Cofact

Package leaflet: Information for the user

Cofact 250 IU powder and solvent for injectable solution

Human prothrombin complex
Please read this leaflet carefully before using this medicine because 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.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Cofact is and what it is used for

Cofact contains, as active substances, factors II, VII, IX, and X, which are clotting factors of human blood.
These factors are normal components of human blood, commonly known as Prothrombin Complex.
They are vitamin K-dependent. If there is a deficiency of one or more of these factors, coagulation disorders may occur. As a result, there is an increased tendency to bleed. Administration of Cofact serves to replace this deficiency, thereby treating or preventing bleeding episodes.
Cofact can be used for:
The treatment or prevention of bleeding due to

• acquired deficiency of the coagulation factors of the prothrombin complex. For example, in cases of deficiency caused by treatment with drugs that reduce the effect of vitamin K (vitamin K antagonists) or due to overdose of such antagonists, when acute correction of the deficiency is required.
• congenital deficiencies of one of the vitamin K-dependent clotting factors, when purified and specific clotting factors are not available.

2. What you need to know before using Cofact

Do not use Cofact

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

1/19
Warnings and precautions
Talk to your specialist doctor in coagulation disorders before using Cofact.

• If you have an acquired deficiency of vitamin K-dependent coagulation factors (e.g. caused by treatment with vitamin K antagonists), Cofact should only be used when rapid correction of prothrombin complex levels is required, such as in cases of severe bleeding or emergency surgery. In other cases, it is usually sufficient to reduce the dose of the vitamin K antagonist and/or administer vitamin K.
• If you are receiving vitamin K antagonists, you may be at increased risk of blood clots. In this case, treatment with Cofact may increase this risk.
• If you were born with a deficiency of one of the vitamin K-dependent coagulation factors (congenital deficiency), specific coagulation factors should be used when available.
• If an allergic or anaphylactic reaction occurs, administration of Cofact must be stopped immediately. There is a risk of thrombosis or disseminated intravascular coagulation (e.g. formation of blood clots in blood vessels) when receiving Cofact, particularly with repeated administration.
• Your doctor will assess whether administration of Cofact poses a risk of thrombosis (see section 4, Possible side effects). The following individuals have a higher likelihood of developing thrombosis:
  • individuals who have had a heart attack or who have had (or currently have) other coronary artery diseases
  • individuals with liver disease
  • newborns
  • individuals about to undergo or who have recently undergone surgery
  • individuals with an increased likelihood of coagulation complications (e.g. with a history of thromboembolic events or disseminated intravascular coagulation)

Your doctor will carefully evaluate the benefits of treatment with Cofact against the risks of such complications.
Viral safety
When medicines are produced from human blood or plasma, certain measures are taken to prevent transmission of infections to patients.
These include:

• careful selection of blood and plasma donors to exclude those at risk of transmitting infections,
• testing of each donation and plasma pool for signs of viral/infectious agents,
• inclusion of virus inactivation/removal steps during the manufacturing process of blood or plasma.

Nevertheless, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to unknown or emerging viruses or other types of infections. The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and the non-enveloped hepatitis A virus (HAV). However, the measures adopted may have limited effectiveness against other non-enveloped viruses such as Parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection) and

2/19
in patients with weakened immune systems or suffering from certain types of anemia (e.g. sickle cell anemia or hemolytic anemia).
It is strongly recommended that the name and batch number of the product be recorded each time you receive a dose of Cofact, in order to maintain traceability of the batches used.
Children and adolescents
There are no data available on the use of Cofact in children and adolescents.
Other medicines and Cofact
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.
No information is available on possible interactions between Cofact and other medicines, except for anticoagulants.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before taking this medicine.
If you are pregnant or breastfeeding, your doctor will prescribe Cofact only if necessary.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been conducted.
Cofact contains sodium
Cofact contains up to 448 mg of sodium (the main component of table salt) per 100 ml.
This corresponds to up to 22% of the maximum daily recommended sodium intake for adults.
This should be taken into consideration if you are on a low-sodium diet.

3. How to use Cofact

Your treatment must be initiated, administered, and monitored by a physician experienced in the management of coagulation disorders.
Your doctor will determine the amount of Cofact you need for the treatment or prevention of bleeding following anticoagulant use or in the case of congenital deficiency of one of the vitamin K-dependent coagulation factors.
The exact dose depends on:

• the severity of your condition
• your body weight
• the coagulation factors you require
• the levels of these factors in your blood (your blood levels).

