КОНФИДЕКС 20 ML Порошок и раствор для инъекционного раствора

Содержание инструкции

1. WHAT IS CONFIDEX AND WHAT IS IT USED FOR
2. WHAT YOU NEED TO KNOW BEFORE USING CONFIDEX
3. HOW TO USE CONFIDEX
4. POSSIBLE SIDE EFFECTS
5. HOW TO STORE CONFIDEX
6. CONTENTS OF THE PACK AND OTHER INFORMATION
7. WHAT IS CONFIDEX AND WHAT IS IT USED FOR
8. WHAT YOU NEED TO KNOW BEFORE USING CONFIDEX
9. HOW TO USE CONFIDEX
10. POSSIBLE SIDE EFFECTS
11. HOW TO STORE CONFIDEX
12. PACKAGE CONTENTS AND OTHER INFORMATION

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT
Confidex 500
Powder and solvent for injectable solution.
Human prothrombin complex

Read this leaflet carefully before you start to use this medicine as it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Do not pass it on to others. It may be harmful for people other than you, even if their symptoms are the same.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

• 1.What Confidex is and what it is used for
• 2.What you need to know before you use Confidex
• 3.How to use Confidex
• 4.Possible side effects
• 5.How to store Confidex
• 6.Contents of the pack and other information

1. WHAT IS CONFIDEX AND WHAT IS IT USED FOR

What is Confidex?
Confidex is presented as a powder and solvent product. It is a white or slightly
colored powder or a friable solid. The solution, once prepared, must be injected intravenously.
Confidex is obtained from human plasma (i.e. the liquid component of blood) and contains human
coagulation factors II, VII, IX and X. Concentrates containing these coagulation factors
are called prothrombin complex-based products. Coagulation factors II, VII,
IX and X are vitamin K-dependent factors and are important for blood coagulation.
The lack of each of these factors does not allow the necessary speed of blood coagulation
resulting in an increased tendency to bleeding. Replacing factors II, VII,
IX and X with Confidex allows restoration of the coagulation mechanism.

What is Confidex used for?
Confidex is used in the prevention (in case of surgery) and treatment of
bleeding phenomena due to congenital or acquired deficiency, in the blood, of coagulation factors II, VII, IX and X dependent on vitamin K, when purified specific coagulation factor-based products are not available.

2. WHAT YOU NEED TO KNOW BEFORE USING CONFIDEX

The following paragraphs contain information that the doctor must consider
before prescribing Confidex.

Do not use Confidex:

• If you are allergic to any of the active ingredients or any of the excipients of this medicine (see section 6). Tell your doctor if you are allergic to any medicines or any food substances.
• if you have a tendency higher than normal to form blood clots (patients at risk of disseminated intravascular coagulation).
• if you have an allergic reaction to heparin, resulting in a decrease in the number of platelets (Heparin-Induced Thrombocytopenia Type II, HIT type II). Tell your doctor or pharmacist if you have any of these disorders.

Warnings and precautions
Consult your doctor or pharmacist before using Confidex in case of:

• Acquired deficiency of vitamin K-dependent coagulation factors: This may be induced by treatment with products that inhibit the effect of vitamin K. Confidex may be appropriately used only in cases where a rapid correction of prothrombin complex levels is necessary, e.g. in cases of more significant bleeding phenomena or in emergency surgery.
• Congenital deficiency of any of the vitamin K-dependent factors: In this case, you should use, when available, products based on the specific coagulation factor.
• Allergic or anaphylactic reactions (severe allergic reaction causing severe difficulty breathing or dizziness): The administration of Confidex must be stopped immediately (e.g.stop the injection).
• Increased risk of blood clot formation in a blood vessel (thrombosis), particularly:
• if you have had a heart attack (history of coronary heart disease or myocardial infarction);
• if you suffer from liver diseases;
• if you have recently undergone surgery (pre- or post-operative patients);
• in newborns;
• if you have a tendency higher than normal to form blood clots (patients at risk of thromboembolic episodes or disseminated intravascular coagulation or concurrent inhibitor deficiency).
• Increased risk of coagulation due to increased consumption of platelets or blood coagulation factors. Treatment with Confidex can only be started after treatment of the underlying cause.
• Reduced platelet development due to heparin (Heparin-Induced Thrombocytopenia [HIT] type II). Heparin, a protein capable of dissolving blood clots, is an excipient of Confidex. Severe form of decreased platelet count may be associated with:
• presence of blood clots in a vein or in a leg,
• an increase in blood clot formation,
• in some cases with redness of the skin at the injection site,
• petechial hemorrhages,
• dark stools. In these cases, the effectiveness of heparin may be reduced (tolerance to heparin). If these symptoms occur, you should immediately stop using the product and contact your doctor. In the future, you should no longer use products containing heparin.
• A particular form of kidney inflammation has been reported after treatment of patients with hemophilia B with factor IX inhibitors. These patients also had a history of allergic reactions.

