Prospecto: Information for the user

Beriplex 500 UI

Powder and solvent for injectable solution

Human prothrombin complex

1. What isBeriplexand for what it is used

2. What you need to know before starting touse Beriplex

3. Howto use Beriplex

4. Possible adverse effects

5. Storage ofBeriplex

6. Contents of the package and additional information

What is Beriplex

Beriplex is presented in the form of powder and solvent. It is a white or slightly colored or friable solid powder. The prepared solution must be administered through an injection into a vein.

Beriplex is prepared from human plasma (the liquid part of the blood) and contains human coagulation factors II, VII, IX, and X. Concentrates containing these coagulation factors are called prothrombin complex products. Coagulation factors II, VII, IX, and X are vitamin K-dependent and are important for blood coagulation. The lack of any of these factors means that the blood does not clot as quickly as it should and there is an increased tendency to bleed. The substitution of coagulation factors II, VII, IX, and X with Beriplex repairs the coagulation mechanisms.

What is Beriplex used for

Beriplex is used for the prophylaxis (during surgery) and treatment of bleeding caused by acquired or congenital deficiency of vitamin K-dependent coagulation factors, i.e., coagulation factors II, VII, IX, and X in the blood, when purified products of the specific coagulation factor are not available.

The following sections contain information that your doctor should consider before administering Beriplex to you.

Do not use Beriplex

• If you are allergic to the active ingredients or to any of the other components of this medication (listed in section6).

Inform your doctor if you are allergic to any medication or food.

• If you are more prone to blood clots than usual (patients at risk of disseminated intravascular coagulation).
• If you show an allergic reaction to heparin that causes a decrease in blood platelets (heparin-induced thrombocytopenia type II, HIT type II).

Inform your doctor or pharmacist if you have any of these conditions.

Warnings and precautions

Consult your doctor or pharmacist before starting to use Beriplex in case of:

• Acquired deficiency of vitamin K-dependent coagulation factors: this may be induced by medications that inhibit the effect of vitamin K. Beriplex should only be used when rapid correction of prothrombin complex levels is necessary, for example, in cases of severe bleeding or emergency surgery.
• Congenital deficiency of any of the vitamin K-dependent coagulation factors: in this case, you should use specific coagulation factor products if available.
• Allergic or anaphylactic reactions (a severe allergic reaction that causes significant difficulty breathing or dizziness):immediately discontinue Beriplex administration (e.g., interrupt the injection).
• Increased risk of blood clots in a blood vessel (thrombosis), especially:
• • If you have had a heart attack (history of coronary artery disease or myocardial infarction).
  • If you have any liver disease.
  • If you have recently undergone surgery (patients in the pre- or postoperative period).
  • In newborns (neonates).
  • If you are more prone to blood clots than usual (patients at risk of thromboembolic episodes or disseminated intravascular coagulation or simultaneous deficiency of coagulation inhibitors).
• Increased risk of coagulation due to increased consumption of platelets or coagulation factors. Beriplex treatment can only be initiated once the underlying cause has been treated.
• Decreased platelet generation due to heparin (heparin-induced thrombocytopenia, HIT type II). The heparin, a protein that has a dissolving effect on blood clots, is a component of Beriplex. Severe platelet decrease may be associated with:
• • Blood clots in a vein or leg,
  • increased blood clot formation,
  • in some cases, skin rash at the injection site,
  • petechiae (hemorrhages in the form of points), and

-black stools

In these cases, the effect of heparin may be reduced (heparin tolerance). If you experience these symptoms, discontinue the product immediately and inform your doctor. In the future, you should not use products containing heparin.

• A special form of kidney inflammation has been reported after treatment in patients with hemophilia B with factor IX inhibitors. It was known that these patients had a history of allergic reactions.

Your doctor will carefully weigh the benefits of Beriplex treatment against the risk of these complications.

Viral safety

When preparing medications from human blood or plasma, certain measures are taken to prevent the transmission of infections to patients. These measures include:

• A careful selection of blood and plasma donors to ensure that those with a risk of being carriers of infections are excluded,
• The analysis of each donation and plasma mixtures to detect signs of viruses or infections,
• The inclusion of steps in the processing of blood or plasma that can inactivate or eliminate viruses.

Despite these measures, when administering medications prepared from human blood or plasma, it cannot be completely ruled out that an infection may be transmitted. This is also true for unknown or emerging viruses.

The measures applied are considered effective for viruses with a coat, such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus (liver inflammation), and for the non-enveloped hepatitis A virus and parvovirus B19.

Your doctor may recommend hepatitis A and B vaccination if you are treated periodically/repeatedly with human plasma-derived prothrombin complex products.

It is strongly recommended that each time you receive a dose of Beriplex, the name and batch number of the medication be noted, in order to maintain a record of the batches used.

