VII and X. ATC code B02BD01.

Pharmacological properties.

Pharmacodynamics.

Coagulation factors II, VII, IX, and X, which are synthesized in the liver in a vitamin K-dependent process, are commonly referred to as the prothrombin complex.

Factor VII is a zymogen of the active serine protease factor VIIa, which initiates blood coagulation via the extrinsic pathway. The tissue factor–factor VIIa complex activates coagulation factors X and IX, resulting in the formation of factors IXa and Xa. Subsequent activation of the coagulation cascade leads to the activation of prothrombin (factor II), which is transformed into thrombin. Under the action of thrombin, fibrinogen is converted into fibrin, resulting in clot formation. Normal thrombin generation is also essential for platelet function as part of primary hemostasis.

Isolated severe factor VII deficiency leads to reduced thrombin generation and a tendency to bleeding due to impaired fibrin formation and weakened primary hemostasis. Isolated factor IX deficiency is one of the classical hemophilias (hemophilia B). Isolated deficiencies of factor II or factor X are very rare but, in severe forms, cause bleeding episodes similar to those seen in classical hemophilia.

Acquired deficiency of vitamin K-dependent coagulation factors occurs during treatment with vitamin K antagonists. If this deficiency becomes severe, it leads to a predisposition to severe bleeding, typically retroperitoneal or cerebral rather than intramuscular or intra-articular bleeding. Severe liver failure also results in markedly reduced levels of vitamin K-dependent coagulation factors and a tendency toward clinical bleeding, which, however, is often complicated by concurrent continuous mild intravascular coagulation, low platelet counts, deficiency of coagulation inhibitors, and impaired fibrinolysis.

Administration of human prothrombin complex concentrate provides increased plasma levels of vitamin K-dependent coagulation factors and may temporarily correct coagulation abnormalities in patients with deficiency of one or more of these factors.

Pharmacokinetics.

Preclinical Safety Data

Prothrombin complex concentrate is a natural component of human plasma and acts similarly to endogenous factors.

Single-dose toxicity studies are not considered relevant because high doses cause hypervolemia.

Repeated-dose (multiple-dose) toxicity studies in animals are not feasible due to interference from antibodies formed against the heterologous protein.

Even doses significantly exceeding the recommended human dose per kg of body weight do not demonstrate any toxic effects in experimental animals.

Since clinical experience with human prothrombin complex factors has not confirmed any carcinogenic or mutagenic effects, experimental studies, particularly those involving heterologous species, are not considered necessary.

Clinical characteristics.

Indications.

• For the treatment of bleeding and perioperative prevention of bleeding due to acquired deficiency of vitamin K-dependent coagulation factors, for example, deficiency caused by vitamin K antagonist therapy or overdose of vitamin K antagonists, when rapid correction of the deficiency is required.
• For the treatment of bleeding and perioperative prevention in congenital deficiency of any vitamin K-dependent coagulation factor, when a purified specific coagulation factor concentrate is not available.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Known allergy to heparin or history of heparin-induced thrombocytopenia.

Interaction with other medicinal products and other forms of interaction.

Human prothrombin complex concentrates neutralize the effect of vitamin K antagonists.

Interaction with other medicinal products is unknown.

Effect on biological tests

When performing coagulation tests that are sensitive to heparin in patients receiving high doses of human prothrombin complex, the presence of heparin as a component of the administered product should be taken into account.

Children

Specific data in children are lacking.

Special precautions for use.

Traceability

It is strongly recommended to record the name and batch number of the medicinal product UMAN COMPLEX 500 IU/20 ml each time it is administered to a patient, in order to ensure traceability of the link between the patient and the specific batch of the product.

Treatment of coagulation disorders should be carried out by specialists with appropriate experience.

In patients with acquired vitamin K-dependent coagulation factor deficiency (e.g., caused by vitamin K antagonist therapy), UMAN COMPLEX 500 IU/20 ml should be used only when rapid correction of prothrombin complex levels is required, such as in cases of significant bleeding or emergency surgical interventions. In other cases, reducing the dose of the vitamin K antagonist and/or administering vitamin K is usually sufficient.

Patients receiving vitamin K antagonists may have an underlying hypercoagulable state, and administration of human prothrombin complex concentrate may exacerbate this condition.

In cases of inherited deficiency of any vitamin K-dependent coagulation factor, it is recommended to use a specific coagulation factor preparation if available.

If an allergic or anaphylactic-type reaction occurs, administration of the medicinal product (injection/infusion) must be stopped immediately.

In the event of shock, standard medical anti-shock measures should be implemented.

Important information on excipients of the medicinal product UMAN COMPLEX 500 IU/20 ml

This medicinal product contains up to 92 mg of sodium per vial (20 ml), which corresponds to 4.6% of the WHO recommended maximum daily intake of sodium for adults (2 g).

