Bioclot a
UkraineTable of Contents
I N S T R U C T I O N for medical use of the medicinal product BioClot A® BioClot A®
Composition:
Active substances: Von Willebrand factor and coagulation factor VIII in combination;
1 vial with activity of 250 IU contains*:
human coagulation factor VIII 250 IU, human von Willebrand factor 125 IU
1 vial with activity of 500 IU contains*:
human coagulation factor VIII 500 IU, human von Willebrand factor 250 IU
1 vial with activity of 1000 IU contains*:
human coagulation factor VIII 1000 IU, human von Willebrand factor 500 IU
Excipients: human albumin; glycine (aminoacetic acid); lysine hydrochloride; sodium chloride; sodium citrate; calcium chloride dihydrate;
Solvent: water for injections.
*The activity of human von Willebrand factor (IU) is measured according to ristocetin cofactor activity (VWF:RCo) relative to the International Standard for von Willebrand factor concentrate (WHO).
The activity of coagulation factor VIII (IU) is determined by chromogenic assay according to the European Pharmacopoeia.
Pharmaceutical form. Lyophilisate for solution for injection in a set with solvent (water for injections) and devices for reconstitution and administration.
Main physicochemical properties: white or pale yellow hygroscopic powder or brittle mass.
Pharmacotherapeutic group.
Haemostatics. Blood coagulation factors. Von Willebrand factor in combination with coagulation factor VIII.
ATC code: B02BD06.
Pharmacological properties.
Pharmacodynamics.
BioCLOT A**®** is a highly purified lyophilized concentrate of coagulation factors VIII and von Willebrand, manufactured from human plasma, twice virally inactivated (by heat treatment and solvent-detergent methods).
The factor VIII / von Willebrand factor complex contains two molecules (FVIII, vWF) with different physiological properties. When administered to a patient with hemophilia, factor VIII binds to von Willebrand factor in the patient's circulation.
Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin, which in turn converts fibrinogen into fibrin, resulting in clot formation.
Hemophilia A is an inherited, sex-linked coagulation disorder caused by reduced levels of factor VIII:C, leading to prolonged bleeding into joints, muscles, or internal organs, either spontaneously or following trauma or surgical procedures.
Replacement therapy increases plasma levels of factor VIII, temporarily correcting the deficiency and enabling control of bleeding.
It should be noted that annual bleeding rates (ABR) are not comparable between different factor concentrates or across different clinical studies.
In addition to its role in protecting factor VIII, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.
BioCLOT A contains von Willebrand factor in its composition, which exerts the same action as endogenous factor. Administration of von Willebrand factor allows correction of hemostatic defects in patients with von Willebrand factor deficiency (von Willebrand disease) at two levels:
- Von Willebrand factor restores platelet adhesion to the vascular subendothelium at the site of vessel injury (since it binds both to the subendothelium and to platelet membranes), thereby ensuring primary hemostasis, as evidenced by shortened bleeding time. This effect occurs immediately and is largely dependent on the degree of protein polymerization;
- Von Willebrand factor induces a delayed correction of the associated factor VIII deficiency. After intravenous administration, von Willebrand factor binds to factor VIII, stabilizing it and preventing its rapid degradation.
Administration of FVIII:C-containing VWF restores FVIII:C levels to normal immediately after the first infusion.
Pharmacokinetics.
The plasma factor VIII activity level achieved after administration of the drug is 80–120% of the predicted value.
In the initial phase, distribution occurs between the intravascular and extravascular compartments, with a plasma half-life of 3 to 6 hours; approximately 2/3 to 3/4 of factor VIII remains in the bloodstream. In the subsequent slower phase, the half-life ranges from 8 to 20 hours, with a mean value of 12 hours.
Clinical characteristics.
Indications.
Treatment and prevention of bleeding in patients with hemophilia A (congenital factor VIII deficiency).
Correction of acquired factor VIII deficiency.
Prevention and treatment of bleeding or surgical bleeding in von Willebrand disease (VWD), in cases where treatment with desmopressin (DDAVP) is ineffective or contraindicated.
Contraindications.
