Willfact 2000 j.m.

PACKAGE LEAFLET: INFORMATION FOR THE USER

Willfact 500 j.m.
powder and solvent for solution for injection
Willfact 1000 j.m.
powder and solvent for solution for injection
Willfact 2000 j.m.
powder and solvent for solution for injection
human von Willebrand factor

Please read all of this leaflet carefully before using this medicine, because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm them, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

1. What Willfact is and what it is used for
2. What you need to know before you use Willfact
3. How to use Willfact
4. Possible side effects
5. How to store Willfact
6. Contents of the pack and other information

1. What Willfact is and what it is used for

Willfact is manufactured from human plasma (the liquid part of blood) and contains the active substance called
human von Willebrand factor (vWF).
vWF plays a role in blood clotting. A deficiency of this factor, as occurs in von Willebrand disease, results in blood not clotting as quickly as it should, leading to an increased tendency to bleed. Replacement of vWF with Willfact temporarily corrects the blood clotting mechanisms.
Willfact is indicated for the prevention and treatment of bleeding associated with surgical procedures and other bleeding episodes in patients diagnosed with von Willebrand disease, when treatment with desmopressin (DDAVP) alone is ineffective or contraindicated.
Willfact can be used in all age groups.
Willfact must not be used in the treatment of haemophilia A.

2. Important information before using Willfact

When not to use Willfact

• If the patient is allergic to human von Willebrand factor or to any of the other components of this medicine (listed in section 6).
• If the patient has been diagnosed with haemophilia type A.

Warnings and precautions
Treatment with Willfact must always be supervised by a physician experienced in the treatment of bleeding disorders.
If the patient experiences severe bleeding and blood tests confirm reduced levels of factor VIII, the patient will receive a factor VIII clotting factor preparation and, additionally, a vWF preparation within the first 12 hours.

Hypersensitivity reactions
Hypersensitivity reactions with features of an allergic reaction may occur, as with other intravenous protein-containing medicines derived from human blood or plasma.
The patient will be monitored during infusion to detect early signs of hypersensitivity. These include rash (urticaria or generalized urticaria), feeling of tightness in the chest, wheezing, decreased blood pressure (hypotension), and severe allergic reactions (anaphylaxis).
The physician will inform the patient about warning signs indicating an allergic reaction.
If any subjective or objective symptoms of hypersensitivity occur, treatment must be discontinued immediately and medical assistance must be sought without delay.

Viral safety
When manufacturing medicines from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These include:

• careful selection of blood and plasma donors to exclude individuals at risk of infection,
• testing of each donated batch and plasma pool for the presence of viruses/infections,
• inclusion of steps during blood or plasma processing that inactivate or remove viruses.

Despite these measures, when administering medicines produced from human blood or plasma, it cannot be completely ruled out that transmission of infection may occur. This also applies to unknown or newly emerging viruses or other types of infections.
The measures taken are considered effective against enveloped viruses, such as human immunodeficiency virus (HIV, causing AIDS), hepatitis B virus, and hepatitis C virus.
The measures have limited effectiveness against non-enveloped viruses, such as hepatitis A virus and parvovirus B19. Infection with parvovirus B19 may be serious in pregnant women (because there is a risk of infecting the unborn child) and in patients with weakened immune systems or certain types of anaemia (e.g. sickle cell anaemia or haemolytic anaemia).

Vaccinations
The physician may recommend that the patient receive vaccinations against hepatitis A and hepatitis B if the patient regularly/repeatedly receives human plasma-derived von Willebrand factor.

Batch number recording
It is strongly recommended that, when administering each dose of Willfact, the patient's name and the batch number of the medicine be recorded to document which batches of the medicine have been administered.