Your doctor will carefully assess the benefit-risk ratio of treatment with
Confidex and the risks of these complications.

Viral safety
In the production of medicinal specialties obtained from human blood or plasma, certain precautions are taken to prevent the transmission of infections to patients. These measures
include:

• careful selection of blood and plasma donors to ensure that those at risk of carrying infections are excluded,
• testing of each individual donation and plasma pools to verify the possible presence of viruses/infections,
• adoption, in the processing of blood or plasma, of production steps aimed at inactivating or eliminating viruses.

Despite these measures, when administering products prepared from human blood or plasma,
the transmission of infections cannot be completely excluded. This also applies to emerging or unknown viruses or other types of infection.
The measures taken are considered effective against enveloped viruses such as the human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and against
non-enveloped viruses of hepatitis A and parvovirus B19.
If you receive regular/repeated administrations of products containing prothrombin complex derived from human plasma, your doctor may advise you to get vaccinated against hepatitis A and B.
It is strongly recommended that, with each administration of Confidex, the treating physician records the
name and lot number of the product used, in order to maintain a record of the lots used.

Use of Confidex with other medicines

• Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
• Confidex may inhibit the effectiveness of treatment with vitamin K antagonists. No interactions with other drugs are known.
• This medicine must not be mixed with other products except those mentioned in section 6.

Pregnancy, breastfeeding and fertility

• If you are pregnant or breastfeeding, if you think you may be pregnant or are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
• Confidex should only be administered if clearly indicated during pregnancy or breastfeeding.
• No data on fertility are available.

Driving and operating machinery
No studies have been conducted to assess the effects on the ability to drive vehicles or operate
machinery.

Confidex contains sodium
Confidex contains up to 343 mg of sodium (approx. 15 mmol) per 100 ml. This should be taken into
account if you are following a low-sodium diet.

3. HOW TO USE CONFIDEX

Treatment must be initiated and monitored by a doctor experienced in the therapy of this type of
diseases.

Dose
The amount of Factor II, VII, IX and X needed, as well as the duration of treatment, depend on
numerous parameters such as, for example, your body weight, the severity and nature of the disease, the
location and intensity of the bleeding, or the need to prevent bleeding episodes during
surgery or analysis (see the paragraph “The following information is

intended exclusively for healthcare professionals”).
If you have doubts about the use of this product, consult your doctor or pharmacist.

Overdose
During treatment, the doctor must monitor your coagulation status at regular intervals. The administration of high doses of prothrombin complex concentrate has
been associated with cases of heart attack, disseminated intravascular coagulation and increased
formation of blood clots in blood vessels in patients already at risk for 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 observed commonly (may affect up to 1 in 10 people):

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

The following side effect has been observed uncommonly (may affect up to 1 in 100 people):

• Hypersensitivity or allergic reactions (see section 2)

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

• Excessive coagulation leading to severe bleeding
• Anaphylactic reactions including shock (see section 2)
• Formation of circulating antibodies inhibiting one or more coagulation factors

Paediatric population
No data are available regarding the use of Confidex in the paediatric population.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. You can also report side effects directly through your national
reporting system.
By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE CONFIDEX

• 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 the packaging.
• Do not store at a temperature above 25°C.
• Do not freeze.
• Keep the vial in its outer packaging, in order to protect it from light.
• Confidex does not contain preservatives, therefore the reconstituted solution should preferably be administered immediately.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Confidex contains
Confidex contains 400 – 620 IU of human coagulation Factor IX per vial.

The active substance is:
A concentrate of factors: II, VII, IX and X, Protein C and S of human coagulation.

The excipients are:
Human Antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or
NaOH (in small quantities for pH correction)

Solvent:Water for injections.

How Confidex is presented and contents of the pack
Confidex is presented as a white or slightly colored powder and is supplied together with a
vial of water for injections as a solvent. The powder must be dissolved in
20 ml of water for injections.
The resulting solution should be clear or slightly opalescent, in the sense that it may
show shimmer when examined against the light, but in any case should not contain visible
particles.

