Beriate 2000

PACKAGE LEAFLET: INFORMATION FOR THE

USER
Beriate
Beriate 250, 250 IU Powder and solvent for solution for injection /
for infusion
Beriate 500, 500 IU Powder and solvent for solution for injection /
for infusion
Beriate 1000, 1000 IU Powder and solvent for solution for injection /
for infusion
Beriate 2000, 2000 IU Powder and solvent for solution for injection /
for infusion
Human coagulation Factor VIII
Please read this leaflet carefully before using this medicine, because it
contains important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• 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 or pharmacist. See section 4.

Contents of the leaflet:

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

1. What Beriate is and what it is used for

What is Beriate?
Beriate consists of powder and solvent. The reconstituted solution is intended for intravenous administration as an injection or infusion.
Beriate is manufactured from human plasma (the liquid component of blood) and contains human coagulation Factor VIII. It is used for the prevention and treatment of bleeding episodes caused by a deficiency of Factor VIII (haemophilia A). It may also be used in the treatment of acquired Factor VIII deficiency.
What is Beriate used for?
Factor VIII is involved in the blood coagulation process. A lack of Factor VIII causes blood to clot more slowly than normal, resulting in an increased tendency to bleed. Replacement of Factor VIII with Beriate temporarily restores normal blood clotting mechanisms.

2. Important information before using Beriate

The following sections contain information that should be considered before using
Beriate.
When not to use Beriate

• If the patient is allergic (hypersensitive) to the active substance (human coagulation factor VIII) or to any of the components of this medicine (listed in section 6).

Warnings and precautions
Traceability
It is especially recommended that each time Beriate is administered to a patient, the date of administration, batch number, and volume injected be recorded in the treatment diary.
Before starting treatment with Beriate, discuss this with your doctor or pharmacist.

• Hypersensitivity reactions, including allergic reactions, may occur. Patients should be informed by their doctor about early signs of hypersensitivity reactions, such as hives, generalized skin rash, tightness in the chest, wheezing, hypotension, and anaphylaxis (a severe allergic reaction causing serious breathing difficulties or dizziness). If any of these symptoms occur, patients should immediately discontinue the product and contact their treating physician.
• The development of inhibitors (antibodies) is a known complication that may occur during treatment with any factor VIII-containing product. These inhibitors, especially at high titres, may interfere with effective treatment, and the patient will be closely monitored for their development. If bleeding is not properly controlled with Beriate, inform the doctor immediately.
• If the patient has a heart condition or is at risk of developing one, inform the doctor or pharmacist.
• If a central venous access device (CVAD) is required for administration of Beriate, the doctor should consider the risk of complications associated with CVAD, including local infections, presence of bacteria in the blood (bacteraemia), and formation of blood clots in blood vessels (thrombosis) at the catheter insertion site.

The doctor should carefully weigh the benefits of treatment with Beriate against the risk of these complications.
Viral safety
For medicines produced from human blood or plasma, appropriate measures are taken to prevent transmission of infection to patients.
These measures include careful selection of blood and plasma donors to exclude carriers of infectious diseases, and testing of each donation and plasma pool for viruses/infections.
Manufacturers of these products also include in the production process procedures that inactivate or remove viruses and other pathogens. Despite these measures, when administering medicines derived from human blood or plasma, transmission of infectious agents cannot be completely ruled out, including unknown or newly emerging viruses and other types of infections.
The safety measures used are considered effective against enveloped viruses, such as human immunodeficiency virus (HIV, the virus causing AIDS), hepatitis B virus, hepatitis C virus (hepatitis), and also against non-enveloped viruses such as hepatitis A virus and parvovirus B19.
For patients receiving regular or repeated treatment with products derived from human plasma (e.g. factor VIII), the doctor may recommend vaccination against hepatitis A and B.
Interaction of Beriate with other medicines

• Inform the doctor or pharmacist about all medicines currently or recently taken by the patient, as well as any medicines the patient plans to use.
• Beriate must not be mixed with other medicinal products, diluents or solvents except those recommended by the manufacturer (see section 6).

