BERIPLEX 1000 IU POWDER AND SOLVENT FOR INJECTABLE SOLUTION

2. What you need to know before you use Beriplex

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 substances or to any of the other ingredients of this medicine (listed in section 6).

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

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

Tell your doctor or pharmacist if you have any of these diseases.

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, e.g., in case of severe bleeding or emergency surgery.
• Congenital deficiency of any of the vitamin K-dependent factors: in this case, you should use specific coagulation factor products if available.
• Allergic reactions or anaphylactic reactions (a severe allergic reaction that causes significant difficulty breathing or dizziness): administration of Beriplex should be stopped immediately (e.g., by stopping the injection).
• Increased risk of blood clot formation in a blood vessel (thrombosis), especially:
• • If you have had a heart attack (history of coronary heart disease or myocardial infarction).
  • If you have liver disease.
  • If you have recently undergone surgery (pre- or post-operative patients).
  • In newborns (neonates).
  • If you are more prone to blood clot formation than usual (patients at risk of thromboembolic events or disseminated intravascular coagulation or simultaneous deficiency of coagulation inhibitor).
• Increased risk of coagulation due to increased consumption of platelets or blood coagulation factors. Treatment with Beriplex should only be started once the underlying cause has been treated.
• Decreased platelet production due to heparin (heparin-induced thrombocytopenia, HIT type II). Heparin, a protein with a blood clot-dissolving effect, is a component of Beriplex. Severe platelet count decrease can be associated with
• • blood clots in a vein or leg,
  • increased blood clot formation,
  • skin rash at the injection site,
  • petechiae (bleeding spots), and

• black stools (melena)

In these cases, the effect of heparin may be diminished (heparin tolerance). If such symptoms occur, you should stop using 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 and factor IX inhibitors. It was known that these patients had a history of allergic reactions.

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

Viral safety

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

• careful selection of blood and plasma donors to ensure that those who may be at risk of carrying infections are excluded,
• testing of each donation and plasma pools for signs of viruses or infections,
• inclusion of steps in the processing of blood or plasma that can inactivate or eliminate viruses.

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

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

It is possible that your doctor may recommend vaccination against hepatitis A and B if you are treated periodically/repeatedly with prothrombin complex products derived from human plasma.

It is strongly recommended that each time you are administered a dose of Beriplex, the name and batch number of the medicine should be recorded, in order to maintain a record of the batches used.

Using Beriplex with other medicines

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

Pregnancy, breast-feeding, and fertility

• If you are pregnant or breast-feeding, or think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
• During pregnancy and breast-feeding, Beriplex should only be used if clearly indicated.
• No data are available on fertility.

Driving and using machines

No studies have been performed on the ability to drive or use machinery.

Beriplex contains sodium

Patients on low-sodium diets should be aware that this medicine contains up to 343 mg of sodium (approximately 15 mmol) per 100 ml. This should be taken into account for patients on a controlled sodium diet.

3. How to use Beriplex

Treatment should be initiated and supervised by a doctor experienced in the treatment of 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 disease, the location and severity of the bleeding, or the need to prevent bleeding during surgery or investigation (see the section “This information is intended for healthcare professionals only”).

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

Overdose

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

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

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

The following side effects have been observed with infrequentfrequency (may affect up to 1 in 100 patients):

• Hypersensitivity or allergic reactions (see section 2).

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

• Excessive coagulation resulting in severe bleeding.
• Anaphylactic reactions including shock (see section 2).
• Development of circulating antibodies that inhibit one or more coagulation factors.

Pediatric population

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

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report side effects directly to the Spanish Medicines Agency: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Beriplex

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the label and carton after EXP.

• Do not store above 25°C.
• Do not freeze.
• Keep the container in the outer carton to protect it from light.
• Beriplex does not contain preservatives, so the prepared solution should be used immediately.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container Content and Additional Information

Composition of Beriplex

Beriplex 1000 IU contains 800 – 1240 IU of human coagulation factor IX per vial.

The active principle is:

A concentrate of human coagulation factors II, VII, IX, and X, and 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).

Solvent:Water for injectable preparations.

Product Appearance and Container Content

Beriplex is presented as a white or slightly colored powder and is supplied with water for injectable preparations as a solvent. The powder must be dissolved in 40 ml of water for injectable preparations.

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

Presentation

A container with 1000 IU that contains:

• 1 vial with powder
• 1 vial with 40 ml water for injectable preparations
• 1 transfer device with a 20/20 filter

Marketing Authorization Holder and Manufacturer

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

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

CSL Behring, S.A.

c/ Tarragona 157, 18th floor

08014 Barcelona.

Spain

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Date of the last revision of this leaflet:July 2017

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

This information is intended exclusively for healthcare professionals:

Qualitative and Quantitative Composition

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

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

The specific activity expressed in factor IX is 2.5 IU/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).

Posology and Method of Administration

Posology

The following dosage guidelines are of a general nature only.

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

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

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

The dosage will depend on the INR value before treatment and the INR value to be achieved. The INR value before treatment should be taken as close as possible to the time of administration to calculate the adequate dose of Beriplex. The following table provides approximate doses (ml of reconstituted solution product/kg of body weight and IU of Factor IX/kg of body weight) required to normalize the 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 whose body mass exceeds 100 kg, the maximum single dose (IU of Factor IX) should not exceed 2,500 IU for an INR of 2.0 – 3.9, 3,500 IU for an INR of 4.0 – 6.0, and 5,000 IU for an INR > 6.0.

Correction of the hemostasis disorder induced by vitamin K antagonists is usually achieved approximately 30 minutes after injection. Simultaneous administration of vitamin K should be considered in patients treated with Beriplex for the urgent neutralization of vitamin K antagonists, as the effect of vitamin K is normally achieved after 4 to 6 hours. Repeated administration of Beriplex is not recommended in patients who require urgent neutralization of vitamin K antagonists, as it is not supported by clinical data.

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

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

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

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

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

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

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

The dosage of a specific factor administered is expressed in International Units (IU), which are related to the current WHO standard for each factor. The 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 (IU) of coagulation factor activity 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 (IU) of factor X per kg of body weight increases plasma activity of factor X by 0.019 IU/ml.

The required dose is determined using the following formula:

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

Note that the calculation is based on data from patients who received vitamin K antagonists. A calculation based on data from healthy volunteers would provide a lower estimate of the required dose.

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

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

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 method of administration in elderly patients (over 65 years) correspond to the 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 for the presence of foreign particles and discoloration.
• Do not use cloudy solutions or those containing residues.
• Reconstitution and extraction must be performed under aseptic conditions.

Reconstitution

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

Extraction and Administration

Precautions should be taken to ensure that blood does not enter the syringe loaded with the product, as there is a risk that the blood may coagulate in the syringe and that fibrin clots may be administered to the patient.

If more than one vial of Beriplex is needed, it is possible to combine several vials of Beriplex in a single infusion using a commercially available infusion set.

The Beriplex solution must not be diluted.

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

Disposal of unused medicinal products and all materials that have come into contact with them 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 bleeding due to vitamin K deficiency in neonates.

Guidelines for platelet count monitoring:

Carefully monitor the platelet count.

Interaction with Other Medicinal Products and Other Forms of Interaction

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

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