Hypersensitivity to the active substance or to any of the other components of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
There are no data regarding interactions between human blood coagulation factor VIII and other medicinal products.
Special precautions for use.
Traceability
To improve traceability of biological medicinal products, it is recommended to record the name and batch number of the product in the patient's primary medical records each time the product is administered.
Hypersensitivity
When administering any intravenous protein-containing medicinal products, allergic-type hypersensitivity reactions including anaphylaxis, arterial hypotension, arterial hypertension, tachycardia, chest pain, dyspnea, edema (including facial and periorbital edema), urticaria, rash, erythema, pruritus, chills, fever, and nausea may occur. In addition to factor VIII proteins, the medicinal product contains residual amounts of other human proteins.
Anaphylaxis, including anaphylactic shock, has been reported with other medicinal products containing factor VIII and von Willebrand factor; therefore, such events may also occur during administration of Bioclot A**®**.
Patients should be closely monitored for any symptoms throughout the entire infusion period. If symptoms of anaphylaxis occur, administration of the product should be stopped immediately. In case of anaphylactic shock, current standard shock treatment measures should be applied.
Presence of inhibitors
Prior to prescribing Bioclot A**®**, it is important to determine whether the patient has a coagulation defect: factor VIII deficiency or von Willebrand factor deficiency.
Development of neutralizing antibodies (inhibitors) against factor VIII is a known complication in the treatment of patients with hemophilia A. These inhibitors are usually immunoglobulins IgG directed against the procoagulant activity of factor VIII and are quantified in Bethesda units (BU) per mL of plasma using a modified assay. The risk of inhibitor development correlates with disease severity and exposure to factor VIII, with the highest risk occurring during the first 50 exposure days, although the risk persists throughout life, albeit rarely. The clinical significance of inhibitor development depends on its titer: a low inhibitor titer poses a lower risk of inadequate clinical response compared to a high titer. All patients receiving factor VIII replacement therapy should be closely monitored for the presence of inhibitors through appropriate clinical observations and laboratory testing. If expected plasma factor VIII activity levels are not achieved, or if bleeding is not controlled with an appropriate dose, testing for the presence of a factor VIII inhibitor should be performed. In patients with high inhibitor titers, factor VIII therapy may be ineffective, and alternative treatment options should be considered. Management of such patients should be conducted under the supervision of a physician experienced in treating hemophilia and factor VIII inhibitors.
Von Willebrand disease
In patients with von Willebrand disease, particularly type 3, neutralizing antibodies (inhibitors) against von Willebrand factor may develop. If expected plasma VWF:RCo activity levels are not achieved, or if bleeding is not controlled with an appropriate dose, appropriate testing should be performed to determine the presence of a von Willebrand factor inhibitor. In patients with high inhibitor titers, von Willebrand factor therapy may be ineffective, and alternative treatment options should be considered.
Patients receiving recombinant factor VIII therapy require careful clinical monitoring and laboratory testing for inhibitors.
Long-term treatment with products containing von Willebrand factor may lead to excessive factor VIII accumulation.
This medicinal product contains between 6 mg/vial and 14 mg/vial of sodium per 250 IU dose, and between 12 mg/vial and 28 mg/vial of sodium per 500 IU and 1000 IU doses. Caution should be exercised when administering to patients on a sodium-restricted diet.
Cardiovascular complications
In patients with pre-existing cardiovascular risk factors, factor VIII replacement therapy may increase the risk of cardiovascular complications.
Complications related to venous access
If a central venous access device (CVAD) is required, the risk of complications associated with CVAD should be considered, including local infections, bacteremia, and catheter site thrombosis.
Thrombotic complications
Cases of thromboembolism have been reported in patients with von Willebrand disease receiving factor VIII/von Willebrand factor as replacement therapy. In patients with a history of venous thromboembolism and high endogenous factor VIII levels, an increased risk of further thrombosis has been observed. Prophylaxis for venous thromboembolism should be implemented.
There is a risk of thrombotic events, particularly in patients with clinical or laboratory risk factors. Therefore, patients in high-risk groups should be monitored for early signs of thrombosis. Prophylaxis for venous thromboembolism should be initiated in accordance with current guidelines.
