Package leaflet: Information for the user

Beriplex® P/N 250, 500 and 1000 IU

Powder and solvent for solution for injection Human prothrombin complex ^{1 2}

Warnings and precautions

Talk to your doctor or pharmacist before using Beriplex in case of:

•    Acquired deficiency of the vitamin K-dependent coagulation factors:

This may be induced by treatment with medicines inhibiting the vitamin K effect. Beriplex is only allowed to be used when rapid correction of the prothrombin complex levels is necessary, e.g. in case of major bleedings or emergency surgery

•    Congenital deficiency of any of the vitamin K-dependent factors:

In this case you should use specific coagulation factor products when available

•    Allergic or anaphylactic-type reactions (a serious allergic reaction that causes severe difficulty in breathing or dizziness):

The application of Beriplex should be stopped immediately (e.g. discontinue injection)

•    Increased risk of formation of blood clots in a blood vessel (thrombosis), particularly:

-    if you have had a heart attack (a history of coronary heart disease or myocardial infarction)

-    if you suffer from liver disease

-    if you have just had surgery (patients per- or postoperatively)

-    in new-born infants (neonates)

-    if you are more likely to suffer from blood clots than normal (patients at risk of thromboembolic phenomena or disseminated intravascular coagulation or simultaneous inhibitor deficiency)

•    Increased coagulation risk due to increased consumption of blood platelets or blood coagulation factors. Treatment with Beriplex can only be started after treatment of the underlying cause.

•    Reduced development of blood platelets due to heparin (heparin-induced thrombocytopenia, HIT Type II). Heparin, a protein with a blood clot dissolving effect, is an ingredient of Beriplex. The severe form of a decrease in blood platelets may be associated with

-    blood clots in the vein or leg,

-    an increased formation of blood clots,

-    in some cases with skin rash where the injection was given,

-    pinpoint-sized haemorrhages and

-    tarry stool.

In these cases the effect of heparin may be diminished (heparin tolerance).

If these symptoms occur, you should stop using the product immediately and contact your doctor. In the future no heparin-containing products should be used.

•    A special form of inflammation of the kidneys has been reported after treatment of patients who suffer from haemophilia B with factor IX inhibitors. These patients were also known to have a history of allergic reaction.

Your doctor will consider carefully the benefit of treatment with Beriplex compared with the risk of these complications.

Virus safety

When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include:

•    careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and

•    the testing of each donation and pools of plasma for signs of virus/infections,

•    the inclusion of steps in the processing of the blood or plasma that can inactivate or remove viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any 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 and parvovirus B19 viruses.

Your doctor may recommend that you consider vaccination against hepatitis A and B if you regularly/repeatedly receive human plasma-derived prothrombin complex products.

It is strongly recommended that every time you receive a dose of Beriplex, the name and batch number of the medicine are recorded in order to maintain a record of the batched used.

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The following information is intended for healthcare professionals only:

Qualitative and quantitative composition

Beriplex nominally contains the following IU of the human coagulation factors tabled below:

Name of the ingredients	Content after reconstitution (IU/ml)	Beriplex P/N 250 content per vial (IU)	Beriplex P/N 500 content per vial (IU)	Beriplex P/N 1000 content per vial (IU)
Active Ingredients
Human coagulation factor II	20 - 48	200 - 480	400 - 960	800 - 1920
Human coagulation factor VII	10 - 25	100 - 250	200 - 500	400 - 1000
Human coagulation factor IX	20 - 31	200 - 310	400 - 620	800 - 1240
Human coagulation factor X	22 - 60	220 - 600	440 - 1200	880 - 2400
Further active ingredients
Protein C	15 - 45	150 - 450	300 - 900	600 - 1800
Protein S	12 - 38	120 - 380	240 - 760	480 - 1520

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

The specific activity of factor IX is 2.5 IU per mg total protein.

The activities of all coagulation factors as well as Protein C and S (antigen) have been tested according to the current valid international WHO-Standards. Posology and method of administration Posology

Only general dosage guidelines are given below.

The amount and the frequency of administration depends on the indication for treatment and should be calculated on an individual patient basis. Dosage intervals must be adapted to the different circulating half-lives of the respective coagulation factors in the prothrombin complex. Individual dosage requirements can only be identified on the basis of regular determinations of the individual plasma levels of the coagulation factors of i nterest, or on global tests of the prothrombin complex levels (INR, Quick's test), and a continuous monitoring of the clinical condition of the patient.

In case of major surgical interventions, precise monitoring of the substitution fherapy by means of coagulation assays is essential (specific coagulation factor assays and/or global tests for prothrombin complex levels).

• Bleeding and perioperative prophylaxis of bleedings during vitamin K antagonist treatment.

