KEDCOM 500 UI/20 ML Powder and solvent for intravenous infusion solution

Зміст інструкції

1. KEDCOM 500 UI/20 ml Powder and solvent for infusion solution
   1. What is KEDCOM and what is it 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

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

Factor IX + Factor II + Factor X of human plasma coagulation
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.
• This medicine has been prescribed only for you. Do not give it to other people, even if their symptoms are the same as yours, as it could be dangerous.
• If any side effects occur, 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 you use 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 is KEDCOM and what is it used for

KEDCOM is a solution of coagulation factor IX, II and X derived from human plasma. The
blood coagulation factors IX, II and X are proteins that have antihemorrhagic action.
KEDCOM is used in the following therapies:

• Treatment and perioperative prophylaxis of bleeding (medical procedure in the period before or immediately after surgery to prevent bleeding) in acquired deficiency of prothrombin complex coagulation factors, such as deficiency caused by treatment with vitamin K antagonists, or in case 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 surgery to prevent bleeding) in deficiency

congenital of some of the 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 ingredients of this medicine (listed in section 6);
if you have previously experienced thrombocytopenia (low platelet count) induced by heparin;
if you have previously experienced allergic reactions induced by heparin.

Warnings and precautions
Consult a doctor specializing in the treatment of coagulation disorders before using KEDCOM.
The doctor or another healthcare professional will monitor you closely and observe you carefully during
the entire period of the infusion with KEDCOM to verify that there are no reactions.
As with any intravenous protein product, hypersensitivity reactions of an allergic type are possible.

If you notice any reaction during the administration of the product, you must immediately inform the
doctor present, because you may experience the first signs of an allergic reaction.
The doctor will decide whether to reduce the rate of administration or to stop the infusion.
The doctor will also decide on the necessary treatment based on the nature and the side effect.
If these symptoms appear after administration, contact your doctor.
In case of shock, the doctor must follow the standard treatment for this condition.

Viral safety
Medicines prepared from human blood or plasma undergo a number of safety measures
implemented to prevent the transmission of infections to patients. These measures include careful
selection of blood or plasma donors to ensure that potentially infected donors are
excluded and testing of each donation and plasma pool to highlight any presence of infections/viruses.
Manufacturers of these medicines also introduce some steps into the processing of blood and plasma
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
excluded. This also applies to viruses, or other types of infectious agents, emerging or unknown.
The measures taken are considered effective for enveloped viruses such as the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) and the non-enveloped hepatitis A virus (HAV).
The measures taken may have a limited effect against non-enveloped viruses such as parvovirus
B19. Parvovirus B19 infection can be severe in pregnancy (fetal infection) and in individuals whose
immune system is depressed or who have some type 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
No data are available regarding the use of KEDCOM in case of bleeding due to vitamin K deficiency in the newborn.
The safety and efficacy of KEDCOM in children have not yet been established. No data are currently available.

Other medicines and KEDCOM
Tell your doctor or pharmacist if you are taking, have recently taken or may take
any other medicines.
Human prothrombin complex (KEDCOM) neutralizes the effect of treatment with vitamin K antagonists.
No interactions with other medicines are known.
KEDCOM must not be mixed with other medicinal products.
Only the devices included in the package must be used for infusion, as ineffectiveness of the treatment may occur due to absorption of coagulation factors to the inner walls of some 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 are pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before using this medicine.
The safety of the plasma prothrombin complex concentrate during
pregnancy has not been established by controlled clinical studies.
Animal studies are insufficient to support safety with regard to reproduction, embryo and fetal development, the course of gestation and peri- and post-natal development.
Therefore, human prothrombin complex may be used during pregnancy and breastfeeding only
in case of documented necessity.

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

KEDCOM contains sodium
This medicine contains up to a maximum of 92 mg of sodium (the main component of table salt)
per 20 ml vial.
This is equivalent to 4.6% of the recommended maximum daily intake with the diet of 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 physicians or healthcare professionals”
Treatment must begin 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 hemostatic function disorder, the location and extent of the bleeding, and the patient's clinical condition; the dose to
be administered and the frequency of applications will always be calculated based on the individual response.
Therapeutic ranges must be adapted to the different half-lives of the various coagulation factors of the
prothrombin complex.
The physician will determine the appropriate dose and treatment regimen based on clinical examinations.
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 name and the lot
number of the product are recorded, in order to maintain traceability of the batch used.

4. Possible side effects

Like all medicines, KEDCOM can cause side effects, although not everybody gets 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 anaphylactic reactions due to hypersensitivity to the infused proteins.
• Insufficient clinical response following the formation 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 production of blood clots), disseminated intravascular coagulation (DIC acquired thrombo-hemorrhagic 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”.
Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your
doctor. You can also report side effects directly through the national system of
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 stated on the packaging.
The expiry date refers to the product in intact packaging, correctly stored.
Do not use KEDCOM after the expiry date which is reported on the label and the box.
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 the box, 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 in a single administration.
Do not use KEDCOM if you notice that the solution is cloudy or has deposits.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to eliminate the
medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.

