Wilfactin (Lyophilisate) Instructions for Use

Marketing Authorization Holder

LFB Biomedicaments (France)

ATC Code

B02BD10 (Von Willebrand factor)

Active Substance

Human von Willebrand factor (Ph.Eur.)

Dosage Form

Wilfactin

Lyophilizate for preparation of solution for intravenous administration 1000 IU: fl. 1 pc. in a set with solvent and vial adapter

Dosage Form, Packaging, and Composition

Solvent water for injections 10 ml

1000 IU – vials (1) in a set with solvent (10 ml vial) and vial adapter – cardboard packs.

Clinical-Pharmacological Group

Hemostatic drug. Von Willebrand factor preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

The administration of von Willebrand factor corrects hemostatic abnormalities in patients deficient in this factor (von Willebrand disease) at two levels.

Von Willebrand factor restores platelet adhesion to the vascular subendothelium at the site of injury (can bind to the subendothelium and to the platelet membrane), providing primary hemostasis, which is manifested by a reduction in bleeding time. This effect appears immediately and largely depends on the level of multimerization of the active substance.

Von Willebrand factor promotes delayed correction of the concomitant factor VIII deficiency (produced by the patient’s body), stabilizes the level of this factor, preventing its rapid degradation.

Replacement therapy with von Willebrand factor normalizes the blood clotting factor VIII level after the first injection. This effect is long-lasting and persists during subsequent injections of Wilfactin alone.

Pharmacokinetics

A pharmacokinetic study of Wilfactin was conducted in 8 patients with type 3 von Willebrand disease using the ristocetin cofactor assay (VWF:RCo). The maximum concentration of the drug was noted 30-60 minutes after administration. The mean recovery is 2.1 IU/dL/IU/kg of the administered solution. With a single administration of Wilfactin at a dose of 100 IU/kg, the area under the concentration-time curve (AUC_0-∞) is 3444 IU*h/dL. The mean clearance is 3.0 ml/h/kg. The half-life of the drug ranges from 8 to 14 hours (mean 12 hours).

When Wilfactin is administered, the increase in FVIII:C levels occurs gradually and reaches normal values after 6-12 hours. The FVIII:C level increases by an average of 6% (6 IU/dL) per hour. Therefore, even in patients with an initial FVIII:C level below 5% (5 IU/dL), from the 6th hour the FVIII:C level reaches approximately 40% (40 IU/dL) and was maintained for 24 hours.

Indications

• Prevention and treatment of bleeding (including use before planned and emergency surgical or invasive interventions to reduce blood loss) in patients with von Willebrand disease.

ICD codes

Dosage Regimen

Wilfactin is for intravenous use only!

Treatment with Wilfactin should be carried out under the supervision of a physician experienced in the treatment of coagulation disorders.

As a rule, 1 IU/kg of von Willebrand factor increases the plasma level of VWF:RCo by 0.02 IU/ml (2%). To ensure hemostasis, administration of 40-80 IU/kg of von Willebrand factor is usually recommended. It is necessary to strive to achieve VWF:RCo levels > 0.6 IU/ml (60%) and factor VIII:C > 0.4 IU/ml (40%), since a factor VIII:C level of 0.4 IU/ml (40%) is usually sufficient to ensure hemostasis.

1. Prevention of bleeding before planned or emergency surgical interventions and treatment of bleeding (spontaneous or trauma-induced):

In case of urgent surgical interventions, Wilfactin should be administered one hour before the start of surgery.

For planned surgical interventions, Wilfactin should be administered 12-24 hours before surgery, then the drug should be re-administered 1 hour before surgery. In this case, simultaneous administration of blood clotting factor VIII is not required, since the endogenous factor VIII:C level by the start of surgery already reaches 0.4 IU/ml (40%). Nevertheless, the factor VIII:C level should be determined in each patient.

When von Willebrand factor alone is administered, the plasma factor VIII:C level increases gradually and reaches a maximum after 6-12 hours. Administration of Wilfactin does not lead to an immediate increase in factor VIII:C concentration. Therefore, if patients have an initial plasma factor VIII:C level below critical, and urgent correction of hemostasis is required (for example, in cases of bleeding treatment, severe trauma, or urgent surgery), then a blood clotting factor VIII preparation should be administered simultaneously with Wilfactin in order to achieve a hemostatic factor VIII:C activity. If there is no need for an urgent increase in factor VIII:C level (for example, during planned operations), or if the initial plasma factor VIII:C activity is sufficient to ensure hemostasis, the physician may decide not to administer blood clotting factor VIII together with the first administration of Wilfactin.

The dose and duration of therapy depend on the clinical condition of the patient, the type and severity of bleeding, and the von Willebrand factor level.