Contents of the pack
A 500 IU pack contains:

• 1 vial with the powder
• 1 vial with 20 ml of water for injections
• 1 transfer device with 20/20 filter Marketing Authorisation HolderCSL Behring GmbH Emil-von-Behring-Str. 76 35041 Marburg Germany Legal RepresentativeCSL Behring S.p.A., Viale del Ghisallo, 20 - 20151 Milano Italy Responsible Manufacturer for batch release: CSL Behring GmbH Emil-von-Behring-Str. 76 35041 Marburg Germany

This medicinal product has been authorised in the member states of the European Economic
Area with the following designations:
Austria Beriplex P/N 500 I.E. Powder and solvent for solution for injection
Belgium
Bulgaria
Croatia
Denmark
Confidex 500 I.E., powder and solvent for solution for injection
Beriplex P/N 500, 500 IU, Powder and solvent for solution for injection
Beriplex P/N 500 IU prašak i otapalo za otopinu za injekciju
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
Malta
Confidex 500 UI poudre et solvant pour solution injectable
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
Czech Republic
Romania
Beriplex 500 UI pó e solvente para solução injectável
Beriplex 500 IU
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

The following information is intended exclusively for healthcare professionals:
Qualitative and quantitative composition
Confidex contains nominally the following IU of human coagulation factors
listed in the following table:

The total proteins contained after reconstitution are 6 – 14 mg/ml
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 in accordance with current valid WHO international standards.

Dosage and method of administration
Dosage
The following are only general guidelines for dosage.
The amount and frequency of administration must be calculated for each individual patient. The
intervals of administration must be adapted to the different half-lives in circulation of the
respective coagulation factors contained in the prothrombin complex. The dose required for
each patient can only be established on the basis of regular individual determination of the
plasma levels of the coagulation factors in question, or on the basis of tests for the
determination of the prothrombin complex levels (INR, Quick test) and with continuous
monitoring of the patient's clinical condition.
In cases of major surgery, punctual monitoring of substitute therapy is essential based on the
performance of coagulation tests (tests on specific coagulation factors and/or complete tests
for the determination of prothrombin complex levels).

• Treatment and perioperative prophylaxis of bleeding during therapy withvitamin K antagonists:

The dose will depend on the INR value before treatment and the desired value. The pre-treatment INR
value must be measured as close as possible to the time of dose determination in order to calculate
the appropriate dose of Confidex. The table below shows the
approximate doses (ml of reconstituted product/kg of body weight and Factor IX IU/kg body weight)
required to normalize the INR value (e.g. <1.3) based on the different
initial INR values.
The dose is based on a body weight of up to 100 kg, but not more than 100 kg. Therefore, for
patients weighing more than 100 kg, the single maximum dose (Factor IX IU) must not
exceed: 2500 IU for an INR of 2.0-3.9; 3500 IU for an INR of 4.0-6.0 and 5000 IU for
an INR > 6.0.
Correction of the haemostatic imbalance induced by the vitamin K antagonist is
usually achieved approximately 30 minutes after the injection. Concomitant administration of vitamin K
should be considered in patients receiving
Confidex for the urgent reversal of vitamin K antagonists, as vitamin K
usually takes effect within 4-6 hours. Repeated dosing with Confidex for patients who
require treatment for urgent reversal of vitamin K antagonists is not
supported by clinical data and is therefore not recommended.
These recommendations are based on data from clinical studies conducted on a limited
number of subjects. Recovery and duration of effect may vary, therefore it is
essential to monitor the INR value during treatment.

• Bleeding and perioperative prophylaxis in cases of congenital deficiency of any of thevitamin K-dependent coagulation factors when purified products based on the specificcoagulation factors are not available:

The calculation of the necessary dose of concentrated prothrombin complex is based on data obtained
from clinical trials.

• 1 IU of Factor IX per kg of body weight is considered to increase plasma Factor IX activity by 1.3% compared to normal (0.013 IU/ml);
• 1 IU of Factor VII per kg of body weight increases plasma Factor VII activity by 1.7% compared to normal (0.017 IU/ml);
• 1 IU of Factor II per kg of body weight increases plasma Factor II activity by 1.9% compared to normal (0.019 IU/ml);
• 1 IU of Factor X per kg of body weight increases plasma Factor X activity by 1.9% compared to normal (0.019 IU/ml).

The dose of the specific factor administered is expressed in International Units (IU), with
reference to the current standard for each factor. The plasma activity of each
individual coagulation factor is expressed as a percentage value (relative to normal plasma) or
in International Units (in accordance with the international standard for the specific
coagulation factor).