Thrombosis risk
Blood vessels may become blocked by blood clots (thrombosis). The risk is particularly high if certain risk factors have been identified in the patient's medical history or laboratory tests. In such cases, the patient will be closely monitored for early signs of thrombosis. Medications to prevent (prophylaxis) blockage of blood vessels by blood clots should also be administered.
The physician using a factor VIII preparation containing von Willebrand factor should remember that continued treatment may lead to excessive increase in factor VIII activity. If the patient receives a vWF preparation containing clotting factor VIII, the physician should regularly monitor factor VIII activity in plasma. This will protect the patient from excessive factor VIII activity in plasma, which may increase the risk of thrombotic events.

Reduced efficacy
In patients with von Willebrand disease (especially type 3), proteins that neutralize the action of von Willebrand factor may develop. These proteins are called neutralizing antibodies or inhibitors. The physician will check whether inhibitors to vWF are developing in the patient's body if laboratory test results show inadequate restoration of vWF levels or if bleeding does not decrease despite administration of an appropriate dose of Willfact. If high concentrations of inhibitors are present, treatment with vWF may not be effective. In such cases, alternative treatment methods should be considered. New therapy will be administered by a physician experienced in treating bleeding disorders.

Willfact with other medicines
The patient should inform the physician or pharmacist about all medicines currently used or recently used, as well as any medicines planned for future use.

Pregnancy and breastfeeding
Willfact may be used in pregnant or breastfeeding women only if clearly indicated.
Controlled clinical studies evaluating the safety of Willfact in pregnant and breastfeeding women have not been conducted, and animal studies are insufficient to confirm safety with regard to fertility, pregnancy, and child development during pregnancy and after birth.
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult a physician or pharmacist before using this medicine.

Driving and operating machinery
No effects on the ability to drive or operate machinery have been observed.

Willfact contains sodium
One vial of 5 ml (500 IU) of Willfact contains 0.15 mmol (3.4 mg) of sodium.
This corresponds to 0.17% of the recommended maximum daily sodium intake for an adult.
One vial of 10 ml (1000 IU) of Willfact contains 0.3 mmol (6.9 mg) of sodium.
This corresponds to 0.35% of the recommended maximum daily sodium intake for an adult.
One vial of 20 ml (2000 IU) of Willfact contains 0.6 mmol (13.8 mg) of sodium.
This corresponds to 0.69% of the recommended maximum daily sodium intake for an adult.

3. How to use Willfact

Treatment should be initiated and monitored by a physician experienced in the management of bleeding disorders.
If the physician determines that the patient may self-administer the medication at home, appropriate instructions will be provided to the patient.
Dosage
This medicine should always be used exactly as prescribed by the physician. In case of doubt, consult the
physician.
Ideally, Willfact should be administered by a physician or nurse. However, if the patient has been given Willfact for home use, the physician will ensure that the patient has been informed about the correct method of injection and the appropriate dose. Follow the physician's instructions and seek help if difficulties arise when using the syringe. The syringe must only be used by a trained person.
The physician will calculate the correct dose of Willfact (expressed in international units — IU).
The dose depends on:

• body weight,
• site of bleeding,
• severity of bleeding,
• patient's clinical condition,
• need for surgical intervention,
• vWF activity in blood after a procedure,
• severity of the disease.

The dose ranges from 40–80 IU/kg body weight.
The physician will recommend performing blood tests during treatment to monitor:

• factor VIII (FVIII:C) levels,
• von Willebrand factor (vWF:RCo) levels,
• presence of inhibitors,
• early signs of thrombosis — in patients at risk of such complications.

