Confidex

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

Confidex 500

Powder and solvent for injectable solution.
Human prothrombin complex
Please read this leaflet carefully before using 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. This medicine may be harmful to other people, even if their symptoms are the same as yours.
• If you experience any side effect, including any not listed in this leaflet, inform 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 using 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 coloured powder or a friable solid. The solution, once prepared, must be administered by intravenous injection.
Confidex is derived 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 known as prothrombin complex concentrates. Coagulation factors II, VII, IX and X are vitamin K-dependent factors and are important for blood clotting. The absence of any of these factors prevents the necessary speed of blood coagulation, resulting in an increased tendency to bleed. Replacement of factors II, VII, IX and X with Confidex allows restoration of the coagulation mechanism.
What is Confidex used for?
Confidex is used for the prevention (in case of surgical intervention) and treatment of haemorrhagic events caused by congenital or acquired deficiency in blood of vitamin K-dependent coagulation factors II, VII, IX and X, when purified specific coagulation factor products are not available.

2. WHAT YOU SHOULD KNOW BEFORE USING CONFIDEX

The following sections contain information that your doctor should take into account
before prescribing Confidex to you.
Do not use Confidex:

• If you are allergic to any of the active substances or to any of the excipients of this medicine (see section 6). Inform your doctor if you are allergic to any medicines or food substances.
• if you have an increased tendency to form blood clots (patients at risk of disseminated intravascular coagulation).
• if you have had an allergic reaction to heparin, resulting in a drop in platelet count (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 using Confidex if:

• Acquired deficiency of vitamin K-dependent coagulation factors: This may be caused by treatment with drugs that inhibit the effect of vitamin K. Confidex may be used only when rapid correction of the prothrombin complex levels is required, e.g., in cases of significant bleeding or emergency surgery.
• Congenital deficiency of any of the vitamin K-dependent factors: In this case, you should use, when available, products containing the specific coagulation factor.
• Allergic or anaphylactic reactions (severe allergic reactions causing severe breathing difficulties or dizziness): 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 disease;
• if you have recently undergone surgery (pre- or post-operative patients);
• in newborn children (neonates);
• if you have an increased tendency to form blood clots (patients at risk of thromboembolic episodes, disseminated intravascular coagulation, or concurrent inhibitor deficiency).
• Increased risk of coagulation due to increased consumption of platelets or coagulation factors. Treatment with Confidex should only be initiated after treating the underlying cause.
• Reduced platelet production due to heparin (heparin-induced thrombocytopenia [HIT] Type II). Heparin, a protein capable of dissolving blood clots, is an excipient in Confidex. Severe reduction in platelet count may be associated with:
• presence of blood clots in a vein or leg,
• increased clot formation in the blood,
• in some cases, skin redness at the injection site,
• pinpoint bleeding (petechiae),
• dark stools. In such cases, heparin efficacy may be reduced (heparin resistance). If these symptoms occur, you must immediately stop using the product and contact your doctor. In the future, you should not use products containing heparine.
• 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 known history of allergic reactions.

Your doctor will carefully evaluate the benefit-risk ratio of treatment with
Confidex versus the risks associated with these complications.
Viral safety
In the production of medicinal products derived from human blood or plasma,
certain precautions are taken to prevent transmission of infections to patients. These measures
include:

• careful selection of blood and plasma donors to ensure exclusion of those at risk of carrying infections,
• testing of each individual donation and plasma pools for the presence of viruses/infections,
• inclusion, during blood or plasma processing, of manufacturing steps designed to inactivate or eliminate viruses.

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

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

Pregnancy, breastfeeding and fertility

• If you are pregnant, breastfeeding, think you may be pregnant, or are planning a pregnancy, consult your doctor or pharmacist before taking this medicine.
• During pregnancy or breastfeeding, Confidex should be administered only if clearly indicated.
• There are no data available on fertility.

Driving and using machines
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 on a low-sodium diet.