One International Unit (IU) of activity of the individual coagulation factors is equivalent to
the amount of the same factor in 1 ml of normal human plasma.
For example, the calculation of the necessary dose of Factor X is based on the observation that 1 International
Unit (IU) of Factor X per kg of body weight increases the activity of Factor X in
plasma by 0.019 IU/ml.
The necessary dose is determined using the following formula:
Units required = body weight [kg] x desired increase of Factor X [IU/ml] x 53
where 53 (ml/kg) is the reciprocal of the reciprocal 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 subjects would provide a lower estimate of the dose
required.
If the individual recovery value is known, this must be used to calculate the necessary dose
Specific product information is available from clinical studies on healthy volunteers (N = 15),
in treatment of vitamin K antagonist reversal for acute major bleeding or perioperative prophylaxis of bleeding (N = 98, N = 43).

Paediatric population
The safety and efficacy of Confidex in children and adolescents have not yet been defined
through controlled clinical studies.

Elderly population
The dosage and method of administration in elderly patients (> 65 years) are the same as those
reported with the general recommendations.

Method of administration

General instructions

• The solution must be clear or slightly opalescent. After filtering/withdrawal (see below), the reconstituted product must be visually inspected for the presence of particles or color changes before administration.
• Do not use turbid solutions or those containing residue (deposits/particles).
• Reconstitution and withdrawal must be performed under aseptic conditions.

Reconstitution
Bring the solvent to room temperature. Ensure that the tear-off protective caps of the vials containing the product and the diluent, respectively, have been removed, disinfect the stoppers with an aseptic solution and wait for them to dry before opening the Mix2Vial package.

1	1. Open the Mix2Vial package by detaching the closure. Do not remove the Mix2Vial from the blister package!

2	2. Place the diluent vial on a flat and clean surface, holding the vial firmly. Take the Mix2Vial together with the package and push the blue end downwards into the diluent stopper.
3	a 3. Carefully remove the blister package from the Mix2Vial set by holding the edge and pulling vertically upwards. Make sure to pull only the package and not the Mix2Vial set.
4	a 4. Securely place the product vial on a stable support, invert the diluent vial connected with the Mix2Vial set, and apply the transparent adapter to the stopper of the vial containing the product by pushing it downwards. The diluent will automatically be transferred into the product vial.
i 5	a 5. Holding the Mix2Vial set by the product side with one hand, and the solvent side with the other hand, unscrew the set counterclockwise until two separate parts are obtained. Discard the solvent vial with the blue part of the set attached.
l a t I 6	6. Gently rotate the product vial with the transparent adapter attached until the product is completely dissolved. Do not shake.
a i z 7	7. Draw air into a sterile, empty syringe. With the product vial in a vertical position, connect the syringe to the Luer Lock connector of the Mix2Vial set by screwing it clockwise. Inject the air into the vial containing the product.

Withdrawal and administration

8	8. Holding the syringe plunger pressed down, invert the system and, slowly raising the plunger, draw the solution into the syringe. c a
9	m 9. After all the solution has been transferred into the syringe, firmly grasp the cylinder of the syringe (keeping the syringe plunger facing downwards) and disconnect the transparent adapter of the Mix2Vial set from the syringe by unscrewing it counterclockwise.

Be careful not to allow blood to enter the syringe filled with the product, as there is a risk that the blood will clot in the syringe and that fibrin clots may therefore be administered to the patient.
If more than one vial of Confidex is necessary, several vials of Confidex can be combined for a single infusion using a commercially available infusion device.
The Confidex solution must not be diluted.
The reconstituted solution must be administered intravenously (no more than 8 ml/min*).
Any unused medicinal product or waste materials must be disposed of in accordance with local regulations.

Special warnings and precautions for use
No data are available regarding the use of Confidex in cases of bleeding episodes in the perinatal period due to vitamin K deficiency in the newborn.
Note on platelet count
The patient must be constantly monitored for platelet count

Interactions with other medicinal products and other interactions
When patients receiving high doses of human prothrombin complex are subjected to coagulation tests sensitive to heparin, it should be taken into account that heparin itself is contained in the administered product.
* During clinical studies, patients with a weight < 70 kg were administered Confidex at a maximum infusion rate of 0.12 ml/kg/min (less than 8 ml/min).