Use of Beriplex with other medications

• Inform your doctor or pharmacist that you are using or have recently used or may need to use any other medication.
• Beriplex may inhibit the effect of vitamin K antagonist treatment. No interactions with other medications are known.
• This medication should not be mixed with other medications, except those mentioned in section 6.

Pregnancy, breastfeeding, and fertility

• If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medication.
• Beriplex should only be used during pregnancy and breastfeeding if clearly indicated.
• No data are available on fertility.

Driving and operating machinery

No studies have been conducted on the ability to drive or operate machinery.

Beriplex contains sodium

Patients on low-sodium diets should note that this medication contains up to 343 mg of sodium (approximately 15 mmol) per 100 ml. This should be taken into account by patients on controlled sodium diets.

Treatment must be initiated and supervised by a doctor with experience in treating this type of disorder.

Dosage

The amount of Factor II, VII, IX and X you need and the duration of treatment will depend on various factors, such as your body weight, the severity and nature of your illness, the location and severity of the bleeding or the need to prevent bleeding during an operation or investigation (see the section“This information is intended solely for healthcare professionals”).

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Overdose

Your doctor should periodically examine your blood coagulation status during treatment. High doses of prothrombin complex concentrate have been associated with episodes of heart attacks, disseminated intravascular coagulation and increased formation of blood clots in blood vessels in patients at risk of these complications.

Like all medications, this medication may cause adverse effects, although not everyone will experience them.

The following adverse effects have been observedfrequently(may affect up to 1 in 10 patients):

• There is a risk ofblood clot formation(see section 2).
• Headache.
• Increased body temperature.

The following adverse effects occurred withlow frequency(may affect up to 1 in 100 patients):

• Hypersensitivity or allergic reactions(see section 2).

The frequency of the following adverse effects isunknown(cannot be estimated with the available data):

• Excessive coagulation resulting in severe bleeding.
• Anaphylactic reactionsincluding shock (see section 2).
• Development of circulating antibodiesthat inhibit one or more coagulation factors.

Pediatric Population

No data are available on the use of Beriplex in the pediatric population.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

• Keep this medication out of the sight and reach of children.
• Do not use this medication after the expiration date that appears on the label and on the packaging after EXP.

• Do not store at a temperature above 25 °C.
• Do not freeze.
• Store the packaging in the outer packaging to protect it from light.
• Beriplex does not contain preservatives, so it is preferable to use the prepared solution immediately.

Medications should not be disposed of through drains or in the trash. If in doubt, ask your pharmacist how to dispose of unused packaging and medications. By doing so, you will help protect the environment..

Composition of Beriplex

Beriplex 500 UI contains 400 – 620 UI of human coagulation factor IX per vial.

The active principle is:

A concentrate of human coagulation factors II, VII, IX, and X, Proteins C and S.

The other components are:

Human antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or NaOH (in small quantities to adjust the pH).

Disolvent:Water for injection.

Aspect of the product and content of the package

Beriplex is presented as a white or slightly colored powder and is supplied with water for injection as a solvent. The powder must be dissolved in 20 ml of water for injection.

The prepared solution must be transparent or slightly opalescent, i.e., it may present bubbles when placed in front of the light but must not contain detectable particles.

Presentation

A package with 500 UI that contains:

-1 vial with powder

-1 vial with 20 ml water for injection

-1 filter transfer set with 20/20 filter

Holder of the marketing authorization and responsible for manufacturing

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

CSL Behring, S.A.

c/ Tarragona 157, planta 18

08014 Barcelona. Spain

This medicinal product is authorized in the member states of the European Economic Area with the following names:

Last review date of this leaflet: July 2017

The detailed and updated information about this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)

http://www.aemps.gob.es

This information is intended solely for healthcare professionals:

Qualitative and quantitative composition

The nominal content of human coagulation factors is expressed in the following table, expressed in UI:

The total content in proteins is 6 – 14 mg/ml of reconstituted solution.

The specific activity expressed in factor IX is 2.5 UI/mg of total protein.

The activity of all coagulation factors, as well as proteins C and S (antigen), has been tested according to the current international standards established by the World Health Organization (WHO).

Dosage and method of administration

Dosage

The following dosage guidelines are only general.

The dosage and administration frequency will be established on an individual basis for each patient. The dosing intervals must be adapted to the circulating half-lives of the respective coagulation factors in the complex of prothrombin. Individual dosing requirements can only be identified based on periodic determinations of plasma levels of the coagulation factors in question, or global analysis of the levels of the complex of prothrombin (INR, Quick test) and continuous monitoring of the patient's clinical situation.

In the case of major surgery, precise monitoring of substitution therapy is essential, using coagulation analysis (specific tests for coagulation factors and/or global analysis to measure levels of the complex of prothrombin).

