Beriplex p/n 500

Beriplex P/N 500
Powder and solvent for solution for injection
Human prothrombin complex concentrate
Please read the entire leaflet carefully before using this medicine, as it contains
important information for the patient.

• Keep this leaflet for future reference
• Consult your doctor or pharmacist if you have any further questions
• This medicine has been prescribed for a specific individual. Do not share it with others.
• This medicine may harm other individuals, even if their symptoms appear identical.
• If any adverse reactions occur, including any possible adverse reactions not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Leaflet contents:

1. What Beriplex P/N 500 is and what it is used for
2. Important information before using Beriplex P/N 500
3. How to use Beriplex P/N 500
4. Possible side effects
5. How to store Beriplex P/N 500
6. Contents of the pack and other information

1. What Beriplex P/N 500 is and what it is used for

What Beriplex P/N 500 is
Beriplex P/N 500 is available as a powder with a solvent supplied separately. It is a white or slightly coloured powder or a friable solid mass. The reconstituted solution is intended for intravenous injection.
Beriplex P/N 500 is manufactured from human plasma (the liquid portion of blood) and contains human clotting factors II, VII, IX, and X. Concentrates containing these clotting factors are known as prothrombin complex products. Vitamin K-dependent clotting factors II, VII, IX, and X play an important role in the blood coagulation process. Deficiency of any of these clotting factors results in delayed blood clotting and an increased risk of bleeding. Replacement of clotting factors II, VII, IX, and X by administration of Beriplex P/N 500 helps restore normal coagulation mechanisms.

Why Beriplex P/N 500 is used
Beriplex P/N 500 is used to prevent (during surgical procedures) and treat bleeding caused by acquired or congenital deficiency of vitamin K-dependent clotting factors II, VII, IX, and X in blood, when a medicine containing purified, specific clotting factor is not available.

2. Important information before using Beriplex P/N 500

The following section contains information that both the patient and physician should review before using Beriplex P/N 500.

When NOT to use Beriplex P/N 500:

• if the patient is allergic to the active substances or any of the other ingredients of this medicine (listed in section 6).
• The physician should be informed about any allergies to medicines or food.
• if there is an increased risk of thrombosis (patients at risk of disseminated intravascular coagulation).
• in case of an allergic reaction to heparin causing a reduced platelet count (heparin-induced thrombocytopenia type II, HIT type II).

The physician or pharmacist should be informed if such a condition is present.

Warnings and precautions

Before starting treatment with Beriplex P/N 500, discuss this with your doctor or pharmacist.

• In cases of acquired deficiency of vitamin K-dependent coagulation factors, which may result from taking vitamin K antagonists. Beriplex P/N 500 may be used only when rapid correction of prothrombin complex factor levels is required, for example in cases of severe bleeding or emergency surgery.
• In cases of congenital deficiency of any vitamin K-dependent coagulation factor, a product containing the specific coagulation factor should be used whenever possible.
• If an allergic or anaphylactic reaction (a serious allergic reaction causing severe breathing problems or dizziness) occurs: Administration of Beriplex P/N 500 must be stopped immediately (e.g. stop the injection).
• If there is a risk of increased thrombosis (blood clot formation) in blood vessels, particularly in the following cases:
  • in patients after myocardial infarction (with diagnosed coronary artery disease or myocardial infarction)
  • in patients with liver disease
  • in patients immediately before and after surgical procedures
  • in newborns
  • in patients with an increased risk of thrombosis (patients at risk of thromboembolic disease or disseminated intravascular coagulation, or with spontaneous deficiency of coagulation inhibitors)
• If there is an increased risk of coagulation disorders caused by increased consumption of platelets or coagulation factors. Treatment with Beriplex P/N 500 may be initiated only after treatment of the underlying disease has been completed.
• Heparin-induced reduction in platelet production (heparin-induced thrombocytopenia, HIT type II). Heparin, a protein that acts to dissolve blood clots, is a component of Beriplex P/N 500. A significant decrease in platelet count may be associated with:
  • formation of thrombi in the veins of the lower limbs,
  • increased tendency to form clots,
  • in some cases, skin rash at the injection site,
  • petechiae, and
  • presence of tarry stools. In such cases, heparin activity may be impaired (heparin tolerance). If these symptoms occur, administration of the drug must be stopped immediately and the physician should be contacted. Heparin-containing medications should not be used in the future.
• A specific form of nephritis has been reported after treatment of patients with hemophilia B who have inhibitors to factor IX. These patients had a history of allergic reactions.

