• 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 you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effect not listed in this leaflet. See section 4.

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

• If you are allergic to human von Willebrand factor or to any of the other ingredients of this medicine (listed in section 6).
• If you suffer from Haemophilia A.

Your treatment with Willfact should always be supervised by a doctor experienced in the treatment of haemostatic disorders.

If you experience heavy bleeding and a blood examination shows that your factor VIII blood value is reduced, you will receive the VWF preparation in addition to a factor VIII preparation within the first twelve hours.

Allergic reactions

As with every protein medicine for intravenous use derived from human blood or plasma, hypersensitivity reactions in the form of an allergy may occur. During the injection you will be monitored to detect any early sign of hypersensitivity. These include rash (hives or generalised urticaria), tightness of the chest, wheezing, drop in blood pressure (hypotension) and severe allergic reactions (anaphylaxis).

Your doctor will inform you of the warning signs of an allergic reaction.

Should signs or symptoms of hypersensitivity occur, treatment should be discontinued and you should seek immediate medical attention.

Virus safety

When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include:

• Careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded,
• The testing of each donation and pools of plasma for signs of virus/infections,
• The inclusion of steps in the processing of the blood or plasma that can inactivate or remove viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV-AIDS), hepatitis B virus and hepatitis C virus.

The measures taken may be of limited value against non-enveloped viruses such as hepatitis A virus and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (as there is a risk of infection of the unborn child) and for individuals whose immune system is depressed or who have some types of anaemia (e.g. sickle cell disease or haemolytic anaemia).

Vaccinations

Your doctor may recommend that you consider vaccination against hepatitis A and B if you regularly/repeatedly receive human plasma-derived von Willebrand factor.

Recording of batch number

It is strongly recommended that every time you receive a dose of Willfact, the name and batch number of the medicine are recorded in order to maintain a record of the batches used.

Risk of thrombosis

Blood vessels may also become blocked by blood clots (thromboses). This risk exists particularly if your previous medical history or laboratory results indicate that you present certain risk factors. In this case you will be monitored very carefully for the early signs of thrombosis, and a preventive treatment (prophylaxis) against vein blockages by blood clots should be introduced.

When using a factor VIII-containing von Willebrand factor product, your doctor should be aware that the continued treatment may cause an excessive rise in FVIII. If you receive such FVIII-containing VWF product, your doctor should monitor your FVIII plasma level regularly. This ensures that your FVIII plasma level is not sustained excessively, which may otherwise increase the risk of thrombotic events.

Limited effectiveness

It is possible that, in patients with von Willebrand disease, especially type 3 patients, proteins may be formed that neutralise the effect of VWF. These proteins are called neutralising antibodies or inhibitors. If the laboratory results show that your VWF levels are not being replenished, or if the bleeding does not stop despite a sufficient dose of Willfact, your doctor will check whether VWF inhibitors are being formed in your body. If these inhibitors are present in high concentration, treatment with VWF may not be effective, and other treatment options should be considered. The new treatment will be provided by a doctor who has experience in the treatment of haemostatic disorders.

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Willfact should be used during pregnancy and breastfeeding only if it is clearly indicated. The safety of Willfact during pregnancy and breastfeeding has not been evaluated in clinical studies. Animal studies are not sufficient to establish its safety with respect to fertility, pregnancy and development of the child during pregnancy and after birth.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

No effects on ability to drive or use machines have been observed.

One 5 mL vial (500 IU) of Willfact contains 0.15 mmol (3.4 mg) sodium.

This is equivalent to 0.17 % of the recommended maximum daily dietary intake of sodium for an adult.

One 10 mL vial (1000 IU) of Willfact contains 0.3 mmol (6.9 mg) sodium.

This is equivalent to 0.35 % of the recommended maximum daily dietary intake of sodium for an adult.

One 20 mL vial (2000 IU) of Willfact contains 0.6 mmol (13.8 mg) sodium.

This is equivalent to 0.69 % of the recommended maximum daily dietary intake of sodium for an adult.

Detailed instructions for reconstitution and administration of the medicinal product are given at the end of the Package Leaflet.

No symptoms of overdose with Willfact have been reported.

However, the risk of thrombosis cannot be excluded in case of major overdose.

If you forget to use Willfact, talk to your doctor.

Do not take a double dose to make up for a forgotten dose.

• You notice symptoms of hypersensitivity or allergic reactions (observed uncommonly: may affect up to 1 in 100 people).
  In some cases, these reactions can progress to a severe allergic reaction (anaphylaxis) including anaphylactic shock (observed with an unknown frequency).