Pregnancy, breastfeeding and fertility

• If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.
• Beriate should be used during pregnancy and breastfeeding only if clearly indicated.
• Data on the effect on fertility are not available.

Driving and using machines
Beriate has no influence on the ability to drive and use machines.
Beriate contains sodium
Beriate 250 IU and 500 IU contain less than 1 mmol of sodium (23 mg) per vial and can therefore be considered essentially "sodium-free".
Beriate 1000 IU and 2000 IU contain 27.55 mg of sodium (the main component of table salt) per vial. This is equivalent to 1.4% of the recommended maximum daily intake of sodium for an adult.

3. How to use Beriate

This medicine should always be used exactly as directed by your doctor or pharmacist.
If in doubt, consult your doctor or pharmacist.
Treatment of haemophilia A should be initiated and supervised by a physician experienced
in managing this type of disorder.
Recommended dose
The required amount of factor VIII and duration of treatment depend on several factors, such as
body weight, severity of the disease, site and intensity of bleeding, or the need to prevent
bleeding during surgery or medical procedures.
If home treatment with Beriate has been recommended, your doctor should instruct you
on how to administer the medicine and the dose to be used.
Follow the instructions provided by your doctor or nurse at the haemophilia treatment
centre.
Use in children and adolescents
The dose is determined based on body weight, using the same principle as for adults.
Use of a higher than recommended dose of Beriate
No symptoms of FVIII overdose have been reported.
Missed dose of Beriate
The next dose should be administered immediately, and regular dosing should continue
according to your doctor's instructions. Do not administer a double dose to make up for
a missed dose.
Reconstitution and method of administration
General instructions:

• The powder should be mixed (reconstituted) with the solvent (liquid component) and drawn from the vial under aseptic conditions.
• The reconstituted solution should be clear or slightly opalescent (may shimmer when viewed under light). Occasionally, single clumps or particles may be observed in the vial. The filter contained in the Mix2Vial device removes solid particles. Filtration does not affect dose calculation. Before administration, after filtration and withdrawal of the product into the syringe (see below), the solution should be inspected visually for the presence of small particles or discoloration. Do not use the solution if it is cloudy, contains sediment, or particles in the syringe.
• Once transferred into the syringe, the product should be used immediately. Do not store the product in the syringe.
• Any unused product or waste material should be disposed of in accordance with local regulations and your doctor's instructions.

Reconstitution:
Without opening the vials, warm the Beriate powder and solvent to room temperature or body temperature. This can be achieved either by leaving the vials at room temperature for about one hour or by holding them in your hands for several minutes.
DO NOT expose the vials to direct heat sources. The vials must not be heated above body temperature (37°C).
Carefully remove the protective caps from the vials containing the powder and the solvent, wipe the rubber stoppers with an alcohol-impregnated swab, and allow them to dry before opening the Mix2Vial package. Then proceed according to the instructions below.

1. Open the Mix2Vial package by removing the

cap. Do not remove the Mix2Vial from the blister!

2. Place the vial containing the solvent on a flat and clean

surface and hold it firmly. Do not remove the Mix2Vial from the blister. Press vertically downward with the blue connector to pierce the stopper of the solvent vial.

3. Carefully remove the blister from the Mix2Vial by holding

the edge and pulling vertically upward. Take care to remove only the blister, not the entire Mix2Vial device.
4. Place the vial containing the product on a flat, hard surface.

Invert the solvent vial with the attached Mix2Vial device and press vertically downward with the transparent connector to pierce the stopper of the product vial. The solvent will automatically flow into the vial containing the product.

5. With one hand, hold the vial containing the medicinal product

attached to the Mix2Vial device, and with the other hand, hold the solvent vial also attached to the Mix2Vial device. Carefully unscrew the device into two parts by turning counterclockwise. Remove the solvent vial with the attached blue connector of the Mix2Vial device.

6. Ensure complete dissolution of the substance by gently

rotating the vial containing the product with the attached transparent connector. Do not shake.

7	7. Draw air into an empty, sterile syringe. While holding the vial upright, attach the syringe to the Mix2Vial Luer Lock connector by turning it clockwise. Inject air into the product vial.