In cases of congenital coagulation factor deficiency, it is important to regularly monitor their blood levels.
Information for Healthcare Professionals is provided at the end of this leaflet.
If you take more Cofact than you should
Your doctor must regularly monitor your blood coagulation status during treatment. High doses of prothrombin complex concentrate have been associated with episodes of myocardial infarction, disseminated intravascular coagulation, and increased formation of blood clots in blood vessels in patients at risk of such 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:
Common (may affect up to 1 in 10 people):

• Risk of blood clots formation (see section 2).
  Uncommon (may affect up to 1 in 100 people):

• Risk of low blood pressure.
  The frequency of the following side effects is Not known (frequency cannot be estimated from the available data):

• Hypersensitivity or allergic reactions (see section 2)

• Heart attack

• Nausea, vomiting

• Redness at infusion site, irritation at infusion site, swelling at infusion site, malaise

• Transient increase in liver function test results

• Stroke, dizziness

• Pulmonary embolism, breathing difficulties

• Excessive sweating, itching, hives, skin rash

Patients with a deficiency of one of the coagulation factors II, VII, IX or X may develop antibodies against these factors as a consequence of using Cofact. In such cases, the product's effectiveness may not be optimal.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the Italian Medicines Agency (Agenzia Italiana del Farmaco) website: http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cofact

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the label of the vial after EXP.
The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer packaging to protect the medicine from light.
Cofact may be stored at 25°C or lower for up to six months.
The date when the product was brought to room temperature must be marked on the packaging. If the product is not used within these six months of storage at room temperature, it must be discarded.
Once the product has been removed from the refrigerator, it must not be returned to the refrigerator.
The stability of the reconstituted product has been demonstrated for up to 3 hours at 15-25°C. However, the reconstituted product should be used immediately to avoid contamination.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Cofact contains

• The active substances are coagulation factors II, VII, IX, and X; other active substances are protein C and protein S.
• One vial of Cofact 250 IU contains 250 IU of factor IX; 140–350 IU of factor II; 70–200 IU of factor VII; and 140–350 IU of factor X; 111–390 IU of protein C; 10–80 IU of protein S. After dissolving the powder in the water for injections supplied, the ready-to-use solution for injection contains:
• Not less than 14 IU and not more than 35 IU of factor II per ml;
• Not less than 7 IU and not more than 20 IU of factor VII per ml;
• 25 IU of factor IX per ml;
• Not less than 14 IU and not more than 35 IU of factor X per ml;
• Not less than 11 IU and not more than 39 IU of protein C per ml;
• Not less than 1 IU and not more than 8 IU of protein S per ml.

The other ingredients are trisodium citrate dihydrate, sodium chloride, and antithrombin.
Description of the appearance of Cofact and contents of the pack
Cofact is available as a powder and solvent for injectable solution.
Cofact powder for injectable solution appears as a bluish powder. The solvent is a clear, colourless liquid free from visible particles. The ready-to-use injectable solution is bluish in colour.
Contents of the 250 IU pack:

• One vial of 250 IU powder.
• One vial containing 10 ml of water for injections.
• One transfer needle. It is possible that not all pack sizes are marketed.

Marketing Authorisation Holder and Manufacturer
Prothya Biosolutions Netherlands B.V.
Plesmanlaan 125
NL-1066 CX Amsterdam
The Netherlands
Tel: +31 (0)20 5123355
This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Austria, Belgium, Finland, France, Germany, Iceland, Italy, Luxembourg, the Netherlands and Spain: Cofact.
Sweden: Thyaplex
5/19
This Patient Information Leaflet was last updated on

---

The following information is intended for healthcare professionals only:

Qualitative and quantitative composition
Cofact is supplied as a powder and solvent for injectable solution containing human prothrombin complex. The product contains nominally the following International Units (IU) of human coagulation factors, as shown in the table below:

| Cofact 250 IU | After reconstitution* (IU/ml) | |---------------|-------------------------------| | Active substances | | | Coagulation Factor II | 140 – 350 | 14 – 35 | | Coagulation Factor VII | 70 – 200 | 7 – 20 | | Coagulation Factor IX | 250 | 25 | | Coagulation Factor X | 140 – 350 | 14 – 35 | | Other active substances | | | Protein C | 111 – 390 | 11 – 39 | | Protein S | 10 – 80 | 1 – 8 |

The total protein content per 250 IU vial is 130 – 350 mg. The specific activity of the product is ≥0.6 IU/mg, expressed as Factor IX activity.

