Haemate^® P (Lyophilisate) Instructions for Use

ATC Code

B02BD06 (Von Willebrand factor and blood coagulation factor VIII in combination)

Active Substances

Human blood coagulation factor VIII

Human coagulation factor VIII (Ph.Eur.)

Human von Willebrand factor (Ph.Eur.)

Clinical-Pharmacological Group

Hemostatic agent. Blood clotting factors (VIII and von Willebrand) preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

Hemostatic agent. The complex of human blood coagulation factor VIII/human von Willebrand factor consists of two molecules (human blood coagulation factor VIII and human von Willebrand factor) that perform different physiological functions.

In addition to its protective function for blood coagulation factor VIII, von Willebrand factor induces platelet adhesion at the site of vascular injury and plays an important role in platelet aggregation.

Administration of von Willebrand factor allows for the correction of hemostasis disorders in patients suffering from von Willebrand factor deficiency at two levels: Von Willebrand factor promotes platelet adhesion at the site of vascular injury (as it binds both to the subendothelial layer of vessels and to the platelet membrane), ensuring primary hemostasis, as evidenced by a reduction in bleeding time. This effect occurs immediately. It is known to depend on the presence of a large number of von Willebrand factor multimers with high molecular weight; Von Willebrand factor promotes delayed correction of the associated deficiency of blood coagulation factor VIII. After intravenous administration, von Willebrand factor binds to endogenous blood coagulation factor VIII (which is produced in sufficient quantities by patients) and, by stabilizing this factor, prevents its rapid degradation. Therefore, when administering pure von Willebrand factor (with low content of blood coagulation factor VIII), a slightly delayed normalization of the blood coagulation factor VIII level (FVIII:C) is observed after the first infusion, whereas when administering von Willebrand factor preparations containing blood coagulation factor VIII, normalization of the blood coagulation factor VIII level is observed immediately after the first infusion.

After administration to patients with hemophilia, factor VIII binds to von Willebrand factor in the vascular bed.

Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X.

Activated factor X promotes the conversion of prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin and promotes clot formation. Hemophilia A is a hereditary, sex-linked disorder of the blood coagulation system due to reduced levels of factor VIII.

The disease manifests as profuse bleeding and hemorrhages into joints, muscles, and internal organs, either spontaneously or as a result of accidental trauma or surgery. Replacement therapy for the deficiency of blood coagulation factor VIII in plasma temporarily normalizes the factor level and reduces the tendency to bleed.

Pharmacokinetics

Von Willebrand factor

The T_1/2 of von Willebrand factor VWF:RCo (two-compartment model) is 9.9 h (on average, from 2.8 to 51.1 h). The initial T_1/2 is 1.47 h (on average, from 0.28 to 13.86 h).

The increase in ristocetin cofactor activity VWF:RCo in vivo is 1.9 (IU/dL)/(IU/kg) [on average, from 0.6 to 4.5 (IU/dL)/(IU/kg)]. The mean AUC value is 1664 IU/dL x h (on average, from 142 to 3846 IU/dL x h), the mean residence time (MRT) was 13.7 h (on average, from 3.0 to 44.6 h), and the mean clearance is 4.81 ml/kg/h (on average, from 2.08 to 53.0 ml/kg/h).

The maximum plasma level of von Willebrand factor was usually reached approximately 50 minutes after administration. The maximum level of blood coagulation factor VIII was observed 1-1.5 hours after administration.

Blood coagulation factor VIII

After intravenous administration, a rapid increase in blood coagulation factor VIII activity in plasma is observed initially, followed by a rapid decrease in activity and then a slow decrease in activity. Studies in patients with hemophilia A have shown that the T_1/2 was 12.6 h (on average, from 5.0 to 27.7 h). The increase in blood coagulation factor VIII activity in vivo was 1.73 IU/dL per IU/kg (on average, from 0.5 to 4.13). In one study, the mean residence time was 19.0 h (on average, from 14.8 to 40.0 h), the mean AUC value was 36.1 (% x h) / (IU/kg) (on average, from 14.8 to 72.4) (% x h) / (IU/kg), and the mean clearance was 2.8 ml/kg/h (on average, from 1.4 to 6.7 ml/kg/h).

Indications

Treatment and prevention of bleeding or blood loss during surgery in patients with von Willebrand disease, if monotherapy with desmopressin is ineffective or contraindicated.

Treatment and prevention of bleeding in patients with hemophilia A (congenital deficiency of blood coagulation factor VIII).

May be used for the treatment and prevention of bleeding in patients with acquired deficiency of blood coagulation factor VIII and in patients with antibodies to blood coagulation factor VIII.

ICD codes

Dosage Regimen

Administer this product under the supervision of a physician experienced in the treatment of coagulation disorders.

Determine the dosage and frequency individually based on the severity of hemorrhage, the patient’s clinical condition, and the desired plasma factor level.