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT
Confidex 1000
Powder and solvent for injection.
Human prothrombin complex

Read this leaflet carefully before you take this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Never give it to others. Indeed, it may be dangerous for others, even if their symptoms are the same as yours.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

• 1.What is Confidex and what is it used for
• 2.What you need to know before you use Confidex
• 3.How to use Confidex
• 4.Possible side effects
• 5.How to store Confidex
• 6.Contents of the pack and other information

1. WHAT IS CONFIDEX AND WHAT IS IT USED FOR

What is Confidex?
Confidex is presented as a powder and solvent product. It is a white or slightly
colored powder or a friable solid. The solution, once prepared, must be injected intravenously.
Confidex is obtained from human plasma (i.e. the liquid component of blood) and contains human
coagulation factors II, VII, IX and X. Concentrates containing these coagulation factors are
called prothrombin complex-based products. Coagulation factors II, VII, IX and X are vitamin K-dependent
factors and are important for blood coagulation.
The lack of each of these factors does not allow the necessary speed of blood coagulation, resulting in an
increased tendency to bleeding. Replacing factors II, VII, IX and X with Confidex allows restoration of the
coagulation mechanism.

What is Confidex used for?
Confidex is used in the prevention (in case of surgery) and treatment of
bleeding phenomena due to congenital or acquired deficiency, in the blood, of coagulation factors II, VII, IX and X
dependent on vitamin K, when purified specific coagulation factor-based products are not available.

2. WHAT YOU NEED TO KNOW BEFORE USING CONFIDEX

The following paragraphs contain information that the doctor must consider
before prescribing Confidex.

Do not use Confidex:

• If you are allergic to any of the active ingredients or any of the excipients of this medicine (see section 6). Tell your doctor if you are allergic to any medicine or any food substance.
• if you have a tendency higher than normal to form blood clots (patients at risk of disseminated intravascular coagulation).
• if you have an allergic reaction to heparin, resulting in a decrease in the number of platelets (Heparin-Induced Thrombocytopenia Type II, HIT type II). Tell your doctor or pharmacist if you have any of these disorders.

Warnings and precautions
Consult your doctor or pharmacist before using Confidex in case of:

• Acquired deficiency of vitamin K-dependent coagulation factors: This can be induced by treatment with products that inhibit the effect of vitamin K. Confidex may be appropriately used only in cases where a rapid correction of prothrombin complex levels is necessary, for example, in cases of more significant bleeding phenomena or in emergency surgery.
• Congenital deficiency of any of the vitamin K-dependent factors: In this case, you should use, when available, products based on the specific coagulation factor.
• Allergic or anaphylactic reactions (severe allergic reaction causing severe difficulty breathing or dizziness): The administration of Confidex must be stopped immediately (e.g.stop the injection).
• Increased risk of blood clot formation in a blood vessel (thrombosis), particularly:
• if you have had a heart attack (history of coronary heart disease or myocardial infarction);
• if you suffer from liver diseases;
• if you have recently undergone surgery (pre- or post-operative patients);
• in newborns;
• if you have a tendency higher than normal to form blood clots (patients at risk of thromboembolic episodes or disseminated intravascular coagulation or concurrent inhibitor deficiency).
• Increased risk of coagulation due to increased consumption of platelets or blood coagulation factors. Treatment with Confidex can only be started after treatment of the underlying cause.
• Reduced platelet development due to heparin (Heparin-Induced Thrombocytopenia [HIT] type II). Heparin, a protein capable of dissolving blood clots, is an excipient of Confidex. The severe form of platelet count reduction may be associated with:
• presence of blood clots in a vein or leg,
• an increase in blood clot formation,
• in some cases with skin redness at the injection site,
• petechial hemorrhages,
• dark stools.

In these cases, the effectiveness of heparin may be reduced (heparin tolerance). If these symptoms occur, you should immediately stop using the product and contact your
doctor. In the future, you should no longer use products containing heparin.

• A particular form of kidney inflammation has been reported after treatment of patients with hemophilia B with factor IX inhibitors. These patients also had a history of allergic reactions.

Your doctor will carefully assess the benefit-risk ratio of treatment with
Confidex and the risks of these complications.

Viral safety
In the production of medicinal specialties obtained from human blood or plasma, certain precautions are taken to prevent the transmission of infections to patients. These measures
include:

• careful selection of blood and plasma donors to ensure that those at risk of carrying infections are excluded,
• testing of each individual donation and plasma pools to verify the possible presence of viruses/infections,
• adoption, in the processing of blood or plasma, of production steps aimed at inactivating or eliminating viruses.

