Kedcom

PACKAGE LEAFLET: INFORMATION FOR THE USER

KEDCOM 500 IU/20 ml Powder and solvent for solution for infusion

Coagulation Factor IX + Coagulation Factor II + Coagulation Factor X of human plasma
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.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• 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 KEDCOM is and what it is used for
2. What you need to know before using KEDCOM
3. How to use KEDCOM
4. Possible side effects
5. How to store KEDCOM
6. Contents of the pack and other information

1. What KEDCOM is and what it is used for

KEDCOM is a solution of human plasma-derived coagulation factors IX, II and X.
Coagulation factors IX, II and X are proteins with haemostatic activity.
KEDCOM is used in the following therapies:

• Treatment and perioperative prophylaxis of bleeding (medical procedure in the period before or immediately after a surgical intervention to prevent bleeding) in acquired deficiency of vitamin K-dependent coagulation factors, such as deficiency caused by treatment with vitamin K antagonists, or in cases of overdose of vitamin K antagonists, when rapid correction of the deficiency is required.
• Treatment and perioperative prophylaxis of bleeding (medical procedure in the period before or immediately after a surgical intervention to prevent bleeding) in congenital deficiency of some vitamin K-dependent coagulation factors, when the purified product of the specific coagulation factor is not available.

2. What you need to know before using KEDCOM

Do not use KEDCOM
if you are allergic to any of the proteins in the prothrombin complex (Factor IX, Factor II, and Factor X) or to
any of the other components of this medicine (listed in section 6);
if you have previously experienced heparin-induced thrombocytopenia (low platelet count);
if you have previously experienced allergic reactions caused by heparin.

Warnings and precautions
Consult a physician specialized in treating coagulation disorders before using KEDCOM.
Your doctor or another healthcare professional will closely monitor you and carefully observe you throughout
the entire infusion period with KEDCOM to ensure no adverse reactions occur.
As with any intravenous protein product, allergic-type hypersensitivity reactions may occur.
If you notice any reaction during administration of the product, inform the attending physician immediately,
as this may be the first sign of an allergic reaction.
The physician will decide whether to reduce the infusion rate or to stop the infusion.
Furthermore, the physician will determine the necessary treatment based on the nature and severity of the adverse effect.
If these symptoms occur after administration, contact your doctor.
In case of shock, the physician must follow standard treatment for this condition.

Viral safety
Medicines prepared from human blood or plasma are subject to a number of safety measures implemented
to prevent transmission of infections to patients. These measures include careful selection of blood or plasma donors
to ensure potentially infected donors are excluded, and testing of each donation and plasma pool to detect possible presence of infections/viruses.
Manufacturers of these medicines also incorporate into the manufacturing process several steps capable of inactivating or removing pathogens.
Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting an infection cannot be completely ruled out.
This also applies to emerging or unknown viruses or other infectious agents.
The measures taken are considered effective against lipid-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 taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19.
Parvovirus B19 infection can be severe during pregnancy (fetal infection) and in individuals with a weakened immune system or with certain types of anemia (e.g. sickle cell anemia or hemolytic anemia).
Appropriate vaccination (hepatitis A and B) is recommended for patients receiving human prothrombin complex regularly.

Children
There are no available data regarding the use of KEDCOM for perinatal bleeding due to vitamin K deficiency in newborns.
The safety and efficacy of KEDCOM in children have not yet been established. Currently, no data are available.

Other medicines and KEDCOM
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Human prothrombin complex (KEDCOM) neutralizes the effect of vitamin K antagonist treatment.
No interactions with other medicines are known.
KEDCOM must not be mixed with other medicinal products.
Only the infusion devices supplied in the package must be used for infusion, as treatment inefficacy may occur due to absorption of coagulation factors onto the inner surfaces of certain infusion devices.