Viral safety

Standard measures to prevent infections due to medicinal products derived from human blood or plasma include donor selection, screening of individual plasma donations and plasma pools for specific infectious markers, and implementation of effective viral inactivation/removal steps during manufacturing.

Nevertheless, when administering medicinal products derived from human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded, including unknown or new viruses and other pathogens.

The measures applied are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as against non-enveloped viruses such as hepatitis A virus (HAV). However, the effectiveness of these measures may be limited against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be particularly serious in pregnant women (fetal infection) and in individuals with immunodeficiency or increased erythropoiesis (e.g., hemolytic anemia).

Appropriate vaccination (against hepatitis A and B) should be considered for patients who regularly receive human prothrombin complex concentrate.

The use of human prothrombin complex concentrate is associated with an increased risk of disseminated intravascular coagulation (DIC), thromboembolic complications, and myocardial infarction. Patients receiving human prothrombin complex concentrate should be carefully monitored for signs and symptoms of DIC or thrombosis.

Due to the potential risk of thromboembolic complications associated with administration of this medicinal product, careful monitoring with appropriate laboratory testing is required in patients with coronary heart disease or history of myocardial infarction, liver disease, postoperative patients, neonates, or patients at risk of thromboembolic events or disseminated intravascular coagulation, in order to detect early signs of thrombotic complications and consumption coagulopathy. In each of these cases, the potential benefit of treatment with UMAN COMPLEX 500 IU/20 ml must outweigh the risk of these complications.

There are no data on the use of UMAN COMPLEX 500 IU/20 ml in cases of perinatal bleeding due to vitamin K deficiency in newborns.

Children

Specific data in pediatric patients are lacking.

Use during pregnancy or breastfeeding

The safety of human prothrombin complex concentrate during pregnancy has not been established in controlled clinical trials.

Animal studies are not considered suitable for assessing the safety of the product with regard to reproductive function, embryonic/fetal development, course of pregnancy, and peri- and postnatal development in humans.

Therefore, human prothrombin complex concentrate should be used during pregnancy and lactation only if clearly indicated.

Ability to affect the reaction speed when driving or operating machinery

Studies on the influence on the ability to drive vehicles or operate machinery have not been conducted.

Method of Administration and Dosage

Dosage

The following are general dosage recommendations only. Treatment should be initiated under the supervision of a specialist experienced in managing coagulation disorders. The dosage and duration of replacement therapy depend on the severity of the coagulation disorder, the site and extent of bleeding, and the patient's clinical condition.

The amount and frequency of administration must be individually adjusted for each patient.

Dosage intervals should be adapted according to the different half-lives of the various coagulation factors contained in the prothrombin complex (see section "Pharmacokinetics"). Individual dosage requirements can only be determined based on regular monitoring of plasma levels of the relevant coagulation factors, global tests of prothrombin complex levels (prothrombin time, international normalized ratio (INR)), and continuous monitoring of the patient's clinical status.

In the case of major surgical procedures, careful monitoring of replacement therapy using blood coagulation tests (measurement of specific coagulation factor activity and/or global tests of prothrombin complex levels) is essential.

Bleeding and Perioperative Bleeding Prophylaxis during Treatment with Vitamin K Antagonists

The required dose depends on the initial (pre-treatment) and target international normalized ratio (INR) values. Correction of coagulation disturbances caused by vitamin K antagonists lasts approximately 6–8 hours. However, the effect of concomitantly administered vitamin K usually becomes apparent within 4–6 hours. Therefore, after administration of vitamin K, repeated treatment with human prothrombin complex is generally not required.

Since these recommendations are empirical and recovery and duration of effect may vary, monitoring of INR during treatment is mandatory.

Bleeding and Perioperative Prophylaxis in Congenital Deficiency of any Vitamin K-Dependent Coagulation Factor, when a Specific Coagulation Factor Concentrate is Unavailable

The required dose for treatment is based on empirical data indicating that approximately 1 IU of Factor IX per 1 kg body weight increases plasma Factor IX activity by 0.01 IU/mL; 1 IU of Factor II or Factor X per 1 kg body weight increases plasma Factor II or Factor X activity by 0.02 and 0.017 IU/mL, respectively.

The dose of the administered specific coagulation factor is expressed in International Units (IU) according to the current WHO standard for each factor. Plasma activity of the specific coagulation factor is expressed as a percentage (relative to normal plasma) or in International Units (relative to the international standard for the specific coagulation factor).

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

For example, the calculation of the required dose of Factor X is based on empirical data indicating that 1 International Unit (IU) of Factor X per 1 kg body weight increases plasma Factor X activity by 0.017 IU/mL.