The activities of all coagulation factors as well as of Proteins C and S (antigen) have been tested in accordance with WHO or European Pharmacopoeia standards.

After reconstitution, this medicinal product contains 125 – 195 mmol of sodium per litre, up to 44.8 mg of sodium per 250 IU vial.

Dosage and method of administration
Dosage
The following are general dosage guidelines only. Treatment must be initiated under the supervision of a physician experienced in managing coagulation disorders. The dosage and duration of replacement therapy depend on the severity of the deficiency, the site and extent of bleeding, and the patient's clinical condition.

The dose and frequency of administration should be determined based on the individual patient's condition. Dosing intervals must be adjusted according to the different circulating half-lives of the various coagulation factors present in the prothrombin complex. The individual dosage requirement can only be established by regular monitoring of the patient's plasma levels of the relevant coagulation factor, or by comprehensive assessment of prothrombin complex levels (prothrombin time, INR), along with continuous monitoring of the patient's clinical status.

In the case of major surgical procedures, careful monitoring of replacement therapy using coagulation tests (specific factor assays and/or global tests of prothrombin complex levels) is essential.

Bleeding and perioperative haemorrhage prophylaxis during treatment with vitamin K antagonists:
The required dose depends on the pre-treatment INR, the desired (target) INR, and the patient's body weight. The tables below provide approximate doses required to normalize INR at various initial INR levels.

The dosing tables represent general guidelines only and cannot replace individual dose assessment for each patient, nor careful monitoring of INR and other coagulation parameters during therapy.

Recommended doses of Cofact in ml to achieve a target INR ≤ 2.1

Recommended doses of Cofact in ml to achieve a target INR ≤ 1.5

The doses are calculated based on the factor IX concentration in Cofact, due to its relatively short half-life and lower recovery after infusion compared to other coagulation factors in Cofact.
It is assumed that a mean plasma concentration of factor IX ≥ 30% is sufficient to achieve an INR ≤ 2.1 and ≥ 60% to achieve an INR ≤ 1.5. The calculated volumes are rounded up to multiples of 10 ml, and an upper limit of 60 or 100 ml in total has been set (see tables above). The target INR values are recommended by the Dutch Federation of Thrombosis Services and are of the same order as the English and German recommendations.
Correction of vitamin K antagonist-induced coagulation abnormalities lasts for approximately 6–8 hours. However, the effects of vitamin K, if administered simultaneously, are usually achieved within 4–6 hours. Therefore, repeat treatment with human prothrombin complex concentrate is usually not necessary when vitamin K has been administered.
Since these recommendations are based on empirical observations and recovery as well as duration of effect may vary, it is essential to monitor INR during treatment.

Bleeding and perioperative prophylaxis in congenital deficiency of any vitamin K-dependent coagulation factor when specific coagulation factor products are not available:
The calculation of the required therapeutic dose is based on the empirical observation that approximately 1 IU of factor VII or factor IX per kg of body weight increases plasma factor VII or IX activity, respectively, by 0.01 IU/ml; 1 IU of factor II or X per kg of body weight increases plasma factor II or X activity by 0.02 and 0.017 IU/ml, respectively.
The dose of a specific factor administered is expressed in International Units (IU), which refer to the current WHO standard defined for each factor. The plasma activity of a specific coagulation factor is expressed as a percentage (relative to normal plasma) or in International Units (relative to the international standard for the specific coagulation factor).
One International Unit (IU) of coagulation factor activity is equivalent to the amount present in 1 ml of normal human plasma.
For example, the calculation of the required dose of factor X is based on the empirical observation that 1 International Unit (IU) of factor X per kg of body weight increases plasma factor X activity by 0.017 IU/mL. The required dose is determined using the following formula:

Units required = body weight (kg) × desired increase in factor X (IU/mL) × 60

Where 60 (mL/kg) is the reciprocal of the estimated recovery.
If individual recovery is known, that value should be used for the calculation.

Paediatric population
The safety and efficacy of Cofact in paediatric patients have not been established.