In patients with blood group A, B, or AB, hemolytic reactions may occur after repeated administration of the product at short intervals or at very high doses.
Transmissible agents
Standard precautions are applied when using medicinal products derived from human blood or plasma to minimize the risk of transmitting infectious agents. These include careful donor selection, screening of individual plasma units and plasma pools for markers of viral and other infections, and inclusion of effective manufacturing steps for virus inactivation/removal. Nevertheless, administration of medicinal products derived from human blood or plasma cannot entirely eliminate the possibility of transmitting infectious agents, including unknown or emerging viruses and other pathogens.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, as well as against non-enveloped viruses such as hepatitis A virus. However, these measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may have serious consequences for pregnant women (fetal infection) and individuals with immunodeficiency or increased erythropoiesis (e.g., those with hemolytic anemia). Vaccination (against hepatitis A and B) should be considered for patients who receive factor VIII products regularly or repeatedly.
Paediatric population
The aforementioned warnings and precautions apply to all age groups.
Clinical data on the response to Bioclot A**®** in children under 6 years of age with von Willebrand disease are limited.
Use during pregnancy or breastfeeding
The safety of Bioclot A**®** during pregnancy and lactation has not been established. Therefore, the product should be used during pregnancy or breastfeeding only if clearly indicated and if the potential benefit outweighs the potential risk.
Effect on ability to drive and use machines
No effect on the ability to drive or operate machinery has been observed.
Administration and Dosage
Treatment should be initiated under the supervision of a physician experienced in the management of patients with hemophilia.
Monitoring of Treatment
During the course of treatment, Factor VIII levels should be monitored to ensure accurate dosing and appropriate frequency of repeat infusions. Individual patients may exhibit different responses to Factor VIII, showing varying levels of recovery and half-life. The dose calculated according to body weight may require adjustment in patients with underweight or overweight conditions. In the case of major surgical procedures, careful monitoring of replacement therapy using coagulation tests (plasma Factor VIII activity) is essential.
Dosing
The dosage and duration of replacement therapy depend on the severity of Factor VIII deficiency, the location and intensity of bleeding, and the patient's clinical condition.
The amount of Factor VIII administered is expressed in International Units (IU), calibrated against the WHO international standard for Factor VIII concentrates. Factor VIII activity may be expressed either as a percentage (relative to normal plasma) or in International Units (relative to the international standard for Factor VIII concentrates).
One International Unit (IU) of Factor VIII activity is equivalent to the quantity of Factor VIII present in 1 mL of normal human plasma.
On-demand Treatment
The calculation of required Factor VIII doses is based on the empirical formula: 1 IU of Factor VIII per 1 kg of body weight increases plasma Factor VIII activity by 1.5%–2%.
Taking into account the patient's baseline plasma Factor VIII activity, the dosage can be calculated using the following formula:
dose of BioClot A*®** (IU FVIII) = body weight (kg) × desired increase in Factor VIII (in %) × 0.5.*
The required number and frequency of infusions should be determined based on the clinical response in each individual case.
Bleeding Episodes and Surgical Procedures
In the event of the bleeding episodes listed below, Factor VIII activity should not fall below the recommended plasma activity level (expressed as % of normal) during the specified period.
The table below may serve as a guide for selecting the appropriate dosage and duration of Factor VIII replacement to prevent bleeding during surgical procedures. Higher doses may be required under certain conditions, particularly during initial administration.
| Type of bleeding or surgical intervention |
Necessary level of factor VIII in plasma, (% of normal) |
Dosing frequency (hours) / duration of treatment (days) |
| Bleeding Early hemarthrosis, muscle bleeding, or oral cavity hemorrhage Severe hemarthrosis, muscle hemorrhages, or hematoma Life-threatening bleeding, such as intracranial surgery, throat or gastrointestinal hemorrhage |
20–40 30–60 60–100 |
Every 12–24 hours, for at least 1 day, until bleeding is controlled or wound healed Every 12–24 hours, for 3–4 days or longer, until pain resolves and mobility is restored Every 8–24 hours, until life-threatening risk resolves |
| Surgical procedures Minor surgery, including tooth extraction Major surgery |
30–60 80–100 (before and after surgery) |
Every 24 hours, for at least 1 day, until wound healing Every 8–24 hours, until adequate wound healing, followed by 7 days of maintenance therapy with factor level 30–60% |
Long-term prophylactic treatment
For long-term prophylactic treatment of severe hemophilia A, recommended doses are 20–40 IU of factor VIII per kg body weight every 2–3 days. In some cases, particularly for younger patients, more frequent administration of higher doses may be required.