The physician should weigh the benefits of therapy with Beriplex P/N 500 against the risk of the complications listed above.

Viral safety

When medicines are derived from human blood or human plasma, various methods are used to prevent transmission of infectious agents to the patient. These include:

• careful selection of blood and plasma donors to exclude the possibility of transmission of infectious agents,
• testing individual donors and pooled plasma for the presence of viruses and other infections,
• inclusion of steps in the manufacturing process designed to inactivate or remove viruses.

Despite these safeguards, when using medicines derived from human blood or plasma, it cannot be completely ruled out that infectious diseases may occur due to possible transmission of infectious agents. This also applies to pathogens not yet known and other types of infections.

The methods used are considered effective against enveloped viruses such as human immunodeficiency virus (HIV, the virus causing AIDS), hepatitis B virus, hepatitis C virus (viral hepatitis), and the non-enveloped hepatitis A virus (viral hepatitis) and parvovirus B19.

The physician may recommend appropriate vaccination against hepatitis A and B if medicines derived from human plasma are used regularly or repeatedly.

It is strongly recommended that each time Beriplex P/N 500 is administered, the name and batch number of the medicine be recorded in the patient's medical records to document the batches used.

Beriplex P/N 500 and other medicines

• Inform your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines the patient intends to take.
• Beriplex P/N 500 may inhibit the action of vitamin K antagonists. Interactions with other medicines are not known.
• Beriplex P/N 500 must not be mixed with other medicines, except those mentioned in section 6.

Pregnancy, breastfeeding and fertility

• During pregnancy or breastfeeding, or if pregnancy is suspected or planned, consult a doctor or pharmacist before using this medicine.
• Beriplex P/N 500 should be used in women during pregnancy or breastfeeding only when clearly indicated.
• There are no available data on the effect on fertility.

Driving and using machines
There are no adequate studies documenting the effect of this medicine on the ability to drive vehicles or operate machinery.

Beriplex P/N 500 contains sodium
Beriplex P/N 500 contains up to 343 mg of sodium (approximately 15 mmol) per 100 ml. This amount should be taken into account in patients on a controlled sodium diet.

3. How to use Beriplex P/N 500

Treatment should be initiated under the supervision of a physician experienced in the therapy of this type of disorder.
Dosage
The recommended dose of factors II, VII, IX and X, and the duration of treatment, depend on several factors, such as body weight, severity and course of the disease, location and intensity of bleeding, and the need to prevent bleeding during surgery or diagnostic procedures (see section “Information intended exclusively for healthcare professionals”).
If you have any doubts regarding the use of this medicine, please contact your doctor or pharmacist.
Overdose
During treatment, the physician should regularly monitor coagulation parameters.
Administration of high doses of prothrombin complex concentrate has been associated with myocardial infarction, development of disseminated intravascular coagulation, and formation of blood clots in blood vessels in patients at increased risk of these disorders.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.