Despite these measures, when administering products prepared from human blood or plasma,
the transmission of infections cannot be completely excluded. This also applies to emerging or previously unknown viruses or other types of infection.
The measures taken are considered effective against enveloped viruses such as the human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and against non-enveloped viruses such as hepatitis A virus and parvovirus B19.
If you receive regular/repeated administrations of products containing human plasma-derived prothrombin complex, your doctor may advise you to get vaccinated against hepatitis A and B.
It is strongly recommended that, with each administration of Confidex, the treating physician records the
name and lot number of the product used, in order to maintain a record of the lots used.

Use of Confidex with other medicines

• Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines.
• Confidex may inhibit the effectiveness of treatment with vitamin K antagonists. No interactions with other drugs are known.
• This medicine should not be mixed with other products except those mentioned in section 6.

Pregnancy, breastfeeding and fertility

• If you are pregnant or breastfeeding, if you think you may be pregnant or are planning a pregnancy, ask your doctor or pharmacist for advice before taking this medicine.
• In case of pregnancy or during breastfeeding, Confidex should only be administered if clearly indicated.
• No data on fertility are available.

Driving and operating machinery
Studies have not been conducted to observe the effects on the ability to drive vehicles or operate
machinery.

Confidex contains sodium
Confidex contains up to 343 mg of sodium (approximately 15 mmol) per 100 ml. This should be taken into
consideration if you are following a low-sodium diet.

3. HOW TO USE CONFIDEX

Treatment must be initiated and monitored by a doctor experienced in the therapy of this type of
diseases.

Dose
The necessary amount of Factor II, VII, IX and X, as well as the duration of treatment, depend on
numerous parameters such as, for example, your body weight, the severity and nature of the disease, the
location and intensity of the bleeding, or the need to prevent bleeding episodes during
surgery or analysis (see the paragraph “The following information is

intended exclusively for healthcare professionals”).
If you have doubts about the use of this product, consult your doctor or pharmacist.

Overdose
During treatment, the doctor must check, at regular intervals, the state of your
coagulation. The administration of high doses of prothrombin complex concentrate has been
associated with cases of heart attack, disseminated intravascular coagulation, and increased
formation of blood clots in blood vessels in patients already at risk for 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 observed commonly (may affect up to 1 in 10 people):

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

The following side effect has occurred uncommonly (may affect up to 1 in 100 people):

• Hypersensitivity or allergic reactions (see section 2)

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

• Excessive coagulation leading to severe bleeding
• Anaphylactic reactions including shock (see section 2)
• Formation of circulating antibodies inhibiting one or more coagulation factors

Paediatric population
No data are available regarding the use of Confidex in the paediatric population.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the national reporting system
By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE CONFIDEX

• Keep this medicine out of the reach and sight of children.
• Do not use this medicine after the expiry date which is stated on the label and on the packaging.
• Do not store above 25°C.
• Do not freeze.
• Keep the vial in its outer packaging in order to protect it from light.
• Confidex does not contain preservatives, therefore the reconstituted solution should preferably be administered immediately.

6. PACKAGE CONTENTS AND OTHER INFORMATION

What Confidex contains
Confidex contains 800 – 1240 IU of human coagulation Factor IX per vial.

The active substance is:
A concentrate of factors: II, VII, IX and X, Protein C and S of human coagulation.

The excipients are:
Human Antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or
NaOH (in small quantities for pH correction)

Solvent:Water for injections.

What Confidex looks like and contents of the pack
Confidex is presented as a white or slightly colored powder and is supplied with a
vial of water for injections as a solvent. The powder must be dissolved in
40 ml of water for injections.
The resulting solution should be clear or slightly opalescent, in the sense that it may
show shimmer when examined against the light, but in any case should not contain visible
particles.

Contents of the pack
A pack of 1000 IU contains:

• 1 vial with the powder
• 1 vial with 40 ml of water for injections
• 1 transfer device with 20/20 filter Marketing Authorisation HolderCSL Behring GmbH Emil-von-Behring-Str. 76 35041 Marburg Germany Legal RepresentativeCSL Behring S.p.A., Viale del Ghisallo, 20 - 20151 Milano Italy Responsible Manufacturer for batch release: CSL Behring GmbH Emil-von-Behring-Str. 76 35041 Marburg Germany