3. HOW TO USE CONFIDEX

Treatment must be initiated and supervised by a physician experienced in the therapy of this type of disease.
Dosage
The required amount of Factor II, VII, IX, and X, as well as the duration of treatment, depend on several parameters, such as your body weight, the severity and nature of the disease, the location and intensity of bleeding, or the need to prevent bleeding episodes during surgery or medical procedures (see the section “The following information is intended exclusively for healthcare professionals”).
If you have any doubts regarding the use of this product, consult your doctor or pharmacist.
Overdose
During treatment, your doctor must regularly monitor your coagulation status. 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 ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everybody gets them.
The following adverse reactions have been observed commonly (may affect up to 1 in 10 people):

• Risk of blood clot formation (see section 2)
• Headache
• Increase in 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 adverse reactions is not known (cannot be estimated from the available data):

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

Paediatric population
No data are available regarding the use of Confidex in the paediatric population.
Reporting of adverse reactions
If you experience any side effects, talk to your doctor or pharmacist. This includes any adverse reaction not listed in this leaflet. You can also report side effects directly through the national reporting system.
By reporting adverse reactions, 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 stated on the label and 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. CONTENTS OF THE PACKAGE 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, and human Protein C and S.
The excipients are:
Human antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or
NaOH (in small quantities for pH adjustment).
Solvent: Water for injections.

What Confidex looks like and contents of the pack
Confidex is a white or slightly coloured powder supplied with a vial of water for injections as solvent. The powder must be dissolved in 20 ml of water for injections.
The resulting solution should be clear or slightly opalescent, meaning it may show slight shimmering when examined against the light; however, it must not contain visible particles.

Contents of the pack
A 500 IU pack contains:

• 1 vial containing the powder
• 1 vial containing 20 ml of water for injections
• 1 transfer device with 20/20 filter

Marketing Authorization Holder
CSL Behring GmbH
Emil-von-Behring-Str. 76
35041 Marburg
Germany

Legal Representative
CSL Behring S.p.A.
Viale del Ghisallo, 20 - 20151 Milano
Italy

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

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

Total protein content after reconstitution is 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 (antigen), has been tested in accordance with the current valid international standards of the WHO.

Dosage and method of administration
Dosage
The following are general dosage guidelines only.
The amount and frequency of administration must be individually calculated for each patient. The administration intervals should be adjusted according to the different half-lives in circulation of the respective coagulation factors contained in the prothrombin complex. The required dose for each patient can only be determined based on regular individual assessment of plasma levels of the relevant coagulation factors, or through tests for measuring prothrombin complex levels (INR, Quick test), together with continuous monitoring of the patient's clinical condition.
In the case of major surgical procedures, careful monitoring of replacement therapy based on coagulation tests (assays for specific coagulation factors and/or complete tests for determining prothrombin complex levels) is essential.

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

The dose will depend on the INR value before treatment and the desired INR level. 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 indicates the approximate doses (ml of reconstituted product/kg body weight and IU of Factor IX/kg body weight) required to normalize the INR value (e.g., <1.3), based on different initial INR values.

The dose is based on a body weight of up to 100 kg, but not exceeding 100 kg. Therefore, for
patients weighing more than 100 kg, the maximum single dose (IU of Factor IX) 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 vitamin K antagonists is usually achieved
approximately 30 minutes after injection. Concomitant administration of vitamin K should be
considered in patients receiving Confidex for urgent reversal of vitamin K antagonists, as vitamin K
typically takes effect within 4–6 hours. Repeated dosing with Confidex in patients requiring
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 in a limited number of
subjects. Recovery and duration of effect may vary; therefore, monitoring of INR values during
treatment is essential.