The required dose is calculated using the following formula:

Required number of units (IU) = body weight (kg) × desired increase in Factor X (IU/mL) × 60,

where

60 (mL/kg) is the reciprocal of the assumed volume of distribution (normalization).

If the individual volume of distribution is known, this value should be used for calculation.

Method of Administration

Reconstitute the medicinal product as described below. UMAN KOMPLEX 500 IU/20 mL must be administered intravenously by injection or slow infusion.

It is recommended not to exceed 100 IU/kg body weight per day.

Reconstitution of the powder with solvent

1. Allow both the vial of powder and the vial of solvent to reach room temperature.
2. Maintain room temperature throughout the reconstitution (dissolution) process (maximum 10 minutes).
3. Remove the protective caps from both the vial of powder and the vial of solvent.
4. Disinfect the stopper surfaces of both vials with ethyl alcohol.
5. Open the device package as indicated in Fig. A, without touching the inner part of the package (Fig. A).
6. Do not remove the device from the package.
7. Turn the device package upside down and pierce the solvent vial stopper with the plastic spike of the device, so that the blue part of the device connects to the solvent vial (Fig. B).
8. Holding the edge of the device package, remove the package without touching the device itself (Fig. C).
9. Ensure the powder vial is placed on a stable surface; invert the solvent vial with the attached device so that the solvent vial is above the device; press the transparent adapter on the powder vial stopper to allow the plastic spike to pierce the powder vial stopper; the solvent will automatically begin to transfer into the powder vial (Fig. D).
10. After the transfer of solvent, unscrew the blue part of the system to which the solvent vial is attached and remove it (Fig. E).
11. Gently shake the vial until the powder is completely dissolved. Do not shake vigorously to avoid foaming (Fig. F).

To prevent reduction of the medicinal product's activity, ensure that the powder is completely dissolved in the vial.

Administration of the solution

The reconstituted solution should be clear or slightly opalescent.

Before administration, visually inspect the solution for the presence of particles or discoloration. Do not use the solution if it is cloudy or contains a precipitate.

1. Draw air into the syringe by pulling back the plunger; attach the syringe to the device and inject the air from the sy游戏副本 into the vial containing the reconstituted solution (Fig. E).
2. While holding the plunger, invert the system so that the vial with the reconstituted solution is positioned above the device. Slowly pull back the plunger to draw the concentrate into the syringe (Fig. F).
3. Detach the syringe by rotating it counterclockwise.
4. Visually inspect the solution in the syringe, which should be clear or slightly opalescent and free from particles.
5. Attach a butterfly needle to the syringe and administer the medication intravenously.

After opening, the contents of the vial should be used immediately.

The reconstituted solution filled into a syringe should be used immediately.

Any unused medicinal product or waste material resulting from its use should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of UMAN COMPLEX 500 IU/20 ml in children have not been established.

Overdose.

Administration of high doses of human prothrombin complex products has been associated with cases of myocardial infarction, disseminated intravascular coagulation, venous thrombosis, and pulmonary thromboembolism. Therefore, in case of overdose, the risk of developing thromboembolic complications or disseminated intravascular coagulation is increased.

Children

Specific data in children are lacking.

Adverse reactions.

Summary of safety profile

Allergic reactions or anaphylactic-type reactions have been observed rarely.

Replacement therapy with human prothrombin complex may rarely lead to the development of circulating antibodies inhibiting one or more factors of human prothrombin complex. If such inhibitors develop, this may manifest as a poor clinical response.

Fever has been observed in rare cases.

There is a potential risk of thromboembolic reactions following administration of human prothrombin complex, such as embolism and thrombosis, disseminated intravascular coagulation, and myocardial infarction (see section "Special warnings and precautions for use").

For safety information regarding transmissible agents, see section "Special warnings and precautions for use".

Tabulated list of adverse reactions

Adverse effects that may occur during administration of human prothrombin complex are presented in the table below, classified according to MedDRA system organ classes and preferred terms.

Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Children

Specific data regarding children are lacking.

Reporting suspected adverse reactions

Reporting of adverse reactions following marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of effectiveness of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in a refrigerator at a temperature of 2 to 8 °C.

Keep the vial in the original cardboard package to protect from light.

Do not freeze.

Incompatibilities.

Human prothrombin complex concentrate must not be mixed with other medicinal products.

Only the infusion/injection set supplied should be used, as treatment failure may occur due to adsorption of coagulation factors onto the internal surfaces of certain infusion/injection sets.

Packaging.

1 vial with powder (500 IU) together with 1 vial of solvent (water for injection, 20 ml) and a set for reconstitution and administration, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KEDRION S.P.A.

Manufacturer's address and location of operations.

VIA PROVINCIALE (loc. BOLOGNANA) – 55027 GALLICANO (LU), ITALY.