HAEMATE P 2400/1000 IU POWDER AND SOLVENT FOR INJECTABLE OR INFUSION SOLUTION

Introduction

PACKAGE LEAFLET: INFORMATION FOR THE USER

Haemate P 2400UI VWF/1000 UIFVIII

Powder and solvent for solution for injection and infusion

Human von Willebrand factor (VWF)

Human coagulation factor VIII (FVIII)

Read all of this leaflet carefully before you start 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 or pharmacist.
• 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 experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What Haemate P is and what it is used for

What is Haemate P?

Haemate P is presented as a powder accompanied by a solvent. The solution obtained is administered by injection or infusion into a vein. Haemate P belongs to a type of medicines called antihemorrhagics.

Haemate P is manufactured from human plasma (the liquid part of the blood) and contains human von Willebrand factor (VWF) and human coagulation factor VIII (FVIII).

What is Haemate P used for?

Since Haemate P contains both FVIII and VWF, it is essential to know which factor you need more. If you have hemophilia A, your doctor will prescribe Haemate P with the specified number of FVIII units. If you have von Willebrand disease, your doctor will prescribe Haemate P with the specified number of VWF units.

Von Willebrand disease

Prophylaxis and treatment of hemorrhages or surgical bleedings in von Willebrand disease, when treatment with only desmopressin is ineffective or contraindicated.

Hemophilia A (congenital factor VIII deficiency)

Treatment and prophylaxis of hemorrhages in patients with hemophilia A.

This product may be useful in the management of acquired factor VIII deficiency.

2. What you need to know before you use Haemate P

The following sections contain information that your doctor should consider before prescribing Haemate P.

Do not use Haemate P:

• If you are allergic (hypersensitive) to human von Willebrand factor, human coagulation factor VIII, or any of the other components of this medicine (listed in section 6).

Tell your doctor if you are allergic to any medicine or food.

Warnings and precautions:

Traceability

It is strongly recommended that each time Haemate P is administered, your doctor records the date of administration, the batch number of the medicine to maintain a record of the batches used.

Consult your doctor or pharmacist before starting to use Haemate P:

• In case of allergic reactions or anaphylactic reactions(severe allergic reactions that cause severe breathing difficulties or dizziness). It is possible that hypersensitivity reactions of an allergic type may occur. Your doctor should inform you of the first symptoms of hypersensitivity reactions. These include hives, rash, chest tightness, difficulty breathing, low blood pressure, and anaphylaxis (severe allergic reactions that cause severe breathing difficulties or dizziness). If these symptoms occur, stop using the product immediately and contact your doctor.
• The formation of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII medicines. These inhibitors, especially in large quantities, prevent the treatment from working properly, so you and your child will be carefully monitored for the development of such inhibitors. If your hemorrhage or your child's hemorrhage is not being controlled with Haemate P, consult your doctor immediately.
• If you have heart disease or are at risk of heart disease, inform your doctor or pharmacist.
• If a central venous access device (CVAD) is needed for the administration of Haemate P, your doctor should consider the risk of complications related to the catheter, including local infections, bacteria in the blood (bacteremia), and the formation of blood clots (thrombosis) at the site of catheter insertion.

Von Willebrand disease

• In case of risk of blood clot formation (thrombotic effects, including blood clots in the lung), particularly if you have clinical or laboratory risk factors (e.g., during the perioperative period without receiving thrombosis prophylaxis, late mobilization, obesity, overdose, cancer), you should be monitored for the first symptoms of thrombosis. Thrombosis prevention should be established according to current recommendations. Patients with von Willebrand disease, especially those with type 3 disease, may develop neutralizing antibodies (inhibitors) against von Willebrand factor. Your doctor will perform the necessary tests to detect their presence and consider whether to continue with this therapy.

Your doctor will carefully consider the benefits of treatment with Haemate P compared to the risks of these complications.

Viral safety

When human plasma or blood-derived medicines are administered, the occurrence of diseases due to the transmission of infectious agents cannot be completely excluded. This also applies to the possible transmission of unknown or emerging pathogens or other types of infections. However, the risk of transmitting infectious agents is reduced by:

• careful selection of blood and plasma donors to exclude potential carriers of infections;
• testing of each donation and plasma pool for signs of viruses/infections;
• inclusion of stages in the manufacturing process to inactivate or remove viruses.