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

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

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

The dose of the administered coagulation factor is expressed in International Units (IU),
referencing the current WHO standard for each specific factor. The plasma activity of each
individual coagulation factor is expressed as a percentage (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 each coagulation factor is equivalent to the amount of
that factor present in 1 ml of normal human plasma.
For example, the calculation of the required dose of Factor X is based on the observation that 1
International Unit (IU) of Factor X per kg of body weight increases plasma Factor X activity by
0.019 IU/ml.
The required dose is determined using the following formula:
Units required = body weight [kg] × desired increase in Factor X [IU/ml] × 53
where 53 (ml/kg) is the reciprocal of the recovery.
It should be noted that this calculation is based on data from patients receiving vitamin K
antagonists. A calculation based on data from healthy subjects would yield a lower estimate of the
required dose.
If the individual recovery value is known, it should be used for calculating the required dose.
Product-specific information is available from clinical studies in healthy volunteers (N = 15), and
in patients undergoing reversal of vitamin K antagonists for major acute bleeding or perioperative
bleeding prophylaxis (N = 98, N = 43).
Paediatric population
The safety and efficacy of Confidex in children and adolescents have not yet been established
through controlled clinical trials.
Elderly population
Dosage and method of administration in elderly patients (> 65 years) are the same as those
described in the general recommendations.
Method of administration
General instructions

• The solution should be clear or slightly opalescent. After filtration/withdrawal (see below), the reconstituted product must be visually inspected for the presence of particles or colour changes prior to administration.
• Do not use solutions that are cloudy or contain residues (deposits/particles).
• Reconstitution and withdrawal must be performed under aseptic conditions.

Reconstitution
Allow the diluent to reach room temperature. Ensure that the snap-off caps of the vials containing the product and diluent have been removed, disinfect the stoppers with an antiseptic solution, and allow them to dry before opening the Mix2Vial package.

Collection and administration

Take care to avoid blood entering the syringe filled with the product, as there is a risk that
blood may coagulate in the syringe and fibrin clots could thus be administered to the
patient.
If more than one vial of Confidex is required, several vials of Confidex may 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 (at a rate not exceeding 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
There are no data available regarding the use of Confidex in cases of perinatal hemorrhagic episodes due to vitamin K deficiency in the newborn.
Note on platelet count
The patient must be continuously monitored for platelet count.
Interactions with other medicinal products and other forms of interaction
When patients receiving high doses of human prothrombin complex are subjected to coagulation tests sensitive to heparin, it should be borne in mind that heparin is contained in the administered product.
* During clinical studies, Confidex was administered to patients weighing < 70 kg at a maximum infusion rate of 0.12 ml/kg/min (less than 8 ml/min).

PACKAGE LEAFLET: INFORMATION FOR THE USER

Confidex 1000

Powder and solvent for injectable solution.
Human prothrombin complex concentrate

Read this leaflet carefully before taking 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. This medicine may be harmful to other individuals, even if their symptoms are the same as yours.
• If you experience any adverse reactions, even those not listed in this leaflet, inform 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 using 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 CONFIDEX IS AND WHAT IT IS USED FOR

What is Confidex?
Confidex is supplied as a powder and solvent. It is a white or slightly coloured powder or a friable solid. Once reconstituted, the solution is intended for intravenous injection.
Confidex is derived from human plasma (i.e. the liquid component of blood) and contains the human coagulation factors II, VII, IX, and X. Concentrates containing these coagulation factors are known as prothrombin complex concentrates. Coagulation factors II, VII, IX, and X are vitamin K-dependent and play an important role in blood coagulation. Deficiency of any of these factors impairs the necessary speed of blood clotting, resulting in an increased tendency to bleed. Replacement of factors II, VII, IX, and X with Confidex helps restore the blood coagulation mechanism.
What is Confidex used for?
Confidex is used for the prevention (in the case of surgery) and treatment of bleeding episodes due to congenital or acquired deficiency in blood of the vitamin K-dependent coagulation factors II, VII, IX, and X, when purified specific factor products are not available.