Based on the results of these tests, the physician may adjust the frequency of injections and the dose administered.
In certain cases, it may be necessary to use a factor VIII preparation (another coagulation protein) in addition to Willfact to enable faster treatment or prevent bleeding (in emergency situations or in cases of acute bleeding).
Willfact may also be used for long-term prophylaxis, in which case the dose is individually determined. Administration of Willfact at a dose of 40–60 IU/kg body weight two to three times per week reduces the number of bleeding episodes.
If the patient feels that Willfact is too strong or too weak in effect, medical advice should be sought.
Use in children and adolescents
Dosing in children and adolescents is based on body weight. In some cases, particularly in younger patients (under 6 years of age), higher doses (up to a maximum of 100 IU/kg body weight) may be required.
Method of administration
Detailed instructions for reconstitution and administration of the medicinal product are provided at the end
of this leaflet.
Use of a higher than recommended dose of Willfact
Symptoms of overdose with Willfact have not been reported; however, administration of a large amount cannot exclude the risk of thrombosis.
Missed dose of Willfact
If a dose of Willfact is missed, consult the physician.
Do not use a double dose to make up for a missed dose.
If you have any further questions about the use of this medicine, consult your physician, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will experience them.
You should contact your doctor immediately if any of the following occur:

• Signs of hypersensitivity or allergic reactions (observed not very frequently, may affect up to 1 in 100 patients). In some cases, such reactions may progress into a severe allergic reaction (anaphylaxis), including anaphylactic shock (frequency unknown).

Warning signs indicating an allergic reaction include:

• difficulty breathing or swallowing,
• wheezing,
• chest tightness,
• rapid heartbeat,
• drop in blood pressure,
• fainting,
• extreme fatigue,
• restlessness, nervousness,
• headache,
• chills, feeling cold,
• hot flushes,
• swelling of various body parts,
• skin rash, generalized urticaria,
• burning or stinging sensation at the infusion site,
• tingling,
• vomiting,
• nausea.

If any of these symptoms occur, treatment must be stopped immediately and the doctor informed so that appropriate treatment can be initiated, depending on the type and severity of the reaction.

• Loss of expected therapeutic effect (lack of bleeding control). This may result from inhibition of von Willebrand factor (vWF) (frequency unknown).

In patients with von Willebrand disease, especially type 3, development of proteins that neutralize the action of vWF is possible. These proteins are called neutralizing antibodies or inhibitors. Patients receiving vWF should be closely monitored by a physician for the development of inhibitors through appropriate clinical observation and laboratory testing. The presence of inhibitors may manifest as inadequate clinical response. It may also coexist with severe allergic reactions.

• Signs of circulatory disturbances in limbs (e.g. cold, pale extremities) or vital organs (e.g. severe chest pain). This may result from formation of blood clots in blood vessels (frequency unknown).

There is a risk of blood clot formation (thrombosis), especially in patients at risk. After correction of von Willebrand factor deficiency, patients should be monitored for early signs of thrombosis or disseminated intravascular coagulation, and preventive treatment for thrombosis should be considered in situations where the risk is increased (after surgery, in bedridden patients, in cases of deficiency of coagulation inhibitors or fibrinolytic enzymes).
If the patient is receiving vWF preparations containing FVIII, the risk of thrombosis may be higher due to persistently elevated FVIII plasma levels.

The following adverse reactions have been observed frequently (may affect up to 1 in 10 patients):

• reactions at the infusion site.

The following adverse reactions have been observed not very frequently (may affect up to 1 in 100 patients):

• dizziness,
• paresthesia, hypoesthesia,
• hot flushes,
• itching,
• sensation of chest pressure,
• chills, feeling cold.

The following adverse reactions have been observed with unknown frequency:

• fever.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Willfact

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton.
Do not store above 25°C. Store in the original packaging to protect from light.
Do not freeze.
To maintain sterility, use the product immediately after reconstitution. However, chemical and physical stability of the product has been demonstrated for 24 hours when stored at 25°C.
Do not use this medicine if cloudiness or particulate matter is observed in the solution.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such practices will help protect the environment.

6. Contents of the Package and Other Information

What Willfact Contains
Active substance:
Human von Willebrand factor (500 IU, 1000 IU, 2000 IU), expressed in international units of ristocetin cofactor activity (vWF:RCo).
After reconstitution with 5 mL (500 IU), 10 mL (1000 IU), or 20 mL (2000 IU) of water for injections, one vial contains approximately 100 IU/mL of human von Willebrand factor.
Prior to the addition of albumin, the specific activity of the solution is at least 60 IU vWF:RCo per 1 mg of total protein.