These procedures are considered effective for enveloped viruses such as human immunodeficiency virus (HIV, the AIDS virus), hepatitis B virus, and hepatitis C virus (which cause liver inflammation) and for non-enveloped viruses such as hepatitis A virus (liver inflammation).

The inactivation/removal procedures may have limited value for non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection can be severe for a pregnant woman (fetal infection) and for subjects with immunodeficiency or increased red blood cell production (e.g., with hemolytic anemia).

Your doctor may recommend that you be vaccinated against hepatitis A and B if you regularly or repeatedly receive human von Willebrand factor and human coagulation factor VIII concentrates.

Using Haemate P with other medicines

• Tell your doctor or pharmacist if you are using or have recently used or might use any other medicines.
• This medicine must not be mixed with other medicines, solvents, and diluents.

Pregnancy, breastfeeding, and fertility

• If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.
• Since hemophilia A is rare in women, there is no experience with the use of factor VIII during pregnancy and breastfeeding.
• In the case of von Willebrand disease, women are even more affected than men. According to accumulated experience after marketing, substitution of VWF may be recommended for the prevention and treatment of acute hemorrhages. There are no clinical studies available on replacement therapy with VWF in women during pregnancy and breastfeeding.
• During pregnancy and breastfeeding, Haemate P should only be used if clearly indicated.

Driving and using machines

Haemate P does not affect the ability to drive vehicles and use machines.

Haemate P contains sodium

Haemate P 2400 UI VWF/1000 UI FVIII contains 52.5 mg of sodium (the main component of table/cooking salt) in each vial. This is equivalent to 2.6% of the maximum recommended daily intake for an adult.

3. How to use Haemate P

Treatment should be initiated and supervised by a doctor experienced in the treatment of blood coagulation disorders.

Dosage

The amount of von Willebrand factor and factor VIII you need and the duration of treatment depend on several factors, such as your weight, the severity of the disease, the location and intensity of the hemorrhage, or the need to prevent it during surgery or investigation (see the section "This information is intended only for healthcare professionals").

If you have been prescribed Haemate P for home use, your doctor should ensure that you know how to inject it and the amount to use.

Follow exactly the administration instructions of Haemate P given by your doctor or the healthcare staff of the hemophilia center.

If you use more Haemate P than you should

No symptoms of overdose with VWF and FVIII have been reported. However, the risk of developing blood clots (thrombosis) in the case of an extremely high dose, especially of products with VWF that have a high FVIII content, cannot be excluded.

Reconstitution and administration

Ensure that you work under sterile conditions at all stages of the process.

General instructions

• The lyophilized powder must be mixed (reconstituted) with the solvent (liquid) and withdrawn from the vial under aseptic conditions.
• The solution should be clear or slightly opalescent. After filtration/transference (see below and before administering to the patient), the obtained solution should be visually examined for particles or discoloration. Although the recommendations for preparing the solution (reconstitution) are followed precisely, it is not uncommon for some residues or particles to remain. The filter included in the Mix2Vial device completely removes these particles. Filtration does not affect dosing calculations.
• Do not use visibly cloudy solutions or solutions that still contain particles or residues after filtration.
• After administration, the unused medicine and residual material should be discarded according to local regulations and following your doctor's instructions.

Reconstitution:

Before opening either vial, allow the Haemate P powder and the accompanying solvent to reach room temperature. To do this, you can leave the vials at room temperature for about an hour or hold them in your closed hands for a few minutes. Do not expose the vials to direct heat. The vials should not be heated to a temperature above body temperature (37°C).

Carefully remove the protective caps from the solvent vial and the Haemate P vial. Clean the outer part of the rubber stoppers of both vials with an alcohol-impregnated swab and let them dry. You can now transfer the solvent to the Haemate P vial using the included administration system (Mix2Vial). Please follow the instructions below:

Administration

Once the product has been transferred to the syringe, it must be used immediately.

For the injection of Haemate P, the use of disposable plastic syringes is recommended since the ground glass surface of syringes that are entirely made of glass tends to stick with solutions of this type.

The reconstituted solution should be administered slowly by intravenous route at a rate not exceeding 4 ml per minute. Be careful not to let blood enter the syringe filled with product.

If higher doses need to be administered, this can also be done by infusion. For this purpose, transfer the reconstituted product to an approved infusion system. The infusion should be carried out following the doctor's instructions.