2. WHAT YOU SHOULD KNOW BEFORE USING CONFIDEX

The following sections contain information that your doctor should take into account before prescribing Confidex to you.
Do not use Confidex:

• If you are allergic to any of the active substances or to any of the excipients of this medicine (see section 6). Inform your doctor if you are allergic to any medicines or food substances.
• if you have a higher than normal tendency to form blood clots (patients at risk of disseminated intravascular coagulation).
• if you have an allergic reaction to heparin, resulting in a drop in platelet count (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 using Confidex if:

• You have an acquired deficiency of vitamin K-dependent coagulation factors: This may be caused by treatment with drugs that inhibit the effect of vitamin K. Confidex may be appropriately used only when rapid correction of prothrombin complex levels is required, e.g. in cases of significant bleeding or emergency surgery.
• Congenital deficiency of any of the vitamin K-dependent coagulation factors: In such cases, you should use, when available, products containing the specific coagulation factor.
• Allergic or anaphylactic reactions (severe allergic reactions causing severe breathing difficulties or dizziness): Administration of Confidex must be stopped immediately (e.g. stop the infusion).
• 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 disease;
• if you have recently undergone surgery (pre- or post-operative patients);
• in newborn infants (neonates);
• if you have a higher than normal tendency to form blood clots (patients at risk of thromboembolic episodes or disseminated intravascular coagulation or concomitant deficiency of inhibitors).
• Increased risk of coagulation due to increased consumption of platelets or coagulation factors. Treatment with Confidex should only be initiated after treating 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 in Confidex. Severe reduction in platelet count may be associated with:
• presence of blood clots in a vein or leg,
• increased formation of clots in the blood,
• in some cases, skin redness at the injection site,
• pinpoint bleeding,
• dark stools.

In such cases, heparin efficacy may be reduced (heparin tolerance). If these symptoms occur, you must immediately stop using the product and contact your doctor. In the future, you must not use any products containing heparine.

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

Your doctor will carefully evaluate the benefit-risk ratio of treatment with Confidex versus the risks associated with these complications.
Viral safety
In the production of medicinal products derived from human blood or plasma, certain precautions are adopted to prevent transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to exclude those at risk of carrying infections,
• testing of each individual donation and plasma pools for the presence of viruses/infections,
• inclusion, during blood or plasma processing, of manufacturing steps aimed at inactivating or eliminating viruses.

Despite these measures, when administering products prepared from human blood or plasma,
the possibility of transmitting infections cannot be completely ruled out. This also applies to emerging or previously unknown viruses or other types of infections.
The measures adopted are considered effective against both enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and non-enveloped viruses such as hepatitis A virus and parvovirus B19.
If you receive regular or repeated administrations of products containing human plasma-derived prothrombin complex, your doctor may recommend vaccination against hepatitis A and B.
It is strongly recommended that, with every administration of Confidex, the treating physician records the name and batch number of the product used, in order to maintain a record of batches used.
Use of Confidex with other medicines

• Inform 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, think you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
• During pregnancy or breastfeeding, Confidex should be administered only if clearly indicated.
• There are no data available on fertility.

Driving and using machines
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 consideration if you are on a low-sodium diet.

3. HOW TO USE CONFIDEX

Treatment must be initiated and supervised by a physician experienced in the treatment of this type of disease.
Dosage
The required amount of Factor II, VII, IX, and X, as well as the duration of treatment, depend on several parameters such as your body weight, severity and nature of the disease, location and intensity of bleeding, or the need to prevent bleeding episodes during surgery or medical procedures (see the section "The following information is intended exclusively for healthcare professionals").
If you have any doubts about the use of this product, consult your doctor or pharmacist.
Overdose
During treatment, your doctor should regularly monitor your coagulation status. 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 ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
The following adverse reactions have been observed commonly (may affect up to 1 in 10 people):

• Risk of blood clot formation (see section 2)
• Headache
• Increase in body temperature

The following side effect occurred non-commonly (may affect up to 1 in 100 people):

• Hypersensitivity or allergic reactions (see section 2)

The frequency of the following adverse reactions is unknown (cannot be estimated from the 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
There are no data available regarding the use of Confidex in the paediatric population.
Reporting of adverse reactions
If you experience any side effects, talk to your doctor or pharmacist. This includes any adverse reaction not listed in this patient information leaflet. You can also report side effects directly via the national reporting system. By reporting adverse reactions, 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 stated on the label and packaging.
• Do not store above 25°C.
• Do not freeze.
• Keep the vial in its outer packaging to protect it from light.
• Confidex does not contain preservatives; therefore, the reconstituted solution should preferably be administered immediately.