Interference with biological tests
When coagulation tests sensitive to heparin are performed in patients receiving high doses of human prothrombin complex, the heparin contained in the administered product must be taken into consideration.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before using this medicine.
Clinical experience regarding the safety of using plasma-derived prothrombin complex concentrate during pregnancy has not been established through controlled clinical studies.
Animal experimental studies are insufficient to support safety with respect to reproduction, embryonic and fetal development, course of pregnancy, and peri- and postnatal development.
Therefore, human prothrombin complex may be used during pregnancy and breastfeeding only if clearly needed.

Driving and using machines
No effects on the ability to drive or use machines are known.

KEDCOM contains sodium
This medicine contains up to a maximum of 92 mg of sodium (main component of table salt) per 20 ml vial.
This corresponds to 4.6% of the maximum recommended daily dietary intake of sodium for an adult.

3. How to use KEDCOM

For instructions on correct use and dosage, refer to the section "The following information is
intended exclusively for doctors or healthcare professionals"

Treatment must be initiated under the supervision of a physician experienced in the management of coagulation disorders. The dosage and duration of replacement therapy depend on the severity of the coagulation factor deficiency, the site and extent of bleeding, and the patient's clinical condition. The administered dose and frequency of administration should always be determined based on individual response.

Therapeutic intervals must be adjusted according to the different half-lives of the coagulation factors contained in the prothrombin complex.

The physician will determine the appropriate dose and treatment regimen for you based on clinical assessments.

If you have any doubts about the use of KEDCOM, consult your doctor.

It is strongly recommended that each time you receive a dose of KEDCOM, both the product name and the batch number are recorded, in order to ensure traceability of the batch used.

4. Possible side effects

Like all medicines, KEDCOM may cause side effects, although not everyone experiences them.
Adverse reactions known to be associated with the administration of human prothrombin complex may also
occur with KEDCOM and include:

• Rare cases of allergic or anaphylactoid reactions due to hypersensitivity to the infused proteins.
• Inadequate clinical response following the development of circulating antibodies that inhibit one or more factors of the prothrombin complex.
• Potential risk of thromboembolic events such as embolism and thrombosis (complications due to abnormal formation of blood clots), disseminated intravascular coagulation (DIC, acquired thrombo-haemorrhagic syndrome), and myocardial infarction.
• In rare cases, pyrexia (fever) has been observed.

For information on viral safety, see section 2 "What you need to know before using KEDCOM".
Following the instructions provided in this leaflet reduces the risk of side effects.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor.
You can also report side effects directly via the national reporting system at:
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 KEDCOM

See the expiry date printed on the packaging.
The expiry date refers to the product in its original, unopened packaging, when properly stored.
Do not use KEDCOM after the expiry date stated on the label and on the carton.
The expiry date refers to the last day of the month.
Store in a refrigerator (2 °C - 8 °C). Do not freeze.
Keep the vial in its carton to protect the medicine from light.
Once the infusion container has been opened, the contents must be used immediately.
The contents of the vial must be used for a single administration only.
Do not use KEDCOM if you notice that the solution is cloudy or contains particles.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.

6. Package contents and other information

What KEDCOM contains
KEDCOM is presented as a powder and solvent for solution for infusion containing human
prothrombin complex concentrate. The active substances are contained in the powder vial and are:

• Human plasma coagulation factor IX (Christmas factor).
• Human plasma coagulation factor II (prothrombin).
• Human plasma coagulation factor X (Stuart-Prower factor).

The other components of the powder vial are: sodium chloride, sodium citrate, glycine, heparin, antithrombin III.
The solvent vial contains water for injections.
The product contains nominally the IU of human coagulation factors as shown in the following table:

Factor IX quantified according to the International Standard.
The total protein content in the vial is ≤ 300 mg. The specific activity of the product is greater than 0.6 IU
of factor IX per mg of protein.
The powder vial contains factor IX, factor II, factor X of human plasma coagulation, sodium chloride, sodium citrate, glycine, heparin, antithrombin III.