Method of administration
For instructions on reconstitution of the medicinal product prior to administration, see section “Special precautions for disposal and handling”. Cofact must be administered intravenously.
It is recommended to administer the reconstituted product at a rate of approximately 2 mL per minute.

Incompatibilities
This medicinal product must not be mixed with other medicinal products.
Cofact is compatible with polypropylene materials. Treatment failure may occur as a consequence of adsorption of coagulation factors onto the internal surface of other injection/infusion equipment.

Shelf life
3 years.
After reconstitution, chemical and physical in-use stability has been demonstrated for 3 hours at 15–25°C. From a microbiological standpoint, the product should be used immediately after reconstitution. If not used immediately, the times and conditions of storage of the reconstituted product prior to use are the responsibility of the user.

Special precautions for disposal and handling
Reconstitution
The lyophilized protein fraction must be dissolved in the prescribed volume of water for injections. If stored at 2–8°C, Cofact vials and vials of water for injections should be brought to room temperature (15–25°C) before reconstitution.

Procedure using a transfer needle
9/19

1. Remove the plastic protective cap from both the vial containing water for injections and the vial containing the product.
2. Disinfect the rubber stoppers of both vials with a piece of gauze soaked in alcohol (70%).
3. Remove the protective cover from one end of the transfer needle and insert the needle into the vial containing water for injections (A).
4. Then remove the protective cover from the other end of the transfer needle, invert the vial containing the transfer needle, and immediately insert the free end of the needle into the vial containing the product (B). The vacuum in the vial containing the product will cause the water for injections to be drawn into the vial. Recommendation: while the water for injections flows, hold the vial containing the product at an angle and allow the water to run down the wall of the vial. This helps dissolve the product more quickly. As soon as all the water has flowed through, remove the empty vial and the transfer needle in one motion.

To accelerate the dissolution process, the vial may be gently rotated and, if necessary, warmed to 30°C. The vial must never be shaken and the temperature must not exceed 37°C. If warming in a water bath, care must be taken that water does not come into contact with the protective cap and/or rubber stopper.
Normally, the lyophilized substance should dissolve completely within 10 minutes, forming a blue solution; the blue color is due to the presence of the plasma protein ceruloplasmin.
The solution should be clear or slightly opalescent. Do not use turbid solutions or those containing deposits. Prior to administration, the reconstituted product must be inspected visually for particulate matter and discoloration.
Any unused medicinal product and waste material derived from such medicinal product must be disposed of in accordance with local regulations.
10/19

Package leaflet: Information for the user

Cofact 500 IU 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.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Cofact is and what it is used for

Cofact contains, as active substances, factors II, VII, IX, and X, which are clotting factors of human blood.
These factors are normal constituents of human blood, commonly known as Prothrombin Complex. They are vitamin K-dependent. If there is a deficiency of one or more of these factors, coagulation disorders may occur. As a result, there is an increased tendency to bleed. Administration of Cofact serves to replace this deficiency, thereby treating or preventing bleeding episodes.
Cofact can be used for:
The treatment or prevention of bleeding due to

• acquired deficiency of vitamin K-dependent coagulation factors of the prothrombin complex. For example, in cases of deficiency caused by treatment with medicinal products that reduce the effect of vitamin K (vitamin K antagonists) or due to an overdose of such antagonists, when acute correction of the deficiency is required.
• congenital deficiencies of one of the vitamin K-dependent coagulation factors, when purified and specific coagulation factors are not available.

2. What you need to know before using Cofact

Do not use Cofact

• If you are allergic (hypersensitive) to one of the active substances or to any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your specialist doctor in coagulation disorders before using Cofact.

10/19

• If you have an acquired deficiency of vitamin K-dependent coagulation factors (e.g. caused by treatment with vitamin K antagonists), Cofact should only be used when rapid correction of the prothrombin complex levels is required, such as in cases of severe bleeding or emergency surgery. In other cases, it is usually sufficient to reduce the dose of the vitamin K antagonist and/or administer vitamin K.
• If you are receiving vitamin K antagonists, you may be at increased risk of blood clots. In this case, treatment with Cofact may increase this risk.
• If you were born with a deficiency of one of the vitamin K-dependent coagulation factors (congenital deficiency), specific coagulation factors should be used when available.
• If an allergic or anaphylactic reaction occurs, administration of Cofact must be stopped immediately. There is a risk of thrombosis or disseminated intravascular coagulation (e.g. formation of blood clots in blood vessels) when receiving Cofact, particularly when administered repeatedly.
• Your doctor will monitor whether administration of Cofact poses a risk of thrombosis (see section 4, Possible side effects). The following individuals have a higher likelihood of developing thrombosis:
  o individuals who have had a heart attack or who have had (or currently have) other coronary artery diseases
  o individuals with liver disease
  o newborns
  o individuals about to undergo or who have recently undergone surgery
  o individuals with an increased likelihood of coagulation complications (e.g. with a history of thromboembolic events or disseminated intravascular coagulation)