6. CONTENTS OF THE PACKAGE AND OTHER INFORMATION

What Confidex contains
Confidex contains 800 – 1240 IU of human coagulation Factor IX per vial.
Active substance:
A concentrate of factors: II, VII, IX and X, and human Protein C and S.
Excipients:
Human antithrombin III, heparin, human albumin, sodium chloride, sodium citrate, HCl or
NaOH (in small quantities for pH adjustment).
Solvent: Water for injections.

Presentation of Confidex and contents of the package
Confidex is presented as a white or slightly coloured powder, supplied with a vial of water for injections as solvent. The powder must be dissolved in 40 ml of water for injections.
The resulting solution should be clear or slightly opalescent, meaning it may show slight shimmering when examined against the light; however, it must not contain visible particles.

Package contents
A 1000 IU pack contains:

• 1 vial containing the powder
• 1 vial containing 40 ml of water for injections
• 1 transfer device with 20/20 filter

Marketing Authorization Holder
CSL Behring GmbH
Emil-von-Behring-Str. 76
35041 Marburg
Germany

Legal Representative
CSL Behring S.p.A.
Viale del Ghisallo, 20 - 20151 Milano
Italy

Manufacturer responsible for batch release
CSL Behring GmbH
Emil-von-Behring-Str. 76
35041 Marburg
Germany

This medicinal product has been authorized in the Member States of the European Economic Area under the following names:
Austria Beriplex P/N 1000 I.E. Pulver und Lösungsmittel zur Herstellung einer Injektionslösung
Belgium Confidex 1000 I.E., poeder en oplosmiddel voor oplossing voor injectie
Bulgaria Beriplex P/N 1000, 1000 IU, Powder and solvent for solution for injection
Croatia Beriplex P/N 1000 IU prašak i otapalo za otopinu za injekciju
Denmark Confidex
Finland Confidex 1000 IU injektiokuiva-aine ja liuotin, liuosta varten
France Confidex 1000 UI, poudre et solvant pour solution injectable
Germany Beriplex P/N 1000
Greece Beriplex P/N, Κόνις και διαλύτης για ενέσιμο διάλυμα 1000IU/vial
Hungary Beriplex P/N 1000 por és oldószer oldatos injekcióhoz
Ireland Beriplex P/N 1000 IU, powder and solvent for solution for injection
Italy Confidex 1000
Luxembourg Confidex 1000 UI poudre et solvant pour solution injectable
Malta Beriplex P/N 1000, powder and solvent for solution for injection
Netherlands Beriplex P/N 1000 IE, poeder en oplosmiddel voor oplossing voor injectie
Norway Confidex 1000 IU pulver og væske til injeksjonsvæske, oppløsning
Czech Republic Beriplex 1000 IU
Romania Beriplex P/N 1000 UI pulbere și solvent pentru soluție injectabilă
Poland Beriplex P/N 1000
Portugal Beriplex 1000 UI pó e solvente para solução injectável
Slovakia Beriplex 1000 IU
Slovenia Beriplex P/N 1000 i.e. prašek in vehikel za raztopino za injiciranje
Spain Beriplex 1000 UI polvo y disolvente para solución inyectable
Sweden Confidex 1000 IE, pulver och vätska till injektionsvätska, lösning
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 nominally contains the following IU of human coagulation factors listed in the table below:

The total protein content after reconstitution is 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 of proteins C and S (antigen), has been tested in accordance with current WHO international standards.