Description of the appearance of KEDCOM and contents of the pack
The medicine appears as a highly hygroscopic powder (a powder capable of absorbing moisture) or friable solid, white or slightly colored.
The reconstituted solution appears clear or slightly opalescent.
Before administration, the reconstituted solution must be visually inspected for the presence of suspended particles or abnormal discoloration. Do not use cloudy solutions or those showing deposits.
The KEDCOM pack contains one 500 IU vial of lyophilized prothrombin complex concentrate, one 20 ml vial of solvent for preparing the solution for administration, and a sterile, pyrogen-free, single-use set consisting of a reconstitution device, an injection syringe, and a butterfly needle with PVC tubing.

MARKETING AUTHORISATION HOLDER
Kedrion S.p.A. - Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca).

MANUFACTURER:
Kedrion S.p.A. - 55027 Bolognana, Gallicano (Lucca).

The following information is intended exclusively for physicians or healthcare professionals:

Warnings and Precautions
In patients with acquired deficiency of vitamin K-dependent coagulation factors (e.g., when induced by vitamin K antagonist therapy), KEDCOM should only be used when rapid correction of prothrombin complex levels is required, such as in major bleeding or emergency surgery. In other cases, reducing the dose of the vitamin K antagonist and/or administering vitamin K are usually sufficient.
Patients receiving vitamin K antagonists may have an underlying hypercoagulable state, and infusion of human prothrombin complex concentrate could worsen this condition.
In congenital deficiencies of a vitamin K-dependent factor, the specific factor product should be used if available.
If hypersensitivity or anaphylactic-type (allergic) reactions occur, the infusion must be stopped immediately.
Use of plasma-derived prothrombin complex concentrate has been associated with an increased risk of disseminated intravascular coagulation (DIC, acquired thrombo-hemorrhagic syndrome), thromboembolic complications (abnormal formation of blood clots), and myocardial infarction. Patients receiving plasma-derived prothrombin complex concentrate must be closely monitored for signs or symptoms of disseminated intravascular coagulation (DIC, acquired thrombo-hemorrhagic syndrome) or thrombosis (abnormal formation of blood clots within vessels).
Due to the potential risk of thrombotic complications (complications due to abnormal blood clot formation), clinical monitoring for early signs of thrombotic and consumption coagulopathies, supported by appropriate biological tests, should be initiated when this product is administered to patients with a history of coronary artery disease (anatomical or functional abnormalities of the coronary arteries) or myocardial infarction, to patients with liver disease, postoperative patients, neonates, or patients at risk of thromboembolic events (abnormal blood clot formation) or disseminated intravascular coagulation (DIC, acquired thrombo-hemorrhagic syndrome). In each of these conditions, the potential benefit of treatment with KEDCOM must be weighed against the risk of these complications.

Dosage recommendations:
Therapeutic intervals must be adjusted according to the different half-lives of the various coagulation factors in the prothrombin complex. Individual doses required can only be determined based on regular measurements of individual plasma levels of the relevant coagulation factors or global analyses of prothrombin complex levels (prothrombin time, INR), along with continuous monitoring of the patient's clinical condition.
In the case of major surgical procedures, replacement therapy must be carefully monitored by coagulation tests (assay of the specific coagulation factor and/or global tests for prothrombin complex levels).

Bleeding and perioperative bleeding prophylaxis during treatment with vitamin K antagonists:
The dose will depend on the INR before treatment and the target INR to be achieved. Correction of the hemostatic defect induced by vitamin K antagonists lasts approximately 6–8 hours. However, the effects of vitamin K, if administered simultaneously, are usually achieved within 4–6 hours. Therefore, repeated treatment with human prothrombin complex concentrate is usually not required when vitamin K has been administered.
Since these recommendations are empirical and recovery and duration of effect may vary, INR monitoring during treatment is mandatory.