Drawing up and administration:

8. While keeping the syringe plunger depressed, turn the entire
   set upside down and fill the syringe with the solution by slowly
   pulling back the syringe plunger.

9. The solution is now in the syringe. Firmly hold the
   syringe barrel (with the syringe plunger pointing downward)
   and disconnect the transparent Mix2 Vial connector from the
   syringe by turning it counterclockwise. Insert the needle into a vein using the provided intravenous administration set. Allow blood to flow into the end of the tubing. Attach the syringe to the threaded, securing end of the intravenous administration set. According to the physician's instructions, slowly inject the reconstituted solution intravenously. The injection or infusion rate should not exceed 2 ml per minute. Care should be taken to ensure that blood does not enter the syringe containing the product.
   If a larger volume needs to be administered, this may also be done by infusion.
   To do so, transfer the product after reconstitution into a validated infusion system. The infusion should be carried out according to the physician's instructions.
   Care should be taken to monitor for any adverse reactions. If any such reaction occurs and may be related to the administration of Beriate, the injection or infusion should be discontinued (see also section 2).
   If there are any further doubts regarding the use of this medicinal product, consult a physician or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
If any of the following symptoms occur, contact your doctor or emergency services immediately, or go to the nearest hospital's hemophilia treatment center:

• Symptoms of angioedema, such as:
  • swelling of the face, tongue or larynx
  • difficulty swallowing
  • urticaria and breathing difficulties
    The above adverse reactions have been observed very rarely (may occur in less than 1 in 10,000 patients) and in some cases may lead to severe allergic reactions (anaphylaxis), including shock.
• Loss of treatment efficacy (persistent bleeding). In children previously untreated with factor VIII-containing products, inhibitory antibodies (see section 2) may develop very commonly (in more than 1 in 10 patients). However, in patients previously treated with factor VIII (for over 150 days of treatment), the risk is uncommon (less than 1 in 100 patients). If this occurs, the patient's medication may cease to work properly and persistent bleeding may occur. If this happens, contact your doctor immediately.

Other adverse reactions:

• Allergic (hypersensitivity) reactions, which may include:
  • burning and stinging at the injection or infusion site
  • chills, hot flushes, generalized skin rash, blisters
  • headache
  • drop in blood pressure, restlessness, increased heart rate, chest tightness, wheezing
  • feeling of fatigue (lethargy)
  • nausea, vomiting
  • tingling
    The above adverse reactions have been observed very rarely and in some cases may lead to severe allergic reactions (anaphylaxis), including shock.
• Very rarely, increased body temperature has been observed.

Adverse reactions in children and adolescents
The frequency, type and severity of adverse reactions in children and adolescents are comparable to those in adults.

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions 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 of 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 enables better assessment of the medicine's safety profile.

5. How to store Beriate

Do not use this medicine after the expiry date stated on the label and carton
following the abbreviation (EXP). The expiry date refers to the last day of the specified month.
The batch number is indicated on the label and carton following the abbreviation (Lot).

• Store in a refrigerator (2°C – 8°C).
• Within the shelf-life period, Beriate may be stored at a temperature not exceeding 25°C for a total duration of 1 month. Individual periods of storage at room temperature should be documented in the patient's treatment records to ensure that the cumulative storage time at this temperature does not exceed 1 month.
• Beriate does not contain a preservative and should ideally be administered immediately after reconstitution.
• If the product is not administered immediately after reconstitution, it may be stored in the vial for up to 8 hours at room temperature. Once transferred into a syringe, the product must be used immediately.
• Do not freeze.
• Keep the container in the outer packaging to protect it from light.
• Keep this medicine out of the sight and reach of children.