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 Wilfactin administration should always depend on the clinical effectiveness in each individual case.

First injection

For the treatment of bleeding or in severe trauma, Wilfactin is administered in doses from 40 to 80 IU/kg in combination with the required amount of blood clotting factor VIII to achieve an adequate level of factor VIII:C activity. The blood clotting factor VIII preparation is administered immediately before surgery or as soon as possible after bleeding or trauma; the dose of blood clotting factor VIII is determined by its initial plasma level.

In some cases, Wilfactin should be administered at an initial dose of 80 IU/kg, particularly in patients with type 3 von Willebrand disease, in which maintaining adequate von Willebrand factor levels may require higher doses than in other types of von Willebrand disease.

Subsequent treatment

If necessary, treatment should be continued with a suitable dose of Wilfactin 40-80 IU/kg per day, in one or two injections, for one or several days. The dose and frequency of injections should always correspond to the nature of the surgical intervention, the clinical condition of the patient, the plasma levels of VWF:RCo and FVIII:C, as well as the type and severity of bleeding.

2. Prevention of spontaneous bleeding in patients with von Willebrand disease

Wilfactin can be used for long-term prophylaxis in doses individually selected for each patient. Administration of Wilfactin in doses from 40 to 60 IU/kg 2-3 times a week can reduce the number of bleeding episodes.

Instructions for solution preparation

Wilfactin is a lyophilizate that is dissolved immediately before use with water for injections.

Wilfactin is administered only intravenously, as a single dose, immediately after dissolution, at a rate not exceeding 4 ml per minute.

Solution preparation

Observe the usual rules of asepsis.

1. If necessary, bring the two vials (lyophilizate and solvent) to a temperature not exceeding 25°C (77°F).

2. Remove the plastic caps from the vials. Disinfect the surface of both stoppers.

3. Remove the protective film from the adapter. Place the solvent vial upright, attach the blue side of the adapter to the vial and press the adapter until it stops. The adapter must be securely connected to the vial.

4. Remove the protective cover from the other side of the adapter.

5. Turn the adapter connected to the solvent vial, press its transparent part onto the lyophilizate vial and secure the adapter until it stops. The solvent automatically moves into the powder vial. Holding the connected vials together, mix the solution with gentle swirling movements until the drug is completely dissolved.

6. Holding the vial with the dissolved drug in one hand and the solvent vial in the other, unscrew the blue part of the device together with the solvent vial.

Usually the powder dissolves immediately, it should dissolve completely in less than 10 minutes. The resulting solution should be clear or slightly opalescent, colorless or pale yellow. Do not use a cloudy solution or a solution containing sediment.

7. Holding the vial with the dissolved drug vertically, screw the sterile syringe onto the Mix2Vial device. Slowly draw the drug into the syringe.
After drawing the drug into the syringe, holding it (plunger down), unscrew the Mix2Vial device and replace it with an intravenous or epicranial needle.
Remove air from the syringe, and after disinfecting the skin, insert the needle into the vein.
Administer intravenously, slowly and without interruption, immediately after dissolution of the drug, at a rate not exceeding 4 ml/minute.

From a microbiological point of view, the drug should be used immediately after dissolution. However, it has demonstrated physicochemical stability after 24 hours of storage at 25°C (77°F). Any amount of unused drug or remaining material must be disposed of in accordance with existing regulations.

Adverse Reactions

WHO classification of adverse drug reactions by frequency of occurrence

Very common – 1/10 administrations (≥ 10%)

Common – 1/100 administrations (≥ 1%, but < 10%)

Uncommon – 1/1000 administrations (≥ 0.1%, but < 1%)

Rare – 1/10000 administrations (≥ 0.01%, but < 0.1%)

Very rare – less than 1/10000 administrations (< 0.01%)

Frequency not known – cannot be estimated from the available data.

Below are the adverse drug reactions according to the MedDRA classification.

Immune system disorders uncommon – hypersensitivity reactions or allergic reactions. In very rare cases, severe anaphylactic reactions (angioedema or anaphylactic shock) may develop.

Psychiatric disorders uncommon – anxiety.

Nervous system disorders uncommon – headache, drowsiness.

Cardiac disorders uncommon – tachycardia.

Vascular disorders uncommon – hypotension, flushing.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea.

Gastrointestinal disorders uncommon – nausea, vomiting.

Skin and subcutaneous tissue disorders uncommon – rash, generalized urticaria, pruritus, paresthesia.

General disorders and administration site conditions uncommon – burning or tingling at the injection site, chills, feeling of tightness in the chest, rare – fever.