Continuous infusion
Prior to surgery, a pharmacokinetic analysis (measurement of factor VIII levels over time) should be performed to determine clearance.
The initial infusion rate can be calculated using the following formula:
Clearance × desired steady-state factor VIII plasma level =
infusion rate (IU/kg/hour).
After the first 24 hours of continuous infusion, clearance should be recalculated and reassessed daily by comparing the steady-state factor VIII plasma level with the measured factor VIII plasma level, taking into account the known infusion rate.
Von Willebrand disease with factor VIII deficiency
Treatment of von Willebrand disease should be performed under the supervision of a physician experienced in managing hemostatic disorders.
Generally, 1 IU/kg of VWF:RCo increases circulating VWF:RCo levels by 0.02 IU/mL (2%). Target levels of VWF:RCo > 0.6 IU/mL (60%) and FVIII:C > 0.4 IU/mL (40%) should be achieved.
Typically, to achieve hemostasis, 40–80 IU/kg of von Willebrand factor (VWF:RCo) and 20–40 IU/kg of FVIII:C are recommended.
An initial dose of 80 IU/kg of von Willebrand factor may be required, particularly for patients with type 3 von Willebrand disease, where maintaining adequate levels may require higher doses than in other types of this disease.
The appropriate dose should be repeated every 12–24 hours. The dose and duration of treatment depend on the patient's clinical condition, type and severity of bleeding, as well as VWF:RCo and FVIII:C levels.
When using a von Willebrand factor preparation containing FVIII, the treating physician should be aware that continued treatment may lead to excessive elevation of FVIII:C. After 24–48 hours of treatment, to avoid excessive elevation of FVIII:C, consideration should be given to reducing the dose and/or extending the dosing interval, or switching to a von Willebrand factor preparation containing a low level of factor VIII.
Method of administration
The preparation should be administered intravenously. The recommended maximum rate is not more than 2 mL per minute.
Preparation and administration of the solution
Opening of vials, preparation of the solution, and administration of the preparation must be performed under strict aseptic conditions.
Warm the vial containing the solvent to room temperature (up to a maximum of 37°C).
Remove the caps from the solvent and preparation vials, disinfect the stoppers with an antiseptic solution, and allow them to dry before opening the solvent transfer device with an integrated filter. (The transfer and filtration device is intended for single use only; do not use the device if the packaging is damaged or after the expiry date indicated on the paper part of the blister pack as follows: «EXP. year-month»).
DO NOT remove the filter from the blister pack! |
|
|
|
|
|
The solvent will automatically transfer into the vial with powder. |
|
|
|
After reconstitution and before administration, the solution should be inspected visually for particulate matter and discoloration. However, even when instructions for solution preparation are carefully followed, fine particles may occasionally be observed. These are removed by the filter provided in the kit. The concentration of the active pharmaceutical ingredient is not reduced. |
|
|
|
|
|
|
Before administration, the reconstituted medicinal product must be visually inspected for particulate matter and discoloration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or contain particulate deposits.
Using the provided system or an injection needle, administer the solution intravenously slowly (maximum infusion rate – 2 mL/min).
BioClot A**®** should be reconstituted only immediately before use. The prepared solution in the vial may be stored for 3 hours at a temperature not exceeding 25 °C. The reconstituted solution, drawn into a syringe, must be used immediately (the product does not contain preservatives). Unused solution or waste material should be disposed of according to local requirements.
Children.
Hemophilia A
There are no clinical data on the use of BioClot A**®** in children.
Von Willebrand’s Disease
Clinical data on the response to BioClot A**®** in children under 6 years of age with von Willebrand’s disease are limited.