Your doctor will carefully evaluate the benefits of treatment with Cofact against the risks of such complications.
Viral safety
When medicines are produced from human blood or plasma, certain measures are taken to prevent transmission of infections to patients.
These include:

• careful selection of blood and plasma donors to ensure exclusion of those at risk of transmitting infections,
• testing of each donation and plasma pool for signs of viruses/infections,
• inclusion of virus inactivation/removal steps during the processing of blood or plasma.

Nevertheless, when administering medicinal products prepared from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to unknown or emerging viruses or other types of infections. The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and the non-enveloped hepatitis A virus (HAV). The measures adopted may have limited effectiveness against other non-enveloped viruses such as Parvovirus B19. Infection with Parvovirus B19 can be severe in pregnant women (fetal infection) and in patients with weakened immune systems or suffering from certain types of anaemia (e.g. sickle cell anaemia or haemolytic anaemia). It is strongly recommended that the name and batch number of the product be recorded each time you receive a dose of Cofact, in order to ensure traceability of the batches used.

11/19
Children and adolescents
There are no data available on the use of Cofact in children and adolescents.
Other medicines and Cofact
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including medicines obtained without a prescription.
No information is available on possible interactions between Cofact and other medicines, except for anticoagulants.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or are breastfeeding, consult your doctor before taking this medicine.
If you are pregnant or breastfeeding, your doctor will prescribe Cofact only if necessary.
Driving and using machines
No studies have been conducted on the effects on the ability to drive and use machines.
Cofact contains sodium
Cofact contains up to 448 mg of sodium (the main component of table salt) per 100 ml.
This corresponds to up to 22% of the maximum daily recommended sodium intake for adults.
This should be taken into consideration if you are on a low-sodium diet.

3. How to use Cofact

Your treatment must be initiated, administered and monitored by a physician experienced in the
management of coagulation disorders.
Your doctor will determine the amount of Cofact you need for the treatment or prevention of
bleeding due to anticoagulant use or in case of congenital deficiency of one of the vitamin K-dependent
coagulation factors.
The exact dose depends on:

• the severity of your condition
• your body weight
• the coagulation factors you require
• the levels of these factors in your blood (your blood level).

In case of congenital coagulation factor deficiency, it is important to regularly monitor their blood
levels.
Information for Healthcare Professionals is provided at the end of this leaflet.
If you take more Cofact than you should
Your doctor must regularly monitor your blood coagulation status during treatment. High doses of
prothrombin complex concentrate have been associated with episodes of myocardial infarction,
disseminated intravascular coagulation, and increased formation of blood clots in blood vessels in
patients at risk for such complications.
12/19

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been reported:
Common (may affect up to 1 in 10 people):

• Risk of blood clot formation (see section 2).
  Uncommon (may affect up to 1 in 100 people):

• Risk of low blood pressure.
  The frequency of the following side effects is Not known (frequency cannot be estimated from the available data):

• Hypersensitivity or allergic reactions (see section 2)

• Heart attack

• Nausea, vomiting

• Flushing at infusion site, irritation at infusion site, swelling at infusion site, malaise

• Transient increase in liver function test results

• Stroke, dizziness

• Pulmonary embolism, breathing difficulties

• Excessive sweating, pruritus, urticaria, skin rash

Patients with a deficiency of coagulation factor II, VII, IX, or X may develop antibodies against these factors as a consequence of Cofact use. In such cases, the product's activity may not be optimal.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the Italian Medicines Agency (Agenzia Italiana del Farmaco) website: http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Cofact

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the label of the
vial after EXP.
The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C - 8 °C). Do not freeze. Keep the vial in the outer packaging to
protect the medicine from light.
Cofact may be stored at 25°C or below for up to six months.
The date when the product was brought to room temperature should be marked on the packaging. If the
product is not used within these six months of storage at room temperature, it must be discarded.
Once the product has been removed from the refrigerator, it must not be returned to the refrigerator.
The stability of the reconstituted product has been demonstrated for up to 3 hours at 15-25°C. However, the reconstituted product should be used immediately to avoid contamination.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Cofact contains