6. Contents of the pack and other information

What Beriate contains
Active substance:
Beriate is available as a powder (containing nominally 250 IU, 500 IU, 1000 IU, or 2000 IU of human coagulation factor VIII per vial) and a liquid component (solvent). The reconstituted solution is for injection or infusion.
Reconstituted Beriate 250/500/1000 using 2.5 ml, 5 ml, and 10 ml of water for injections, respectively, contains approximately 100 IU/ml of human coagulation factor VIII.
Beriate 2000 should be reconstituted with 10 ml of water for injections, resulting in a solution containing approximately 200 IU/ml of human coagulation factor VIII.
Other ingredients:
Glycine, calcium chloride, sodium hydroxide (in small amounts) to adjust pH, sucrose, sodium chloride. Solvent: water for injections 2.5 ml, 5 ml, and 10 ml, respectively.

What Beriate looks like and contents of the pack
Beriate is available as a white powder and is supplied with water for injections.
The reconstituted solution should be clear to slightly opalescent (i.e. may shimmer when held to light), but must not contain any visible particles.

Available pack sizes
Pack containing 250 IU:
1 vial of powder
1 vial of water for injections (2.5 ml)
1 transfer system 20/20 with filter
Administration set (inner packaging):
1 single-use syringe, 5 ml capacity
1 vial adapter
2 alcohol swabs
1 non-sterile plaster

Pack containing 500 IU:
1 vial of powder
1 vial of water for injections (5 ml)
1 transfer system 20/20 with filter
Administration set (inner packaging):
1 single-use syringe, 5 ml capacity
1 vial adapter
2 alcohol swabs
1 non-sterile plaster

Pack containing 1000 IU:
1 vial of powder
1 vial of water for injections (10 ml)
1 transfer system 20/20 with filter
Administration set (inner packaging):
1 single-use syringe, 10 ml capacity
1 vial adapter
2 alcohol swabs
1 non-sterile plaster

Pack containing 2000 IU:
1 vial of powder
1 vial of water for injections (10 ml)
1 transfer system 20/20 with filter
Administration set (inner packaging):
1 single-use syringe, 10 ml capacity
1 vial adapter
2 alcohol swabs
1 non-sterile plaster

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Str. 76
35041 Marburg
Germany

This medicinal product is authorised in the European Economic Area under the name:
Austria:
Beriate 100 I.E./ml Pulver und Lösungsmittel zur Herstellung einer Injektions- oder Infusionslösung (250 I.E., 500 I.E., 1000 I.E.)
Beriate 200 I.E./ml Pulver und Lösungsmittel zur Herstellung einer Injektions- oder Infusionslösung (2000 I.E.)

Bulgaria:
Beriate 250 IU Powder and solvent for solution for injection or infusion
Beriate 500 IU Powder and solvent for solution for injection or infusion
Beriate 1000 IU Powder and solvent for solution for injection or infusion
Beriate 2000 IU Powder and solvent for solution for injection or infusion

Croatia:
Beriate 250 IU prašak i otapalo za otopinu za injekciju ili infuziju
Beriate 500 IU prašak i otapalo za otopinu za injekciju ili infuziju
Beriate 1000 IU prašak i otapalo za otopinu za injekciju ili infuziju
Beriate 2000 IU prašak i otapalo za otopinu za injekciju ili infuziju

Czech Republic:
Beriate 250 IU, Beriate 500 IU, Beriate 1000 IU, Beriate 2000 IU

Estonia:
Beriate

Latvia:
Beriate 250 SV pulveris un šķīdinātājs injekciju vai infūziju šķīduma pagatavošanai
Beriate 500 SV pulveris un šķīdinātājs injekciju vai infūziju šķīduma pagatavošanai
Beriate 1000 SV pulveris un šķīdinātājs injekciju vai infūziju šķīduma pagatavošanai
Beriate 2000 SV pulveris un šķīdinātājs injekciju vai infūziju šķīduma pagatavošanai

Lithuania:
Beriate® 250 TV milteliai ir tirpiklis injekciniam ar infuziniam tirpalui
Beriate® 500 TV milteliai ir tirpiklis injekciniam ar infuziniam tirpalui
Beriate® 1000 TV milteliai ir tirpiklis injekciniam ar infuziniam tirpalui
Beriate® 2000 TV milteliai ir tirpiklis injekciniam ar infuziniam tirpalui