This medicinal product is authorised in the member states of the European Economic
Area under the following designations:
Austria Beriplex P/N 1000 I.E. Powder and solvent for solution for injection
Belgium Confidex 1000 I.E., powder and solvent for solution for injection
Bulgaria Beriplex P/N 1000, 1000 IU, Powder and solvent for solution for injection
Croatia Beriplex P/N 1000 IU powder and solvent for solution for injection
Denmark Confidex
Finland Confidex 1000 IU injektiokuiva-aine ja liuotin, liuosta varten
France Confidex 1000 UI, powder and solvent for injectable solution
Germany Beriplex P/N 1000
Greece Beriplex P/N, Powder and solvent for injectable solution 1000IU/vial
Hungary Beriplex P/N 1000 powder and solvent for solution for injection
Ireland Beriplex P/N 1000 IU, powder and solvent for solution for injection
Italy Confidex 1000
Luxembourg
Malta
Confidex 1000 UI powder and solvent for injectable solution
Beriplex P/N 1000, powder and solvent for solution for injection
Netherlands Beriplex P/N 1000 IE, powder and solvent for solution for injection
Norway
Czech Republic
Romania
Confidex 1000 IU powder and liquid for injection fluid, solution
Beriplex 1000 IU
Beriplex P/N 1000 UI powder and solvent for injectable solution
Poland Beriplex P/N 1000
Portugal Beriplex 1000 UI powder and solvent for injectable solution
Slovakia Beriplex 1000 IU
Slovenia Beriplex P/N 1000 i.e. powder and vehicle for solution for injection
Spain Beriplex 1000 UI powder and solvent for injectable solution
Sweden Confidex 1000 IE, powder and liquid for injection fluid, solution
United Kingdom Beriplex P/N 1000 IU, powder and solvent for solution for injection

The following information is intended exclusively for healthcare professionals:
Quantitative and qualitative composition
Confidex contains nominally the following IU of human coagulation factors
listed in the following table:

The total proteins contained after reconstitution are 6 – 14 mg/ml
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 in accordance with current valid WHO international standards.

Dosage and method of administration
Dosage
The following are only general guidelines for dosage.
The amount and frequency of administration must be calculated for each individual patient. The
intervals of administration must be adapted to the different half-lives in circulation of the
various coagulation factors contained in the prothrombin complex. The dose required for
each patient can only be established on the basis of regular individual determination of
plasma levels of the coagulation factors in question or on the basis of tests for the
determination of prothrombin complex levels (INR, Quick test) and with continuous
monitoring of the patient's clinical condition.
In case of major surgery, timely monitoring of substitute therapy is essential based on the
performance of coagulation tests (tests on specific coagulation factors and/or complete tests for the determination of prothrombin complex levels).

• Treatment and perioperative prophylaxis of bleeding during therapy withvitamin K antagonists:

The dose will depend on the INR value before treatment and the desired value. The pre-treatment INR value must be measured as close as possible to the time of dose determination in order to calculate the appropriate dose of Confidex. The following table shows the
approximate doses (ml of reconstituted product/kg body weight and Factor IX IU/kg body weight)
approximately required to normalize the INR value (e.g. <1.3) based on the
different initial INR values.

The dose is based on a body weight of up to 100 kg, but not more than 100 kg. Therefore, for
patients weighing more than 100 kg, the single maximum dose (Factor IX IU) must not
exceed: 2500 IU for an INR of 2.0-3.9; 3500 IU for an INR of 4.0-6.0 and 5000 IU for
an INR > 6.0.
Correction of the hemostatic imbalance induced by the vitamin K antagonist is
usually achieved approximately 30 minutes after the injection. Concomitant administration of vitamin K should be considered in patients receiving
Confidex for the urgent reversal of vitamin K antagonists, as vitamin K
usually takes effect within 4-6 hours. Repeated dosing with Confidex for patients who
require treatment for urgent reversal of vitamin K antagonists is not
supported by clinical data and is therefore not recommended.
These recommendations are based on data from clinical studies conducted on a limited
number of subjects. Recovery and duration of effect may vary, therefore it is
essential to monitor the INR value during treatment.

• Bleeding and perioperative prophylaxis in cases of congenital deficiency of any of thevitamin K-dependent coagulation factors when purified products based on the specific coagulation factors are not available:

The calculation of the required dose of concentrated prothrombin complex is based on data obtained
from clinical trials.

• 1 IU of Factor IX per kg of body weight is believed to increase plasma activity of Factor IX by 1.3% compared to normal (0.013 IU/ml);
• 1 IU of Factor VII per kg of body weight increases plasma activity of Factor VII by 1.7% compared to normal (0.017 IU/ml);
• 1 IU of Factor II per kg of body weight increases plasma activity of Factor II by 1.9% compared to normal (0.019 IU/ml);
• 1 IU of Factor X per kg of body weight increases plasma activity of Factor X by 1.9% compared to normal (0.019 IU/ml).