Bleeding and perioperative bleeding prophylaxis in congenital deficiency of a vitamin K-dependent coagulation factor when the specific factor product is not available:
Therapeutic dose calculation is based on the empirical observation that approximately 1 IU of factor IX per kg of body weight increases plasma factor IX activity by 0.01 IU/ml; 1 IU of factor II or factor X per kg of body weight increases plasma factor II or factor X activity by 0.02 and 0.017 IU/ml, respectively.
The administered dose of a specific factor is expressed in International Units (IU), which are related to the current WHO standard for each factor. The activity of a specific coagulation factor in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for the specific coagulation factor).
The activity of one International Unit (IU) of a coagulation factor is equivalent to the amount of factor contained in one milliliter 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 observed recovery for factor X.
If the individual recovery is known, that value should be used for the calculation.

Method of administration
Reconstitute the lyophilized powder as described in the following section Instructions for correct use.
The product must be administered intravenously.

Instructions for correct use
It is recommended not to administer doses exceeding 100 IU/kg body weight per day.
Only the injection/infusion devices supplied in the pack should be used. Other devices may also be used provided they are authorized for use with prothrombin complex concentrate medicines.
Unapproved devices may lead to treatment failure, as part of the prothrombin complex may adhere to the device walls.

Reconstitution of the powder with the solvent:

1. Bring the vial of powder and the solvent vial to room temperature;

2. This temperature must be maintained throughout the entire reconstitution process (maximum 10 minutes);

3. Remove the protective caps from the powder and solvent vials;

4. Clean the stoppers of both vials with alcohol;

5. Open the device package by removing the top; take care not to touch the inside (fig. A);

6. Do not remove the device from its packaging;

7. Invert the device box and insert the plastic spike through the stopper of the solvent vial so that the blue part of the device is connected to the solvent vial (fig. B);

8. Grasp the edge of the device box and pull it off, releasing the device without touching it (fig. C);

9. Ensure the vial containing the powder is placed on a stable surface; invert the system so that the solvent vial comes above the device; push the transparent/white adapter onto the stopper of the powder vial so that the plastic spike pierces the stopper of the powder vial; the solvent will be automatically drawn into the powder vial (fig. D);

10. After solvent transfer, unscrew the blue part of the transfer system with the attached solvent vial and remove it (fig. E);

11. Gently rotate the vial until the powder is completely dissolved. Do not shake vigorously to avoid foam formation (fig. F).

Check that the powder is completely dissolved; otherwise, there will be a loss of product activity.

Administration of the solution
The reconstituted medicine must be inspected visually before administration for particulate matter or discoloration. The solution should be clear or slightly opalescent. Do not use cloudy solutions or those containing deposits.

1. Draw air into the syringe by pulling back the plunger, attach it to the device, and inject the air into the vial containing the reconstituted solution (fig. G);
2. Keeping the plunger steady, invert the system so that the vial with the reconstituted solution is above the device, and slowly draw the concentrate into the syringe by pulling back the plunger (fig. H);
3. Disconnect the syringe by rotating it counterclockwise;
4. Visually inspect the solution in the syringe, which should appear clear or slightly opalescent and free of particulate matter;
5. Attach the butterfly needle to the syringe and infuse or inject slowly intravenously.

Once the vials have been opened, the contents must be used immediately.
The reconstituted solution transferred into the syringe must be administered immediately.
Unused medicine and waste materials derived from this medicine must be disposed of in accordance with local regulations.

Warnings and precautions
Patients must be closely monitored and carefully observed for any symptoms during the infusion period.

If more KEDCOM has been administered than intended
The use of high doses of plasma-derived prothrombin complex concentrate has been associated with cases of myocardial infarction, disseminated intravascular coagulation, venous thrombosis, and pulmonary embolism. Therefore, in case of overdose, the risk of developing thromboembolic complications or disseminated intravascular coagulation is increased.
In case of accidental administration of an excessive dose of KEDCOM, contact a physician immediately.