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

The dosage will depend on the INR value before treatment and the desired INR value. The INR value before treatment should be taken as close as possible to the time of administration to calculate the appropriate dose of Beriplex. The following table shows approximate doses (ml of reconstituted solution product/kg body weight and UI of Factor IX/kg body weight) required to normalize INR (e.g. <1.3) at different initial INR levels.

The dose is based on body weight up to, but not exceeding 100 kg. For patients with a body weight exceeding 100 kg, the maximum single dose (UI of Factor IX) must not exceed 2,500 UI for an INR of 2.0 – 3.9, 3,500 UI for an INR of 4.0 – 6.0, and 5,000 UI for an INR > 6.0.

Correction of the bleeding disorder induced by vitamin K antagonists is usually achieved approximately 30 minutes after injection. Administration of vitamin K should be considered in patients treated with Beriplex for urgent neutralization of vitamin K antagonists, as the effect of vitamin K is usually achieved within 4-6 hours. Repeated administration of Beriplex in patients requiring urgent treatment for neutralization of vitamin K antagonists is not recommended, as it is not supported by clinical data.

These recommendations are based on clinical trial data with a limited number of individuals. Recovery and duration of effect may vary, so INR monitoring during treatment is mandatory.

• Bleeding and perioperative prophylaxis in congenital deficiency of some vitamin K-dependent coagulation factors, when specific factor products are not available.

The calculation of the required dose of the prothrombin complex concentrate is based on clinical trial data:

?1 UI of factor IX per kilogram of body weight can increase plasma activity of factor IX by 1.3% (0.013 UI/ml) of normal activity.

?1 UI of factor VII per kg of body weight increases plasma activity of factor VII by 1.7% (0.017 UI/ml) of normal activity.

?1 UI of factor II per kg of body weight increases plasma activity of factor II by 1.9% (0.019 UI/ml) of normal activity.

?1 UI of factor X per kg of body weight increases plasma activity of factor X by 1.9% (0.019 UI/ml) of normal activity.

The dosage of a specific factor administered is expressed in International Units (UI), which are related to the current WHO standard for each factor. Plasma activity of a specific coagulation factor is expressed either as a percentage (relative to normal plasma) or in International Units (relative to the international standard for the specific coagulation factor).

One International Unit (UI) of activity of a coagulation factor is equivalent to the amount contained in 1 ml of normal human plasma.

For example, the calculation of the required dose of factor X is based on the finding that 1 International Unit (UI) of factor X per kilogram of body weight increases plasma activity of factor X by 0.019 UI/ml.

The required dose is determined using the following formula:

Units required = body weight [kg] x desired increase in factor X [UI/ml] x 53, where 53 (ml/kg) is the reciprocal of the estimated recovery.

It should be noted that the calculation is based on data from patients receiving vitamin K antagonists. A calculation based on data from healthy volunteers would provide an estimate lower than the required dose.

If individual recovery is known, this value should be used in the calculation.

Specific information about the product from clinical trials with healthy volunteers (N = 15), neutralization of vitamin K antagonists in the treatment of severe bleeding or perioperative prophylaxis of bleeding (N = 98, N = 43) is available.

Pediatric population

The safety and efficacy of Beriplex in children and adolescents have not been established through controlled clinical trials.

Geriatric population

The dosage and administration in elderly patients (over 65 years) correspond to general recommendations.

Method of administration

General instructions

-The solution must be transparent or slightly opalescent. After filtration/extraction (see below), and before administration, the reconstituted product must be visually inspected to detect the presence of foreign particles and discoloration.

Do not use turbid or particle-containing solutions.

-Reconstitution and extraction must be performed under aseptic conditions.

Reconstitution

Bring the solvent to room temperature. Check that the product and solvent vials have been removed from their packaging and that the stoppers have been treated with an antiseptic solution, allowing it to dry before opening the package of the Mix2Vial device.

Extraction and administration

Care must be taken to prevent blood from entering the syringe loaded with the product, as there is a risk of fibrin clots forming in the syringe and being administered to the patient.

If more than one vial of Beriplex is needed, it is possible to group several vials of Beriplex in a single infusion using a perfusion accessory available on the market.

Beriplex solution must not be diluted.

The reconstituted solution must be administered intravenously (at a maximum of 8 ml/min*).

Elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Special warnings and precautions for use

No data are available on the use of Beriplex in the case of perinatal hemorrhage due to vitamin K deficiency in neonates.

Guidelines for platelet count control:

Carefully monitor platelet count.

Interaction with other medications and other forms of interaction

When performing coagulation tests sensitive to heparin, in patients treated with high doses of human prothrombin complex, consideration should be given to the heparin contained in the product administered.

*In clinical trials with Beriplex, doses were administered at a maximum infusion rate of 0.12 ml/kg/min to patients with a weight <70