Monitor for any immediate reaction. If any reaction occurs that may be related to the administration of Haemate P, the injection or infusion should be interrupted immediately (see also section 2).

If you use more Haemate P than you should

No symptoms of overdose with VWF and FVIII have been reported. However, the risk of developing blood clots (thrombosis) in the case of an extremely high dose, especially of products with VWF that have a high FVIII content, cannot be excluded.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

The following adverse effects have been observed very rarely (in less than 1 in 10,000 patients):

• A sudden allergic reaction (such as angioedema, burning or itching at the infusion site, chills, hot flashes, generalized urticaria, headache, rash, hypotension, lethargy, nausea, restlessness, tachycardia, chest pressure, tingling sensation, vomiting, or difficult breathing) and in some cases may progress to severe anaphylaxis (including shock).
• Increased body temperature (fever).

Von Willebrand Disease

• Very rarely, there is a risk of thrombotic or thromboembolic events, including blood clots in the lungs (risk of formation and migration of blood clots in the vascular system, formed by arteries and veins, with a potential impact on organs).
• In patients receiving products with FVW, excessively high plasma levels of FVIII:C in a sustained manner may increase the risk of blood clot formation (see also section 2).
• Patient with von Willebrand disease may very rarely develop inhibitors (neutralizing antibodies) of FVW. If such inhibitors appear, a lack of clinical response leading to continuous bleeding occurs. This happens especially in patients with a specific form of von Willebrand disease, called type 3. These antibodies precipitate and may appear at the same time as anaphylactic reactions. Therefore, the presence of an inhibitor should be evaluated in patients who experience anaphylactic reactions. In such cases, it is recommended to contact a specialized hemophilia center.

Hemophilia A

• In children who have not previously received treatment with medicines composed of factor VIII, inhibitor antibodies (see section 2) may occur very frequently (more than 1 in 10 patients); however, in patients who have received previous treatment with factor VIII (more than 150 days of treatment), the risk is infrequent (less than 1 in 100 patients). If this happens, the medicines you or your child are taking may stop working properly, and you or your child may suffer from persistent bleeding. In that case, contact your doctor immediately.

Other Adverse Effects in Children and Adolescents

It is expected that the frequency, type, and severity of adverse effects in children will be the same as in adults.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es.

For information on viral safety, see "Warnings and Precautions" (section 2).

5. Storage of Haemate P

• Keep this medicine out of sight and reach of children.
• Do not use this medicine after the expiration date shown on the label and on the carton after EXP. The expiration date is the last day of the month indicated.
• Store below 25°C.
• Do not freeze.
• Keep the vial in the outer packaging to protect it from light.
• Haemate P does not contain preservatives, so the prepared solution must be used immediately.
• If the prepared solution is not administered immediately, it must be used within a period of 3 hours.
• Once the product is transferred to the syringe, it must be used immediately.

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Haemate P

The active ingredients are: Human von Willebrand factor and human coagulation factor VIII.

The other components are: Human albumin, glycine, sodium chloride, sodium citrate, sodium hydroxide or hydrochloric acid (in small amounts to adjust the pH).

Solvent:water for injectable preparations.

Appearance of the Product and Package Contents

Haemate P is presented as a white or pale yellow powder or friable solid and is supplied with water for injectable preparations as a solvent. The prepared solution must be transparent or slightly opalescent, i.e., it could shine when held against the light, but it must not contain any detectable particles.

Presentation

Box containing:

1 vial with powder

1 vial with 15 ml of water for injectable preparations

1 transfer device with 20/20 filter

Administration equipment (inner box):

1 single-use 20 ml syringe

1 venipuncture device

2 alcohol swabs

1 non-sterile adhesive dressing

Marketing Authorization Holder and Manufacturer

CSL Behring, S.A.

c/ Tarragona 157, 18th floor

08014 Barcelona (Spain)

Manufacturer

CSL Behring, GmbH

Emil-von-Behring-Str. 76

35041 Marburg (Germany)

Date of Last Revision of this Prospectus:July 2023

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)

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This information is intended only for healthcare professionals:

Dosage

Von Willebrand Disease

It is essential to calculate the dose using the specified number of FVW:RCo units.

Generally, the administration of 1 unit of FVW:RCo/kg of body weight increases the circulating levels of VWF:RCo by 0.02 units/ml, representing a 2% increase.