Overdose.
There are no data regarding symptoms of overdose with human coagulation factor VIII. In case of significant overdose, thromboembolic complications may occur. Symptomatic treatment is indicated in such cases.
Adverse reactions.
Hypersensitivity or allergic reactions, including angioneurotic edema, burning sensation, erythema and acute pain at the injection site, chills, flushing, generalized urticaria, headache, rash, arterial hypotension, arterial hypertension, lethargy, nausea, restlessness, tachycardia, chest tightness, tinnitus, vomiting, and wheezing, weakness. In some cases, these may progress to severe anaphylaxis (including anaphylactic shock). Patients should be informed about the necessity to seek medical attention if these symptoms occur.
In rare cases, an increase in body temperature and fever may occur.
In patients with hemophilia A, antibodies (inhibitors) to factor VIII may develop, clinically manifested as lack of hemostatic response to administration of Bioclot A**®. In such cases, referral to specialized hemophilia treatment centers is recommended. The use of high doses of Bioclot A®** in patients with blood groups A, B, or AB may lead to the development of hemolytic reactions.
| Organ systems |
Adverse reactions |
Frequency of cases |
| Blood and lymphatic system disorders |
Coagulopathy, factor VIII inhibitors |
Unknown |
| Psychiatric disorders |
Anxiety |
Unknown |
| Immune system disorders |
Increased sensitivity, anaphylactic reaction, anaphylactic shock |
Unknown |
| Nervous system disorders |
Paresthesia, dizziness, headache |
Unknown |
| Eye disorders |
Periorbital edema, conjunctivitis |
Unknown |
| Cardiac disorders |
Tachycardia, palpitations |
Unknown |
| Vascular disorders |
Arterial hypotension, arterial hypertension, hyperemia, pallor |
Unknown |
| Respiratory, thoracic and mediastinal disorders |
Cough, dyspnea, labored breathing |
Unknown |
| Gastrointestinal disorders |
Nausea, vomiting |
Unknown |
| Skin and subcutaneous tissue disorders |
Erythema, rash, neurodermatitis, pruritus, erythematous rash, papular rash, urticaria, increased sweating, facial flushing |
Unknown |
| Musculoskeletal and connective tissue disorders |
Myalgia, cramps |
Unknown |
| General disorders and administration site conditions |
Chest pain, chest discomfort, edema (including peripheral, facial), chills/fever, injection site reactions (including inflammation), pain, hyperthermia, unpleasant taste in mouth, marked weakness, limb numbness, urticaria, angioedema |
Unknown |
Pediatric population
The frequency, type, and severity of expected adverse reactions apply to all age groups. Clinical data on the response to Bioclot A**®** in children under 6 years of age with von Willebrand disease are limited.
Shelf life.
2 years.
The reconstituted solution may be stored for 3 hours at a temperature not exceeding 25 °C.
Storage conditions.
Store in the original packaging protected from light at 2 to 8 °C. Storage at temperatures not exceeding 25 °C is permitted for up to 6 months at any point during the shelf life.
Keep out of the reach of children.
Incompatibilities.
Bioclot A**®** should not be mixed with other medicinal products prior to administration due to the potential reduction in treatment efficacy that may occur as a result of adsorption of human coagulation factor VIII and human von Willebrand factor onto the internal surfaces of the infusion system. It is recommended to use a separate intravenous administration system for Bioclot A**®**.
Packaging.
250 IU of the drug and 5 mL of solvent per vial. 500 IU or 1000 IU of the drug and 10 mL of solvent per vial.
One vial of the drug and one vial of solvent, together with accessories for reconstitution and administration (one transfer and filtration device, one single-use syringe with injection needle, one butterfly infusion set), in a cardboard box.
Prescription status.
Prescription only
Manufacturer.
LLC "BIOFARMA PLAZMA", Ukraine.
Manufacturer's location and address of place of business.
Legal address: 37-V Kyivska Street, Bila Tserkva, Kyiv Oblast, 09100, Ukraine.
Address of place of business:
37-V Kyivska Street, Bila Tserkva, Kyiv Oblast, 09100, Ukraine.