The following adverse reactions have been observed frequently (in less than 1 in 10 patients):

• Risk of increased thrombosis (see section 2)
• Headache
• Increase in body temperature

The following adverse reactions have been observed uncommonly (in less than 1 in 100 patients):

• Hypersensitivity or allergic reactions (see section 2)

The frequency of the following adverse reactions is unknown (cannot be estimated from the available data):

• Severe bleeding due to excessive coagulation
• Anaphylactic reactions including anaphylactic shock (see section 2)
• Formation of circulating antibodies inhibiting one or more coagulation factors

Children and adolescents
There is a lack of data on the use of Beriplex in children and adolescents.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. 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 may also be reported to the marketing authorization holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Beriplex P/N 500

• Keep the medicine out of the sight and reach of children.
• Do not use Beriplex P/N 500 after the expiry date stated on the label and carton.
• Do not store above 25°C.
• Do not freeze.
• Store the vial in the outer packaging to protect from light.
• Beriplex P/N 500 does not contain preservatives; the reconstituted product should be used immediately.

6. Contents of the pack and other information

What Beriplex P/N 500 contains
Beriplex P/N 500 contains 400–620 IU of human blood coagulation factor IX per vial.
The active substance is:
Concentrate of human coagulation factors II, VII, IX and X, protein C and S.
The other components are:
Human antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or NaOH
(in small amounts, for pH adjustment).
Solvent: Water for injections.

What Beriplex P/N 500 looks like and contents of the pack
Beriplex P/N 500 is a white or slightly coloured powder supplied with water for injections as solvent.
The powder should be dissolved in 20 ml of water for injections.
The resulting solution should be clear or slightly opalescent (may shimmer when viewed under light), and must not contain any solid particles.

Available pack sizes
The 500 IU pack contains:

• 1 vial of powder
• 1 vial of water for injections (20 ml)
• 1 transfer system 20/20 with filter

Name and address of the marketing authorisation holder and name and address of the manufacturer:
CSL Behring GmbH
Emil-von-Behring-Str. 76
35041 Marburg
Germany

This medicinal product is authorised for sale in the European Economic Area under the following names:
Austria Beriplex P/N 500 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung
Belgium Confidex 500 I.E., poeder en oplosmiddel voor oplossing voor injectie
Bulgaria Beriplex P/N 500, 500 IU, Powder and solvent for solution for injection
Croatia Beriplex P/N 500 IU prašak i otapalo za otopinu za injekciju
Czech Republic Beriplex 500 IU
Denmark Confidex
Finland Confidex 500 IU injektiokuiva-aine ja liuotin, liuosta varten
France Confidex 500 UI, poudre et solvant pour solution injectable
Germany Beriplex P/N 500
Greece Beriplex P/N
Κόνις και διαλύτης για ενέσιμο διάλυμα 500 IU/vial
Hungary Beriplex P/N 500 por és oldószer oldatos injekcióhoz
Ireland
Beriplex P/N 500 IU, powder and solvent for solution for injection
Italy Confidex 500
Luxembourg Confidex 500 UI poudre et solvant pour solution injectable
Malta Beriplex P/N 500, powder and solvent for solution for injection
Netherlands Beriplex P/N 500 IE, poeder en oplosmiddel voor oplossing voor injectie
Norway Confidex 500 IU pulver og væske til injeksjonsvæske, oppløsning
Poland
Beriplex P/N 500
Portugal Beriplex 500 UI pó e solvente para solução injectável
Romania Beriplex P/N 500 UI pulbere și solvent pentru soluție injectabilă
Slovakia Beriplex 500 IU
Slovenia Beriplex P/N 500 i.e. prašek in vehikel za raztopino za injiciranje
Spain Beriplex 500 UI polvo y disolvente para solución inyectable
Sweden Confidex 500 IE, pulver och vätska till injektionsvätska, lösning
United Kingdom Beriplex P/N 500 IU, powder and solvent for solution for injection

Date of preparation of the leaflet:

Information intended exclusively for medical professionals

Qualitative and quantitative composition
Beriplex P/N 500 nominally contains the following amounts of I.U. of human coagulation factors, as stated
in the table below:

The total protein content after reconstitution is 6–14 mg/ml in solution.
The specific activity of factor IX is 2.5 IU per mg of total protein.
The activity of all coagulation factors as well as proteins C and S (antigens) has been tested according to current WHO international standards.