Other very rare – formation of neutralizing antibodies (inhibitors) to von Willebrand factor, especially in patients with type 3 von Willebrand disease. In a clinical study of Wilfactin in 62 patients, of which 23 had type 3 von Willebrand disease, no formation of neutralizing antibodies after Wilfactin administration was recorded. Presence is manifested as an inadequate clinical response (the expected plasma VWF:RCo level is not achieved, or bleeding is difficult to control with an adequate dose of the drug) and may be associated with an increased risk of developing anaphylactic reactions.

Contraindications

• Hypersensitivity to any component of the drug.
• Wilfactin should not be used in the treatment of hemophilia A due to the low content of factor VIII.
• Age under 6 years (use of the drug in children under 6 years of age has not been studied in clinical trials).

Use in Pregnancy and Lactation

No controlled studies of Wilfactin in pregnant women have been conducted. Data on the reproductive toxicity of Wilfactin and its transfer into animal milk are lacking. The safety of Wilfactin for pregnant women has not been established, therefore it is not recommended for use during pregnancy and breastfeeding, except in cases where the potential benefit to the mother significantly outweighs the possible risk to the fetus and infant.

Pediatric Use

The drug is contraindicated in children under 6 years of age.

Special Precautions

The use of Wilfactin in patients who have not previously received von Willebrand factor therapy has not been studied in clinical trials.

In cases of bleeding in patients at the initial stage of treatment, it is recommended to administer factor VIII simultaneously with Wilfactin.

Patients should be monitored throughout the entire period of drug administration to detect early signs of allergic or anaphylactic reactions. Patients should be informed about the early manifestations of hypersensitivity reactions, including itching, urticaria, chest tightness, shortness of breath, hypotension, and anaphylactic reactions. If such symptoms occur, administration of the drug should be stopped immediately. In case of anaphylactic shock, treatment is carried out in accordance with current guidelines.

There is a risk of thromboembolic complications, especially in patients with risk factors. Therefore, patients at risk should be monitored for early signs of thrombosis. Prevention of venous thromboembolism should be carried out in accordance with current guidelines.

After correction of von Willebrand factor deficiency, due to the possible risk of thrombosis, early signs of thrombosis or disseminated intravascular coagulation should be detected and thromboembolic complications prevented in accordance with current guidelines. In patients with von Willebrand disease, especially type 3, neutralizing antibodies (inhibitors) to von Willebrand factor may form. The presence of inhibitors is manifested as an inadequate clinical response (the expected plasma VWF:RCo level is not achieved, or bleeding is difficult to control with an adequate dose of the drug). If the expected plasma VWF:RCo level is not achieved, or if bleeding is difficult to control with an adequate dose, laboratory tests should be performed to determine the presence of VWF inhibitors. In patients with high levels of inhibitors, the use of Wilfactin may be insufficiently effective and other treatment options should be considered. Treatment of such patients should be carried out by a physician experienced in the treatment of coagulation disorders.

The presence of inhibitory antibodies to von Willebrand factor may be associated with an increased risk of anaphylactic reactions. Therefore, in all patients with anaphylactic reactions or in case of treatment failure, appropriate biological tests should be performed to determine the presence of inhibitors.

Standard measures to prevent the risk of transmission of infectious agents through medicinal products prepared from human blood or plasma include: clinical selection of donors, screening of individual blood samples and plasma batches for specific markers of infections. Virus inactivation and removal procedures are included in the manufacturing process. Nevertheless, when using drugs made from human blood or plasma, the risk of transmission of infectious agents cannot be completely excluded. This also applies to unknown or emerging viruses or other types of infectious agents.

The drug is effectively protected against enveloped viruses: HIV, hepatitis B and C. There is no complete guarantee of protection against non-enveloped viruses – hepatitis A and parvovirus B19. Parvovirus B19 is most dangerous for pregnant women (fetal infection), for immunocompromised individuals, and for patients with hemolytic anemia. Patients systematically receiving therapy with blood clotting factor preparations are recommended to undergo the necessary vaccination against hepatitis A and B. It is strongly recommended to record the batch number of the drug, indicated on the vial, with each administration, to enable tracking of the relationship between the patient and the drug used.

Effect on ability to drive vehicles and operate machinery

Wilfactin does not affect the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

No cases of Wilfactin overdose have been reported.

Thromboembolic complications may develop in case of significant overdose of the drug.

Drug Interactions

Wilfactin should not be mixed with other drugs.

Only polypropylene devices for injection/infusion should be used, because adsorption of human plasma proteins on the inner surfaces of some infusion materials can lead to treatment failure.

Clinically significant interactions of Wilfactin with other drugs are not known.

Storage Conditions

Store in the original packaging, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of the reach of children. Do not freeze.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.