Calculate the required dose in International Units (IU) based on body weight and the desired increase in factor activity.

For von Willebrand disease, base dosing on von Willebrand factor: Ristocetin Cofactor (VWF:RCo) activity.

For hemophilia A, base dosing on Factor VIII (FVIII:C) activity.

For minor bleeding or minor surgical procedures, maintain a target factor level of 30-50% for 1-3 days.

For major bleeding or major surgery, maintain a target factor level of 80-100% pre-operatively, followed by 50-80% for 7-14 days post-operatively.

Monitor plasma factor levels regularly to guide dosing and ensure adequate hemostasis.

Adjust the dosing interval based on the individual pharmacokinetic profile and clinical response; typically, administer every 8 to 24 hours.

In patients with von Willebrand disease, monitor FVIII:C levels to avoid a prolonged excessive increase, which may increase thrombotic risk.

Reconstitute the lyophilisate strictly according to the manufacturer’s instructions using the provided solvent.

Administer the solution intravenously at a rate not exceeding 4 ml per minute.

Discontinue administration immediately if signs of a hypersensitivity reaction occur.

Adverse Reactions

Blood and lymphatic system disorders: unknown – hypervolemia, hemolysis.

Vascular disorders very rarely – thromboses, especially in patients with known risk factors (e.g., in the perioperative period without thromboprophylaxis, without early mobilization, with obesity), thromboembolism (including pulmonary embolism).

Immune system disorders very rarely – hypersensitivity (allergic reactions), formation of inhibitors to von Willebrand factor, formation of inhibitors to factor VIII.

General reactions : in very rare cases, fever, burning and tingling at the injection site have been reported.

Contraindications

Hypersensitivity to the components of the combination.

Use in Pregnancy and Lactation

Since hemophilia A is rare in women, there is no experience with the use of the drug during pregnancy and lactation.

The situation is different with von Willebrand disease, as it is inherited in an autosomal manner. Women are affected even more often than men due to the additional risk associated with blood loss during menstruation, pregnancy, childbirth, and the development of gynecological diseases. Based on post-marketing studies, the use of von Willebrand factor substitutes for the treatment and prevention of bleeding can be recommended. Clinical data on replacement therapy with von Willebrand factor during pregnancy and lactation are lacking.

Thus, during pregnancy and lactation, the drug should be used only if there are clear indications.

Pediatric Use

The dosage regimen in children is calculated taking into account body weight, i.e., it is based on the same principles as in adults. The frequency of administration should always depend on the clinical effectiveness in each individual case.

Special Precautions

Patients should be informed about the possible occurrence of early symptoms of hypersensitivity reactions, such as rash, generalized urticaria, chest tightness, wheezing, arterial hypotension, and anaphylaxis. If these symptoms occur, patients are advised to immediately discontinue use of the drug and consult a doctor. Standard methods for treating shock should be followed in case of shock development.

Patients who regularly or repeatedly receive factor VIII preparations derived from human plasma are recommended to be vaccinated against hepatitis A and B.

There is a risk of thrombosis, including pulmonary embolism, especially in patients with known clinical and laboratory risk factors (e.g., lack of thromboprophylaxis in the perioperative period, lack of early mobilization, obesity, overdose, cancer). Therefore, patients at risk should be monitored for early symptoms of thrombosis. Prophylaxis of venous thromboembolism should be carried out in accordance with current guidelines.

When using preparations containing this combination for von Willebrand disease, the treating physician should be aware that prolonged treatment may lead to an excessive increase in the level of blood coagulation factor VIII activity (FVIII:C). In patients receiving von Willebrand factor preparations containing blood coagulation factor VIII, monitoring of the plasma level of blood coagulation factor VIII activity (FVIII:C) should be performed to avoid a prolonged increase in factor VIII activity (FVIII:C), which is associated with an increased risk of thrombotic complications. Appropriate thrombosis prophylaxis should also be carried out.

In patients with von Willebrand disease, especially type 3, neutralizing antibodies (inhibitors) to von Willebrand factor may develop. If the expected level of von Willebrand factor ristocetin cofactor activity in plasma is not achieved, or if bleeding cannot be stopped with an adequate dose, an analysis for the presence of von Willebrand factor inhibitors should be performed. If a patient has a high level of von Willebrand factor inhibitors, therapy may be ineffective, and in this case, the possibility of using other treatment methods should be considered.

The development of neutralizing antibodies – inhibitors to blood coagulation factor VIII is a known complication of treatment in patients with hemophilia A.

Patients receiving Human blood coagulation factor VIII should be under careful medical and laboratory supervision for the detection of antibodies to factor VIII. Treatment with this combination in patients with a high level of antibodies to factor VIII may be ineffective, in which case the possibility of selecting other treatment methods should be considered.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.