Dosage and method of administration
Dosage
The following provides only general dosage guidelines.
The dose and frequency of administration should be individually calculated for each patient. The intervals between doses should be adjusted according to the half-life of the individual coagulation factors belonging to the prothrombin complex. The individual dose is determined based on regular measurements of plasma activity of individual coagulation factors, or on the basis of laboratory test results generally assessing the function of the prothrombin complex (INR, Quick's index), and through continuous monitoring of the patient's clinical status.
In the case of major surgical procedures, careful monitoring of substitution therapy is required (tests for individual coagulation factors as well as general tests for prothrombin complex factors).

• Bleeding and perioperative bleeding prophylaxis during treatment with vitamin K antagonists:

The dose of the medicinal product depends on the INR value measured before starting treatment and the target INR value to be achieved by the patient. The pre-treatment INR should be measured as close as possible to the time of administration to allow accurate calculation of the required dose of Beriplex. The table below provides approximate doses (ml/kg body weight of reconstituted product and IU of factor IX/kg body weight) required to achieve normalization of the INR (i.e., INR ≤1.3) at various initial INR values.

Dosing is based on body weight when it does not exceed 100 kg. In patients with body weight above 100 kg, the maximum single dose (IU of factor IX) should not exceed 2500 IU for INR values of 2.0–3.9; 3500 IU for INR values of 4.0–6.0; and 5000 IU for INR values >6.0.
Normalization of coagulation disorders caused by vitamin K antagonists is usually achieved within approximately 30 minutes after injection. Concomitant administration of vitamin K should be considered in patients receiving Beriplex for urgent reversal of vitamin K antagonists, since the effect of vitamin K is typically observed after 4–6 hours.
Repeated dosing of Beriplex in patients requiring urgent reversal of vitamin K antagonists is not supported by clinical studies and therefore is not recommended.
These recommendations are based on clinical studies conducted in a limited number of subjects. Monitoring of INR values during treatment is necessary, as efficacy and duration of action may vary among individual patients.

• Bleeding and perioperative prophylaxis in patients with congenital deficiencies of any vitamin K-dependent clotting factor when specific factor concentrate is not available

Calculation of the required dose of prothrombin complex concentrate based on clinical studies:

• 1 IU of factor IX per kg of body weight results in an expected increase in plasma factor IX activity of 1.3% (0.013 IU/mL) relative to normal,
• 1 IU of factor VII per kg of body weight increases plasma factor VII activity by 1.7% relative to normal (0.017 IU/mL),
• 1 IU of factor II per kg of body weight increases plasma factor II activity by 1.9% relative to normal (0.019 IU/mL),
• 1 IU of factor X per kg of body weight increases plasma factor X activity by 1.9% relative to normal (0.019 IU/mL).

The dose of each clotting factor is expressed in international units (IU), consistent with the official standard for each clotting factor approved by the World Health Organization (WHO). Clotting factor activity in plasma is expressed as a percentage (relative to normal human plasma) or in international units (according to the international standard for the specific clotting factor in plasma).
One international unit (IU) of clotting factor activity corresponds to the activity of that factor present in 1 mL of normal human plasma.
For example, the calculation of the required dose of factor X is based on the empirical observation that 1 IU of factor X per kg of body weight increases plasma factor X activity by 0.019 IU/mL.
The required dose is calculated using the following formula:
Required number of units = body weight [kg] × desired increase in factor X activity [IU/mL] × 53,
where 53 (mL/kg) is the reciprocal of the estimated recovery value.
It should be noted that these calculations are based on data from patients receiving vitamin K antagonists. Calculations based on data from healthy individuals would yield a lower required dose.
If an individual recovery value is known, it should be used for calculations.
Product data are available from clinical studies conducted in healthy volunteers (N=15), and in the reversal of vitamin K antagonist effects in the treatment of acute major bleeding or perioperative bleeding prophylaxis (N=98, N=43).