Germany:
Beriate 250, Beriate 500, Beriate 1000, Beriate 2000

Hungary:
Presentations of Beriate 250, 500 and 1000:
BERIATE 100 NE/ml por és oldószer oldatos injekcióhoz vagy infúzióhoz
Presentation 2000:
BERIATE 200 NE/ml por és oldószer oldatos injekcióhoz vagy infúzióhoz

Italy:
Beriate

Poland:
Beriate 250
Beriate 500
Beriate 1000
Beriate 2000

Portugal:
Beriate

Romania:
Beriate 250 pulbere şi solvent pentru soluţie injectabilă/perfuzabilă
Beriate 500 pulbere şi solvent pentru soluţie injectabilă/perfuzabilă
Beriate 1000 pulbere şi solvent pentru soluţie injectabilă/perfuzabilă
Beriate 2000 pulbere şi solvent pentru soluţie injectabilă/perfuzabilă

Spain:
Beriate 250 UI polvo y disolvente para solución inyectable o perfusión
Beriate 500 UI polvo y disolvente para solución inyectable o perfusión
Beriate 1000 UI polvo y disolvente para solución inyectable o perfusión
Beriate 2000 UI polvo y disolvente para solución inyectable o perfusión

Slovakia:
Beriate 250 IU
Beriate 500 IU
Beriate 1000 IU
Beriate 2000 IU

Slovenia:
Beriate 250 i.e. prašek in vehikel za raztopino za injiciranje/infundiranje
Beriate 500 i.e. prašek in vehikel za raztopino za injiciranje/infundiranje
Beriate 1000 i.e. prašek in vehikel za raztopino za injiciranje/infundiranje
Beriate 2000 i.e. prašek in vehikel za raztopino za injiciranje/infundiranje

Information intended exclusively for medical professionals:

Dosage
Monitoring of treatment
During treatment, appropriate measurement of factor VIII levels should be performed to determine
the correct dose to be administered to the patient and the frequency of repeated infusions.
Individual patient responses to factor VIII may vary due to differences in recovery levels and half-life.
Dosing based on body weight may require adjustment in patients who are overweight or underweight.
Particularly during major surgical procedures, careful monitoring of replacement therapy is essential
by controlling the coagulation process (factor VIII activity level in plasma).
Patients should be monitored for the development of factor VIII inhibitors.
See also section 2.
The number of factor VIII units administered to the patient is expressed in International Units (IU),
corresponding to the current WHO standards for factor VIII clotting factor concentrates.
Factor VIII clotting activity in plasma is expressed as a percentage (relative to normal human plasma)
or preferably in IU (relative to international standards for factor VIII content in plasma).
One International Unit of factor VIII activity is equivalent to the activity of factor VIII present in 1 ml of normal human plasma.

Treatment on demand
The calculation of the required factor VIII dosage is based on the empirical observation that
1 IU of factor VIII per kg of body weight raises plasma factor VIII activity by approximately 2% of normal activity (2 IU/dL). The required dosage is calculated using the following formula:
Required number of units = body weight [kg] × desired increase in factor VIII level [% or IU/dL] × 0.5.
The dose of the product and the frequency of administration should always be individually adjusted according to the clinical efficacy observed in individual patients.

In the event of the following bleeding episodes, factor VIII activity should not fall below the specified plasma activity levels (% of normal or IU/dL) during the corresponding time period. The table below provides recommended dosage regimens for bleeding episodes and surgical procedures:

Prophylaxis
For long-term prophylactic treatment against bleeding in patients with
severe hemophilia A, the usual dose is 20 to 40 IU of factor VIII per kilogram
of body weight administered every 2 to 3 days. In some cases, particularly in younger
patients, more frequent administration or higher doses may be required.
Children and adolescents
Dosing in children depends on body weight; therefore, the dose is determined
on the same basis as in adults. The frequency of administration should always be set
individually, depending on clinical efficacy. Cases of treatment in children younger
than 6 years of age have been reported.
Information on pharmacological properties of VWF
In addition to its role as a protective protein for factor VIII, von Willebrand factor mediates
platelet adhesion at the site of vessel injury and plays a role in platelet aggregation.