Dosage and method of administration
Dosage
The following are general dosage guidelines only.
The amount and frequency of administration must be calculated for each individual patient. The administration intervals should be adjusted according to the different plasma half-lives of the various coagulation factors contained in the prothrombin complex. The required dose for each patient can only be determined based on regular individual assessment of plasma levels of the relevant coagulation factors, or by means of tests for determining prothrombin complex levels (INR, Quick test), together with continuous monitoring of the patient's clinical condition.
In the case of major surgical procedures, careful monitoring of replacement therapy based on coagulation tests (assays for specific coagulation factors and/or comprehensive tests for determining prothrombin complex levels) is essential.

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

The dose will depend on the INR value before treatment and the desired INR level. 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 reports the approximate doses required (ml of reconstituted product/kg body weight and IU of Factor IX/kg body weight) to normalize the INR value (e.g., <1.3), based on different initial INR values.

The dose is based on a body weight of up to 100 kg, but not exceeding 100 kg. Therefore, for
patients weighing more than 100 kg, the maximum single dose (IU of Factor IX) 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 coagulation imbalance induced by vitamin K antagonists is usually achieved
approximately 30 minutes after injection. Concomitant administration of vitamin K should be
considered in patients receiving Confidex for urgent reversal of vitamin K antagonists, as vitamin K
typically takes effect within 4–6 hours. Repeated dosing with Confidex in patients requiring
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 in a limited number
of subjects. Recovery and duration of effect may vary; therefore, monitoring of INR values during
treatment is essential.

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

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

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

The dose of the administered coagulation factor is expressed in International Units (IU),
referencing the current WHO standard for each factor. The plasma activity of each individual
coagulation factor is expressed as a percentage (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 a specific coagulation factor is equivalent to the amount
of that factor present in 1 ml of normal human plasma.
For example, the calculation of the required dose of Factor X is based on the observation that
1 International Unit (IU) of Factor X per kg of body weight increases Factor X plasma activity by
0.019 IU/ml.
The required dose is determined using the following formula:
Units required = body weight [kg] × desired increase in Factor X [IU/ml] × 53
where 53 (ml/kg) is the reciprocal of the recovery.
It should be noted that this calculation is based on data from patients receiving vitamin K
antagonists. A calculation based on data from healthy subjects would yield a lower estimate of the
required dose.
If the individual recovery value is known, it should be used for calculating the required dose.
Specific product information is available from clinical studies in healthy volunteers (N = 15), and in
patients undergoing reversal of vitamin K antagonists for acute major bleeding or perioperative
bleeding prophylaxis (N = 98, N = 43).
Paediatric population
The safety and efficacy of Confidex in children and adolescents have not yet been established
through controlled clinical trials.
Elderly population
The dosage and route of administration in elderly patients (> 65 years) are the same as those
described in the general recommendations.
Method of administration
General instructions

• The solution must be clear or slightly opalescent. After filtration/withdrawal (see below), the reconstituted product must be inspected visually for the presence of particles or discoloration prior to administration.
• Do not use solutions that are cloudy or contain residues (deposits/particles).
• Reconstitution and withdrawal must be performed under aseptic conditions.

Reconstitution
Allow the diluent to reach room temperature. Ensure that the pull-off caps of the vials containing the product and the diluent have been removed, disinfect the stoppers with an antiseptic solution, and allow them to dry before opening the Mix2Vial package.

Collection and administration

Take care to ensure that blood does not enter the syringe filled with the product, because there is a risk that blood may clot in the syringe and fibrin clots could thus be administered to the patient.
If more than one vial of Confidex is required, several vials of Confidex may 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
There are no data available regarding the use of Confidex in cases of perinatal haemorrhagic episodes due to vitamin K deficiency in the newborn.
Note on platelet count
The patient must be continuously 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 borne in mind that heparin is contained in the administered product.
* During clinical studies, Confidex was administered to patients weighing < 70 kg at a maximum infusion rate of 0.12 ml/kg/min (less than 8 ml/min).