The dose of the specific factor administered is expressed in International Units (IU), with
reference to the current standard for each factor. The plasma activity of each
individual coagulation factor is expressed as a percentage value (relative to normal plasma)
or in International Units (in accordance with the international standard for the specific
coagulation factor).
An International Unit (IU) of activity of the individual coagulation factors is equivalent to
the amount of the same factor in 1 ml of normal human plasma.
For example, the calculation of the required dose of Factor X is based on the observation that 1 International
Unit (IU) of Factor X per kg of body weight increases the activity of Factor X in
plasma by 0.019 IU/ml.
The required dose is determined using the following formula:
Units required = body weight [kg] x desired increase of Factor X [IU/ml] x 53
where 53 (ml/kg) is the reciprocal of the reciprocal 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 subjects would provide a lower estimate of the dose
required.
If the individual recovery value is known, this must be used to calculate the required dose.
Specific product information is available from clinical studies on healthy volunteers (N = 15),
in treatment of vitamin K antagonist reversal for acute major bleeding or perioperative prophylaxis of bleeding (N = 98, N = 43).

Paediatric population
The safety and efficacy of Confidex in children and adolescents has not yet been defined
through controlled clinical studies.

Elderly population
The dosage and method of administration in elderly patients (> 65 years) are the same as those
reported with the general recommendations.

Method of administration

General instructions

• The solution must be clear or slightly opalescent. After filtering/withdrawal (see below), the reconstituted product must be visually inspected for the presence of particles or colour changes before administration.
• Do not use turbid solutions or those containing residue (deposits/particles).
• Reconstitution and withdrawal must be carried out under aseptic conditions.

Reconstitution
Bring the solvent to room temperature. Ensure that the tear-off protective caps of the vials containing the product and the diluent, respectively, have been removed, disinfect the stoppers with an aseptic solution and wait for them to dry before opening the Mix2Vial package.

1	o 1. Open the Mix2Vial package, detaching the closure. Do not remove the Mix2Vial from the blister pack! a
2	m 2. Place the diluent vial on a flat and clean surface, holding the vial firmly. Take the Mix2Vial together with the package and push the blue end downwards into the diluent stopper.
3	F 3. Carefully remove the blister pack from the Mix2Vial set by holding the edge and pulling vertically upwards. l Make sure to pull only the package and not the Mix2Vial set.
4 i l	d 4. Securely place the product vial on a stable support, invert the diluent vial connected with the Mix2Vial set, and apply the transparent adapter to the stopper of the vial containing the product by pushing downwards. The diluent will automatically be transferred into the product vial.
a t I a 5	5. Hold the Mix2Vial set by the product side with one hand, and hold it by the solvent side with the other hand, and unscrew the set counterclockwise until two separate parts are obtained. Discard the solvent vial with the blue part of the set attached.
i z n 6	6. Gently rotate the product vial with the transparent adapter attached until the product is completely dissolved. Do not shake.
e g 7	7. Draw air into a sterile, empty syringe. With the product vial in a vertical position, connect the syringe to the Luer Lock connector of the Mix2Vial set by screwing clockwise. Inject the air into the vial containing the product.

Withdrawal and administration
Be careful not to allow blood to enter the syringe filled with the product, as there is a risk that the blood will clot in the syringe and that fibrin clots may therefore be administered to the patient.
If more than one vial of Confidex is necessary, several vials of Confidex can be combined for a single infusion using a commercially available infusion device.
The Confidex solution must not be diluted.
The reconstituted solution must be administered intravenously (not more than 8 ml/min*).
Any unused medicinal product or waste materials must be disposed of in accordance with current local regulations.

Special warnings and precautions for use
There are no data available regarding the use of Confidex in cases of perinatal bleeding due to vitamin K deficiency in the newborn.
Note on platelet count
The patient must be constantly monitored for platelet count

Interactions with other medicinal products and other interactions
When patients receiving high doses of human prothrombin complex are subjected to coagulation tests sensitive to heparin, it should be noted that heparin itself is contained in the administered product.
* During clinical studies, patients with a weight < 70 kg were administered Confidex at a maximum infusion rate of 0.12 ml/kg/min (less than 8 ml/min).

8	o 8. While pressing the syringe plunger, invert the system and, slowly lifting the plunger, draw the solution into the syringe. a m
9	r 9. After all the solution has been transferred into the syringe, firmly grasp the syringe cylinder (keeping the syringe plunger facing downwards) and disconnect the transparent adapter of the Mix2Vial set from the syringe by unscrewing counterclockwise.