Other components:
Powder: human albumin, arginine hydrochloride, glycine, sodium citrate, and calcium chloride dihydrate.
Solvent: water for injections.

What Willfact Looks Like and Contents of the Package
Willfact is supplied as a white or pale yellow powder or fragile solid, together with a clear, colourless solvent for reconstitution into an injection solution using a transfer system.
Available pack sizes of Willfact are 500 IU/5 mL, 1000 IU/10 mL, and 2000 IU/20 mL.
After reconstitution, the solution should be clear or slightly opalescent, colourless to slightly yellow.

Marketing Authorisation Holder and Manufacturer
LFB-BIOMEDICAMENTS
3, avenue des Tropiques,
ZA de Courtaboeuf,
91940 LES ULIS,
FRANCE
[email protected]

Manufacturers
LFB-BIOMEDICAMENTS
3, avenue des Tropiques,
ZA de Courtaboeuf,
91940 LES ULIS,
FRANCE
LFB-BIOMEDICAMENTS
59 Rue de Trévise
59000 LILLE
FRANCE

This medicinal product is authorised in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Austria Willfact
Czech Republic WILLFACT
Denmark Willfact
Spain Willfact
Germany WILLFACT
Norway Willfact
Poland Willfact
Slovakia Willfact
Sweden Willfact
Hungary Willfact
United Kingdom (Northern Ireland) Willfact
01.2024

USER INSTRUCTIONS:
Dosage
Generally, administration of 1 IU/kg body weight of von Willebrand factor increases circulating vWF:RCo activity by approximately 0.02 IU/mL (2%).
The target is to achieve vWF:RCo levels >0.6 IU/mL (60%) and FVIII:C levels >0.4 IU/mL (40%).

Achievement of haemostasis remains uncertain until factor VIII coagulant activity (FVIII:C) reaches 0.4 IU/mL (40%). Administration of von Willebrand factor alone does not result in maximal increase in FVIII:C activity within the first 6–12 hours and is insufficient for immediate normalization of FVIII:C activity. Therefore, if the patient's baseline FVIII:C activity is below the critical threshold and rapid correction of haemostasis is required—such as in the treatment of bleeding, severe trauma, or during emergency surgery—factor VIII should be administered together with the first dose of von Willebrand factor to achieve plasma FVIII:C activity sufficient for haemostasis.

However, if immediate increase in FVIII:C activity is not required—e.g., in the case of elective surgery—or if the patient's baseline FVIII:C activity allows for adequate haemostasis, the physician may decide to omit concomitant administration of factor VIII with the first dose of von Willebrand factor.

• Initiation of treatment: The initial dose of Willfact is 40–80 IU/kg body weight in the treatment of bleeding or trauma. This should be administered in combination with the required amount of a factor VIII-containing product, calculated based on the patient’s baseline plasma FVIII:C activity, to achieve appropriate plasma FVIII:C activity immediately before surgery or as rapidly as possible after the onset of a bleeding episode or severe trauma. For surgical procedures, the first dose should be administered one hour before surgery. An initial dose of 80 IU/kg body weight of Willfact may be necessary, particularly in patients with von Willebrand disease type 3, in whom maintaining adequate activity may require higher doses than in other types of vWD.

In the case of elective surgery, the first dose of Willfact should be administered 12–24 hours before surgery, and the second dose immediately before surgery. In such cases, concomitant administration of factor VIII product is not necessary, as endogenous FVIII:C levels usually reach the critical value of 0.4 IU/mL (40%) before surgery. However, this should be confirmed in each individual patient.