The dose will depend on the INR before treatment and the targeted INR. The pretreatment INR should be measured as close as possible to the time of dosing in order to calculate the appropriate dose of Beriplex. In the following table approximate doses (ml/kg body weight of the reconstituted product and IU Factor IX/kg b.w.) required for normalisation of INR (e.g. < 1.3) at different i nitial INR levels are given.

Pre-treatment INR	2.0 - 3.9	4.0 - 6.0	> 6.0
Approximate dose ml/kg body weight	1	1.4	2
Approximate dose IU (Factor IX)/kg body weight	25	35	50

Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg the maximum single dose (IU of Factor IX) should therefore not exceed 2500 IU for an INR of 2.0 - 3.9, 3500 for an INR of 4.0 - 6.0 and 5000 IU for an INR of > 6.0.

The correction of the vitamin K antagonist-induced impairment of haemostasis is commonly reached approximately 30 minutes after the injection. The simultaneous administration of vitamin K should be considered in patients receiving Beriplex for urgent reversal of vitamin K antagonists since vitamin K usually takes effect within 4 - 6 hours.

Repeated dosing with Beriplex for patients requiring urgent reversal of vitamin K antagonists treatment is not supported by clinical data and therefore not recommended.

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•    Bleedings and perioperative prophylaxis in congenital deficiency of any of the vitamin K-dependent coagulation factors when specific coagulation factor products are not available.

The calculation of the required dosage of prothrombin complex concentrate is based on data from clinical studies:

•    1 IU of factor IX per kg body weight can be expected to raise the plasma factor IX activity by 1.3 % (0.013 IU/ml) of normal

•    1 IU of factor VII per kg body weight raises the plasma factor VII activity by 1.7 % (0.017 IU/ml) of normal

•    1 IU of factor II per kg body weight raises the plasma factor II activity by 1.9 % (0.019 IU/ml) of normal

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

The dose of a specific factor administered is expressed in International Units (IU), which are related to the current WHO standard for each factor. The activity in the plasma 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 a coagulation factor activity is equivalent to the quantity in one ml of the normal human plasma.

For example, the calculation of the required dosage of factor X is based on the finding that 1 International Unit (IU) of factor X per kg body weight raises the plasma factor X activity by 0.019 IU/ml.

The required dosage is determined using the following formula:

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

Note that the calculation is based upon data from patients receiving vitamin K antagonists. A calculation based upon data from healthy subjects would provide a lower estimate of the required dose.

If the individual recovery is known, that value should be used for calculation. Product specific information is available from clinical studies in healthy volunteers (N = 15), in reversal of vitamin K antagonist treatment for acute major bleeding or perioperative prophylaxis of bleeding (N = 98, N = 43).

Paediatric population

The safety and efficacy of Beriplex in children and adolescents has not yet been established in controlled clinical studies (see section 4.4).

Older population

The posology and method of administration in older people (>65 years) is equivalent to the general recommendations.

Method of administration

General instructions

-    The solution should be clear or slightly opalescent. After filtering/withdrawal (see below) reconstituted product should be inspected visually for particulate matter and discoloration prior to administration. Do not use solutions that are cloudy or have deposits.

-    Reconstitution and withdrawal must be carried out under aseptic conditions. Reconstitution

Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.

1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package!

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What is in this leaflet

1.    What Beriplex is and what it is used for

2.    What you need to know before you use Beriplex

3.    How to use Beriplex

4.    Possible side effects

5.    How to store Beriplex

6.    Contents of the pack and further information

1. What Beriplex is and what it is used for What is Beriplex?

Beriplex is presented as powder and solvent. It is a white or slightly coloured powder or friable solid. The made up solution is to be given by injection into a vein. Beriplex is made from human plasma (this is the liquid part of the blood) and it contains the human coagulation factors II, VII, IX and X. Concentrates including these coagulation factors are called prothrombin complex products. The coagulation factors II, VII, IX and X are vitamin K-dependent and are important for blood clotting (coagulation). Lack of any of these factors means that blood does not clot as quickly as it should and so there is an increased tendency to bleed. The replacement of factors II, VII, IX and X with Beriplex will repair the coagulation mechanisms.

What is Beriplex used for?

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

2. What you need to know before you use Beriplex

The following sections contain information that your doctor should consider before

you are given Beriplex.

Do NOT use Beriplex:

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   if you are allergic to any of the active substances or other ingredients of this medicine (listed in section 6).

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

•    if you are more likely to suffer from blood clots than normal (patients at risk of disseminated intravascular coagulation)

•    if you show an allergic response to heparin, causing a fall in the number of blood platelets (heparin-induced thrombocytopenia Type II, HIT Type II).

Please inform your doctor or pharmacist if you suffer from such a

disease.

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