Children and adolescents
The safety and efficacy of the medicinal product Beriplex P/N 500 in children and adolescents have not yet been established in controlled clinical trials.

Elderly patients
Dosing and administration in elderly patients (>65 years of age) are consistent with general recommendations.

Administration instructions

General instructions

• The solution should be clear or slightly opalescent. After filtration and withdrawal of the reconstituted solution (see below), before administration, visually inspect the solution for particles or discoloration. Do not use solutions that are cloudy or contain sediment or particles.
• Reconstitution and withdrawal from the vial must be performed under aseptic conditions.

Reconstitution
Allow the solvent to reach room temperature.
Ensure that the caps of the vials containing the powder and the solvent have been removed, disinfect the rubber stoppers with an aseptic solution, and allow them to dry before opening the Mix2Vial package.

1	1. Open the packaging containing the Mix2Vial by removing the protective foil. Do not remove the Mix2Vial from the blister.
2	2. Place the vial containing the solvent on a clean, flat surface and hold it firmly. Without removing the Mix2Vial from the blister, place the blue-ended needle part of the Mix2Vial system onto the solvent vial's stopper and press vertically downward to pierce the stopper of the solvent vial.
3	3. Holding the edge of the Mix2Vial system, carefully remove the blister by pulling it vertically upward. Take care to remove only the blister, not the entire Mix2Vial assembly.
4	4. Firmly hold the vial containing the medicinal product on a clean, flat surface. Invert the solvent vial with the attached Mix2Vial system and place the transparent connector part onto the stopper of the medicinal product vial. Press vertically downward to pierce the stopper of the medicinal product vial. The solvent will automatically transfer into the vial containing the medicinal product.
5	5. Hold the vial with the medicinal product attached to the Mix2Vial system with one hand, and with the other hand hold the solvent vial also attached to the Mix2Vial system, and gently unscrew the assembly in a counterclockwise direction into two parts. Remove the solvent vial together with the blue end of the Mix2Vial system.
6	6. Gently swirl the vial containing the medicinal product with the attached transparent end of the Mix2Vial system to ensure complete dissolution of the product. Do not shake.
7	7. Draw air into an empty sterile syringe. Holding the medicinal product vial upright with the stopper facing upward, attach the syringe to the Luer Lock connector of the Mix2Vial system by turning it clockwise. Inject air into the medicinal product vial.

Administration and administration

8	8. Holding the syringe plunger, turn the vial with the syringe upside down and slowly draw the solution into the syringe by pulling back the plunger.
9	9. After filling the syringe with the solution, firmly grasp the syringe barrel (keeping the syringe with the plunger facing downward) and disconnect the Mix2Vial system from the syringe by turning counterclockwise.

Care should be taken to ensure that blood does not enter the syringe filled with the product. This could cause a reaction of the clotting factors present in the product and formation of fibrin clots, which may be administered to the patient.
If more than one vial of Beriplex product is required, it is possible to combine several vials for administration as a single infusion using a commercially available administration set.
The Beriplex medicinal product solution must not be diluted.
The reconstituted solution should be administered intravenously (no faster than 8 ml/min*).
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
Special warnings and precautions for use.
There are no available clinical data on the use of Beriplex P/N 500 in the treatment of perinatal haemorrhage due to vitamin K deficiency in newborns.
_________________________________________________
*In clinical trials of Beriplex, patients weighing less than 70 kg had a recommended dosage with a maximum infusion rate of 0.12 ml/kg/min (below 8 ml/min).
Notes regarding platelet count monitoring:
Platelet count should be closely monitored.
Interactions with other medicinal products and other forms of interactions
When performing coagulation tests sensitive to the presence of heparin, the dose of heparin contained in the product should be taken into account in the test results obtained from patients receiving high doses of prothrombin complex factors.