• Subsequent doses: If required, treatment with Willfact should be continued as monotherapy at a dose of 40–80 IU/kg body weight per day, administered in one or two doses daily for one to several days. The dose and frequency of administration should always be adjusted according to the type of procedure, the patient’s clinical and biological status (vWF:RCo and FVIII:C), and the type and severity of the bleeding episode.
• Long-term prophylaxis: Willfact may be administered for long-term prophylaxis at a dose individually adjusted for each patient. Willfact at a dose of 40–60 IU/kg body weight administered 2–3 times per week reduces the number of bleeding episodes.
• Home treatment: With physician approval, especially in cases of minor or moderate bleeding or for long-term prophylaxis, home treatment may be initiated.

Children and Adolescents
Dose size for each indication is based on body weight. The dose and duration of treatment should be adjusted according to the patient’s clinical condition and plasma levels of vWF:RCo and FVIII:C.

• Initiation of treatment
• In children under 6 years of age, the initial dose may be determined based on the patient’s incremental recovery (IR). If IR data are not available, an initial dose of 60 to 100 IU/kg body weight may be required to increase the patient’s vWF:RCo concentration to 100 IU/dL.
• In children over 6 years of age and adolescents, dosing is the same as in adult patients.
• Subsequent doses: In children and adolescents, subsequent doses should be individually determined based on clinical status and vWF:RCo levels, and adjusted according to clinical response.

Elective surgery

• In children under 6 years of age, after the first dose administered 12 to 24 hours before surgery, a repeat dose may be given 30 minutes before surgery.
• In children over 6 years of age and adolescents, dosing is the same as in adult patients.
• Prophylaxis: In children and adolescents, the dose and frequency of administration should be individually determined based on incremental recovery and vWF:RCo levels, and adjusted according to clinical response.

Method and Route of Administration
Intravenous administration
Reconstitution
Current guidelines for aseptic technique must be strictly followed. The transfer system is intended exclusively for reconstituting the medicine, as described below, and is not intended for administration of the medicine to the patient.

Warm both vials (powder and solvent) to a temperature not exceeding 25°C. Remove the protective caps from the vial containing the solvent (water for injections) and from the vial containing the powder. Disinfect the surfaces of both stoppers.

Remove the cap from the Mix2Vial connector package. Without removing the connector from its packaging, attach the blue end of the Mix2Vial connector to the stopper of the solvent vial. Remove and discard the connector packaging. Be careful not to touch the exposed part of the connector. Invert the solvent vial with the attached connector and connect it to the powder vial using the transparent part of the connector. The solvent will automatically flow into the vial containing the powder. Hold the system and gently mix with a swirling motion until the drug is completely dissolved. Then, holding one hand on the connector part attached to the reconstituted drug vial and the other hand on the connector part attached to the solvent vial, unscrew the Mix2Vial connector to separate the vials.

The powder should dissolve within less than 5 minutes, usually dissolving immediately.
The resulting solution should be clear or slightly opalescent, colourless or slightly yellow. Before
administration, the reconstituted product should be inspected visually for the presence of particulate matter
and discoloration.
Do not use cloudy solutions or those containing a precipitate.
Do not mix with other medicinal products.
Do not dilute the product after reconstitution.
Administration

Hold the vial upright after reconstitution while attaching the sterile syringe to the Mix2Vial connector. Then slowly withdraw the product into the syringe. After transferring the product into the syringe, firmly hold the syringe (with the plunger pointing downward) and unscrew the Mix2Vial connector, replacing it with an intravenous injection needle or a butterfly-type needle. Expel air from the syringe, disinfect the skin, and insert the needle into the vein. Administer slowly by direct intravenous route immediately after reconstitution as a single dose at an infusion rate not exceeding 4 ml/min.

Storage after reconstitution
To maintain sterility, the product should be used immediately after reconstitution. However, chemical and physical stability of the product has been demonstrated for up to 24 hours when stored at 25°C.
Any unused portions or waste material should be disposed of in accordance with local regulations.