• The active substances are coagulation factors II, VII, IX, and X; other active substances are protein C and protein S.
• One vial of Cofact 500 IU contains: 500 IU of factor IX; 280 – 700 IU of factor II; 140 – 400 IU of factor VII; 280 – 700 IU of factor X; 222 – 780 IU of protein C; 20 – 160 IU of protein S. After reconstitution of the powder with the water for injections supplied, the ready-to-use solution for injection contains:
• Not less than 14 IU and not more than 35 IU of factor II per ml;
• Not less than 7 IU and not more than 20 IU of factor VII per ml;
• 25 IU of factor IX per ml;
• Not less than 14 IU and not more than 35 IU of factor X per ml;
• Not less than 11 IU and not more than 39 IU of protein C per ml;
• Not less than 1 IU and not more than 8 IU of protein S per ml.

The other ingredients are trisodium citrate dihydrate, sodium chloride, and antithrombin.
Description of the appearance of Cofact and package contents
Cofact is available as a powder and solvent for injectable solution.
Cofact powder for injectable solution appears as a bluish powder. The solvent is a clear, colourless liquid free from visible particles. The ready-to-use injectable solution is bluish in colour.
Contents of the 500 IU pack:

• One vial of 500 IU powder.
• One vial containing 20 ml of water for injections.
• One nextaro transfer device. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Prothya Biosolutions Netherlands B.V.
Plesmanlaan 125
NL-1066 CX Amsterdam
The Netherlands
Tel: +31 (0)20 5123355
This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Austria, Belgium, Finland, France, Germany, Iceland, Italy, Luxembourg, The Netherlands, and Spain: Cofact.
Sweden: Thyaplex
This patient information leaflet was last updated on

---

14/19
The following information is intended exclusively for healthcare professionals:
Qualitative and quantitative composition
Cofact is supplied as a powder and solvent for solution for injection containing human prothrombin complex. The product contains nominally the following IU of human coagulation factors as shown in the table below:

| Cofact 500 IU | After reconstitution* (IU/ml) | |---------------|-------------------------------| | Active substances | | | Coagulation factor II | 280 – 700 | 14 – 35 | | Coagulation factor VII | 140 – 400 | 7 – 20 | | Coagulation factor IX | 500 | 25 | | Coagulation factor X | 280 – 700 | 14 – 35 | | Other active substances | | | Protein C | 222 – 780 | 11 – 39 | | Protein S | 20 – 160 | 1 – 8 |

The total protein content per 500 IU vial is 260 – 700 mg. The specific activity of the product is ≥0.6 IU/mg, expressed as factor IX activity.
The activities of all coagulation factors, as well as proteins C and S (antigen), have been tested according to WHO or European Pharmacopoeia standards.
After reconstitution, this medicinal product contains 125 – 195 mmol of sodium/l, up to 89.6 mg of sodium per 500 IU vial.
Dosage and method of administration
Dosage
Only general dosage guidelines are provided below. Treatment must be initiated under the supervision of a physician experienced in the treatment of coagulation disorders. The dosage and duration of replacement therapy depend on the severity of the disorder, the site and extent of bleeding, and the clinical condition of the patient.
The dose and frequency of administration must be calculated based on the individual patient's condition. Dosing intervals should be adjusted according to the different circulating half-lives of the various coagulation factors present in the prothrombin complex. The individual dosage requirement can only be determined based on regular measurements of the patient's plasma levels of the relevant coagulation factor, or complete tests of prothrombin complex levels (prothrombin time, INR), and continuous monitoring of the patient's clinical condition.
In the case of major surgical procedures, careful monitoring of replacement therapy through coagulation tests (specific factor assays and/or global tests of prothrombin complex levels) is essential.
Bleeding and perioperative haemorrhage prophylaxis during treatment with vitamin K antagonists:
The dose will depend on the pre-treatment INR, the desired (target) INR, and body weight. The following tables provide approximate doses required to normalise INR at various initial INR levels.
15/19
The dosing tables represent only general dosage guidelines and cannot replace individual dose assessment for each patient, nor careful monitoring of INR and other coagulation parameters during therapy.
Recommended doses of Cofact in ml to achieve a target INR ≤ 2.1