Levels above 0.6 units of FVW:RCo/ml (60%) and levels above 0.4 units of FVIII:C/ml (40%) should be achieved.

The recommended doses to achieve hemostasis are 40-80 units of FVW:RCo/kg of weight and 20-40 units of FVIII:C/kg of weight.

In certain cases, an initial dose of 80 units of von Willebrand factor may be required, especially in patients with type 3 von Willebrand disease, in whom maintenance therapy to achieve adequate levels may require higher doses than those required for other types of von Willebrand disease.

Prevention of bleeding in cases of surgery or severe injuries:

To prevent profuse bleeding during or after surgery, administration of the product should start 1-2 hours before surgery begins.

An adequate dose should be repeated at intervals of 12-24 hours. The dose and duration of treatment depend on the patient's clinical condition, the type and severity of bleeding, and the levels of FVW:RCo and FVIII:C.

When administering products containing factor VIII and von Willebrand factor, the treating physician should consider that continued treatment may cause an excessive increase in FVIII:C. After 24-48 hours of treatment, and in order to avoid an undesirable increase in FVIII:C, a reduction in doses and/or an increase in the intervals between administrations, or the use of von Willebrand factor products containing low levels of factor VIII, should be considered.

Pediatric Population

The dosage in pediatrics is based on body weight and therefore generally follows the same guidelines as for adults. The frequency of administration should always be aimed at achieving clinical efficacy in each particular case.

Hemophilia A

Treatment Monitoring

During the course of treatment, it is recommended to adequately monitor the levels of factor VIII to determine the dose to be administered and the frequency of repeated infusions. The individual response of patients to factor VIII therapy may vary, achieving different levels of in vivo recovery and demonstrating different half-lives. The dose based on body weight may require adjustment in patients with low weight or overweight.

In the case of major surgical interventions, it is essential to precisely monitor the substitution therapy through coagulation tests (plasma activity of factor VIII).

Patients should be monitored for the development of factor VIII inhibitors. See also section 2.

The dose and duration of treatment depend on the degree of factor VIII deficiency, the location and severity of bleeding, and the patient's clinical condition.

It is essential to calculate the dose using the specified number of FVIII:C units.

The number of units of factor VIII administered is expressed in International Units (IU), in relation to the current standard of the World Health Organization (WHO) for factor VIII concentrates. The plasma activity of factor VIII is expressed as a percentage (in relation to normal human plasma) or preferably in International Units (in relation to an international standard for factor VIII in plasma).

The activity of one international unit of factor VIII is equivalent to the amount of factor VIII contained in one ml of normal human plasma.

On-Demand Treatment

The calculation of the necessary dose of factor VIII is based on the empirical observation that 1 unit of factor VIII per kg of body weight raises the plasma activity of factor VIII by approximately 2% (2 units/dl). The necessary dose is determined by the following formula:

Units needed = body weight (kg) x desired increase in factor VIII (% or units/dl) x 0.5

The dose and frequency of administration will always be determined based on the observed clinical efficacy in each case.

In the case of bleeding episodes, such as those detailed below, the activity of factor VIII should not be lower than the established plasma activity level (in % of normal plasma or units/dl) during the corresponding period. The following table can be used as a dosing guide for bleeding episodes and surgery:

Prophylaxis

For long-term prophylaxis in patients with severe hemophilia A, the usual doses are 20-40 units of factor VIII per kg of body weight, at intervals of 2 or 3 days. In certain cases, especially in young patients, it may be necessary to shorten the intervals between administrations or use higher doses.

Pediatric Population

There is no clinical experience in the treatment of children with Haemate P.

Special Warnings and Precautions for Use

When using a product containing von Willebrand factor, the treating physician should consider that continued treatment may cause an excessive increase in FVIII:C. In patients receiving products with FVW that contain FVIII, it is necessary to monitor plasma levels of FVIII:C to avoid excessively high plasma levels in a sustained manner, which could increase the risk of thrombotic effects, and it is necessary to evaluate antithrombotic measures.

Adverse Reactions

When very large or frequently repeated doses are needed, when inhibitors are present, or when pre- or post-surgical care is involved, the appearance of symptoms of hypervolemia should be monitored in all patients. Additionally, in patients with blood groups A, B, and AB, symptoms of intravascular hemolysis and/or a decrease in hematocrit values should be monitored.