6. Contents of the pack and other information

What KEDCOM contains
KEDCOM is presented as powder and solvent for infusion solution containing human prothrombin complex. 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 nominally contains the IU of human coagulation factors as shown in the following
table:

Factor IX titrated 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/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 is presented as a very hygroscopic powder (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 checked for the presence of
particles in suspension, or abnormal coloration. Do not use turbid solutions or those with deposits.
The pack of KEDCOM contains a vial of powder of 500 IU of prothrombin complex, a
solvent vial of 20 ml with which the solution to be administered is prepared and a sterile and
apyrogenic, single-use set consisting of a reconstitution device, a syringe for injection 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).
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The following information is intended exclusively for doctors or healthcare professionals:

Warnings and Precautions.
In patients with acquired deficiency of vitamin K-dependent coagulation factors (e.g. if induced
by treatments with vitamin K antagonists), KEDCOM should be used only when rapid correction of prothrombin complex levels is necessary, such as in major bleeding or emergency surgery. In other cases, reducing the dose of the vitamin K antagonist and/or administering
vitamin K is usually sufficient.
Patients receiving vitamin K antagonists may have an underlying hypercoagulable state and
an infusion of human prothrombin complex may exacerbate this situation.
In congenital deficiencies of a vitamin K-dependent factor, the specific product should be used if
available.
If hypersensitivity or anaphylactic (allergic) reactions occur, the infusion must be stopped
immediately.
The use of plasma prothrombin complex concentrate has been reported to be associated with an increased
risk of disseminated intravascular coagulation (DIC acquired thrombo-hemorrhagic syndrome),
thromboembolic complications (abnormal blood clot formation) and myocardial infarction. Patients
receiving plasma prothrombin complex concentrate should be carefully monitored for
signs or symptoms of disseminated intravascular coagulation (DIC acquired thrombo-hemorrhagic
syndrome) or thrombosis (abnormal blood clot formation).
Due to the potential risk of thrombotic complications (complications due to abnormal blood clot
formation), clinical surveillance to identify early signs of thrombotic and consumption coagulopathies must
be initiated with appropriate biological tests when this product is administered to patients with a history
of coronary artery disease (anatomical or functional alterations of the coronary arteries) or myocardial infarction,
patients with liver disease, post-operative patients, newborns or patients at risk for thromboembolic phenomena (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.

Recommendations for dosage:
Therapeutic ranges must be adapted to the different half-life of the different coagulation factors of the
prothrombin complex. Individual doses required can only be identified on the basis of
regular determinations of individual plasma levels of the coagulation factors involved or on global analysis of prothrombin complex levels (prothrombin time, INR), and on continuous monitoring of
the patient's clinical condition.
In the case of major surgery, accurate monitoring of replacement therapy is essential by means of coagulation analysis (specific coagulation factor dosage and/or global tests for prothrombin complex levels).
Bleeding and perioperative prophylaxis of bleeding during treatment with vitamin K antagonists:
The dose will depend on the INR before treatment and the INR to be achieved. Correction of
hemostasis impairment induced by the vitamin K antagonist persists for 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 is usually not required when vitamin K has been
administered.
Since these recommendations are empirical and recovery and duration of effect may vary, it is
mandatory to monitor the INR during treatment.
Bleeding and perioperative prophylaxis of bleeding in congenital deficiency of some vitamin K-dependent coagulation factor when the specific coagulation factor product is not available:
The calculation of the therapeutic dose required 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 UI/ml; 1 IU of factor
II or factor X per Kg of body weight increases factor II or factor X activity respectively
by 0.02 and 0.017 UI/ml.
The administered dose of a specific factor is expressed in International Units (IU), which are correlated to
the current standard of the WHO 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 an 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 factor X dose required 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
UI/ml.
The necessary dose is determined using the following formula:

Units required = body weight (Kg) x desired increase of factor X (UI/ml) x 60
where 60 (ml/Kg) is the reciprocal of the recovery observed for factor X.
If individual recovery is known, that value must be used for the calculation.

Mode of administration
Dissolve the lyophilized powder as described in the following paragraph Instructions for correct use.
The product must be administered intravenously.

Instructions for correct use
It is recommended not to administer doses greater than 100 IU/Kg of body weight per day.
Only injection/infusion devices included in the package must be used. Others may also be used if they are authorized for use with prothrombin complex-based medicines.
Failure of treatment may occur with non-approved devices because some of the prothrombin complex may remain on the walls of the device.

Reconstitution of the powder with the solvent:

• 1. Bring the powder and solvent vial to room temperature;
• 2. This temperature must be maintained throughout the reconstitution process (maximum 10 minutes);
• 3. Remove the protective caps of the powder and solvent vials;
• 4. Clean the surfaces of the caps of the two vials with alcohol;
• 5. Open the device packaging by removing the top part; be careful not to touch the inside (fig. A);
• 6. Do not remove the device from the packaging;
• 7. Turn the device box over and insert the plastic tip through the cap of the solvent vial so that the blue part of the device is connected to the solvent vial (fig. B);
• 8. Grab the edge of the device box and pull it off, freeing the device without touching it (fig. C);
• 9. Make sure that the vial containing the powder is positioned on a secure support surface; turn the system over so that the solvent vial is above the device; push the transparent/white adapter onto the cap of the vial containing the powder so that the

plastic tip passes through the cap of the powder vial; the solvent will be automatically
aspirated into the powder vial (fig. D);

• 10. After transferring the solvent, unscrew the blue part of the transfer system with the solvent vial attached and remove it (fig. E);
• 11. Gently rotate the vial until all the powder is completely dissolved. Do not shake the vial vigorously to avoid foaming (fig. F).

Verify that the powder is completely dissolved otherwise there is a loss of product activity.

Administration of the solution
The reconstituted medicine must be visually inspected before administration for particles or chromatic alterations. The solution should be clear or slightly opalescent. Do not use
turbid solutions or those with deposits.

• 1. Fill the syringe with air by pulling back the plunger, attach it to the device and inject the air into the powder vial containing the reconstituted solution (fig. G);
• 2. Holding the plunger steady, turn the system over so that the powder vial with the reconstituted solution is above the device and slowly aspirate 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 be clear or slightly opalescent and free of particles;
• 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 and transferred to the syringe must be administered immediately.
Unused medicine and waste derived from such 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 than KEDCOM is administered than should be
The use of high doses of plasma 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.
If an accidental overdose of KEDCOM is administered, immediately notify the
doctor.