Recommended doses of Cofact in ml to achieve a target INR ≤ 1.5

The doses are calculated based on the factor IX concentration in Cofact, due to its relatively short half-life and lower recovery after infusion compared to other coagulation factors in Cofact.
It is assumed that a mean plasma concentration of factor IX ≥ 30% is sufficient to achieve an INR ≤ 2.1, and ≥ 60% to achieve an INR ≤ 1.5. Calculated volumes are rounded up to multiples of 10 ml, and an upper limit of 60 or 100 ml in total has been set (see tables above). The target INR values are recommended by the Dutch Federation of Thrombosis Services and are in line with English and German recommendations.
Correction of vitamin K antagonist-induced coagulation abnormalities lasts for approximately 6–8 hours. However, the effects of vitamin K, if administered concurrently, are usually achieved within 4–6 hours. Therefore, repeat treatment with human prothrombin complex concentrate is generally not necessary when vitamin K has been administered.
Since these recommendations are based on empirical observations and recovery and duration of effect may vary, monitoring of INR during treatment is essential.

Bleeding and perioperative prophylaxis in congenital deficiency of any vitamin K-dependent coagulation factor, when specific coagulation factor products are not available:

The calculation of the required therapeutic dose is based on the empirical observation that approximately 1 IU of factor VII or factor IX per kg of body weight increases plasma factor VII or IX activity by 0.01 IU/ml, respectively, and 1 IU of factor II or X per kg of body weight increases plasma factor II or X activity by 0.02 and 0.017 IU/ml, respectively.

The dose of a specific coagulation factor administered is expressed in International Units (IU), which are referenced to the current WHO standard defined for each factor. The plasma activity of a specific coagulation factor is expressed as a percentage (relative to normal plasma) or in International Units (relative to the international standard for the specific coagulation factor).

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

For example, the calculation of the required dose of factor X is based on the empirical finding that 1 International Unit (IU) of factor X per kg of body weight increases plasma factor X activity by 0.017 IU/mL. The required dose is determined using the following formula:

Required units = body weight (kg) × desired increase in factor X (IU/ml) × 60

Where 60 (ml/kg) is the reciprocal of the estimated recovery.

If the individual recovery is known, that value should be used for the calculation.

Paediatric population
The safety and efficacy of Cofact in paediatric patients have not been established.

Method of administration
For instructions on reconstitution of the medicinal product prior to administration, see section "Special precautions for disposal and handling". Cofact must be administered intravenously.
It is recommended to administer the reconstituted product at a rate of approximately 2 ml per minute.

Incompatibilities
This medicinal product must not be mixed with other medicinal products.
Cofact is compatible with polypropylene materials. Treatment failure may occur due to adsorption of coagulation factors onto the internal surfaces of other injection/infusion equipment.

Shelf life
3 years.
After reconstitution, chemical and physical in-use stability has been demonstrated for 3 hours at 15–25°C. From a microbiological standpoint, the product should be used immediately after reconstitution. If not used immediately, the times and conditions of storage of the reconstituted product prior to use are the responsibility of the user.

Special precautions for disposal and handling
General instructions for use of the nextaro transfer device

• The lyophilized protein fraction must be dissolved in 20 ml of water for injections. If stored at 2°C–8°C, bring the closed vials of powder and solvent (water for injections) to room temperature (15°C–25°C) before dissolving the preparation. This temperature must be maintained during reconstitution. If warming in a water bath is used, care must be taken to prevent water from contacting the rubber stoppers or peel-off caps. The water bath temperature must not exceed 37°C.

• During the procedure described below, aseptic technique must be used. Before opening the transfer device packaging, remove the peel-off caps from the powder and solvent vials, disinfect the rims and rubber stoppers with antiseptic solution, and allow to dry. Do not touch the rubber stoppers of the solvent or powder vials.

• The vacuum in the powder vial will automatically draw in the solvent.

• As a general rule, the powder should be completely dissolved within 10 minutes, forming a blue solution. The solution should appear clear or slightly opalescent. Do not use cloudy solutions or those containing deposits. Before administration, the solution must be inspected visually for particulate matter and discoloration.

• Unused medicinal product and waste material arising from its use must be disposed of in accordance with local applicable regulations.

Procedure using the nextaro transfer device

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