The warning signs of allergic reactions are:

• Difficulty breathing and swallowing
• Wheezing
• Tightness of the chest
• Increased heart rate
• Decrease or drop in blood pressure
• Fainting
• Extreme fatigue
• Restlessness, nervousness
• Headache
• Chills, feeling cold
• Flushing, hot flashes
• Swelling in different parts of the body
• Skin rash, generalised urticaria
• Burning and stinging at the infusion site
• Tingling
• Vomiting
• Nausea

If one of these effects occurs, immediately stop the treatment and alert a doctor to start appropriate treatment depending on the type and severity of the reaction.

• You notice that the medicine stops working properly (bleeding is not controlled). This can be due to von Willebrand’s factor inhibition (observed with an unknown frequency).

Proteins may be formed in patients with von Willebrand disease, especially type 3 patients, which neutralise the effect of VWF. These proteins are called neutralising antibodies or inhibitors. Patients treated with VWF should be carefully monitored by their doctors for the development of inhibitors by appropriate clinical observations and laboratory tests. If such inhibitors occur, the condition can manifest itself as an inadequate clinical response or occur concomitantly to severe allergic reactions.

• You notice any symptoms of an impaired perfusion in your extremities (e.g. cold and pale extremities) or vital organs (e.g. severe chest pain). This can be due to the formation of blood clots in the blood vessels (observed with an unknown frequency).

There is a risk of formation of blood clots (thrombosis), particularly in patients with known risk factors. After correction of the von Willebrand factor deficiency, you must be monitored for early signs of thrombosis or disseminated intravascular coagulation and receive treatment to prevent thrombosis in situations involving an increased risk of thrombosis (after operations, during confinement to bed, in cases of deficiency in a coagulation inhibitor or fibrinolytic enzyme).

If you receive FVIII-containing VWF preparations, the risk of thrombosis may also be increased due to persistently elevated FVIII plasma levels.

The following side effect has been observed commonly (may affect up to 1 in 10 people):

• Infusion site reactions

The following side effects have been observed uncommonly (may affect up to 1 in 100 people):

• Dizziness
• Paraesthesia, Hypoaesthesia
• Hot flush
• Itching
• Sense of oppression
• Chills, feeling cold

The other following side effect has been observed with an unknown frequency:

• Fever

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

The active substance is: human von Willebrand factor (500 IU, 1000 IU or 2000 IU), expressed in International Units (IU) 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.

Before the addition of albumin, the specific activity is greater than or equal to 60 IU of VWF:RCo/mg of total protein.

The other ingredients are:

Powder: human albumin, arginine hydrochloride, glycine, sodium citrate and calcium chloride dihydrate.

Solvent: water for injections.

Willfact is presented as a white or pale yellow powder or friable solid and a clear or colourless solvent for solution for injection after reconstitution with a transfer system.

Willfact is available in pack sizes of 500 IU/5 mL, 1000 IU/10 mL and 2000 IU/20 mL. Not all pack sizes/strengths may be marketed.

The reconstituted solution should be clear or slightly opalescent, colourless or slightly yellow.

To report a suspected side effect that has not been reported via the Yellow Card Scheme (above), please contact:

Intravenous administration.

Reconstitution

The currently applicable guidelines for aseptic procedures must be followed. The transfer system is only used to reconstitute the drug, as described below. It is not intended in administering the drug to the patient.

• Bring the two vials (powder and solvent) to a temperature not above 25°C.
• Remove the protective cap from the solvent vial (water for injections) and from the powder vial.
• Disinfect the surface of each stopper.
• Remove the cap from the Mix2Vial device. Without removing the device from its packaging, attach the blue end of the Mix2Vial to the stopper of the solvent vial.

• Remove and discard the packaging. Take care not to touch the newly-exposed part of the device.

• Turn the solvent vial-device assembly over and attach to the powder vial using the transparent part of the device. The solvent will automatically transfer to the powder vial. Hold the assembly and gently swirl to completely dissolve the product.

• Now, holding the reconstituted product part in one hand and the solvent part in the other, unscrew the Mix2Vial device to separate the vials.

The powder generally dissolves instantaneously and should have dissolved in less than 5 minutes.

The solution should be clear or slightly opalescent, colourless or slightly yellow. The reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.

Do not use solutions that are cloudy or have deposits.

Do not mix with other medicines.

Do not dilute the reconstituted product.

Administration

• Hold the vial of reconstituted product in vertical position while screwing a sterile syringe onto the Mix2Vial device. Then slowly draw the product up into the syringe.
• Once the product has been transferred to the syringe, firmly hold the syringe (with the piston pointing downward), unscrew the Mix2Vial device and replace it with an intravenous or butterfly needle.
• Expel the air from the syringe and insert into the vein after disinfecting the surface.
• Inject slowly by intravenous route immediately after reconstitution as a single dose at a maximum rate of 4 mL/minute.

Storage after reconstitution

For sterility reasons, the product should be used immediately after reconstitution. Chemical and physical in-use stability has, however, been demonstrated for 24 hours at +25°C.

Any unused product or waste material should be disposed of in accordance with local requirements.